Poster Presentations: Wednesday, July 27, 2016
between 1 and 3 years in 4 of the 5 methods. FSL/FIRST was slightly noisier in both left and right hippocampi over 1 year than 3 years (p¼0.002 & p¼0.002). For example, the noise for the left hippocampus of FreeSurfer longitudinal was 2.0% over 1 year and 2.2% over 3 years while the corresponding median atrophy rates were 1.9% and 5.2%. Conclusions: The noise of measuring hippocampal atrophy rates over 3 years was no worse than over 1 year. Therefore, if the atrophy rate was stable over the 3 years, the 3 year study would be at least 3 times as sensitive as the 1 year study to changes in atrophy rate. P4-221
WHITE MATTER DAMAGE IN CHOLINERGIC SYSTEM CONTRIBUTES TO COGNITIVE IMPAIRMENT IN SUBCORTICAL VASCULAR COGNITIVE IMPAIRMENT NO DEMENTIA
Qing Liu1, Zude Zhu2, Stefan J. Teipel3,4, Jianwei Yang1, Yi Tang5, Jianping Jia5,6,7, 1Xuan Wu Hospital, Capital Medical University, Beijing, China; 2Jiangsu Normal University, Xuzhou, China; 3University Medicine Rostock, Rostock, Germany; 4German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany; 5Beijing Friendship Hospital, Capital Medical University, Beijing, China; 6Beijing Key Laboratory of Geriatric Cognitive Disorders and Neurodegenerative, Beijing, China; 7 Center of Alzheimer’s Disease, Beijing Institute for Brain Disorders, Beijing, China. Contact e-mail:
[email protected] Background: Cholinergic deficiency has been implicated in the pathogenesis of vascular cognitive impairment (VCI), the second common cause of dementia, but the extent of involvement remains unclear. Importantly, even less is known about the underlying mechanism. Methods: To investigate the role of cholinergic system changes in the pathogenesis of VCI, firstly, we focused on patients with subcortical subcortical vascular cognitive impairment no dementia (VCIND), which is a relatively homogeneous condition and supposed to reflect early pathophysiological changes in VCI. Secondly, using probabilistic tractography analysis, we tracked the two major cholinergic pathways. In combination with previously developed stereotaxic cytoarchitectonic maps of the nucleus basalis of Meynert (NbM), we investigated the involvement of NbM and cholinergic pathways, and their contribution to cognitive impairment in 25 VCIND patients compared to 24 healthy elderly subjects. Results: By applying stereotaxic cytoarchitectonic maps of NbM, no significant atrophy was identified in VCIND. Using probabilistic tractography analysis, for the first time our study successfully tracked the two major pathways carrying cholinergic fibers. We identified significantly altered diffusivity indices, including lower fractional anisotropy (FA) and higher mean diffusivity (MD) in VCIND. Partial correlation analysis revealed that FA was correlated with general cognitive performance and performance in specific cognitive domains, i.e. in memory, language and executive function. Mediation analysis further demonstrated that FA in cholinergic pathways could fully account for the executive dysfunction, and partly mediate the memory and global cognition impairment. Conclusions: Our study suggests that the cholinergic pathways, but not the NbM, are significantly impaired in VCIND. MRI-based in vivo tracking of cholinergic pathways together with NbM measurement may become a valuable in vivo marker for evaluating the cholinergic system in VCI and other cognitive disorders, including Alzheimer’s disease. P4-222
HOW AGE AT INJURY AFFECTS THE LONG-TERM OUTCOMES OF TRAUMATIC BRAIN INJURY
Wei Li1, Shannon L. Risacher2, Andy J. Saykin2, 1Indiana University, Indianapolis, IN, USA; 2Indiana University School of Medicine, Indianapolis, IN, USA. Contact e-mail:
[email protected]
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Background: Traumatic brain injury (TBI) is a risk factor for dementia. The effects of age at injury (AAI) are controversial on the longterm cognition function outcome. This study was aimed to investigate how AAI affects age at onset (AAO) of cognitive impairment as well as changes in brain structure and cognition function. Methods: Subjects with a TBI history were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants by searching keywords from their medical history records. 81 participants with a TBI history were divided a childhood TBI (cTBI) group with an AAI< or ¼ 21 years old) and an adult TBI (aTBI) group with an AAI>21 years old. The cTBI and aTBI groups have 36 and 45 participants respectively. Results: The AAI is weakly correlated with the AAO among participants with TBI (coefficient¼0.321). The AAOs for the cTBI and aTBI groups are 65.77+/-1.75 years and 70.63+/-1.58 years respectively. In addition, the average 18FFDG SUVr from thalamus is 1.30+/-0.03 for the cTBI group, which is lower than the corresponding measure of 1.38+/-0.02 for the aTBI group. Further, the cTBI group has significant worse performance than the aTBI group on everyday cognition function assessments. Conclusions: The cTBI group has an earlier AAO than the aTBI group for about 5 years. Structurally, the cTBI group has a lower hippocampal fissure volume than the aTBI group. Functionally, the worse performance on everyday cogition function tests for the cTBI group than the aTBI group may be explained by the significantly lower glucose metabolic rate in thalamus. P4-223
A QUANTITATIVE INVESTIGATION OF THE LOCUS COERULEUS (LC) IN EARLY ALZHEIMER’S DISEASE STAGES: A POSSIBLE SUBSTRATE FOR PRODROMAL NEUROPSYCHIATRIC DISORDERS
Alexander J. Ehrenberg1,2, Panos Theofilas1, Austin K. Nguy1,2, Sara Dunlop1, Claudia K. Suemoto3, Ana T. Alho3,4, Renata Elaine Paraizo Leite3, Roberta Diehl Rodriguez3, Maria B. Mejia1, Julia M. Thackrey1,2, Jose M. Farfel3, Renata Eloah de Lucena Ferretti-Rebustini5, Livia Polichiso3, Camila F. Nascimento6, William W. Seeley1, Ricardo Nitrini3, Carlos Augusto Pasquallucci3, Wilson Jacob-Filho3, Udo Rueb7, Helmut Heinsen3,8, Lea T. Grinberg1,3, 1University of California, San Francisco, San Francisco, CA, USA; 2University of California, Berkeley, Berkeley, CA, USA; 3University of S~ao Paulo Medical School, S~ao Paulo, Brazil; 4Hospital Albert Einstein, S~ao Paulo, Brazil; 5 University of S~ao Paulo, School of Nursing, S~ao Paulo, Brazil; 6University of Sao Paulo Medical School, Sao Paulo, Brazil; 7University of Frankfurt, Frankfurt, Germany; 8Universiy of W€uerzburg, W€uerzburg, Germany. Contact e-mail:
[email protected] Background: Alzheimer’s Disease (AD) features a long prodrome during which phosphorylated tau (p-tau), neurofibrillary tangles (NFT), and b-amyloid plaques accumulate in the brain without causing cognitive decline. Understanding AD neurobiology during early stages may inform treatment options to inhibit progression and significant neuronal loss. NFT are the best protein-correlate of clinical decline in AD. Qualitative evidence identifies NFT accumulating in the LC before it does in the entorhinal cortex. The LC is the main producer of norepinephrine and widely connects to different brain areas. Here, NFT burden in the LC is quantified across disease stages with an aim to characterize the impact of AD pathology in the nucleus. Methods: We utilized unbiased stereology in a sample of 41 well-characterized subjects enriched for controls and early AD stages (Tables 1-2). NFT counts were estimated in 60mm-thick sections immunostained for p-tau (CP-13;1:500, gift of Peter Davies) throughout the LC. Data were integrated with unbiased estimates of LC neuronal population for
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Poster Presentations: Wednesday, July 27, 2016
Table 1 DATA AND CASE DEMOGRAPHICS (n¼41) Case
LC p-Tau+ Cell Population
LC Cell Population
Braak
Age
Sex
Race
Education
Brain Volume (ml)
Brain Weight (g)
CDR
1 3 9 11 12 13 14 15 16 17 18 19 25 33 34 35 36 38 39 40 65 73 74 75 44 48 51 53 66 67 70 71 72 76 78 83 59 61 63 64 69
1968 1682 2091 1969 2470 1224 4944 3085 4565 3832 5611 5511 5013 5725 2385 7181 1406 5197 10625 9708 6348 5740 4112 7394 8057 3528 1881 4294 342 8546 4991 2745 1938 7806 3562 1116 4883 1679 5174 4184 4171
35531 40046 45739 47702 58107 59284 43580 47899 44365 42402 55358 – 50843 51825 40439 50451 47899 64388 36513 – 37102 – – – 35335 39850 58303 71455 – – – – – – – – 12760 14527 6674 15116 –
0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 2 2 2 2 2 2 2 2 2 2 2 2 5 6 6 6 6
58 44 75 65 49 71 47 48 64 56 58 62 53 56 67 53 70 55 61 59 67 61 51 71 72 53 46 71 71 70 81 58 68 77 69 84 54 88 60 82 78
M F M F M M F F F M M M F M F M F M F M M M F M M M F F M F F F M F M M F F M M F
Cau Cau – Cau Cau Black Brown Cau Black Cau Brown Cau Cau Cau Cau Black Black Cau Brown Cau Asian Brown Cau Brown Cau Black Brown Cau Cau Black Brown Cau Cau Cau Black Cau Brown Cau Cau Cau Cau
8 10 – 4 0 4 5 – 0 8 4 4 2 11 1 15 11 13 0 5 11 4 4 2 4 4 6 0 11 4 4 4 4 0 2 11 4 0 16 16 4
880 – 1050 816 1284 1290 1162 1074 910 1190 1068 1080 – 1098 1068 1242 1238 1236 988 1068 1330 1100 1180 – – 1252 – 920 1014 1080 1078 1052 – 904 1094 966 1012 – – – 1026
1114 – 1224 1020 1410 1402 1202 1228 1026 1284 1168 1100 1266 1252 1114 1344 1242 1306 1212 1170 1378 1074 1300 – 1304 1314 1176 1002 1040 1136 1246 1170 – 1128 1180 1136 1202 1052 1140 1133 1080
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 3 2 2 3 3
Table 2 DEMOGRAPHICS BROKEN DOWN BY ANALYSIS Analysis
N Cases per BraajAge
Sex
Race
Early stage tau burden (Figure 1)
36 BB0: 11 Mean: 62
Male: 20
Cau: 20
Percentage of p-tau+ neurons (Figure 2)
Total
BB1: 13 Range: 44-84 Female: 16 Brown: 7 BB2: 12 Black: 7 Asian: 1 Unknown: 1 27 BB0: 11 Mean: 61 Male: 14 Cau:15 BB1: 8 Range: 44-88 Female: 13 Brown: 5 BB2: 4 Black: 5 BB5: 1 Asian: 1 BB6: 3 Unknown: 1 41 BB0: 11 Mean: 63.5 Male: 22 Cau: 24 BB1: 13 Range: 44-88 Female: 19 Brown: 8 BB2: 12 Black: 7 BB5: 1 Asian: 1 BB6: 4 Unknown: 1
a subset of cases. Results: 6% of the LC neuronal population, on average, already showed NFT in controls with no cortical NFT (Braak 0). Braak stages had a positive association with NFT+ cells in the LC in early stages (Braak 0-II) of AD [p¼0.02] (Figure 1). A Tukey multiple-comparison of means identified a significant [p¼0.02] increase in NFT+ cell population (x1.9) from Braak 0-I but no significant difference between Braak I-II. For the subset of cases with estimated neuronal populations (Table 2), a regression analysis suggests that the percentage of NFT+ cells in the LC increase at an average rate of 5.36% by Braak stage [p¼0.0003] (Figure 2). No association was detected between NFT burden and age, education, sex, or total neuronal population. Conclusions: NFT+ neurons are present in Braak 0 subjects and represent an increasing fraction of the LC neuronal population as the disease advances. Neuronal loss may explain the absence of significant NFT+ count changes from Braak I-II. Early LC involvement in AD may underlie the high prevalence of mood and sleep-cycle disorders observed years before the onset of cognitive decline. Therapies to
Poster Presentations: Wednesday, July 27, 2016
Figure 1. Cytoplasmic neuronal p-tau inclusions in the left LC.
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Mixed Models (LMM), that included terms for OSAS, diagnosis, and the interactions between OSAS and diagnosis. All models were adjusted for APOE E4 status. Results: In the total sample there was no association between OSAS and CSF biomarkers. The relationship between OSAS and tau tended to be different between diagnostic groups (p-value interaction .095). Post-hoc analysis showed that AD patients with a history of OSAS had higher tau levels than those without OSAS (estimated mean [95% CI]: 845 [715-976] vs. 647 [549-744] pg/ml, p-value ¼ .02). OSAS was not associated with tau in SCD and MCI patients. There was no interaction between OSAS and diagnosis for CSF AB42 and ptau. Conclusions: We found that a history of OSAS is associated with higher CSF tau levels in AD. These findings could fit with the idea that hypoxia might have an additive effect to neuronal injury in AD, or vice versa, that patients with high tau levels are at increased risk of OSAS. However, inferences on causal relationships cannot be made given the observational nature of the study. P4-225
ANALYSIS OF SPATIO-TEMPORAL FEATURES OF HISTOPATHOLOGY IN MURINE ALZHEIMER’S DISEASE MODELS AND HUMAN ALZHEIMER’S DISEASE SAMPLES
Vera Niederkofler1, Christina Hoeller1, Joerg Neddens1, Ewald Auer1, Heinrich Roemer2, Johannes Attems3, Birgit Hutter-Paier1, 1QPS Austria, Grambach, Austria; 2University of Graz, Graz, Austria; 3Newcastle University, Newcastle, United Kingdom. Contact e-mail: vera.
[email protected] Background: Alzheimer’s disease (AD) is one of the most common
Figure 2. Percent of left LC population with cytoplasmic neuronal p-tau inclusions.
modulate norepinephrine and to protect LC neurons may benefit AD patients. P4-224
ALZHEIMER’S DISEASE PATIENTS WITH OSAS HISTORY HAVE HIGHER CSF TAU LEVELS
Astrid M. Hooghiemstra1, Pieter Jelle Visser1,2, Rosalinde E. R. Slot1, Charlotte E. Teunissen1, Philip Scheltens1, Wiesje M. van der Flier1, 1VU University Medical Center, Amsterdam, Netherlands; 2Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands. Contact e-mail: a.hooghiemstra@ vumc.nl Background: Obstructive sleep apnea syndrome (OSAS) occurs more frequently in Alzheimers disease (AD) than in controls. OSAS is characterized by the obstruction of the upper airway resulting in nocturnal intermittent hypoxia. Hypoxia has been found to be related to the Alzheimer biomarkers amyloid-beta and tau in animal studies. The aim of the present study was to investigate whether a history of OSAS is associated with cerebrospinal fluid (CSF) levels of amyloid-beta 42 (AB42), total tau (tau) and phosphorylated tau (ptau) in patients with subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD. Methods: We included 59 patients who reported OSAS in their medical history (age 63 (8) years, 11 (19%) female; 14 AD, 15 MCI, 30 SCD) from the Amsterdam Dementia Cohort. We matched these patients for baseline diagnosis, gender, age, and year of evaluation, on a 1:2 basis to patients without an OSAS history (N¼118). CSF AB42, tau and ptau were assessed using ELISA (Innotest). We assessed the association between OSAS and the CSF biomarkers with Linear
neurodegenerative diseases of the world. One of its major hallmarks is the hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangles (NFTs) in neurons. These tangles represent an end stage of paired helical filament (PHF) aggregation, which are found in neuropil threads in early stages of dementia. The hyperphosphorylation occurs at different tau protein residues like serine, threonine and tyrosine, including several phospho-sites especially related to AD. However, appearance, quantity and location of NFTs are still not fully understood. Methods: Using indirect immunofluorescence and quantitative image analysis, tau pathologies in diseased and healthy human brain, as well as transgenic and non-transgenic APPSL mice were investigated. We analyzed three different phospho-sites (pSer199, pSer396 and pSer422) in cortical regions and the hippocampus of both specimens. This study thus attempts -to test if the antibodies work equally well on mouse and human tissue, and to analyze if tau protein load increases with age and Braak staging, respectively. Further, immunofluorescent labelings using the murine tissue were performed to check if APPSL mice present at all with a quantifiable tau pathology and can therefore be used as a dual model of APP and Tau pathology. Results: Results show that the antibodies worked well on both tissues. The immunofluorescent labelings with pSer199, pSer396 and pSer422 show an increase of tau positive signal with age and Braak stage for murine and human samples, respectively. Conclusions: Except for pSer199 the quantification of tau shows the same trend in both types of tissue so that APPSL mice could potentially be established as a useful model for human Tau histopathology. P4-226
QUANTIFICATION OF TAU OLIGOMERS FROM MOUSE BRAIN TISSUE
Seung-Pil Yang1, Yanfei Wang1, Marcy Taylor1, Christopher Barden1, Anandi Bhattacharya1, Erhu Lu1, Mark Reed1, Braden Sweeting1, Donald F. Weaver2, Fan Wu1, Arun Yadav1, 1Treventis Corporation,
