PLASMA AMYLOID BETA LEVELS, CEREBRAL SMALL-VESSEL DISEASES AND COGNITION: THE ROTTERDAM STUDY

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SERUM S100B MEDIATES DEPRESSION’S EFFECT ON COGNITION

Safa Rubaye1, Donald R. Royall1,2, Raymond F. Palmer1,3, 1 University of Texas Health Science Center at San Antonio, San Antonio, TX, USA; 2South Texas Veterans Health Administration Geriatric Research Education and Clinical Center (GRECC), San Antonio, TX, USA; 3The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA. Contact e-mail: alrubaye@ uthscsa.edu Background: The latent variable “d” (for “dementia”) appears to be

uniquely responsible for the dementing aspects of cognitive impairment. Age, depression, and the apolipoprotein E (APOE) e4 allele are independently associated with d. S100b is a calcium- binding protein that is secreted mainly by astrocytes. S100b has been identified as a biomarker for mood/ depressive disorders. In addition, Brain level of S100b is altered in response to chronic use of anti-depressants. In this analysis, we combine SEM (Structural Equation Model) with longitudinal data from the Texas Alzheimer’s Research and Care Consortium (TARCC) to explore whether S100b is a mediator of depression’s specific effect on d. Methods: We employed structural equation models (SEM) to examine the mediation effect of S100b on depression’s association with d in a well characterized cohort (TARCC). Subjects included n¼ 3385 TARCC participants [1240 cases of Alzheimer’s Disease (AD), 688 “Mild Cognitive Impairment “(MCI) cases, and 1384 normal controls (NC)]. Serum S100b levels were determined at baseline by Luminex assay (Rules Based Medicine /Austin, TX). All observed measures were adjusted for education, ethnicity, gender, Geriatric Depression Scale (GDS) scores, Hb1Ac, apoE4 and HCY. S100b was additionally adjusted for batch effects. We used an ethnicity equivalent d homolog (i.e., “dEQ”). Wave 2 dEQ scores were used. Thus, the model is longitudinal and arguable causal. Furthermore, we randomly divided the cohort into 2 groups. Group A (n ¼ 1691) was used to construct the model, while Group B (n¼1694) was used to replicate and verify the parameters of interest. Analyses were conducted in Analysis of Moment Structures (AMOS). Results: Model fit was excellent [c2 ¼ 519.912(49), p ¼0.0; CFI ¼ 0.89; RMSEA ¼ 0.053]. Serum S100b was found to mediate 18.3% of depression’s association with Wave 2 dEQ scores (p<0.001). The effect generalized across random subsets of TARCC’s sample. Conclusions: S100B plays a role in mediating depression’s independent effects on dementia severity. High levels of serum S100B are dementing. S100B is a possible serum biomarker of depression in the elderly. S100B is a target for rational anti-dementia intervention, and may be amenable to modulation by SSRI.

P3-247

PLASMA UREA IN ALZHEIMER’S DISEASE: AN OBSERVATIONAL STUDY

Said Ramdane, Algerian Society of Neurology and Clinical Neurophysiology, Skikda, Algeria. Contact e-mail: ramdanesk@ hotmail.com Background: Systemic over-production of urea, leading to elevated

urea levels, in the plasma, is not known to occur in Alzheimer’s disease (AD). Nevertheless previous observations indicated the potential involvement of the urea cycle in the pathophysiological process in AD. In the present study, plasma urea levels in patients with Alzheimer’s disease were analyzed and compared with a control group. Methods: Measures of fasting plasma urea levels were studied in 88 patients with AD, (Mean age 70.769.2 years, range 55-87 years, 44

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women), (DSM-IV; NINCDS-ADRDA criteria); recruited in a community elderly in Skikda-Algeria (2015-2016); and in 88 elderly controls, (Mean age 70.668.9 years, range 55-88 years, 44 women). We assessed the relation between serum urea levels and the odds ratio (OR) for AD. Correlation between dementia severity (Clinical dementia rating scale global score), and plasma urea was also examined. (Plasma urea mg/dL x 0.466 ¼ Blood Urea Nitrogen mg/dL). Results: The mean plasma urea level was 33.8 6 8.0 mg/dL (Range 19-54) among cases and 28.8 6 8.8 mg/dL (range 10-55) among the controls; (p¼ 0.0001). By gender, the difference in plasma urea level between cases and controls was significant in men 36.0 6 6.7 vs. 30.0 6 8.7 mg/dL respectively (p¼0.0004); and in women 31.6 6 8.5 vs. 27.6 6 8.9 mg/dL (p¼ 0.036). The odds ratio [95 percent confidence interval] of AD for the highest tertile of urea levels compared to the lowest tertile, was 4.435 [2.027–9.705], p¼ 0.0001. This association was strongly significant in men (OR: 8.944 [2.72–29.413], p¼0.0002), but not in women. Plasma urea was negatively correlated with dementia severity, r¼ - 0.4586; p< 0.0001. Conclusions: The results show, a significantly higher plasma urea levels (Within normal range) in patients with Alzheimer’s disease compared to controls; male subjects in the “high normal range” of urea levels have an increased risk for developing Alzheimer’s disease; while plasma urea levels negatively correlate with dementia severity in men and women AD patients. Taken together these findings suggest that urea cycle might be up regulated in the earliest stage of the disease in a large subgroup of AD patients.

P3-248

PLASMA AMYLOID BETA LEVELS, CEREBRAL SMALL-VESSEL DISEASES AND COGNITION: THE ROTTERDAM STUDY

Saima Hilal1, Saloua Akoudad1, Cornelia M. van Duijn1, Hugo Marcel Vanderstichele2, Erik Stoops2, Wiro J. Niessen3,4, M. Arfan Ikram1, Meike W. Vernooij5, 1Erasmus University Medical Center,

Table 1 Association of plasma amyloid beta levels with cerebral small vessel disease in two cohorts Lacunar number (n¼151) RR (95%CI)* Plasma Ab1-38 Older cohort Younger cohort Meta-analysis Plasma Ab1-40 Older cohort Younger cohort Meta-analysis Plasma Ab1-42 Older cohort Younger cohort Meta-analysis

White matter hyperintensities Mean difference (95%CI)*

1.28 (1.10-1.49) 1.71 (1.38-2.12) 1.41 (1.24-1.59)

0.01 (-0.10; 0.13) 0.05 (0.00; 0.10) 0.04 (0.00; 0.09)

1.28 (1.09-1.51) 1.63 (1.34-1.98) 1.42 (1.25-1.61)

0.04 (-0.08; 0.16) 0.05 (0.00; 0.10) 0.05 (0.00; 0.10)

1.26 (1.08-1.48) 1.25 (1.03-1.51) 1.26 (1.12-1.42)

-0.08 (-0.19; 0.03) 0.01 (-0.03; 0.06) -0.00 (-0.04; 0.04)

Abbreviations: RR, risk ratios: CI, confidence interval. *Adjusted for age, sex, mean arterial blood pressure, total cholesterol, diabetes, Apolipoprotein ε4 carrier, smoking and presence of other SVD marker (where applicable).

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Table 2 Association of plasma amyloid beta levels with cognition in two cohorts

Younger cohort Meta-analysis Ab-40 Older cohort Younger cohort Meta-analysis Ab-42 Older cohort Younger cohort Meta-analysis

Stroop test 1 b (95%CI)*, p value

Stroop test 2 b (95%CI)*, p value

Stroop test 3 b (95%CI)*, p value

Word fluency test b (95%CI)*, p value

Immediate recall b (95%CI)*, p value

Delayed recall b (95%CI)*, p value

Recognition b (95%CI)*, p value

0.21 (-0.53; 0.95) p¼0.573 -0.41 (-0.91; 0.08) P¼0.103 -0.22 (-0.63; 0.19) P¼0.29

-0.07 (-0.54; 0.39) P¼0.754 -0.16 (-0.41; 0.10) P¼0.233 -0.14 (-0.36; 0.09) P¼0.23

0.00 (-0.69; 0.69) P ¼0.990 0.10 (-0.23; 0.44) P¼0.538 0.09 (-0.22; 0.39) P¼0.58

-1.73 (-4.69; 1.24) P¼0.255 0.37 (-0.58; 1.32) P ¼0.445 0.18 (-0.58; 1.32) P¼0.70

-0.14 (-0.74; 0.47) P¼0.658 -0.22 (-0.67; 0.24) P¼0.348 -0.19 (-0.55; 0.17) P¼0.31

-0.58 (-1.11; -0.06) P[0.030 -0.39 (-0.88; 0.10) P[0.115 -0.48 (-0.84; -0.12) P[0.008

-0.21 (-0.47; 0.06) P¼0.129 -0.34 (-0.56; -0.11) P[0.004 -0.28 (-0.45; -0.11) P[0.002y

-0.17 (-0.38; 0.04) P ¼0.106 -0.24 (-0.38; -0.10) P[0.001 -0.22 (-0.34; -0.10) P[<0.001y

0.19 (-0.60; 0.98) P ¼0.644 -0.29 (-0.80; 0.21) P¼0.252 -0.16 (-0.58; 0.27) P¼0.47

0.02 (-0.47; 0.51) P¼0.933 -0.26 (-0.52; 0.01) P¼0.055 -0.19 (-0.43; 0.04) P¼0.10

0.26 (-0.47; 0.98) P¼0.489 0.01 (-0.33; 0.35) P¼0.957 0.05 (-0.26; 0.37) P¼0.73

-0.07 (-3.19; 3.05) P ¼0.965 0.52 (-0.45; 1.49) P¼0.294 0.47 (-0.46; 1.39) P¼0.32

-0.60 (-1.23; 0.02) P¼0.06 -0.07 (-0.53; 0.40) P¼0.778 -0.26 (-0.63; 0.12) P¼0.18

-0.44 (-0.99; 0.11) P¼0.120 -0.21 (-0.70; 0.28) P¼0.403 -0.31 (-0.68; 0.06) P¼0.10

-0.13 (-0.41; 0.14) P ¼0.346 -0.27 (-0.50; -0.04) P[0.023 -0.21 (-0.39; -0.04) P[0.02

-0.18 (-0.40; 0.03) P¼0.100 -0.21 (-0.36; -0.06) P[0.005 -0.20 (-0.32; -0.08) P[0.001y

0.76 (0.10; 1.43) P[0.026 -0.17 (-0.62; 0.28) P ¼0.463 0.13 (-0.25; 0.50) P¼0.51

-0.09 (-0.52; 0.34) P¼0.679 -0.00 (-0.24; 0.23) P ¼0.992 -0.02 (-0.23; 0.18) P¼0.84

0.15 (-0.48; 0.79) P¼0.637 0.03 (-0.28; 0.33) P¼0.870 0.05 (-0.23; 0.33) P¼0.72

-0.32 (-3.05; 2.41) P ¼0.820 0.18 (-0.69; 1.05) P¼0.678 0.14 (-0.69; 0.97) P¼0.74

-0.56 (-1.11; -0.01) P[0.045 -0.13 (-0.55; 0.29) P¼0.556 -0.29 (-0.62; 0.05) P¼0.09

-0.11 (-0.59; 0.38) P¼0.660 -0.15 (-0.60; 0.29) P¼0.508 -0.13 (-0.46; 0.20) P¼0.43

0.10 (-0.14; 0.35) P¼0.415 0.03 (-0.19; 0.24) P¼0.818 0.06 (-0.10; 0.22) P¼0.48

0.11 (-0.08; 0.30) P¼0.255 -0.01 (-0.09; 0.06) P¼0.716 0.00 (-0.07; 0.07) P¼0.96

*Adjusted for age, sex, education, mean arterial blood pressure, total cholesterol, diabetes, Apolipoprotein ε4 carrier, smoking and presence of other SVD marker (where applicable). yStatistically significant after Sidak correction (w 0.0071).

Poster Presentations: Tuesday, July 18, 2017

Ab-38 Older cohort

Letter digit substitution test b (95%CI)*, p value

Poster Presentations: Tuesday, July 18, 2017 Rotterdam, Netherlands; 2ADx NeuroSciences, Ghent, Belgium; 3Delft University of Technology, Delft, Netherlands; 4Erasmus MC - University Medical Center Rotterdam, Rotterdam, Netherlands; 5Erasmus MC University Medical Center Rotterdam, Rotterdam, Netherlands. Contact e-mail: phchs@ nus.edu.sg Background: Plasma amyloid beta (Ab1) levels are increasingly

studied as a low cost and accessible potential marker of cognitive impairment and dementia. However, it remains underexplored whether plasma Ab1 levels relate to vascular brain disease and cognition in a preclinical-phase. We examined the association of plasma Ab1 levels (i.e. Ab1-38, 40 and 42) with markers of cerebral small vessel disease (SVD) and cognition in a large population-based setting. Methods: We analyzed plasma Ab1 levels in 1202 subjects from two cohorts of the Rotterdam study [older cohort (mean age:72.5 years, 51% women) and younger cohort (mean age:58.7 years, 54% women)]. Markers of SVD [lacunes, white matter hyperintensity (WMH) volume] were assessed on brain MRI (1.5T). Cognition was assessed by a detailed neuropsychological battery. In each cohort, the association of Ab1 levels with SVD and cognition was performed using regression models. Estimates were then pooled across cohorts using inverse variance meta-analysis with fixed effects. All models were adjusted for age, sex, education, mean arterial blood pressure, total cholesterol, diabetes, Apolipoprotein ε4 carrier, smoking and presence of other SVD marker. Results: Higher levels of plasma Ab1-38, 40 and 42 were associated with increasing lacunar counts [Ab1-38 Rate ratios (RR)¼ 1.41;95%Confidence Interval (CI),1.24-1.59], [Ab1-40 RR¼1.42; 95%CI, 1.25-1.61], [Ab1-42 RR¼1.26; 95%CI,1.12-1.42]. Moreover, higher levels of Ab1-38 and 40 were significantly associated with higher WMH volumes. With regards to cognition, a higher level of Ab1-38 was associated with worse performance on memory tests i.e. delayed recall [mean difference in scores (b) ¼ -0.28; 95%CI, -0.45 to -0.11, p¼0.002] and recognition [b¼ -0.22; 95%CI, -0.34 to -0.10, p¼<0.001]. Similarly, a higher level of Ab1-40 was also associated with worse performance on memory test, i.e. recognition [b¼ -0.20; 95%CI, -0.32 to -0.08, p¼0.001]. Conclusions: Higher plasma levels of Ab1-38, 40 and 42 were associated with subclinical markers of vascular disease. Moreover, Ab1-38 and 40 were linked to worse performance on memory tests. Plasma Ab1 levels thus, mark the presence of vascular brain pathology. Future studies should examine whether inclusion of novel plasma Ab1-38 levels as an additional biomarker can provide further information on microvascular damage in the brain.

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MN, USA; 5Mayo Clinic, Rochester, MN, USA. Contact e-mail: AMurray@ bermancenter.org Background: Low hemoglobin level is a common finding in chronic kidney disease and potentially treatable. Anemia can lead to insufficient brain oxygenation and high metabolic demand that may result in higher burden of cerebral small vessel disease. We investigated the association between hemoglobin levels and changes in brain microstructural integrity in participants with mild to severe kidney disease and explored whether the association is confined to specific regions of the brain. Methods: We included 233 participants (mean age: 69 years, 53% male, mean eGFR: 47 ml/min/1.73 m2) from the BRINK (Brain IN Kidney Disease) study. Hemoglobin was assessed from nonfasting blood samples. Brain microstructural changes of white and gray matter were assessed using Diffusion Tensor Imaging (DTI) MRI. Fractional anisotropy of white matter (FAWM) and mean diffusivity of white matter (MD-WM) and gray matter (MD-GM) were parameters to quantify brain microstructural integrity. Generally, lower FA and higher MD are associated with poorer brain microstructural integrity. We

LOW HEMOGLOBIN LEVEL IS ASSOCIATED WITH BRAIN MICROSTRUCTURAL INTEGRITY IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Sanaz Sedaghat1, Christine Burns2,3, Clifford R. Jack Jr.4, Robert I. Reid5, Prashanthi Vemuri5, Anne Murray2,3, 1Erasmus MC, Rotterdam, Netherlands; 2Berman Center for Clinical Research, Minneapolis Medical Research Foundation, Minneapolis, MN, USA; 3Hennepin County Medical Center, Minneapolis, MN, USA; 4Mayo Clinic College of Medicine, Rochester,

Figure 1. Associations of hemoglobin level with brain microstractural integrity in different regions.