Plasma markers and cognitive decline in the ADAPT clinical trial

Plasma markers and cognitive decline in the ADAPT clinical trial

P234 Poster Presentations: P1 Table 2 Diagnostic performances of serum levels of Albumin-Ab complexes for detecting patients with Alzheimer’s diseas...

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Poster Presentations: P1

Table 2 Diagnostic performances of serum levels of Albumin-Ab complexes for detecting patients with Alzheimer’s disease in all study participants (n¼89). Serum Albumin-Ab complex cutoff value (mg/ml)*

Number of cases under the cutoff value, (%)

Sensitivity, % (95% CI)

13.0 11.0 9.0 7.0 5.0 3.0

64 (72) 57 (64) 49 (55) 37 (42) 25 (28) 15 (17)

93 (82-99) 80 (65-90) 73 (58-85) 64 (49-78) 44 (30-60) 27 (15-42)

Specificity, %

Negative predictive value, %

Positive predictive value, %

50 (35-65) 52 (37-68) 64 (48-78) 82 (67-92) 89 (75-96) 93 (81-99)

66 (53-77) 63 (49-76) 67 (53-80) 78 (62-90) 80 (59-93) 80 (52-96)

88 (69-98) 72 (53-86) 70 (54-83) 69 (55-81) 61 (48-73) 55 (43-67)

*Equivalent to albumin preparation.

Table 3 Diagnostic performance of the composite of serum levels of Albumin-Ab complexes (SLAAC) and ApoE4 phenotype in the detection of patients with Alzheimer’s disease among all study participants (n¼89).

SLAAC (mg/ml)*  13.0

 11.0

 9.0

 7.0

5.0

 3.0

ApoE4 phenotype number 0 1 2 Total 0 1 2 Total 0 1 2 Total 0 1 2 Total 0 1 2 Total 0 1 2 Total

Control, n

Alzheimer’s disease, n

Total, n

16 6 0 22 15 6 0 21 12 4 0 16 7 1 0 8 5 0 0 5 3 0 0 3

15 22 5 42 14 17 5 36 11 17 5 33 10 14 5 29 7 8 5 20 5 3 4 12

31 28 5 64 29 23 5 57 23 21 5 49 17 15 5 37 12 8 5 25 8 3 4 15

Composite criteria of SLAAC and ApoE4 phenotype

Number of cases fulfilling the criteria, (%)

Sensitivity, % (95% CI)

SLAAC13.0 and 1ApoE4

33 (37)

60 (44-74)

86 (73-95)

82 (65-93)

68 (54-80)

11.0 and 1

28 (31)

49 (34-64)

86 (73-95)

79 (59-92)

62 (49-74)

9.0 and 1

26 (29)

49 (34-64)

91 (78-98)

85 (65-96)

64 (50-75)

7.0 and 1

20 (22)

42 (28-58)

98 (88-100)

95 (75-100)

62 (50-74)

5.0 and 1

13 (15)

29 (16-44)

100 (88-100)

100 (66-100)

58 (46-69)

3.0 and 1

7 (8)

16 (7-30)

100 (88-100)

100 (47-100)

54 (42-65)

P1-222

PLASMA MARKERS AND COGNITIVE DECLINE IN THE ADAPT CLINICAL TRIAL

Specificity, %

Negative predictive value, %

Positive predictive value, %

*Equivalent to albumin preparation.

Jeannie-Marie Leoutsakos1, Dingfen Han2, Sarah Tighe1, Constantine Lyketsos3, 1Johns Hopkins School of Medicine, Baltimore, Maryland, United States; 2Johns Hopkins University, Baltimore, Maryland, United States; 3Johns Hopkins University, Baltimore, Maryland, United States. Contact e-mail: [email protected]

Figure 3. Receiver operating characteristic curves of serum Albumin-Ab complexes and other blood biomarkers for Alzheimer’s disease in all the study participants (A, n¼89), and in the participants with plasma sample data (B, n¼36).

Background: Several plasma markers including cholesterol, bilirubin, and uric acid have been linked to cognitive decline and/or dementia. In the ADAPT clinical trial, both cognition and plasma markers were assessed yearly, allowing for examination of these relationships. Methods: 2,388 subjects, dementia-free at baseline, provided 2-6 yearly plasma samples and 3MS scores. Markers included cholesterol (total, ldl, hdl), creatinine kinase, bilirubin, urea nitrogen, glucose, and uric acid. 3MS scores were

Poster Presentations: P1 modeled using longitudinal mixed effects models with random intercepts and slopes, time was modeled with both linear and quadratic terms. For each plasma marker, two types of models were fit: 1) to assess the effect of baseline marker value on 3MS trajectory over time, and 2) to assess the time-varying effect of marker value on 3MS score at each time point. Models were fit for the full sample, and then for the subsamples of individuals who developed AD or MCI during the trial. Results: In the full sample, there were no statistically significant effects for any plasma markers on 3MS. As baseline predictors of 3MS trajectory, among 57 who converted to AD, a 1-unit difference in total cholesterol was associated with an additional decrease of 0.07 points/year (p¼0.004). A 1-unit difference in ldl was associated with an additional decrease of 0.06 points/year (p¼0.021). There were no significant baseline predictors of trajectory among 64 who converted to MCI. As time-varying predictors of 3MS, among AD converters, ldl (beta ¼ -0.05, p¼0.01) was associated with lower 3MS scores. Among MCI converters, a 1-unit difference in glucose was associated with higher scores (beta ¼ 0.02, p¼0.02), and a 1-unit difference in urea nitrogen (beta ¼ -0.19, p¼0.004) was associated with lower scores. Conclusions: Consistent with existing reports, cholesterol was associated with slightly greater decline among AD converters. Though higher uric acids levels have been previously associated with reduced dementia risk, and creatinine kinase and bilirubin have been identified as possible protective agents, we found no associations between these markers and decline. The negative effect of urea nitrogen may be reflective of a relationship between poor general health and cognitive decline.

P1-223

PENTRAXIN INFLAMMATORY BIOMARKERS AND ASSOCIATIONS WITH RISK OF DEMENTIA AND ALZHEIMER’S DISEASE IN OLDER ADULTS

Annette Fitzpatrick1, Gloria Chi1, Elizabeth Hom1, Nancy Jenny2, Oscar Lopez3, Steven DeKosky4, 1University of Washington, Seattle, Washington, United States; 2University of Vermont, Burlington, Vermont, United States; 3University of Pittsburgh, Pittsburgh, Pennsylvania, United States; 4University of Virginia, Charlottesville, Virginia, United States. Contact e-mail: [email protected] Background: Recent studies suggest that the development of Alzheimer’s disease (AD) may involve vascular as well as neurodegenerative components and that inflammation may be an early marker of this progression. Methods: We investigated two vascular endothelial biomarkers from the pentraxin family, pentraxin-3 (PTX-3) and serum amyloid protein (SAP), and subsequent development of dementia, AD and mixed dementia (vascular and AD) among 1,319 participants of the Ginkgo Evaluation of Memory Study (GEMS) over an average follow-up of 5.2 years. Cox proportional hazards regression was used to evaluate risk of dementia and AD in models adjusted for demographics, cardiovascular risk factors, physical function, and ApoE genotype. Results: Participants were a mean age of 79.0 years (SD 3.4), primarily Caucasian (95%) and 45% were female. Mean baseline levels of serum PTX-3 were 1.00 ng/mL (SD: 0.67) and mean SAP was 44,936 ng/mL (SD: 12,678). Using Cox proportional hazards regression, a 20% increased risk of dementia was found for each standard deviation increase in PTX-3 adjusted for age, gender, race, education and clinic (HR 1.20, 95% CI: 1.12 to 1.29, p < 0.001). The association remained statistically significant after adjustment for cardiovascular risk factors, physical function and ApoE-4 genotype (HR: 1.16, 95% CI: 1.06 to 1.26, p¼0.001). Associations between PTX-3 and both AD and mixed dementia were similar in the fully adjusted model (For AD -HR: 1.12, 95%CI: 1.00 -1.26, p¼0.06; mixed dementia - HR:1.16 , 95% CI: 0.99 to 1.35, p¼0.07). While no associations were found between SAP and dementia in adjusted models, evaluation of AD alone found that an increase of one SD of SAP decreased the risk of AD by 16% (HR: 0.84, 95% CI: 0.75 0.95, p¼0.004) adjusted for demographics. The association remained significant after adjustment for CVD risk factors and physical function, but was attenuated after adjustment for ApoE genotype (HR: 0.92, 95% CI: 0.79 -1.07, p¼0.28). Conclusions: As PTX3 may represent damaged endothelium while SAP may act to inhibit fibril formation of amyloid deposits as-

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sociated with Alzheimer’s disease, use of these biomarkers may be important for early prediction of dementia and AD in older adults. P1-224

INCREASED MYELOPEROXIDASE (MPO) PLASMA LEVELS IN PATIENTS WITH ALZHEIMER’S DISEASE

Brigitte Schreitm€uller1, Christoph Laske1, Elke Stransky2, Konstantinos Stellos3, 1Department of Psychiatry, T€ubingen, Germany; 2 Department of Psychiatry, T€ubingen, Germany; 3Department of Cardiology, Frankfurt, Germany. Contact e-mail: [email protected] uni-tuebingen.de Background: Increasing evidence supports the role of cerebrovascular risk factors in the development of Alzheimer’s disease (AD). However little is known about the molecular mechanisms involved. In the present pilot-study we investigated plasma concentrations of the pro-atherogenic marker myeloperoxidase (MPO) and its possible association with plasma amyloid-beta (Ab) 1-42/1-40 ratio - a well established predictor for the development of AD - in AD patients and healthy elderly controls. Methods: The study sample included 28 AD patients and 27 gender-matched elderly individuals with a normal cognitive status as a control group. The Mini-Mental Status Examination (MMSE) was used to determine the severity of dementia. MPO, Ab1-40 and Ab 1-42 plasma concentrations were measured by enzyme linked immunoabsorbent assay. Results: AD patients showed significantly higher plasma concentrations of MPO in comparison to healthy elderly controls (AD vs. healthy elderly controls (mean 6 SD): 132.86114.8 ng/mL vs. 55.06 42.6 ng/mL; p¼0.002). MPO plasma concentrations were negatively associated with the baseline score of MMSE (r¼-0.274; p¼0.043) and positively with plasma Ab1-42/1-40 ratio (r¼0.400; p¼0.048). In a binary logistic regression model plasma MPO concentrations were independently associated with the presence of AD (p¼0.010). Conclusions: AD patients showed significantly increased plasma levels of pro-atherogenic MPO, which could be an important molecular link between atherosclerosis and AD. Its close association with plasma Ab 1-42/Ab 1-40 ratio indicates that MPO might be a useful biomarker for the detection and risk stratification of AD patients and a potential new treatment target in AD. P1-225

IL7 AND DEPRESSION: THE IMPORTANCE OF GENDER AND BLOOD FRACTION

James Hall1, Leigh Johnson2, Melissa Edwards2, Tori Como2, Robert Barber3, Neill Graff-Radford4, Michael Devous5, Sid O’Bryant3, 1 University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas, United States; 2UNTHSC, Fort Worth, Texas, United States; 3 University of North Texas Health Science Center, Fort Worth, Texas, United States; 4Mayo Clinic Jacksonville, Jacksonville, Florida, United States; 5 University of Texas Southwestern Medical Center, Dallas, Texas, United States. Contact e-mail: [email protected] Background: Interleukin 7 (IL7) is involved in B and T cell development and differentiation. Recent work suggests serum IL7 may be altered in depression. We have shown depression, and biomarkers related to depression are impacted by gender and disease status. The current study examined the link between IL7 (serum and plasma) and depression scores by gender. Methods: Serum (150 AD cases150 controls) and plasma (100 AD cases, 100 controls) levels of IL7 were assayed from the Texas Alzheimer’s Research & Care Consortium (TARCC). Non-fasting samples were collected according to standardized protocols using serum-separating and EDTA plasma tubes. IL7 was assayed via electochemiluminescense (ECL). Results: Box-Cox transformation was used. The correlation between serum and plasma for IL-7 was 0.34. In the total sample, serum (r 2 ¼ 0.16, p¼0.006) and plasma (r 2 ¼ -0.20, p¼0.007) IL7 levels were significantly, but inversely, correlated with GDS-30 scores. When split by gender, serum IL7 levels were significantly positively associated GDS scores among men (r 2 ¼0.34, p¼0.001) whereas plasma IL7 levels (r 2 ¼-0.23, p¼0.008) were significantly negatively associated with GDS scores among women. A logistic regression model predicting depression status (GDS30 >¼10) included age, gender, education, plasma and serum IL7 levels, found both significantly associated with depression status but in opposite directions. Plasma