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ADWP3: news from the field

ADWP3: news from the field. 14 September 2015. Biomarker news from Alzheimer’s Association International Conference 2015. Differences in CSF TREM2 Levels in AD Cases and Controls. STUDY 1 Heslegrave et al. University College London Methods

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ADWP3: news from the field

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  1. ADWP3: news from the field 14 September 2015

  2. Biomarker news from Alzheimer’s Association International Conference 2015

  3. Differences in CSF TREM2 Levels in AD Cases and Controls STUDY 1 • Heslegrave et al. University College London • Methods • CSF samples: 34 AD patients and 20 control individuals • tandem mass spectrometry to quantify levels of soluble TREM2 • Results • significantly higher TREM2 level in AD CSF as compared to control CSF • AD 257.3 pg/ml ± 83.92, Control 184.22pg/ml ±54.8, p = 0.0022 STUDY 2 • Haass et al. Ludwig-Maximilians University in Munich • Methods • 800 CSF samples from people who are cognitively normal, preclinical, prodromal or AD patients • TREM2 ELISA assay • Results • This ongoing study finds soluble TREM2 in CSF to be increased, particularly at the prodromal stage • The TREM2 elevation correlates with elevated CSF tau

  4. Plasma MCP-1 Is Associated with a Faster Decline of Cognitive Function in MCI and AD • Fuh et al. National Yang-Ming University Schools of Medicine, Taipei, Taiwan • Methods • Measured the levels of MCP-1 in plasma of 321 AD and 67 MCI patients and 125 controls at baseline • All patients underwent clinical functional assessment and a neuropsychological test battery at baseline and one year later (68% completed the 1-year clinical follow-up) • Results • Among the 264 patients undergoing 1-year follow-up, the MCP-1 level of the patients with rapid cognitive decline (1-year Mini-Mental State Examination (MMSE) scores decline ≥ 3) was higher than patients with stable cognition (1-year MMSE scores decline < 3) • 258.84 ± 132.88 μg/ml vs. 230.97 ± 87.53 μg/ml, p=0.04

  5. MMP-9 in the CSF of Patients with MCI • Muszynski et al. Medical University of Bialystok, Bialystok, Poland • Methods • 20 patients with MCI and 20 elderly individuals without cognitive impairment • CSF concentrations of MMP-9 and Ab1-42 were determined using ELISA • Assessed the diagnostic sensitivity and area under ROC curves (AUC) of MMP-9 and Ab1-42 in differentiation between MCI patients and non-demented controls • Results • percentage of positive results for MMP-9 (95%) was higher than for Ab1-42 (60%) • AUCs were 0.985 for MMP-9 and 0.763 for Ab1-42

  6. papers

  7. This study looks at combining molecular markers with cognitive measures for purposes of enhancing diagnostics

  8. Background • Previously examined the implications of using serum-based biomarkers to create an algorithm to detect AD presence • Generated a blood test based profile consisting of 21 serum proteins • The top five serum proteins included in the blood-test were IL-5, IL-6, IL-7, TNF-a and CRP • The current study sought to further refine prior research by examining the strength of the relationship of the top five molecular markers with neuropsychological test scores • And determine the predictive ability of combined molecular markers and select neuropsychological tests in detecting disease presence

  9. Methods • 300 participants (AD n=150 and controls n=150) • Serum was assayed in duplicate via a multiplex biomarker assay platform using electrochemiluminescence (ECL) on the SECTOR Imager 2400A from Meso Scale Discovery • Neuropsychological testing • Linear regression models were used to examine the link between the top five molecular markers (IL-5, IL-6, IL-7, TNF-a, CRP) and neuropsychological test scores • Logistical regressions were used to predict AD presence using the serum biomarkers in combination with the select neuropsychological measures that were least related to the biomarker profile

  10. Results

  11. The combined molecular markers were significantly related to cognitive test scores and accounted for a significant amount of variance • The COWAT (Controlled Oral Word Association Task) was found to have the least amount of variance overlap with the molecular markers and was selected for combination with the markers for predicting AD presence • This was done to maximize the strengths of the approach by minimizing overlap • The COWAT requires participants to generate words that begin with a specific letter of the alphabet within a predetermined time frame • designed to test for verbal fluency, specifically, phonemic fluency • In prior work, the COWAT has been shown to distinguish mild cognitive impairement from normal controls due to its requirement for concurrent manipulation of information

  12. Analysis of biomarker-cognitive profile to detect AD

  13. Conclusions • Combining a measure of verbal fluency that reflects executive functioning with biomarkers that are more strongly related to memory processes produces a highly accurate tool to detect Alzheimer’s disease • This work provides the foundation for the generation of a point-of-care device that can be used to screen for AD with screen positives referred for a comprehensive dementia examinations • Additionally, a point-of-care device has the opportunity to serve as a means of screening in clinical trials and may also aid in the differential diagnoses as several neurodegenerative diseases present with similar symptoms at onset

  14. Caroline O’Hagan Cardiff University

  15. Introduction • Neuroinflammation plays a pivotal role in numerous neurodengenerative diseases inc. Alzheimer’s Disease and Parkinson’s Disease. • Protent inflammatory cytokines – IL-1α, IL-1β and IL-6 Upregulated in AD brain (McGeer & McGeer, 2001) • IL-6 exhibits both pro- and anti- inflammatory properties Inhibits TNFα Inhibits IL-1 Induces IL-10 Induces IL-1ra IL-1 β TNF α IL-6

  16. Alpha -2 macroglobulin (α2M) inhibits any protease. • Binds to both IL-1β and IL-6; inhibits IL-1 and TNFα, IL-6 remains active. • Protects IL-6 from proteolysis. • TNFα & IL-6 are the most frequently studied cytokines in neurodegenerative disease with inconsistent findings.

  17. Due to the bidirectional relationship between these proteins, this set was examined in different patient groups AD (late and early onset) MCI & PD. • Purpose : to determine a pattern of investigated cytokines in neurodengerative disorders with differing molecular backgrounds. • Also compared BDNF, TNFα, heat shock protein (Hsp90), FH and IL-10 in previous cohort of AD patients (late and early onset)

  18. Method • 197 patients; Exclusions: history of inflammatory disease, auto-immune disease, infectious or psychiatric disease, non-Alzheimer’s Disease dementia(other than MCI), chronic heart disease, use of antibiotics or NSAIDs. • Groups AD – late onset 21 AD – early onset 53 MCI 30 PD 40 Control for EOAD 21 Control for LOAD, MCI & PD 32 • ELISA performed on serum; IL-1α, IL-1β, a2M. • Correlation analyses of age, age of onset and neurological impairment (using MMSE). • Multiple regression analysis including previous cohort.

  19. Results: Comparisons with age-matched controls

  20. Results: Between group comparisons EOAD* LOAD* MCI* EOAD* PD*(**) IL-1a IL-6 a2M IL-1β PD* MCI* EOAD* LOAD PD EOAD* LOAD* MCI* MCI* LOAD** PD*

  21. Results: Correlation analyses Examining age, age of onset and neurological impairment (MMSE) • PD patients with higher MMSE scores have low IL-1β. • LOAD; inverse correlation of age & age of onset with IL-6. • MCI; positive correlation of age & age of onset with α2M.

  22. Results: Multiple regression analysis • EOAD increased IL-6 correlated with decreased IL-1a lower IL-1a correlated with lower Hsp90 levels • MCI decreased IL-1a correlated with increased IL-1β, a2M & BDNF • LOAD IL-6 levels correlated with TNFa & IL-10 • No correlations were found in cytokine levels of PD patients

  23. Discussion • MCI group was the only group which reported no difference in any of the measured analytes compared with age-matched controls. • IL-1a was significantly lower in all groups except MCI; unrelated to age, age of onset or MMSE score. Correlates with Hsp90 & IL-6 in EOAD only. • IL-lβ was elevated in EOAD and PD groups only; unrelated to age, age of onset. • IL-6 significantly elevated in EOAD, elevated in LOAD but not significant. Suggested to increase with disease progression. • Correlation between IL-6, TNFa and IL-10 in LOAD only, indicating IL-6 is a significant contributor to inflammatory process in LOAD.

  24. Implications for current research • Results from correlation study indicate differing cytokine activation patterns in LOAD, EOAD and MCI therefore accurate patient data is paramount in analysis of current sample set. • No information is provided on conversion from MCI to AD, however, targeting analytes which consistently show differences between diseases may provide more accurate assessments of the likelihood of conversion (and possible timeframe i.e. EOAD vs LOAD). • Correlating data on interlinked analytes in healthy controls may be useful in determining accuracy of testing protocol.

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