Goran Šimić , MD , PhD

1. CSF biomarkers in neurodegeneration: Preliminary findings and cut-offs recommendations of the Croatian projecton early detection of Alzheimer’s diseaseLikvorski biološki biljezi u neurodegeneraciji: Preliminarni rezultati i preporučene isključne vrijednostihrvatskog projekta ranog otkrivanja Alzheimerove bolesti Goran Šimić, MD, PhD Full Professor of Neuroscience and AnatomyRedoviti profesor neuroznanosti i anatomije Department of Neuroscience, Croatian Institute for Brain Research Zavod za neuroznanost, Hrvatski institut za istraživanje mozga Medical School Zagreb Medicinski fakultet Zagreb 6th Croatian Congress on Alzheimer’s disease 6. hrvatski kongres o Alzheimerovoj bolesti Primošten, 15 Oct 2012 Hrvatska zaklada za znanost Projekt br. 09/16 (2012-2014) Croatian Science Foundation

2. Croatian Science Foundation projectProjekt Hrvatske zaklade za znanost

3. Collaborators / Suradnici na projektu Matea Nikolac, Nela Pivac, Dorotea Mück Šeler, Gordana Nedić, Maja Mustapić, Mirjana Babić, Fran Borovečki, Dubravka Švob Štrac, Maja Jazvinšćak Jembrek, Sanja Hajnšek, Ratimir Petrović, Svjetlana Kalanj Bognar, Željka Vukelić, Patrick R. Hof, Milan Radoš, Ninoslav Mimica, Paola Presečki, Danira Bažadona, Nataša Jovanov Milošević, Gabrijela Stanić, Neven Henigsberg Hrvatska zaklada za znanost Projekt br. 09/16 (2012-2014) Croatian Science Foundation

4. Major issues in dementia syndrome Ključni problemi sindroma demencije 1. Similarclinicalpictureofdementia – manyhistologies / Slična klinička slika – različiti neuropatološki supstrati 2. Late th intervention is lessefficient / kasna th intervencija nije učinkovita

5. Main goals of the projectGlavni ciljevi projekta • 1. To use/identifybiomarkerssuitable for betterdifferentiationoftheprimarycausesofdementia / pospješiti razlikovanje primarnih uzroka demencije pomoću za tu svrhu prikladnih bioloških biljega • 2. To establishreliableearlydiagnosis (inthepreclinicalstage) ofthediseaseby „patternrecognition” i.e. byusing a combinationofclinical/genetical/imaging/biomarkerdatauspostaviti pouzdanu ranu dijagnozu (po mogućnosti u predkliničkom stadiju bolesti) uz pomoć kombinacije kliničkih/genetskih/slikovnih/bioloških podataka

6. Autosomal dominant ADAutosomno dominantna AB Schellenberg et al., 2012

7. Autosomal dominant ADAutosomno dominantna AB Schellenberg et al., 2012

8. Autosomal dominant ADAutosomno dominantna AB Bielschowsky H-E, 200x Schellenberg et al., 2012

9. Sporadic late-onset ADSporadična AB s kasnim početkom Schellenberg et al., 2012

10. Sporadic late-onset ADSporadična AB s kasnim početkom Bielschowsky

11. Hypothetical time line for the onset and progression of sporadic AD Trojanowski et al., 2011

12. Nagao prijelaz zbog superponiranog age-associated gubitka sinapsi i neurona.

13. Current approaches to early assessment of MCI to AD conversionDanašnje mogućnosti u ranoj dijagnostici konverzije MCI u AD • Early concern (ADI 10 warning signs) www.alzheimer.hr • Dementia severity psychological assessment tools (lack early power as well as MMSE) • Positive diagnostic tests (still too invasive and expensive for screening): 1. Structural MRI (hipp. & entorh. cx lower volumes, whole cx lower volume) 2. F-nal PET brain scan (FDGlucose, NFT: DDNP, BA: Thioflavin-S & Congo-red derivatives - radioisotopes) 3. CSF – elevated total tau and phospho-tau levels, low -amyloid levels

14. Fox et al. Lancet ‘04 Fox et al. Lancet ‘04

16. AD – parijeto-temporalni hipometabolizam (perfuzijski SPECT KBC Zagreb, Dr. Ratimir Petrović )

17. + Nordberg A. et al. Lancet Neurology 2004

19. Major pitfalls (1)Glavne poteškoće (1) • The first major pitfall when studying CSF biomarkers to predict AD in MCI cohorts is the fact that conversion from MCI to AD in specialist clinical setting is only about 9.6% per year (in contrast, only 1-2% of healthy older population convert to AD per year), whereas the rest of MCI patients have a less progressive form of memory impairment (Mitchell et al., 2009); • Therefore, only an extensive follow-up time (5 – 10 years) of patients with stable MCI might further increase the specificity of CSF/other biomarkers • Only then (after 5-10 years) we will be able to conclude which cut-off levels are best to distinguish MCI that will progress to AD from those who will not

20. Major pitfalls (2)Glavne poteškoće (2) • The second major pitfall when studying CSF biomarkers to predict AD in MCI cohorts is the fact that use of clinical diagnosis instead of neuropathological diagnosis lead to a 14-17% underestimation of the CSF biomarker accuracy (Toledo et al., 2012); • Therefore, to increase the accuracy for the early diagnosis of AD (and neurodegenerative disease in general) CSF diagnostic panels much be standardized and established based on neuropathological rather than clinical diagnoses!

21. Preliminary data /Preliminarni podatci N=126:54 AD, 30 MCI, 9 VaD, 4 LBD, 11 FTD, 18HC

22. Preliminary data according to clinical dgPreliminarni podatci prema kliničkim dg

23. ROC analysis of preliminary data

24. MCI to ADp-tau199 Urakami, Psychogeriatrics ‘06

25. p-tau231 Vrijednosti p-tau231 markera iz likvora bile su statistički značajno više u skupini bolesnika s AB u odnosu na skupinu bolesnika s MCI (U=45; Z=-2,938; p=0,003), odnosno kontrolnu skupinu (U=15; Z=-2,155; p=0,031). No, nije nađena statistički značajna razlika za p-tau231 između skupine bolesnika s MCI i kontrolne skupine (U=30; Z=-0,463; p=0,687).

26. Toxicity of soluble tauToksičnost topljivih tau proteina

27. Toxicity of soluble tauToksičnost topljivih tau proteina Kopeikina et al., 2012

28. Thank you for your attention!Zahvaljujem na pažnji! http://alzbiotrack.hiim.hr/