CN1 CSF biomarkers in neurodegeneration Preliminary findings and

CN-1 CSF biomarkers in neurodegeneration: Preliminary findings and cut-offs recommendations of the Croatian project on early detection of Alzheimer’s disease Likvorski biološki biljezi u neurodegeneraciji: Preliminarni rezultati i preporučene isključne vrijednosti hrvatskog projekta ranog otkrivanja Alzheimerove bolesti Goran Šimić, MD, Ph. D Full Professor of Neuroscience and Anatomy Redoviti 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 Hrvatska zaklada za znanost Projekt br. 09/16 (2012 -2014) 6 th Croatian Congress on Alzheimer’s disease 6. hrvatski kongres o Alzheimerovoj bolesti Primošten, 15 Oct 2012 Croatian Science Foundation

CN-2 Croatian Science Foundation project Projekt Hrvatske zaklade za znanost

CN-3 Collaborators / Suradnici na projektu Hrvatska zaklada za znanost Projekt br. 09/16 (2012 -2014) 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 Croatian Science Foundation

Major issues in dementia syndrome CN-4 Ključni problemi sindroma demencije 1. Similar clinical picture of dementia – many histologies / Slična klinička slika – različiti neuropatološki supstrati 2. Late th intervention is less efficient / kasna th intervencija nije učinkovita

Main goals of the project CN-5 Glavni ciljevi projekta u 1. To use/identify biomarkers suitable for better differentiation of the primary causes of dementia / pospješiti razlikovanje primarnih uzroka demencije pomoću za tu svrhu prikladnih bioloških biljega u 2. To establish reliable early diagnosis (in the preclinical stage) of the disease by „pattern recognition” i. e. by using a combination of clinical/genetical/imaging/biomarker data uspostaviti pouzdanu ranu dijagnozu (po mogućnosti u predkliničkom stadiju bolesti) uz pomoć kombinacije kliničkih/genetskih/slikovnih/bioloških podataka

CN-6 Autosomal dominant AD Autosomno dominantna AB Schellenberg et al. , 2012

CN-7 Autosomal dominant AD Autosomno dominantna AB Schellenberg et al. , 2012

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

CN-9 Sporadic late-onset AD Sporadična AB s kasnim početkom Schellenberg et al. , 2012

CN-10 Sporadic late-onset AD Sporadična AB s kasnim početkom Bielschowsky

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

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

CN-13 Current approaches to early assessment of MCI to AD conversion Današnje mogućnosti u ranoj dijagnostici konverzije MCI u AD u Early concern (ADI 10 warning signs) www. alzheimer. hr u Dementia severity psychological assessment tools (lack early power as well as MMSE) u 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

CN-14 Fox et al. Lancet ‘ 04

CN-15

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

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

CN-18

Major pitfalls (1) Glavne poteškoće (1) CN-19 u 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); u Therefore, only an extensive follow-up time (5 – 10 years) of patients with stable MCI might further increase the specificity of CSF/other biomarkers u 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

Major pitfalls (2) Glavne poteškoće (2) CN-20 u 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); u 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!

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

CN-22 Preliminary data according to clinical dg Preliminarni podatci prema kliničkim dg

CN-23 ROC analysis of preliminary data AD vs CON (Number of patients) T-tau (102) Aβ (102) P-tau 231 (36) AD vs MCI T-tau (102) Aβ (102) P-tau 231 (36) Cut off Sensitivity (%) Specificity (%) AUC P-value 226, 5 pg/ml 309, 75 pg/ml 7, 61 U/ml 75, 9 90, 7 76, 5 72, 2 44, 4 80 0, 744 0, 661 0, 824 0, 002* 0, 042* 0, 031* Specificity (if sensitivity ≥ 85%) 55, 6 44, 4 61 249, 2 pg/ml 245, 8 pg/ml 3, 76 U/ml 70, 4 79, 6 88, 2 73, 3 46, 7 64, 3 0, 754 0, 595 0, 811 <0, 001* 0, 151 0, 003* 43, 3 64, 3

CN-24 MCI to AD p-tau 199 Urakami, Psychogeriatrics ‘ 06

CN-25 p-tau 231 Vrijednosti p-tau 231 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-tau 231 između skupine bolesnika s MCI i kontrolne skupine (U=30; Z=-0, 463; p=0, 687).