goran Šimić , md , phd

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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, PhDFull Professor of Neuroscience and AnatomyRedoviti profesor neuroznanosti i anatomije

Department of Neuroscience, Croatian Institute for Brain ResearchZavod za neuroznanost, Hrvatski institut za istraživanje mozga

Medical School ZagrebMedicinski fakultet Zagreb

6th Croatian Congress on Alzheimer’s disease

6. hrvatski kongres o Alzheimerovoj bolesti

Primošten, 15 Oct 2012

Hrvatska zaklada za znanostProjekt br. 09/16 (2012-2014)

Croatian Science Foundation

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Croatian Science Foundation projectProjekt Hrvatske zaklade za znanost

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Hrvatska zaklada za znanostProjekt br. 09/16 (2012-2014)

Croatian Science Foundation

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

CN-4Major issues in dementia syndrome

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

CN-5Main goals of the project

Glavni ciljevi projekta

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

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

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Autosomal dominant ADAutosomno dominantna AB

Schellenberg et al., 2012

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H-E, 200x

Bielschowsky

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Sporadic late-onset ADSporadična AB s kasnim početkom


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Sporadic late-onset ADSporadična AB s kasnim početkom

Bielschowsky

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Hypothetical time line for the onset and progression of sporadic AD

Trojanowski et al., 2011

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Nagao prijelaz zbogsuperponiranog age-associated gubitkasinapsi i neurona.

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Current approaches to early assessment of MCI to AD conversion

Današnje 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

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Fox et al. Lancet ‘04

Fox et al. Lancet ‘04

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

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+ Nordberg A. et al.Lancet Neurology2004

CN-19Major 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

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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!

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

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Preliminary data according to clinical dgPreliminarni podatci prema kliničkim dg

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ROC analysis of preliminary data

AD vs CON(Number of

patients)

Cut off Sensitivity (%)

Specificity (%) AUC P-value Specificity (if sensitivity ≥

85%)T-tau (102) 226,5 pg/ml 75,9 72,2 0,744 0,002* 55,6Aβ (102) 309,75 pg/ml 90,7 44,4 0,661 0,042* 44,4P-tau231 (36) 7,61 U/ml 76,5 80 0,824 0,031* 61

AD vs MCI

T-tau (102) 249,2 pg/ml 70,4 73,3 0,754 <0,001* 43,3Aβ (102) 245,8 pg/ml 79,6 46,7 0,595 0,151 43,3P-tau231 (36) 3,76 U/ml 88,2 64,3 0,811 0,003* 64,3

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MCI to ADp-tau199

Urakami, Psychogeriatrics ‘06

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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).

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Toxicity of soluble tauToksičnost topljivih tau proteina

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Toxicity of soluble tauToksičnost topljivih tau proteina

Kopeikina et al., 2012

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Thank you for your attention!Zahvaljujem na pažnji!

http://alzbiotrack.hiim.hr/

goran Šimić , md , phd

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