Download - 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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Schellenberg et al., 2012
Autosomal dominant ADAutosomno dominantna AB
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Autosomal dominant ADAutosomno dominantna AB
Schellenberg et al., 2012
H-E, 200x
Bielschowsky
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Sporadic late-onset ADSporadična AB s kasnim početkom
Schellenberg et al., 2012
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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
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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/