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Goran Šimić , MD , PhD

CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih tau proteina u cerebrospinalnoj tekućini pri postavljanju dijagnoze Alzheimerove bolesti u osoba s blagim kognitivnim oštećenjem.

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Goran Šimić , MD , PhD

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  1. CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairmentPrediktivna vrijednost fosforiliranih tau proteina u cerebrospinalnoj tekućini pri postavljanju dijagnoze Alzheimerove bolesti u osoba s blagim kognitivnim oštećenjem Goran Šimić, MD, PhD Assistant Professor of Neuroscience, Anatomy and Clinical AnatomyIzvanredni profesor Neuroznanosti, Anatomije i kliničke anatomije Department of Neuroscience, Croatian Institute for Brain Research Zavod za neuroznanost, Hrvatski institut za istraživanje mozga Medical School Zagreb Medicinski fakultet Zagreb 5th Croatian Congress of Pharmacology and 2nd Congress of Croatian Physiological Society Osijek, 20 Sept 2007

  2. Differential diagnosis of primary causes of dementia syndrome:lines thickness is proportional to strength of association, and key anatomical regions are written in capital lettersDd primarnih uzroka sindroma demencije: debljina linija proporcionalna je jačini povezanosti, a ključna anatomska područja otisnuta su velikim slovima Ball, 1977: AD = hippocampal dementia

  3. Eksplozija nasljednih tauopatija: kako definirati bolest? • HDDD (hereditary dysphasic dishinhibition dementia) • FTDP-17 (frontotemp. demencija s parkinsonizmom) • DDPAC (disinhibition dementia parkinsonism amyotrophy complex) • FMT (familial multisystem tauopathy) • SLBAD (schizophrenia-like behavior with amygdala degeneration)... P301L

  4. POSTMORTAL CRITERIA - Silver stain (AgNO3)POSTMORTALNI KRITERIJI - Srebrno bojenje sa srebrnim nitratom (Bielschowsky, 1902) Modification of Bielschowsky stain Since Alzheimer’s times, pathological substrates of AD didn’t change…

  5. Alzheimer’s Disease– PathologyAlzheimerova bolest - Patologija Neuritic plaques (NPs) Neurofibrillary tangles (NFTs) Modification of Bielschowsky stain Plaques and tangles . . . what has changed is our thinking about their content, localization, importance and development.

  6. NIA diagnostic neuropathological criteriaNIA dijagnostički neuropatološki kriteriji(Khachaturian ZS, Arch Neurol, 1985) • First, it was thought that only SPs matter: criteria were based on quantification of minimal SPs cortical densities • However, these first NIA criteria were not accepted because: 1. Clinical history and NFTs were not considered 2. SPs were shown to be partly a benign age-related phenomenon Campbell-Switzer-Martin stain

  7. Broj ili volumen plakova ne koreliraju s težinom kliničke slike demencije u AD Braak H, Braak E. 1991

  8. (Mirra SS et al.,Neurology 1991) • Semiquantitative assessment of NPs in sup. temp. gyrus, prefrontal cx and lower pariet. lobule • 3 levels of dg certainty (definite, probable, possible AD) • Combination of clinical history and NPs score • Major weaknesses: • Rely exclusively upon amyloid cascade hypothesis • Do not consider neocx NFTs, which correlate best with dementia severity (Bierer L et al., Arch Neurol 1995) • Hippocampal formation is absent from criteria

  9. Broj neurofibrilarnih snopića pokazuje dobru korelaciju s težinom demencije u AD Braak H, Braak E. 1991

  10. NIA-RI neuropathological criteria for ADNIA-RI neuropatološki kriteriji za AD(Reagan Institute, 1997) • Reconciliate the amyloid cascade hypothesis with the major role of NFTs in clinico-pathological correlations • Include semiquantitative assessment of AD lesions in hippocampus, susbstantia nigra and locus coeruleus • Integrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementia(Braak and Braak, Acta Neuropathol 1991; Neurobiol Aging. 1997;18(4 suppl):S1-2.) • High - CERAD frequent/Braak V or VI • Intermediate - CERAD moderate/Braak III or IV • Low - CERAD sparse/Braak I or II • Major weakness: • Since there is a considerable number of demented patients with AD who have low numbers of neocx NFTs NIA-RI criteria are more specific than CERAD, but LESS SENSITIVE

  11. AD pathogenesis - Current mainstream thinking (in fAD)Patogeneza AD - Trenutno stanje (Vickers et al., Prog. Neurobiol. 2005) Genetics (fAD) diffuse A deposits (alpha helix structure) fibrillogenesis - beta strand (sheet) (accelerated by Cu2+, Zn2+, HSV?…) http://talaga.rutgers.edu/research/images .. causes physical obstruction of axoplasmic flow, SPs

  12. ... resulting in axonal sprouting, tau mobilization and excessive tau phosphorylation NFTs + NPs (best clinico- pathological correlation) NFTs sAD? NFT NP NFT NFT NPs An inappropriate re-expression or re-activation of developmentally regulated protein kinase(s) (e.g. fetal 100kDa protein kinase that phosphorylate Ser 262) could contribute to the abnormal phosphorylation of tau, and thus play a role in pathogenesis of AD Bielschowsky stain

  13. AD Pathologic Change in Non-Demented ElderlyPatol. promjene karakteristične za AD u nedementnih starijih osoba (Knopman et al. JNeuropathol Exp Neurol 2003) • 39 longitudinally followed non-demented cases • Mean age 85 years (74 - 95) • AD pathologic change: • 38 Braak stage I or greater, 4 Braak stage IV or V • 37 with sparse or absent neuritic plaques, ~50% with moderate to frequent diffuse plaques CONCLUSION: We still don’t have definitive neuropathological criteria; for now… • “...cut off point should be set to Braak stage ? (≥ IV)”

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

  15. Clinicopathological correlationKliničkopatološka korelacija

  16. Current approaches to early assessment of MCI to AD conversionDanašnjie 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) • Positive diagnostic tests (too invasive for screening): 1. CSF – tau levels elevated, BA levels low 2. Structural MRI (hipp. & entorh. cx lower volumes, whole cx) 3. F-nal PET brain scan (FDGlucose, NFTs: DDNP, BA: Thioflavin-S, Congo-red derivatives)

  17. Herrmann et al. Eur Neurol ‘99

  18. Herrmann et al. Eur Neurol ‘99 Category 0 – absence of NFT (ICC) Category 1 – presence of NFT (ICC)

  19. .

  20. Cave!

  21. Ptau231 =94% sensitive, 64% specific AD vs FTD; similar numbers shown for LBD Hampel H et al. Measurement of phosphorylated tau epitopes in the differential diagnosis of Alzheimer’s disease: A comparative cerebrospinal fluid study. Arch Gen Psychiat 2004; 61:95-102.

  22. Fox et al. Lancet ‘04 Fox et al. Lancet ‘04

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

  24. AD – parijeto-temporalni hipometabolizam 18-Fluoro-2-deoksi-D-glukoza (18FDG) PET KBC Rebro Ljubazno ustupio za korištenje dr. Ratimir Petrović

  25. Je li moguće povećati specifičnost CSF biomarkera?

  26. Je li moguće povećati specifičnost CSF biomarkera? Teško, jer…

  27. Major pitfall • The major pitfall when studying CSF biomarkers to predict AD in MCI cohorts is the fact that conversion from MCI to AD is only about 12-15% 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 (DeCarli, Lancet Neurol ’03; Petersen, J Int Med ’04) • Therefore, only an extensive follow-up time (>5years) of patients with stable MCI might further increase the specificity of CSF biomarkers!

  28. Kako spriječiti nastanak F3 fragmenta? F3

  29. Since tau proteins behave differently in different neurodegenerative conditions…

  30. …they represent the future of neurodegenerative disease diagnosis 4R = 3R 4R > 3R 3R > 4R Type I Type II Type III Aging GSS PDC Guam, etc. Type I Familial multisyst. tauopathy Pallido-ponto-nigral degeneration, etc. AGD ... more accurate analysis of CSF helps to discriminate between tau protein types present in physiological conditions and tau released during the progression of a particular neurodegenerative disease

  31. Pattern of some tau Mabs, their epitopes, putative kinases and the respective cellular pathology (sAD?) extracell. tangle pre-tangle stage intracell. tangle

  32. MCI to AD Selective phospho-tau epitopes were recently shown to be the best for detection of MCI to AD conversion! Urakami, Psychogeriatrics ‘06

  33. Multidimensional cluster analysis using all available biological and psychometric data 1 AD, 2 CBD, 3 FTD, 4 VaD, 5 MCI, 6 ND P-tau S181 AD vs DLBD: 91% sens. 94% specif. T-tau AD vs VD: 91% sensitivity, 95% specificity

  34. Sažetak: CSF biomarkeri

  35. Hvala na pažnji! Pitanja? Posjetite: www.alzheimer.hr http://dementia.hiim.hr

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