CN1 CSF phosphorylated tau proteins as predictors of

CN-1 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 Goran Šimić, MD, Ph. D Assistant Professor of Neuroscience, Anatomy and Clinical Anatomy Izvanredni 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 5 th Croatian Congress of Pharmacology and 2 nd Congress of Croatian Physiological Society Osijek, 20 Sept 2007

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

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CN-4 Eksplozija nasljednih tauopatija: kako definirati bolest? è HDDD (hereditary dysphasic dishinhibition dementia) è FTDP-17 (frontotemp. demencija s parkinsonizmom) è DDPAC (disinhibition dementia parkinsonism amyotrophy complex) è FMT (familial multisystem tauopathy) è SLBAD (schizophrenia-like behavior with amygdala degeneration). . . P 301 L

POSTMORTAL CRITERIA - Silver stain (Ag. NO 3) CN-5 POSTMORTALNI KRITERIJI - Srebrno bojenje sa srebrnim nitratom (Bielschowsky, 1902) Modification of Bielschowsky stain Since Alzheimer’s times, pathological substrates of AD didn’t change…

CN-6 Alzheimer’s Disease – Pathology Alzheimerova 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.

NIA diagnostic neuropathological criteria CN-7 NIA dijagnostički neuropatološki kriteriji (Khachaturian ZS, Arch Neurol, 1985) u First, it was thought that only SPs matter: criteria were based on quantification of minimal SPs cortical densities Campbell-Switzer-Martin stain u 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

CN-8 Broj ili volumen plakova ne koreliraju s težinom kliničke slike demencije u AD Braak H, Braak E. 1991

CN-9 (Mirra SS et al. , Neurology 1991) u Semiquantitative assessment of NPs in sup. temp. gyrus, prefrontal cx and lower pariet. lobule u 3 levels of dg certainty (definite, probable, possible AD) u Combination of clinical history and NPs score Major weaknesses: 1. Rely exclusively upon amyloid cascade hypothesis 2. Do not consider neocx NFTs, which correlate best with dementia severity (Bierer L et al. , Arch Neurol 1995) 3. Hippocampal formation is absent from criteria

CN-10 Broj neurofibrilarnih snopića pokazuje dobru korelaciju s težinom demencije u AD Braak H, Braak E. 1991

NIA-RI neuropathological criteria for AD CN-11 NIA-RI neuropatološki kriteriji za AD (Reagan Institute, 1997) u Reconciliate the amyloid cascade hypothesis with the major role of NFTs in clinico- pathological correlations u Include semiquantitative assessment of AD lesions in hippocampus, susbstantia nigra and locus coeruleus u Integrate CERAD and Braak staging evaluating “likelihood” AD changes led to dementia (Braak and Braak, Acta Neuropathol 1991; Neurobiol Aging. 1997; 18(4 suppl): S 1 -2. ) • High - CERAD frequent / Braak V or VI • Intermediate - CERAD moderate / Braak III or IV • Low - CERAD sparse / Braak I or II Major weakness: 1. 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

CN-12 AD pathogenesis - Current mainstream thinking (in f. AD) Patogeneza AD - Trenutno stanje (Vickers et al. , Prog. Neurobiol. 2005) Genetics (f. AD) diffuse A deposits (alpha helix structure) fibrillogenesis - beta strand (sheet) (accelerated by Cu 2+, Zn 2+, HSV? …) http: //talaga. rutgers. edu/research/images SPs . . causes physical obstruction of axoplasmic flow,

CN-13 . . . resulting in axonal sprouting, tau mobilization and excessive tau phosphorylation NFTs + NPs (best clinicopathological correlation) NFTs s. AD? NFT NP NFT An inappropriate re-expression or re-activation of developmentally regulated protein kinase(s) (e. g. fetal 100 k. Da protein kinase that phosphorylate Ser 262) could contribute to the abnormal phosphorylation of tau, and thus play a role in pathogenesis of AD NPs Bielschowsky stain

AD Pathologic Change in Non-Demented Elderly CN-14 Patol. promjene karakteristične za AD u nedementnih starijih osoba (Knopman et al. J Neuropathol Exp Neurol 2003) u 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)”

CN-15 Nagao prijelaz zbog superponiranog age-associated gubitka sinapsi i neurona

Clinicopathological correlation Kliničkopatološka korelacija CN-16

CN-17 Current approaches to early assessment of MCI to AD conversion Današnjie 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) u 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)

Herrmann et al. Eur Neurol ‘ 99 CN-18

Herrmann et al. Eur Neurol ‘ 99 CN-19 Category 0 – absence of NFT (ICC) Category 1 – presence of NFT (ICC)

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CN-21 Cave!

CN-22 Ptau 231 =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.

CN-23 Fox et al. Lancet ‘ 04

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CN-26 + Nordberg A. et al. Lancet Neurology 2004

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CN-28 AD – parijetotemporalni hipometabolizam 18 -Fluoro-2 -deoksi. D-glukoza (18 FDG) PET KBC Rebro Ljubazno ustupio za korištenje dr. Ratimir Petrović

CN-29 Je li moguće povećati specifičnost CSF biomarkera?

CN-30 Je li moguće povećati specifičnost CSF biomarkera? Teško, jer…

CN-31 Major pitfall u 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 (De. Carli, Lancet Neurol ’ 03; Petersen, J Int Med ’ 04) u Therefore, only an extensive follow-up time (>5 years) of patients with stable MCI might further increase the specificity of CSF biomarkers!

CN-32 Kako spriječiti nastanak F 3 fragmenta? F 3

CN-33 Since tau proteins behave differently in different neurodegenerative conditions…

CN-34 …they represent the future of neurodegenerative disease diagnosis 4 R = 3 R Type I Aging GSS PDC Guam, etc. 4 R > 3 R Type II 3 R > 4 R Type III Type I Familial multisyst. tauopathy AGD Pallido-ponto-nigral degeneration, etc. . 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

CN-35 Pattern of some tau Mabs, their epitopes, putative kinases and the respective cellular pathology (s. AD? ) pre-tangle stage intracell. tangle extracell. tangle

CN-36 MCI to AD Selective phospho-tau epitopes were recently shown to be the best for detection of MCI to AD conversion! Urakami, Psychogeriatrics ‘ 06

CN-37 Multidimensional cluster analysis using all available biological and psychometric data P-tau S 181 AD vs DLBD: 91% sens. 94% specif. T-tau AD vs VD: 91% sensitivity, 95% specificity 1 AD, 2 CBD, 3 FTD, 4 Va. D, 5 MCI, 6 ND

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CN-39 Sažetak: CSF biomarkeri

CN-40 Hvala na pažnji! Pitanja? Posjetite: www. alzheimer. hr http: //dementia. hiim. hr