goran Šimić , md , phd

CN-1CSF 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, PhDAssistant Professor of Neuroscience, Anatomy and Clinical Anatomy

Izvanredni profesor Neuroznanosti, Anatomije i kliničke anatomije

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

Medical School ZagrebMedicinski fakultet Zagreb

5th Croatian Congress of Pharmacology and

2nd Congress of Croatian Physiological Society

Osijek, 20 Sept 2007

CN-2Differential diagnosis of primary causes of dementia syndrome: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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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

CN-5POSTMORTAL CRITERIA - Silver stain (AgNO3)

POSTMORTALNI KRITERIJI - Srebrno bojenje sa srebrnim nitratom (Bielschowsky, 1902)

Since Alzheimer’s times, pathological substrates of AD didn’t change…

Modification of Bielschowsky stain

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Plaques and tangles

Alzheimer’s Disease – Pathology

Alzheimerova bolest - Patologija

Neuritic plaques(NPs)

Neurofibrillarytangles (NFTs)

. . . what has changed is our thinking about theircontent, localization, importance and development.

Modification ofBielschowsky stain

CN-7NIA diagnostic neuropathological criteria

NIA 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

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Broj ili volumen plakova ne koreliraju s težinom kliničke slike demencije u AD

Braak H, Braak E. 1991

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(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:

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

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Broj neurofibrilarnih snopića pokazuje dobru korelaciju s težinom demencije u AD

Braak H, Braak E. 1991

CN-11NIA-RI neuropathological criteria for AD

NIA-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:

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

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fibrillogenesis - beta strand (sheet) (accelerated by Cu2+, Zn2+, HSV?…)

diffuse Adeposits (alpha helix structure)

http://talaga.rutgers.edu/research/images

.. causes physical obstruction of axoplasmic flow,

AD pathogenesis - Current mainstream thinking (in fAD)

Patogeneza AD - Trenutno stanje (Vickers et al., Prog. Neurobiol. 2005)

SPs

Genetics (fAD)

CN-13... resulting in axonal sprouting, tau mobilization and excessive tau phosphorylation

NFTs

Bielschowsky stain

NPs

NP

NFT

NFT

NFT

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

NFTs + NPs (best clinico-pathological correlation)

sAD?

CN-14AD Pathologic Change in Non-Demented Elderly

Patol. promjene karakteristične za AD u nedementnih starijih osoba (Knopman et al. J Neuropathol 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)”

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Nagao prijelaz zbogsuperponiranog age-associated gubitkasinapsi i neurona

CN-16Clinicopathological correlation

Kliničkopatološka korelacija

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Current approaches to early assessment of MCI to AD conversion

Današnjie 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)

CN-18Herrmann et al. Eur Neurol ‘99

CN-19Herrmann et al. Eur Neurol ‘99

Category 0 – absence of NFT (ICC)Category 1 – presence of NFT (ICC)

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.

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Cave!

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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.

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Fox et al. Lancet ‘04

Fox et al. Lancet ‘04

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+ Nordberg A. et al.Lancet Neurology2004

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AD – parijeto-temporalni hipometabolizam

18-Fluoro-2-deoksi-D-glukoza (18FDG) PET KBC RebroLjubazno ustupio za korištenje dr. Ratimir Petrović

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Je li moguće povećatispecifičnost CSFbiomarkera?

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Je li moguće povećatispecifičnost CSFbiomarkera?Teško, jer…

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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!

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Kako spriječiti nastanak F3 fragmenta?

F3

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Since tau proteins behave differently in different neurodegenerative conditions…

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…they represent the future of neurodegenerative disease diagnosis

AGD

3R > 4R4R > 3R4R = 3R

... 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

Type I Type

I

Type II

Type IIIAging

GSS

PDC Guam, etc.

Familial multisyst. tauopathy

Pallido-ponto-nigral degeneration, etc.

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Pattern of some tau Mabs, their epitopes, putative kinases and the respective cellular pathology (sAD?)

pre-tangle stage intracell. tangle extracell. tangle

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MCI to AD

Urakami, Psychogeriatrics ‘06

Selective phospho-tau epitopes were recently shown to be the best for detection of MCI toAD conversion!

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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

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Sažetak: CSF biomarkeri

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Hvala na pažnji!

Pitanja?

Posjetite:

www.alzheimer.hr

http://dementia.hiim.hr