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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, PhD 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

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Page 1: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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

Page 2: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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

Page 3: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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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

Page 5: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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1991: The first Alzheimer gene mutation (in APP)

HCHWA-D

London’s mutation

Goate A, Chartier-Harlin MC, Mullen M, Hardy J. Segregation of a missense mutation in the amyloid presursor protein gene with familial Alzheimer's disease. Nature 1991;349: 704-6. (on Allen Roses’ blood samples from Duke University)

I

Page 6: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

CN-6POSTMORTAL 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

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CN-8

http://www.nia.nih.gov/Alzheimers/Resources/ProgressReportImages.htm

Amyloid cascade hypothesis(supported by geneticsin familial cases)

Tau hypothesis(supported by clinico-pathological correlations in bothknown genetic and sporadic cases)

Page 9: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

CN-9NIA 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

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CN-13NIA-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

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

SPs

Genetics (fAD)

Page 15: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

CN-15... 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

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Amyloid cascade hypothesis 1990

Esch FS, Keim PS, Beattie EC. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science 1990;248:1122-4.

Sisodia SS, Koo EH, Bayreuther K, Unterbeck A, Price DL. Evidence that beta-amyloid protein in Alzheimer’s disease is not derived by normal processing. Science 1990;248:492-5.

Page 17: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

CN-17AD 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.

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CN-19Clinicopathological 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)

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CN-21Herrmann et al. Eur Neurol ‘99

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Tau phosphorylationin AD – early changes

ADAT8 ICC

Open arrows=subicular axons

Arrowheads=perforant pathway collaterals

Page 23: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

CN-23Herrmann et al. Eur Neurol ‘99

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

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CN-24

.

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CN-25

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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Tau phosphorylationin AD – CSF changes

Hansson et al. ‘06

Hampel et al. ‘04 Phosphorylated tau proteins are the mostpromising biological markers of AD!

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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

(FDG PET Rebro)

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Je li moguće povećatispecifičnost CSFbiomarkera?

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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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Tau gene

Tau is expressed primarily in neurons (Binder, 1985)

Single neuron-specific promoter has 3 binding sites for transcription factors; its activity increases with axon initiation and outgrowth

Since differentially expressed during development, each isoform is likely to have particular physiological role

Andreadis, 1992

More efficient at promoting MTs assembly than fetal tau

Goedert

, 1

98

9Brandt & Eidenmüller, 1998Buée et al., 2000

Fetal tau

Page 37: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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Tau protein

Microtubules binding domain

Proline R1

R2

E10R3 R4E2 E3

0 100 200 300 400

PO4

S/T - P

Cysteines

Phosphorylation change the shape of tau and regulates its activity. In turn, tau change physical characteristics of MTs such as rigidity, length & stability.Tau in a more phosphorylated state has a decreased affinity for MTs and is less able to promote MT assembly and stabilize MTs (Lindwal & Cole ‘84).

Nt Ct

Acidic region

441

R1

R2R3

R4

TAUPROTEIN

Page 38: CN-1 CSF phosphorylated tau proteins as predictors of Alzheimer's disease in subjects with mild cognitive impairment Prediktivna vrijednost fosforiliranih

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Kako spriječiti nastanak F3 fragmenta?

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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

pre-tangle stage intracell. tangle extracell. tangle

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MCI to AD

Urakami, Psychogeriatrics ‘06

Selective phospho-tau epitopes are 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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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

Take-home messages:

1. Phosphorylated tau proteins are the most promising biological markers of AD (taken from CSF), particularly for detection of MCI to AD conversion

2. The unique expression pattern of tau proteins is considered as a possible link to the particular vulnerability of human to neurodegerative diseases, such as AD and FTD (an evolutionary price to pay for enhanced connectivity?)

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Hvala na pažnji!

Pitanja?

Posjetite:

www.alzheimer.hr

http://dementia.hiim.hr