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
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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
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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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)
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
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)
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.
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.
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)
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
CN-23Herrmann 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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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
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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
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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