Le indagini strumentali nella diagnostica

della malattia di Alzheimer e della

demenza frontotemporale
Introduction
Neurodegenerative Brain Diseases
• Alzheimer’s Disease (AD)
• Vascular Dementia (VaD)
• Lewy Body Dementia (LBD)-
Parkinson’s Disease (PD)
with Dementia
• Frontotemporal Dementia
(FTD)
• Others e. g. Creutzfeldt-
Jakob disease (CJD),
Huntington’s disease (HD)
 Abnormal Protein Aggregates

Neurofibrillary Senile
tangles plaques

Lewy Neurodegeneration
Bodies PrPSc
plaques

Pick Poly-Q
Bodies inclusions
 Cerebral Proteinopathies
Aggregated Pathological
Disease Proteopathy
protein lesion

Amyloid β
Amyloid β Amyloidosis
Plaques
AD
Neurofibrillary
Tau Tauopathy
tangles

CAA, HCHWA-D Amyloid β Vasculature Amyloidosis

Pick’s disease Tau Pick bodies Tauopathy

PD/LBD Synuclein α Lewy bodies/neurites Synucleinopathy

CJD/GSS Prion Prion plaques Prionopathy

Alzheimer’s dementia
 Occipital

Frontal

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 trans-entorhinal cortex

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 Entorhinal cortex

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likely asymptomatic
 Hippocampus

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possible MCI
 Temporal pole (BA 38)

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probable MCI
 inferior temporal cortex

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very probable MCI
 mid temporal cortex

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Subtle but significant cognitive impairment
 polymodal association cortex

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First stage of clinical Alzheimer’s disease
 Broca area(BA 44)

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Intermediate stage of AD
 Unimodal areas

Unimodal areas

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Moderate to severe AD
All neocortical areas are affected, and
many subcortical areas as well

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Taupathies
FTD spectrum
FTD spectrum
CSF Brain Blood
Neuroimaging techniques
 In vivo amyloid imaging

• PET ligands with affinity for amyloid plaques

– 18FFDDNP
– 11CSB13
• Pittsburgh compound B or PiB
– N-methyl-11C2-(4′-methylamino-phenyl)-6-
hydroxybenzothiazole (Thioflavine T derivative)
• PiB PET imaging in AD patients reveals a
distribution of binding consistent with the
amyloid pathology (Thal et al, 2002; Klunk et al., 2004)
PiB PET in AD
PiB PET in AD
 PiB PET in AD

• Confirmation of AD diagnosis
• Insight into the role of Aβ in AD
pathophysiology and clinical manifestations
– No change in PiB levels regardless of AD
progression after about 2 years; only FDG-PET
metabolism significantly declined → “amyloid
deposition plateau” hypothesis (Engler et al., 2006)
– On autopsy studies, amyloid pathology weakly
correlates with cognition relative to other markers
of disease severity, i.e. NFT burden (Terry et al., 1991)
 PiB PET in AD

• Assessment of brain reserve in modifying the

relationship between AD pathology and
phenotype
– Education may reduce AD risk (Stern et al., 1994)
– Equivalent loads of AD pathology may be
associated to different degrees of cognitive
dysfunction, being more highly educated patients
less affected (Roe et al., 2007)
– ↑PiB uptake in beJer educated than less
educated AD patients matched for disease
severity (Kemmpainen et al., 2008)
PiB PET in AD
 PiB PET in FTD

• Differential diagnosis of FTD spectrum

– 40% of patients with PNFA had AD pathology at
autopsy rather than the spectrum of pathology
changes associated to FTD (Alladi et al., 2007)
• A minority of FTD paLents presents ↑ PiB
binding
– Amyloid deposition
 MRI in early detection and predicting the
progression of AD
• Hippocampal volumes may be useful in
differentiating individuals with very mild
dementia (CDR 0.5 or MCI) from cognitively
normal population (de Leon et al., 2007)
• Inclusion of the fusiform gyrus further allows the
differentiation of MCI from advanced stages (Convit
et al., 2000)
• Automated measurement of thickness of the
entorhinal cortex is valuable in differentiating AD
from controls (Lerch et al., 2005)
MRI in early detection and predicting the
progression of AD
MRI in early detection and predicting the
progression of AD
• Alzheimer Disease Neuroimaging Initiative
(ADNI) (Jack et al., 2008; Petersen et al., 2010)
– multicenter MRI longitudinal study of MCI and AD
with standardized data acquisition and processing
• MCI individuals converting to AD present a
very similar pattern of atrophic changes to the
AD up to 1 year before AD diagnosis (Risacher et
al., 2009)
• Medial temporal lobe atrophy is the best
indicator of progression to AD (Risacher et al., 2009)
MRI in early detection and predicting the
progression of AD
• Voxel-based morphometry (VBM) is reliable in
detecting atrophy of specific brain regions in AD
• Mediotemporal lobes and lateral temporal and
parietal association areas in AD and MCI (Baron et
al., 2001; Pennanen et al., 2005)
• Patterns of atrophy in MCI at risk for conversion
resemble those of AD patients (Chetelat et al., 2005)
• Atrophy of mediotemporal, laterotemporal, and
parietal association areas may be present in
genetically predisposed individuals prior to the
onset of cognitive dysfucntion (Teipel et al., 2004)
MRI in early detection and predicting the
progression of AD
• Some studies suggest that MRI is not superior to
CSF biomarkers in predicting AD conversion
(Bouwman et al., 2007)
• Other studies, which employ automated scoring
systems, indicate MRI as a more sensitive
predictor of cognitive decline with respect to CSF
biomarkers (Vemuri et al., 2009)
• Utility of MRI and CSF biomarkers together in
identifying those individuals with very mild (CDR
0.5) or mild (CDR 1) AD at higher risk of
progression to advanced disease (Hampel et al., 2008)
 MRI as an indicator of AD severity

• Cognitive dysfunction correlates with cortical

atrophy on MRI (Ridha et al., 2008; Jack et al., 2005; Stoub et al.,
2005)

• MRI is a good surrogate of neuropathologic

findings (Bobinski et al., 2000; Zarow et al., 2005)
• Rates of change on MRI, but not CSF tau,
correlate with change in MMSE scores (Sluimer et
al., 2010)
– NFT pathology precedes neuronal loss in AD affected areas
– MRI variations reflect the final outcome of the numerous intricate
pathological processes that characterize AD (Vemuri et al., 2009)
 FDG-PET in AD

• ↓ Metabolic rate for glucose (CMRglc)

posterior cingulate, parietal, temporal, and
prefrontal cortex in patients with AD or mild
dementia (Silverman et al., 2001)
– Correlation with severity and progression
(Alexander et al., 2002; Minoshima et al., 1995)

– Prediction of the rate of (1) cognitive

decline in individuals with very mild
dementia and of (2) AD pathology (Silverman et
al., 2001)
 FDG-PET in AD

• ↓ Hippocampal glucose metabolism predict

decline to MCI in normal individuals and
conversion to AD in MCI subjects (de Leon et al.,
2001; Drzezga et al., 2003)
• ↓ Glucose metabolism in enthorhinal cortex
predict decline to MCI with a sensitivity of
83% and a specificity of 85% (de Leon et al., 2007)
• FDG-PET correlates with CSF Aβ42 and
cognitive dysfunction (Jagust et al., 2009)
FDG-PET in AD
 FDG-PET as a research tool in AD

• Detection of AD changes (bi-parietal and

temporal hypometabolism) in individuals with
genetic susceptibility to AD and with no sign
of cognitive decline.
• Correlation with AD progression (differently
from CSF biomarkers)
• Secondary outcome measures in clinical trials
• Lack of neuropathologic correlations and costs
 Functional MRI in AD

• Measures changes in blood flow associated brain

activation during cognitive tasks
• Alterations in neuronal function likely precede
neuronal loss detectable with volumetric MRI
• Alterations in function during cognitive tasks may be
more sensitive then resting state function - “Stress
test”
• Provide a link between the pathology of AD and the
early clinical symptomatology and perhaps lack of
symptoms in occult amyloid pathology
 Functional MRI in AD

• “The default network”: brain regions activated

during several internally focused tasks such as
remembering past events or imagining future
events (Gusnard and Raichle, 2001)
– Medial temporal lobe and hippocampus, medial
frontal association area, posterior cingulate,
retrosplenial, inferior parietal cortex and lateral
temporal lobe (Buckner et al., 2005)
Functional MRI in AD
 Functional MRI in AD

• The “default network” is disrupted in

subjects with amyloid deposition, even in the
preclinical period (Sheline et al., 2010; Sperling et al., 2009)
 Imaging in FTD

• Up to 90% sensitivity of detecting FTD with

SPECT or PET (Mendez et al.,2007)
• Differentiation of FTD from AD
• Automated methods for quantifying regional
atrophy
• Functional studies (metabolites, regional
cerebral blood flow, glucose metabolism)
 Structural MRI in FTD

• “Typical” (?) MRI findings in FTD

– Frontal and temporal lobes atrophy (often
asymmetric)
– Ventricle enlargement
– Caudate atrophy
• “Typical” (?) MRI findings in AD
– mesial temporal lobe and hippocampal atrophy
 Structural MRI in FTD

• Hippocampal/mesial temporal atrophy alone

does not distinguish AD from FTLD (Bocti et al.,
2006; Galton et al.,2001)
• FTD may be indicated by:
– A severe or asymmetrical pattern of amygdala
atrophy (along with hippocampal atrophy) (Barnes
et al.,2006)
– An atrophy pattern involving the frontal lobes and
anterior temporal regions (Bocti et al.,2006)
 Structural MRI in FTD

Distribution of cerebral atrophy in a patient with

AD (A) and frontotemporal dementia (FTD) (B)
Both patients had similar interscan intervals (1 1 months). Areas of
volume loss are highlighted in red.
 MR Spectroscopy in FTD

• In vivo noninvasive estimation of brain

metabolites
– N-acetyl aspartate (NAA) → neuronal acLvity
– Myoinositol (MI) → gliosis
• Significant ↑MI and ↓NAA and glutamate in
the frontal region in FTD vs AD
• ↑ MI prior to ↓ NAA in temporal regions
(glial proliferation in early stages of FTD)
(Ernst et al.,1997)
 FDG-PET in FTD

• Pattern of hypometabolic regions in

differential diagnosis of dementias (Foster et al.,
2007; Ibach et al., 2004; Silverman et al., 2002)

• The metabolic decline occurs quite early in

FTD course
– Recently, the Centers of Medicaid and Medicare
approved reimbursement of FDG-PET for the
indication of distinguishing AD from FTD
 FDG-PET in FTD

• Frontal and anterior temporal cortices in FTD

vs posterior cingulate and parietotemporal
cortices in AD (Diehl-Schmid et al., 2007; Ishii et al., 1998; Jeong
et al., 2005a; Mosconi et al., 2008)

• Also other areas i.e. anterior cingulate, uncus,

insula, and subcortical regions including basal
ganglia are involved in FTD (Jeong et al., 2005)
• Hemispheric metabolic asymmetry is common
(Garraux et al., 1999; Jeong et al., 2005)
 FDG-PET in FTD
NC

AD

FTD

DLB

R L R L R L R L
 SPECT in FTD

• Uptake of Tc99m lipid-soluble radionucleotide

(perfusion marker)
• Correct diagnosis in 100% of FTD and 90% of
AD (Charpentier et al., 2000)
• Sensitivity of 87.5% and specificity of 76.8% in
FTD vs AD diagnosis (Sjogren et al., 2000)
• Hypoperfusion of posterior cingulate cortex in
AD vs FTD (‘‘posterior cingulate sign’’) (Bonte et al.,
2004)
Biomarkers
 Dementia biomarkers

• Biomarker discovery research

– Genomics
– Proteomics
– Metabolomics
(Hu et al., 2007; Ray et al., 2007)

• Inflammation, oxidative stress,

apolipoproteins, neurodegeneration markers
(Maes et al., 2007)
 Holistic approach
(genome, proteome, transcriptome,
metabolome…)

Pathophysiologic approach
(“candidate marker”)
 Plasma biomarkers

• Baseline plasma levels of Aβ1-42 are higher

in patients with AD
• The Plasma Aβ40/42 ratio predicts a high risk
of progression to dementia in cognitively
normal individuals
(Mayeux et al., 2003; van Oijen et al., 2006)

Reproducibility
Standardization
• Problems Short half-life
Peripheral production
 Biomarkers and neurodegenerative
diseases

• Diagnosis
• Classification Early diagnosis
• Prognosis Differential diagnosis
• Therapy
 Limiti della diagnosi clinica
Il caso dell’AD
• Sensibilità elevata (93%) ma specificità
relativamente bassa (55% in una casistica
neuropatologica)
• Corrispondenza tra clinica e patologia nel 80-90%
in centri specializzati
• Difficoltà sia di diagnosi precoce sia diagnosi
differenziale con forme atipiche o con
manifestazioni non usuali

Mayeux, Neurobiol Aging 1998

 Caratteristiche di un biomarker ideale

• Base razionale
• Convalida su casi “definiti”
• Sensibilità e specificità > 80%
• Riproducibilità, accessibilità, facilità di analisi,
convenienza
• Precocità
Consensus Report of the Working Group on Molecular and
Biochemical Markers of Alzheimer’s Disease, Neurobiol Aging 1998
N Controlli FTD AD

a
Amyloid Precursor Protein (APP)
 β42 nel CSF
Dosaggio Aβ

• Moderata riduzione di Aβ42 nell’AD (50%)

• Correlata al deposito della proteina nelle
placche
• Correlazione con la patologia a livello
dell’ippocampo
 β42 nell’AD
CSF Aβ
 β42 and Aβ
CSF Aβ β40

• Strong evidence across many cross-sectional

studies that CSF Aβ42 levels are reduced by
about 50% in AD compared to controls, even in
the early clinical stages of disease (Blennow et al., 2001)
• ↓ CSF Aβ42 appears to precede amyloid
retention as detected by amyloid imaging (PIB):
first evidence of AD pathology in cognitively
normal individuals (?) (Fagan et al., 2006, 2009)
 β42 and Aβ
CSF Aβ β40

• Aβ42 alone is less useful in differentiating AD

from other dementias, since low levels have
also been documented in FTD and in DLB
(amyloid deposition?)
• Aβ42 levels do not correlate well with disease
duration or severity
– PIB-PET
– Neuropathology (Braak & Braak)
 β42 and Aβ
CSF Aβ β40

• Limitations
– lack of standardization for among different
laboratories and assays
– relatively small amount of data from longitudinal
studies on normal individuals
– Influences of normal aging on CSF turnover and
clearance
– Normal hour-to-hour or day-to-day variability

(Bateman et al., 2007)

Total tau
 Tau

• Proteina associata ai microtubuli

• Legame con la tubulina
• Favorisce l’assemblaggio dei microtubuli
• Oltre 30 siti di fosforilazione
• Tau iperfosforilata nelle lesioni caratteristiche
dell’AD (neurofibrillary tangles)
 Tau

• Increase of total tau by approximately 2-3 fold in

AD vs non-demented elderly subjects (Blennow et al.,
2001)

• Tau elevation seems to occur at the early stages of

disease and in some cognitively normal individuals,
where its levels correlate with the amount of
amyloid deposition, who may represent individuals
with preclinical AD (Fagan et al., 2009).
 CSF Tau

• ↑ tau elevaLon may be observed also in other

diseases, potentially limiting the utility of tau alone
in the differential diagnosis of dementia (Arai et al.,
1997b)

• Tau levels seem to remain relatively stable

throughout the disease process and do not
correlate with dementia severity (Sunderland et al., 1999)
• Age effect (de Leon et al., 2007)
Phosphorilated tau (pTau)
 CSF pTau

• Determinata in ELISA
• Stato di fosforilazione della tau
• Invariata nello stroke
• Aumenta lievemente nella CJD
• Aumenta significativamente nell’AD
CSF Tau nell’AD
CSF pTau nell’AD
 β42 nell’AD
Tau e Aβ
Combinazione dei parametri liquorali
nella diagnosi di AD

Tau Aβ42 pTau Sens. Spec.

81% 91%
86% 89%
81% 91%
89% 90%
86% 97%
 444 pg/mL

195 pg/mL

Aβ
β42
17 studi
AD group: n=849
control group: n=427 Sensibilità 92%
Tau
34 studi
Specificità 89%
AD group: n=2284
control group: n=1054
JAMA (2003) 289: 2094-2103
Lancet Neurology, 2007
Neurology 2002;58:1622–1628
Tau 908 pg/ml (FTD vs AD) sens 86% spec 26%
Tau 193 pg/ml (FTD vs CTR) sens 86% spec 41%
Aβ42 315 pg/ml (FTD vs AD) sens 86% spec 59%

Con Tau tra 193 e 908 pg/ml e Aβ42 >315 pg/ml si

identificano solo il 60% dei FTD
34 FTLD, 76 AD, 93 CTRL

FTLD vs CTRL
• Tau/Aβ42 ratio
– Spec. 86.7%, sens. 80.6%
• Tau (FTLD vs CTRL)
– Spec. 95.7%, sens.
64.75%

FTLD from AD
• Tau/Aβ42
– sens. 64.5%, spec. 90.3%
• p-Tau
– Spec. 85.7%, sens. 68.4%
 CSF biomarkers in predicting dementia
progression
• ↓CSF Aβ42 is present in asymptomatic elderly
at higher risk to develop AD (Blennow, 2004)
• Lower CSF Aβ42/40 ratios seem to indicate
risk of progression to AD in individuals with
very mild dementia (CDR0.5) (Brys et al., 2009)
• ↑ CSF tau in MCI who later progressed to AD
(Brys et al., 2009)
 CSF biomarkers in predicting dementia
progression
• ↑ RR of progression from MCI to AD in
paLents with baseline ↑tau, ↑p-tau, and
↓Aβ42 (90% sens.; 100% spec.) (Arai et al., 1997)
• ↑ tau/Aβ42 in 90% of converter MCI (vs 10%
of non-converter) at 18 months (Riemenschneider et
al., 2002)

• ↑ tau + Aβ42/P-tau181 may predict

progression of MCI into more advanced AD at
4-6 years (Hansson et al., 2006)
 CSF biomarkers in predicting dementia
progression
• Utility of AD CSF profile - ↑tau & ↓Aβ42 - in
predicting MCI-AD progression
– longitudinal study of 100 individuals with mild AD,
196 individuals with MCI, and 114 controls (Shaw et
al., 2009)
– large multicenter study (Mattsson et al., 2009)
– prediction of the rate of progression of cognitive
decline as measured by the CDR-sum of boxes and
neuropsychological test scores (Snider et al., 2009)
 CSF biomarkers in predicting dementia
progression
• Utility of AD CSF profile - ↑tau & ↓Aβ42 - in
predicting normal-MCI progression
– 70% of those with a high ratio, compared to only
10% of those with a normal ratio, converted from
normal to MCI over a 3 year period (Fagan et al., 2007)
– All MCI converters had elevated tau/Aβ42 ratios,
while no conversions occurred in the normal ratio
group over a 42 month period (Li et al., 2007)
Prediction of 1 year cortical change from baseline CSF biomarker levels. One
year change in cortical volume in MCI was predicted from baseline CSF
biomarker values point by point across the cortical surface, with age and sex
used as covariates. The top shows uncorrected p values, and the bottom
shows the p maps thresholded at FDR < 0.05.