La diagnosi di “Alzheimer”

sta cambiando NUOVI ORIENTAMENTI BASATI SULL’EVIDENZA

12.2.2019

Alfredo Costa

Istituto Neurologico Nazionale IRCCS C. Mondino

Università di Pavia

Outline

La diagnosi di Alzheimer: una lunga storia

Una nuova visione del problema

Le evidenze a supporto di nuovi criteri diagnostici

Impatto dei nuovi criteri diagnostici nella clinica

I marcatori di patologia: neuropsicologici, biologici, di imaging

Limiti e problemi aperti nell’uso dei marcatori

Le prospettive future

Malattia di Alzheimer PROBABILE:

• Demenza stabilita dall'esame clinico e documentata da test neuropsicologici.

• Deficit di 2 o più aree cognitive.

• Peggioramento progressivo della memoria e di altre funzioni cognitive.

• Assenza di disturbi di coscienza.

• Esordio tra i 40 e i 90 anni, più spesso dopo i 65.

• Assenza di patologie sistemiche o di altre malattie cerebrali responsabili di

deficit cognitivi e mnesici di tipo progressivo.

The NINCDS-ADRDA criteria (McKahnn et al., 1984)

Malattia di Alzheimer POSSIBILE:

• Sindrome demenziale in assenza di disturbi neurologici, psichiatrici o

sistemici in grado di causare demenza e in presenza di variazioni

nell'esordio, nella presentazione o nel decorso clinico.

• Presenza di una patologia neurologica o sistemica concomitante

sufficiente a produrre demenza, ma non considerata la vera causa della

demenza (coesistono altre patologie oltre la dementigena)

Malattia di Alzheimer DEFINITA:

• Presenza dei criteri clinici per la diagnosi di AD probabile ed evidenza

neuropatologica autoptica.

The NINCDS-ADRDA criteria (McKahnn et al., 1984)

NINCDS-ADRDA

Neurology 1984

IWG

Lancet Neurology

2007

IWG

Lancet Neurology

2010

NIAA-AA

Alzheimer’s &

Dementia

2011

IWG-2

Lancet Neurology

2014

The NINCDS-ADRDA criteria

neuropathology

CLINICAL

POST-MORTEM

MCI dementia

probable/possible AD [

1) The clinical diagnosis of AD cannot be certified and needs a post-mortem confirmation to be ascertained

2) The clinical diagnosis of AD can only be ‘probable’ 3) The clinical diagnosis of AD can only be made when the disease is

advanced and reaches the threshold of dementia

1984 A clinico-pathological approach: the tenets

from Dubois, 2013, mod.

Threshold of dementia

Dementia of the Alzheimer type

The NINCDS-ADRDA Criteria : a 2-step process

AD

McKhann et al, 1984

1984

from Dubois, 2010, mod.

VaD FTD PPA DLB

The current diagnosis of AD has several limitations

Objectives:

1) to be earlier

2) to be timely

3) to be more accurate

A low accuracy (60 to 80%)

because it does not take into account the specific

features of the disease

Late in the course of the disease

only when the dementia threshold is reached !

Diagnosis made

in pre-symptomatic or preclinical phase

To be accurate

To be timely

Diagnosis made

when symptoms are initial (prodromic phase)

Symptoms attributed

to evidence of ongoing AD pathology

To be earlier: potential benefits in diagnosing Alzheimer’s disease as soon as possible

• Obtain appropriate treatment earlier

• Stop searching for other causes

• Help the family to understand and accept

• Financial and legal plans while competent

• Enable the patient and family to make lifestyle choices

• Induce better adherence and management of other medical conditions

• Take appropriate steps to prevent injury (driving, weapons)

• Get greater access to help within the healthcare system and within communities

• Participate in clinical trials with disease modifier treatments

To be timely: potential benefits in diagnosing Alzheimer’s disease promptly

• Quick intervention on the cause underlying reversible forms

• Use of strategies aimed at slowing disease progression and enhance residual cognitive performance

• Application of measures reducing the impact of comorbidity

• Application of measures aimed at sorting out the problems associated with disease progression

Preclinical

states

Current

point of

diagnosis

4–8 yrs

Specific

memory

disorders

Dementia

First

symptoms

Biomarkers

AD? AD? AD?

What is Alzheimer’s disease?

A progressive dementing illness which starts many years before dementia is detectable; dementia is the last stage of a longstanding process and may theoretically be absent

Defining «early» or «timely» in diagnosis

From Sperling RA, 2011

Mod. from Padovani, 2015

Subjects of 65 years and over

• Preclinical or asymptomatic phase: amyloid deposition in the

absence of signs and symptoms of disease.

• Prodromal phase: symptomatic stage, but in the absence of dementia

(MCI attributed to Alzheimer’s disease).

• Dementia phase: deficits involving multiple cognitive domains, with

impaired functioning of the patient in the activities of daily living

Albert MS, et al., The diagnosis of mild cognitive impairment due to Alzheimer’s disease:

reccomandation from the National Institute on Aging-Alzheimer’s Association workgroup on

diagnostic guidelines for Alzheimer’s disease. Alzheimer Dement. 2011.

McKhann GM, et al., The diagnosis of dementia due to Alzheimer’s disease: Recommendations

from the National Institute on Aging and the Alzheimer’s Association workgroup. Alzheimers

Dement 2011.

Need of expanding coverage of the full range of disease states

«The concept of a preclinical phase of disease should not be too foreign, because medical professionals readily acknowledge that cancer can be detected at the stage of «carcinoma in situ»… Type II diabetes, hypertension, renal insufficiency and osteoporosis are frequently detected through laboratory tests (i.e. biomarkers), and effective treatment can prevent the emergence of symptoms. Thus, we should be open to the idea that AD could one day be diagnosed preclinically by the presence of biomarker evidence of AD-P, which may eventually guide therapy before the onset of symptoms ».

No reference to

biomarkers in the

NINCDS – ADRDA

criteria (1984)

Cognitive tests: no specification for the

memory profile

CT or MRI: proposed for excluding

vascular lesions, tumors…

CSF: proposed for excluding

meningitis etc…

FDG-PET not mentioned, and

amyloid PET not known

AD is an amnestic dementia in 86-94% of the cases

• secondarily associated with changes in executive functioning, language, praxis and complex visual processing, and with neuropsychiatric changes, in relation with the diffusion of Alzheimer pathology to neocortical areas

Braak et Braak Neurobiol Aging 1997

• Typical AD starts as a progressive amnesic disease, in relation with an early involvement of the hippocampus;

Amnestic syndrome of the hippocampal type

Verbal episodic memory:

– low free recall

– total recall performance not normalized despite

facilitation procedure with cueing

RT > 40

RT < 40

Cut off

Sens Spec

Free recall 17 71 % 92 %

Total recall 40 80 % 90 %

Sarazin et al., 2007

Free and Cued Selective

Remainding test (FCRST) in MCI

Total recall

Months

FCSRT (cued recall measures) is the best predictor of AD pathology

memory measures CSF (+) n = 74

CSF (–) n = 111

effect size (d)

FCSRT Total Recall 13.4 15.4 0.97

Logical Memory Delayed Recall 8.12 13.59 0.74

CERAD verbal Delayed recall 4.22 5.63 0.71

Wagner M et al, Neurology 2012

AD: can the exam predict the pathology?

Hippocampal

atrophy (MRI)

cortical hypometabolism

(FDG-PET)

CSF Abeta and

tau levels

PET amyloid

radio-ligands

PA

TH

OP

HY

SIO

LO

GIC

AL

MA

RK

ER

S

TOPOGRAPHICAL MARKERS

location

nature

AD BRAIN

LESIONS

Amnestic syndrome of

the hippocampal type

Discovery of biomarkers of AD

from Dubois, 2013, mod.

Before 2007 1) dementia: loss of autonomy 2) elimination of other causes of dementia:

blood exams : endocrinopathies, infectious or inflammatory disorders…

CT-Scan/MRI : vascular lesions, tumor, hydrocephalus…

Diagnosis based on an exclusionary process

Since 2007 1) an amnestic syndrome of the hippocampal type 2) integration of biomarkers in the diagnostic process:

a biological signature on CSF the visualisation of brain lesions with PET amyloid tracer

Diagnosis based on positive arguments

New diagnostic approach

neuropathology

CLINICAL

POST-MORTEM

MCI dementia probable/possible

Biomarkers

CLINICAL

BIOLOGICAL

typical / atypical [

[

Alzheimer’s disease

Alzheimer’s disease

The conceptual shift

1984 NINCDS-ADRDA

2007 IWG

Clinico-pathological

entity

Clinico-biological

entity

New criteria: impact of the conceptual shift

AD can be recognised:

- IN VIVO

- INDEPENDENTLY OF DEMENTIA

The evolution of the lexical-semantics of Alzheimer’s Disease

• Preclinical AD Long asymptomatic period between the first brain lesions and the first symptoms (asymptomatic “at risk” / presymptomatic)

• Prodromal AD Symptomatic pre-dementia phase of AD, including mild cognitive impairment, MCI

• AD dementia Symptoms sufficiently severe to meet

currently accepted dementia and AD criteria

Dubois et al, Lancet Neurol, 2010

Biological: changes in biomarkers (CSF)

Structural: atrophy of medial temporal lobe (MRI)

Functional: temporo-parietal hypometabolism on FDG-PET

Molecular: ligand retention on amyloid-PET

Amnestic syndrome of the ‘hippocampal type’

(that can be isolated or associated to other cognitive / behavioral changes)

1 major clinical criterion

+ 1 or more biomarker present

Dubois et al., Lancet Neurol., 2007

IWG research criteria for the diagnosis of AD:

revising the NINCDS-ADRDA criteria

1) In research settings: a high diagnostic accuracy is needed for:

• study of specific outcomes: requires well phenotyped cohorts • research projects: not on heterogeneous population with a

low/intermediate likelihood of diagnostic accuracy • inclusion in clinical trials : most of ongoing trials are based on

the new criteria (γ secretase inhibitors, immunotherapy, BACE inhibitors, Food-Souvenaid)

2) In specific clinical conditions: biomarkers increase diagnostic accuracy that may be required in case of:

• young onset AD • complex cases: PCA, PPA

Applicability of the New Criteria: When?

Cognition Likelihood of AD Biomarker Evidence

MCI High likelihood (+) amyloid-β biomarker AND (+) neuronal injury biomarker*

MCI Intermediate likelihood (+) amyloid-β biomarker OR (+) neuronal injury biomarker*

MCI Uninformative situation Biomarkers fall in ambiguous ranges, conflict, not obtained

MCI Unlikely due to AD Demonstrated absence of AD-type molecular marker and

possible presence of marker suggestive of non-AD disorder

The NIA/AA criteria acknowledge that :

• brain changes can occur long before dementia symptoms

• disease biomarkers might be useful for the diagnosis

3 recognized stages with 3 different diagnostic algorithms

• AD dementia stage

• MCI stage (4 cathegories)

• preclinical stage

2 types of MCI criteria : • for clinical setting • for research purposes that are based on the use of biomarkers:

2011

NIA-AA 2011 framework: conceptual similarities and differences

• Similar recognition that the disease starts before the occurrence of

clinical symptoms;

• Similar coverage of full staging of the disease: asymptomatic

(preclinical AD), predementia (MCI due to AD), and dementia (due to

AD).

• Similar integration of biomarkers in the diagnostic process and

recognition of an asymptomatic biomarker-positive stage.

• Different proposal of 3 sets of diagnostic criteria, one for each disease

stage.

• Different levels of probabilistic likelihood (high, intermediate, or

unlikely) that the syndrome is due to AD based on biomarker

information.

• Diagnosis of AD in asymptomatic individuals with biomarker evidence

of Aβ accumulation (in IWG criteria only “at risk of disease” state)

The NIA–AA criteria have the advantage of being applicable

when no supportive biomarkers are available, albeit at the

expense of diagnostic specificity.

The IWG criteria are less complex in their semiology, have

the advantage of consistency, and are more readily applicable

in clinical trials and in clinical diagnosis when biomarkers are

available.

Lancet Neurology 2014

Compared to 2007 criteria, hippocampal atrophy at MRI is no longer considered a valid biomarker as there is no in vivo evidence of the pathogenic process (amyloid driven); Comorbidity and relation with brain ageing mentioned briefly. Emphasis on “mixed AD”, and atypical presentations (logopenic variant of PPA, posterior cortical atrophy, frontal variant AD).

Sweeney MD, 2019

Vascular imaging biomarkers of small vessel disease of the brain, which

is responsible for dementia including AD, are already established, well

characterized, and easy to recognize. We suggest that these vascular

biomarkers should be incorporated into the AD Research Framework

Jagust et al, 2019

Vascular factors contribute to the Alzheimers’s clinical syndrome

and dementia, but the evidence that they contribute to AD

pathological changes is very limited. These vascular biomarkers

should not be incorporated into the AD Research Framework

The term “Alzheimer’s disease” refers to an aggregate of

neuropathologic changes and thus is defined in vivo by

biomarkers and by postmortem examination, not by clinical

symptoms

“Characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacological responses to a therapeutic intervention” Biomarker Definition Working Group, 2001

Topographical /Physiopathological biomarkers Diagnostic / Progression biomarkers

Biomarker

Redefinition of AD biomarker IWG, 2014

CSF biomarkers

• Measured using ELISA / CLEIA kits

• Cut-off values of normality according to

literature data

• AD profile: positivity for Ab42 associated with

positivity for t-Tau or p-Tau

CSF biomarkers

Biomarker Pathological values

Hampel et al, 2010

Specific diagnostic CSF biomarkers in AD

C. Mulder et al, Clin Chem 2010;56:248-53

ROC curve

85% sensitivity

and specificity

- CSF

- ELISA

Sensitivity: ability to classify AD patients

Specificity: ability to classify controls

Specific profile of CSF biomarkers even in patients at a prodromal stage

(Hansson, 2006) 1.0

0.8

0.6

0.4

0.2

0

No p

rogre

ssio

n t

o A

D

0 10 20 30 40 50 60 Time (months)

Normal CSF

Pathological CSF (low A beta,

high tau/p-tau)

Normal CSF 67 66 62 56 47 40 28

Pathological CSF 67 65 49 31 27 15 3

CSF Aβ42 best predictor for evolution to AD in patients with subjective complaints

Aβ42 tau

HR 14.9 (3.8-58.9) 3.0 (0.9-9.5) 6.8 (1.7-27.3)

AD combined profile

Van Harten et al., Alzheimers Dement. 2013

Using biomarkers, dementia could be discriminated from

controls (sensitivity= 86%, specificity= 89%).

Combined T-tau and Aβ42 optimally discriminated AD from

other dementias and controls (S = 90%, Sp = 89%)*

Combined P-Tau181 and Aβ42 optimally discriminated AD

from other dementias (S = 80%, Sp = 93%)*

* t-tau/Aβ42 and p-tau/Aβ42 ratios outperform any other individual marker

Levels of Aβ42 are already fully decreased at least 5-10 years before conversion to AD dementia, whereas T-tau and P-tau seem to be later markers. Direct support for the hypothesis that altered Aβ metabolism precedes tau-related pathology and neuronal degeneration A meta-analysis of 131 studies (Olsson, 2016) showed a mean reduction to 56% of Abeta 1-42 levels found in cognitively unimpaired elderly.

Evers et al., 2015

CSF Ab1–42 showed the best diagnostic accuracy among the CSF biomarkers. At a sensitivity of 85%, the specificity to differentiate AD dementia against other diagnoses ranged from 42% (for LBD) to 77% (for FTD). Thus, CSF Ab1–42 discriminates AD dementia from FTD, but shows significant overlap with other non-AD forms of dementia, reflecting the underlying mixed pathologies.

CSF biomarkers are increasingly being

used in clinical practice, and have been

incorporated into the majority of clinical

trials to:

- demonstrate target engagement

- enrich or stratify patient groups

- show disease modification.

Lléo et al., Nat Rev Neurology, 2015

Structural, Functional, Molecular Biomarkers (Imaging)

Atrophy in Alzheimer’s disease Prodromal AD 15% Mild dementia 25%

Moderate dementia 40%

Lehericy. Eur Radiol 2007

Structural MRI: MTL atrophy

4

3

2

N N 1

N N N 0

Hippocampus

height

Temporal

horn width

Choroid fissure

width

Scheltens et al., 1992

Accuracy in the prediction of conversion of MCI to AD has not yet reached clinically acceptable levels, MRI-based sequences might provide complementary information about a patient’s risk. Volumetric measures are not better than detailed clinical assessments for the prediction of progression from MCI to AD, but highest prediction is achieved when the two types of information are combined.

MTL is not specific for AD (it may also be present in normal aging), and has limited value in the differential diagnosis of AD.

Beyond structural MRI

Voxel-based pattern distribution map (axial view) for the classification between MCIc and MCInc. Voxel-based pattern distribution (normalized to a range between 0 and 1) is expressed according to the color scale (threshold= 35%) and superimposed on a standard stereotactic brain for spatial localization ,

Salvatore et al, ADNI, Front. Neurosci. 2015

A computer-based approach with optimized machine learning algorithms with extraction of spatially-distributed multivariate biomarkers from sMR brain images. Classification accuracy increases, identifying MCI subjects which will convert to AD

Analysis of hippocampus, entorhinal cortex, basal ganglia, gyrus rectus, precuneus, cerebellum

PET in AD

FDG-PET (marker of disease stage – neuronal injury), and Amyloid PET (marker of disease state – amyloid burden): • investigate in vivo pathophysiological mechanisms (“in

vivo hystopathology”) • support clinical diagnosis and differential diagnosis • provide disease evidence in early and preclinical phase • evaluate prognosis and progression • monitor response to treatments

These biomarkers are sufficiently validated, incorporated into research diagnostic criteria and commonly used in therapeutic trials

Nordberg et al. Nat. Rev. Neurol. 2010; Ossenkoppele et al. Alz & Dem 2013; Sanchjez-Juan et al. Neurology 2014; Jack et al. ; Neuron 2013

In vivo PET molecular measures Tracers

FDG-PET Pooled sensitivities and

specificities (9 studies) of 86% for temporo-parietal hypometabolism

(Patwardhan, 2004)

A specific pattern in FDG PET

FDG PET: early diagnosis of dementia in MCI Smailagic et al., 2015

FDG PET conversion to AD

PET is a unique diagnostic tool, since it can assess pathophysiologic and metabolic processes before any anatomic changes have taken place. F-FDG PET is becoming increasingly accepted in the diagnostic approach to AD, but given the considerable variability and specificity values, the heterogeneity in the conduct and interpretation of the test, and the lack of defined thresholds for determining test positivity, the current evidence does not support its routine use in clinical practice.

from Perani, 2015

Amyloid PET imaging in dementia

Source: SCOPUS

[11C]PIB the more diffuse and clinically tested amyloid ligand •short half life •low cost, few production centres [18F] fluorbetaben [18F] fluorbetapir [18F] flutemetamol in clinical trials sponsored by the industries •long half life, commercial use •high cost for public health system

Amyloid PET ligands

Villemagne, 2013

Amyloid PET in AD

Scan of a single individual with mild

AD with PiB (SUVR, standardized

uptake value ratio units, relative to

cerebellar gray matter)

Central gray region: 2-dimensional axial

(top), sagittal (middle) and coronal

(bottom) views at two levels (left and

right). Around this, in a clock-like fashion:

3-dimensional views of the same PiB

scan overlaid on the subject's MRI scan

rotated in 45 degree increments to show

the prominent medial, lateral and inferior

frontal, medial and lateral parietal and

lateral temporal neocortex and striatum.

Deposition is much greater in grey matter

areas than in white matter areas and in

association cortices than in sensory-

motor cortices

Cohen et al, 2019 Simultaneous, «rising tide» (>< tau)

Typical topology of Aβ deposition in AD

measured with Aβ PET.

• PiB-PET peaks early in the disease course

Jack CR, Brain, 2009 Engler H, Brain, 2006

Amyloid PET positivity occurs early

Amyloid beta marches through phases 0-5

Murray et al., 2015

Thal: 1. neocortex. 2. + allocortical brain regions 3. + diencephalic nuclei, striatum, cholinergic nuclei of the basal

forebrain 4. + several brainstem nuclei 5. + cerebellum . SUVR, standardized uptake value ratio units

Amyloid positivity predicts clinical conversion in MCI

- Forsberg et al., Neurobiol Aging 2008 - Wolk et al., Annals of Neurology 2009 - Okello et al., Neurology 2018

2 YEARS of follow-up in 115 MCI • PIB+ 76 (66%) • PIB- 39 (34%) PIB+ AD converters 47/76 = 62% PIB- AD converters 2/39 = 5%

Nordberg et al, 2013

PIB-positive scans in

MCI patients are an

indicator of prodromal

AD.

In a multicentre setting,

none of the MCI PIB-

negative patients

converted to AD, and

thus PIB negativity had

a 100 % negative

predictive value for

progression to AD. Significantly higher PIB uptake in cortical regions in AD patients compared to HC; low, intermediate or high PIB uptake in MCI

Amyloid negativity predicts no clinical conversion in MCI

The prevalence of amyloid positivity was associated with clinical diagnosis, age, and APOE genotype. These findings indicate the potential clinical utility of amyloid PET for differential diagnosis in early-onset dementia and to support the clinical diagnosis of participants with AD dementia and noncarrier APOE ε4 status who are older than 70 years.

Amyloid positivity differentiates AD from other dementias

In 83% of subjects data (inversely related) were concordant.

The others were more “CSF + only” than “PET + only” and

reflect the fact that CSF changes precede PET changes.

Cohen et al, 2019

192 cognitively normal,

93 subject memory complaint

273 early MCI

119 late MCI

152 AD

Florbetapir PET SUVRs and CSF Aβ1–42 in 888 subjects

Amyloid PET positivity agrees with CSF positivity

CSF and amyloid PET provide partially independent information about a wide range of AD measures, and probably represent partly different aspects of Alzheimer's pathology. A mismatch, with positive CSF amyloid- but normal amyloid PET is relatively common in cognitively healthy people and must be considered. Reduced CSF amyloid-β may be more strongly related to early stage AD, whereas increased PET amyloid-β may be more strongly related to disease progression.

ADAD, 2019

Excellent agreement between CSF and (18)F-florbetapir PET: these examinations may have

the same validity in detecting in vivo evidence of AD pathology in PPA clinical variants.

Amyloid PET positivity and CSF in Atypical AD

Abnormal

Normal Time Presymptomatic Prodromal

(MCI)

Dementia

CSF Aβ42

Amyloid imaging FDG-PET MRI hippocampal volume CSF Tau Cognitive performance Function (ADL)

FDG-PET

MRI hippocampal volume

CSF Aβ42

Amyloid imaging

Cognitive performance

Function (ADL)

CSF Tau

Mod. from Jack C - Aisen PS, et al. , Alzheimers Dement. 2010

A model of dynamic biomarkers of the AD pathological cascade

Issues and limitations with biomarker-assisted AD diagnosis

Sensitivity/specificity in oldest old (>75 yrs)

Technical problems with LP procedure

Laboratory issues (variability, definition of

reference values, etc.)

Mismatch between markers

Cost/efficacy ratio analysis

Issues and limitations on CSF biomarkers

Due to variability in absolute levels between laboratories, there is no consensus on medical cut-off value for the CSF AD signature. Variability can be explained both by pre-analytical and analytical factors. For example, the plastic tubes used for CSF collection and storage, the lack of reference material and the variability of the analytical protocols were identified as important sources of variability.

5 different storage tubes Same sample in each ELISA plate

Verwey et al., AnnClin Biochem 2009

Analytical factors: amyloid beta interlaboratory variation

Across 18 laboratories, there was a high variation between, and within centres.

Alzheimer’s Association Global Biomarker Standardization Consortium (GBSC)

Referencence methods for Abeta 42 validated against amyloid PET and

released (Kuhlmann, 2017)

- Uniform study design, e.g control group names and applications; - Consensus on terminology (“novel biomarker language“); - Proteomics: novel biomarkers in AD

Neurology, 2009

Shaw et al., 2018

1992 2015

Mismatch between CSF markers

• The amyloid accumulation period can last for up to 15 years and during this period the positivity level gradually increases. A dichotomous evaluation (positive vs negative exam) is inadequate for interpretation. A quantification of the exam (level of positivity) is mandatory. New processing imaging algorithms for more precise diagnosis of AD are underway.

• Different conformations of Ab deposits in the brain may affect the uptake and retention pattern of the tracers. Ab imaging modalities may not recognize all types of Ab pathologies with equal sensitivity. A negative amyloid PET scan should not be equated with the complete absence of Aβ in the brain or even with absent neuritic plaques.

• False positivity • Appropriateness

Issues and limitations with amyloid PET

Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by PET or CSF findings increased from age 50 to 90 years of 10% and was affected by age (>70 yrs), APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

Jansen WJ et al, JAMA 2015

Appropriateness of amyloid PET

Alzheimers Dementia 2013

Though biomarkers are all in line with recommendations by the 1998 Biomarker Working

Group (stating that an ideal AD biomarker should have sensitivity and specificity > 80%),

performance is imperfect; this relates to the use of patients possibly misdiagnosed or

harbouring mixed pathologies, the use of amyloid-positive “controls” and the high overlap in

pathology (Composite = APP669–711/Aβ1-42 to Aβ1-40/Aβ1-42). (Leuzy et al, 2018)

Overall Performance of AD biomarkers. AD dementia versus controls.

CSF and/or amyloid PET?

Many parallels between CSF Aβ measurements and PET

Aβ measurements, but 2 great differences:

1) CSF assessments reflect more proximal “state”

phenomena, while PET assessments more closely

approximate an integrated measure of Aβ deposition

over many years;

2) PET measurements reveal topological information that

is not available with CSF (both quantitative and

qualitative information)

In which order?

The issue of incremental diagnostic value

Incremental Diagnostic Value of Amyloid-PET versus CSF

in the Diagnosis of Alzheimer’s Disease

Cotta Ramusino et al., 2019

71 pts, diagnostic workup

including amyloid-PET and

CSF, in 4 specialized imaging

and clinical centers.

3 rounds, based on: 1) clinical, neuropsychological and structural MRI information alone; 2) adding one amyloid biomarker (CSF or PET); 3) adding the second biomarker.

Amyloid-PET demonstrated

greater impact than CSF on

diagnostic confidence, even

when used as a second-line

biomarker after CSF.

The Incremental Diagnostic Value of [18F]Florbetaben

PET and the Pivotal Role of the Neuropsychological

Assessment in Clinical Practice Objective: to evaluate the incremental value of a PET scan with [18F]florbetaben, in terms of

changes of diagnosis, diagnostic confidence, and treatment plan when added to a standardized

diagnostic workup for cognitive disorders, with particular focus on the role of the neuropsychological

assessment, including the Free and Cued Selective Reminding Test (FCSRT).

Methods:A total of 104 patients were recruited from our memory clinic. [18F]florbetaben PET scans

were interpreted as amyloid negative or positive on the basis of a semi-quantitative visual rating..

Results:There were 69/104 (66%) [18F]florbetaben positive scans, 51/62 (82%) patients were

suspected as having AD before the PET scan and 18/42 (43%) were not. Overall, the data obtained

at PET changed 18/104 diagnoses (17%) and increased diagnostic confidence from 69.1±8.1% to

83.5±9.1 (p < 0.001), with the greatest impact on diagnosis and confidence in PET negative

patients with an initial diagnosis of AD (p < 0.01) and in early-onset patients (p = 0.01).

Conclusion: Amyloid PET represents a source of added value in dementia diagnosis, with a

significant effect on diagnosis and diagnostic confidence. However, the use of a complete

neuropsychological assessment has an add-on value on limiting the amyloid PET influence

on change of diagnosis, and the real impact of amyloid PET should always be weighed up

together with an accurate standardized diagnostic workup.

Spallazzi et al, Journal of Alzheimer’s Disease, 2019

Numero di centri clinici

partecipanti: 20 con

procedura competitiva

Tipo di studio:

multicentrico,

osservazionale

di coorte.

Numero di

pazienti in

studio: 500

*

*

PERSPECTIVES

ON NOVEL BIOMARKERS

Fluid biomarkers: the present, the future

Molinuevo and Blennow, 2018

AD mechanisms and fluid biomarkers. Arrows reflect hypothetical relationships, not direct

causal links. COU is important. hFABP heart-type fatty acid-binding protein, IP-10 interferon-γ-induced protein 10, NF-L neurofilament light, SNAP-25 synaptosome-associated protein 25, TDP-43 transactive response DNA-binding protein 43, TREM2 triggering receptor expressed on myeloid cells 2, VILIP-1 visinin-like protein 1

In Tau-PET+ and Tau-PET- subjects, plasma t-tau

/amyloid b42 in plasma was highly predictive of brain tau

deposition, with 80% sensitivity and 91% specificity.

Kaplan–Meier curves of cognitive decline with low

(orange), medium (green), or high (blue) baseline

plasma Abeta42 or plasma Abeta42/Abeta40 ratio..

Neuroimaging in AD: the present, the future

FDG PET seems to be a very well established method for the

prognosis of dementia in MCI and remains recommended particularly

if a reliable short-term prediction of cognitive decline is needed.

Structural MRI might provide a more widely available, albeit less

sensitive, alternative to FDG PET, which is used for staging of

neuronal loss, particularly with quantitative analysis methods.

Amyloid imaging might be preferable if very early (highly sensitive)

information on the underlying neuropathological changes are relevant

(e.g, confirmation of presence of the drug target for treatment trials),

but not a prediction of dementia in a short timeframe.

The move from use of sequential to parallel multimodal

imaging, with the availability of new-generation hardware such as

integrated PET/MRI systems might provide solutions while reducing

costs.

Lancet Neurology, 2015

Multimodal imaging, in the future

may help to make a diagnosis and

decide about potential therapies

for AD.

FDG PET and structural MRI are

at the multicentre studies phase,

amyloid PET is approaching this

stage, functional MRI and DTI are

still in the phase of single-centre

studies.

Structural MRI and FDG PET have

already become part of clinical

trials and diagnostic algorithms in

tertiary care.

Lancet Neurology, 2015

First and second generation tau PET tracers:

uptake images in amyloid-β-positive AD patients

Leuzy, 2018

Tau protofibril

Preferential binding of the first- and second-generation tracers in AD-relevant areas of the temporal

lobes (MTL, but also inferior lateral temporal lobe), posterior cingulate, and lateral parietal regions,

and the broader dynamic range among second generation tracers (also precuneus, occipital lobes,

and prefrontal cortex). Data fairly consistent with Braak’s staging of neurofibrillary tau.

DVR distribution volume ratio,

SUVR standardized uptake

value ratio

Use of selective in-vivo tau imaging will enable improved understanding of tau aggregation in the brain, facilitating research into causes, diagnosis, and treatment of major tauopathies such as AD, PSP, CBS, FTD. Tau imaging might be useful as a diagnostic, prognostic, and progression biomarker, and a surrogate marker for the monitoring of efficacy and recruitment for anti-tau therapeutic trials.

CONCLUSIONS

The current impact of biomarkers throughout AD stages

The most common target of treatments (76%) is still amyloid, reflecting the

urgent need for deeper understanding pathophysiology (Cummings, 2016)

• New criteria provide a framework for diagnosis of AD throughout

any phase of AD (entire continuum), with 4 diagnostic groups.

This modest complexity facilitates their uniform application

• They take advantage of recent rapid advances in our

understanding of the biology of AD and identify the presence of

AD pathology in vivo.

• Conceptually, they advance the idea of AD as a clinico-

biological entity

Biomarkers are the cornerstone of new criteria

IWG, 2014

Are we ready to manage ?