The new conceptualization of Alzheimer’s Disease

Dr. José L Molinuevo

Alzheimer’s disease and other cognitive disorders unitICN, Hospital Clinic I Universitari, Barcelona

BarcelonaBeta Brain Research CentreFundació Pasqual Maragall

Where are we know?

Clinic pathological dual diagnosis:1

• Definitive AD diagnosis: Dementia + pathological lesions on

postmortem exam• Probable AD diagnosis• Possible AD diagnosis

Current clinical AD diagnostic methods shows much variability among studies

General impression that clinical diagnosis is accurate

Dr Alzheimer’s original publication (Bielchowsky's technique)

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AD, Alzheimer’s disease, NINCDS-ADRDA, Mational Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; 1. McKhann G, et al. Neurology 1984;34:939‒44; 2. Beach TG, et al. J Neuropathol Exp Neurol 2012;71(4):266‒73.

NINCDS-ADRDA CRITERIA are considered the “Gold Standard”2

Assessing the accuracy of the clinical diagnosis

Study performed on US-NACC data 2005‒2010:

- N = 919 demented with neuropathological diagnosis

- Mean age: 79

- Gender: 368 women, 551 male

- Clinical diagnoses prob/poss AD: 70.5%

- Pathological diagnoses: AD in 67.2%

Non AD pathological diagnosis (clinical diagnosis AD): tauopathies (15), other FTLD (16), CVD (11), LBD (9), hippocampal sclerosis (9) Hallervorden-Spatz (2), amyloid angiopathy (2), limbic encephalities, no pathology

No AD pathology

Yes AD pathology

No probable AD (clinical)

213 180 NPV=54%

Probable AD(clinical)

88 438 PPV=83%

Specificity =

70.8%

Sensitivity =

70.9%

Pathological diagnosis: moderate or frequent plaques AND Braak* IV‒VI

*Braak IV-VI it is the needed pathological threshold to make the pathological diagnosis of ADAD, Alzheimer’s disease, NINCDS-ADRDA, Mational Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; 1. Beach TG, et al. J Neuropathol Exp Neurol 2012;71(4):266‒73; Consensus recommendations for the postmortem diagnosis of Alzheimer's disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's Disease. Neurobiol Aging 1997;18:S1–S2

Normal pathologyNo symptoms

Moderate pathology

Memory disorders

Intense pathology

Dementia

Clinical ResearchMedical attentionDifferential diagnosis

Incipient AD pathology

No symptoms

Pathological continuum

Normal Dementia due to ADMild Cognitive

Impairment due to ADAD Preclinical Stage

The new AD conceptualization

AD is a clinical-biological entity with a clinical phenotype ranging from normal cognition to severe dementia

Preclinical AD

• The preclinical stage has been postulated to be a long asymptomatic period during which the pathophysiological process is progressing.

• Preclinical AD subjects have been defined as individuals who have evidence of early AD pathological changes but do not meet clinical criteria for MCI or dementia (Sperling et al., 2011).

• Presymptomatic subjects: this state applies to individuals who will develop AD (monogenic AD)

• Asymptomatic at risk state for AD: this state can be identified in vivo by evidence of amyloidosis of the brain (PET or CSF).

Alzheimer Biomarker Pathochronology in Autosomal Dominant AD

Morris et al., Clin Invest 2012

Presymptomatic subjects

41 participants (May 2014): 11 symptomatic mutations carriers

(SMC)16 asymptomatic mutation carriers

(AMC) (mean age -16y Estimated age of onset)

14 asymptomatic non-carriers (NC)Clinical and cognitive evaluationsBlood and CSF biomarkersStructural and functional MRIAmyloid-PET FDG-PET

AMCAβ42 or Aβ42/ptau vs EAOSpearman rho 0,771p= 0,036

Presymptomatic subjects

Symptomatic mutation carriers Asymptomatic mutation carriers N=6

Interpretation: At early preclinical stages, CTh in PPC and posterior association areas and caudate volume increase in PSEN1 MC and decrease thereafter with disease progression. These findings are concurrent with reduced MD suggesting underlying microstructural changes in the GM. Reactive neuronal hypertrophy or/and inflammation may account for these features in AMC.

• 13 AMC vs 14 NC• AMC: mean age -16,6y EAO

Cross-sectional study Longitudinal study

Statistical maps of the clusters with significant differences(corrected p<0.05) between AMC and NC

Results of the longitudinal analysis comparing CTR with AMC. (A) Statistical maps of the clusters with significant differences in spc

between AMC and CTR (corrected p<0.05).

The analysis of resting-state fMRI data revealed alterations in the default mode network in PSEN1 mutation carriers, with increased frontal connectivity and reduced posterior connectivity in AMC and decreased frontal and increased posterior connectivity in SMC

Preclinical AD: asymptomatic at risk

Presymptomatic AD Asymptomatic at risk

~12/13 years

When does cognitive dysfunction start?

Sperling et al. Neurol Aging 2012

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WMS immediate WMS delayed

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WMS=Wechsler Memory Scale

Study of florbetapir (18F AV-45) in normal elderly subjects

Neuropsychological differences between SMD patients with positive and negative A1-42

Subjective memory complaint (SMC)

A1-42 (>495 pg/ml)

A1-42 (<495 pg/ml)

n 11 6

Age (years) 66.0 (6.4) 73.6 (6.3)A1-42 680.2 (139.6) 315.8 (81.3)**t-tau 401.1 (294.3) 585.3 (750.1)p-tau 67.3 (40.2) 82.7 (74.2)Mini Mental State Examination

28.2 (1.3) 26.5 (1.8)Boston naming test 51.3 (4.6) 50.0 (2.8)FCSRT-total recall 14.4 (1.3) 10.8 (1.6)**

**p<0.005

FCSRI=Free and Cued Selective Reminding Test

In subjective memory complaint patients, Aβ1-42 levels positively correlated with the total recall score of the Free and

Cued Selective Reminding Test (FCRST) Scatter plot showing CSF Aβ1-42 levels and total recall from the

FCSRT in subjective memory complaint subjects

(r=0.666; p<0.005)

Rami et al. J Alzheimers Dis 2011; 23 (2): 319–326

Scatter plot showing CSF Aβ1-42 levels and learning from the CERAD in subjective memory complaint subjects

(r=0.697; p<0.005)

In subjective memory complaint patients, Aβ1-42 levels positively correlated with the CERAD word list

learning

Rami et al. J Alzheimers Dis 2011; 23 (2): 319–326CERAD=Consortium to Establish a Registry for AD

Cortical thickness and VBM in preclinical AD

The relationship between Aß and Cortical thickness in different automatically extracted ROIs. A and B show two AD related areas; C and D show two unrelated or control areas.

CT

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We decided to analyzed tha samples divide in tertiles

Increased cortical thickness in AD areas in subjects with ß-amyloid levels in the middle tertiles (transitional

levels) respect those with normal levels

Cortical thickness in “early” preclinical AD

GRAY MATTER THICKNESS AS A FUNCTION OF PATHOLOGICAL “LOAD”

Preclinical AD exhibit increased activation of precuneus

Preclinical AD with high CR exhibit more gray matter loss

Tracts showing increased AxD in Pre-AD subjects compared with controls (blue)

Relationship between the areas showing increased AxD and the level of Aβ42 on CSF (r=-0.52, p<0.0001) and cognitive reserve (Pre-AD group r=0.57, p<0.012).

YKL40: GLIAL INFLAMMATORY RESPONSE

YKL40: GLIAL INFLAMMATORY RESPONSE

Correlations between CSF YKL-40 levels with Aβ42), t-tau and p-tau, performed by partial correlation models with age as co-variate. (A) all sample excluding iRBD group, (B) Preclinical AD (Pre-AD) subjects. Statistical significance was observed for tau biomarkers in both

Preclinical AD

• CSF and imaging biomarkers present interactive dynamics along the AD continuum

• The preclinical stage is “biologically” active, showing AD signature areas an initial increase in cortical thickness and posterior decrease before the clinical appearance of cognitive impairment

• Preclinical AD present distinct functional activity in key encoding regions

• This stage may last around 15-20 years

Normal pathologyNo symptoms

Moderate pathology

Memory disorders

Intense pathology

Dementia

Clinical ResearchMedical attentionDifferential diagnosis

Incipient AD pathology

No symptoms

Pathological continuum

Normal Dementia due to ADMild Cognitive

Impairment due to ADAD Preclinical Stage

The new AD conceptualization

• Prodromal AD can be defined through the presence of a specific symptom plus biomarker

Probable AD: A plus one or more supportive features B, C, D, or ECore diagnostics criteriaPresence of an early and significant episodic memory impairment that includes the following features:

Gradual and progressive change in memory function over more than 6 monthsObjective evidence of significantly impaired episodic memory consists of recall deficit that does not improve signficantly with cueing or recognition testing and after effective encoding of informationThe episodic memory impairment can be isolated or associated with other cognitive changes at the onset of AD or as AD advances to dementia

 Supportive featuresPresence of medial temporal lobe atrophyVolume loss of hippocampi, entorhinal cortex, amygdala evidenced on MRIAbnormal cerebrospinal fluid biomarkerLow amyloid 1-42 concentrations, increased total tau or p-tau concentrationsOther well validated markers to be discovered in the futureSpecific pattern on functional neuroimaging with PETReduced glucose metabolism in bilateral temporal-parietal regionsOther well validated ligands, including amyloid imagingProven AD autosomal dominant mutation

IWG diagnostic criteria

Rami et al. Int J Geriatr Psychiatry 2012; 27 (2): 127–134

Prodromal DA diagnosis: MRI and neuropsychology

Brain regions representing increased GM volume in controls compared to: A) PrdAD patients B) mild AD patients (corrected at FDR p<0.05)

New research criteria

• Presence of an objective episodic memory loss, defined through the Free and Cued Selective Recall Reminding Test (Grober & Buschke, 1987)

• CDR of 0.5 with memory box of 0.5 or 1 • Essentially preserved activities of daily living • Absence of dementia• AD CSF profile (low beta-amyloid <495 pg/mL,

and high t-tau >356 or p-tau181 >75 pg/mL)

Association between cognition and CSF in the prodromal AD subjects

• Higher total tau levels associated to poorer memory:– CERAD list (r = -0.487; p<0.005) – FCSRT (free recall) (r = -0.420; p <0.005)

• Higher p-tau levels associated to poorer memory:– M@T (r = -0.521; p<0.001) – CERAD retention list (r = -0.527; p<0.001) – Total Learning (Buschske) (r = 0.518; p<0.005)

• Aβ1-42 associated to poorer semantic fluency (r=0.54; p<0.005)

FCSRT=Free and Cued Selective Recall Reminding Test

FEW correction: parahippocampal gyrus, uncus, precuneus and medial frontal gyrus (left)

Control versus prodromal AD

Correlation of FCSRT with neuroimaging

Clinical evolution

• All patients followed over 2 years converted to AD according to NINCDS-ADRDA criteria (2 or more cognitive areas affected plus significant daily living activities impairment – according to FAQ).

• All patients followed one year had lower cognition (3 of them with 2 or more cognitive areas affected) and one with lower functionality (only memory affected)

• Patients followed less than one year no significantly cognitive (number of cognitive areas affected) or functional changes.

Prodromal or predementia AD

• Alzheimer’s disease may be diagnosed through a clinic-biological approach

• The prodromal, predementia or MCI stage represents the earliest phase to establish a clinical diagnosis– Biologic: biomarkers correlate with pathology– Clinic: episodic memory is a specific symptom

• There are active trials with disease modifying drugs in this population

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IWG diagnostic criteria

A. SPECIFIC CLINICAL PHENOTYPEPresence of an early and significant episodic memory impairment (isolated or associated with other cognitive changes suggestive of a mild cognitive impairment or of a dementia syndrome) which includes the following features: i) Gradual and progressive change in memory function reported by patient or informant over more than 6 monthsii) Objective evidence of an amnestic syndrome of the hippocampal type (*), based on a defective performance on an episodic memory test with established specificity for AD, which is high in case of cued recall paradigm with control of encoding.  B. IN VIVO EVIDENCE OF AD PATHOLOGY (one of the following)- Decreased Aβ1-42 together with increased T-tau or P-tau in CSF- Increased tracer retention on amyloid PET- AD related autosomal dominant mutation (in PSEN1, PSEN2, or APP)

MCI Clinical diagnostic Criteria

• Amyloid Markers – Imaging: PET with amyloid tracer – Biochemical: low Aβ42 CSF levels

• Injury markers– Imaging:

• FDG PET • SPECT• MRI: hippocampal volume or atrophy rate

– Biochemical: high Ptau or Ttau CSF levels

COMBINING BOTH GREATER DIAGNOSTIC CERTAINTY

Alzheimer’s disease diagnostic biomarkers

Biomarker probability of

AD aetiology

Amyloid Markers Injury markers

Uninformative

Untested, conflicting, indeterminant or non informative results

Untested, conflicting, indeterminant or non informative results

IntermediatePositiveUnavailable

UnavailablePositive

Highest Positive Positive

Lowest: Unlikely due

to AD

Negative Negative

TAKE HOME MESSAGE• The preclinical stage is “biologically” active, showing

AD signature areas an initial increase in cortical thickness followed by a decrease cognitive impairment

• Different brain areas evolve with distinct patterns• An earlier and more specific diagnosis is feasible

through biomarkers• Therefore, new diagnostic approaches include

– Clinical information– Biomarker results

Thank You