Imaging Biomarkers For Alzheimer’s Disease...Imaging techniques have proven to be promising...
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ALZHEIMER’S DISEASE MEASURE OF BRAIN ATROPHY BIOMARKERS FOR AD MUST REFLECT NEUROPATHOLOGIC CHARACTERISTICS ACCURATE (>80% S and SP) REFLECT DISEASE PROGRESSION AND TREATMENT EFFICACY MUST BE EVALUATED BY 2 INDEPENDENT STUDIES (reproducible) EASY TO USE INEXPENSIVE NON - INVASIVE There’s no parameter that fully met this criterion • Meanwhile, the use of biomarkers helps to exclude other dementia or conditions with AD-like symptoms. • The new diagnostic guidelines classifies them as biomarkers for neurodegeneration and for β-amyloid abnormalities. • Although these abnormalities can occur during normal aging or in other dementias, they have specific patterns of changes for AD. • Combinations of biomarkers are being investigated to improve diagnosis accuracy for AD. Biomarkers recommend by the new guidelines for diagnosis: STRUCTURAL IMAGING - CT and MRI techniques Provide detailed images of the brain structure in vivo with high resolution FUNCTIONAL IMAGING - fMRI and FDG-PET techniques Detect alterations in brain blood flow and glucose metabolism Fig. 3 Voxed-based assessment of gray matter differences between AD and MCI subjects. Brain areas indicated have decreased gray matter volume in AD when compared with MCI. 3 CT and MRI are applied as standard workup for AD diagnosis and drug trials to: • Rule out other conditions, such as tumours or strokes. • Calculate the rate of brain atrophy Brain atrophy is related to the magnitude of neuronal loss, extent of NFT and disease progression. 2 different approaches: Whole-brain volume ROI measures Whole-brain volume ROI measure: hippocampal atrophy Fig. 4 Ten-year time serie demonstrating hippocampal, EC and ventricular changes on MRI in association with clinical decline from CN to MCI to AD. 4 fMRI is a non-invasive technique (no radiation is used) that detect changes in blood flow associated to brain activity. Data can be obtained by task-free and task-based fMRI. Findings: •Decrease in neural activity in prefrontal regions, supramarginal gyrus and MTL in AD; in MCI subjects findings are less consistent. •Abnormalities in functional connectivity between brain networks in both MCI and AD. Fig. 5 Group statistical comparison showing regions with decreased activation in AD patients compared to age-matched NC using task-based fMRI 5 MOLECULAR IMAGING - PIB-PET technique Use of radiotracers for the in vivo detection and quantification of β-amyloid plaques • Earlier affectation • Hyppocampal atrophy is the gold estandard but also MTL, EC and other structures are affected • No automated methods available BIOMARKERS IMAGING BIOMARKERS Fig. 7 PIB-PET scans from a CN negative (left), a CN positive (middle) and from AD patient (right). PIB + show high retention in frontal, temporal and occipital cortices. 7 Deposition in frontal, temporoparietal and occipital cortices + PCC + striatum CONCLUSIONS Imaging techniques have proven to be promising biomarkers for detecting Alzheimer’s disease pathological processes, but still more research is needed to address some aspects: • General validation and standardization of methods. • Hippocampal atrophy is gold-standard approach for structural imaging but automated methods are required. • Functional abnormalities must be further investigated in MCI patients with both fMRI and FDG-PET for assess if some variables (such as cognitive reserve) could be responsible for the variability of the results. Further research is also needed to study the anomalies seen between brain networks. • Molecular imaging is a new field still developing new and better tracers for tau and activated microglia. As for amyloid tracers, more longitudinal studies should be done to evaluate whether or not amyloid deposition will invariable lead to clinical dementia. 1. © 2000 BrightFocus Foundation 2. © 2005 LECMA Vaincre Alzheimer 3. Hampel H, Bürger K, Teipel SJ, Bokde ALW,Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease. Alzheimers Dement [Internet]. 2008 Jan [cited 2015 Jan 4];4(1):38–48. 4. Cohen AD, Klunk WE. Early detection of Alzheimer’s disease using PiB and FDG PET. Neurobiol Dis [Internet]. Elsevier Inc.; 2014 Dec [cited 2015 Apr 6];72:117–22. 5-6. Dickerson BC, Sperling RA. Neuroimaging Biomarkers for Clinical Trials of Disease- Modifying Therapies in Alzheimer ’ s Disease. 2005;2(April):348–60. 7. Sperling R, Mormino E, Johnson K. The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials. Neuron [Internet]. Elsevier Inc.; 2014 Nov [cited 2014 Nov 6];84(3):608–22. REFERENCES BIOMARKERS FOR NEURODEGENERATION BIOMARKERS FOR AMYLOID MATERIAL AND METHODS Scientific literature search on Pubmed database: papers and reviews selected by relevance journal and publication date. Articles cited in other publications were also consulted. Official websites of Alzheimer’s disease organizations Key words: Alzheimer’s disease, diagnosis, biomarkers, imaging biomarkers, structural imaging, functional imaging, FDG-PET, PIB- PET and similar combinations. Fig. 2 Neurofibrillary tangle and senile (β-amyloid) plaque 2 Dementia is a growing epidemic and Alzheimer’s disease (AD) represents 60-80% of cases Fig. 1 Dementia prevalence worldwide 1 Antemortem diagnosis is a clinical diagnosis only for ‘PROBABLE/POSSIBLE AD’ NO CURE NO PATHOGENESIS NO DIAGNOSIS Definitive diagnosis is made postmorem by the demonstration of sufficient amount of AD molecular hallmarks of pathology New revised diagnostic guidelines propose the introduction of biomarkers to support AD clinical diagnosis β-AMYLOID PLAQUES – extracellular deposits of fibrillar β-amyloid proteolytic fragment (Aβ42), first generated in the frontal cortex NEUROFIBRILLARY TANGLES (NFT) – intracellular microtubule- associated tau protein misfolded caused by an aberrant hyperphosphorylation. First originate in MTL and spread in a centrifugal manner. NEURODEGENERATION – progressive loss of neurons and synapses resulting in brain atrophy. Correlates with NFT development and cognitive decline. Disease-changing treatments are likely to be more effective before this phase, when the damage caused by the neurodegeneration can be reversible ABBREVIATIONS AND ACRONYMS CN – Cognitive normal CT – Computed Tomography FDG – Fluorodeoxyglucose EC – Entorhinal cortex MCI – Mild cognitive impairment (f)MRI – (functional) Magnetic Resonance Imaging Biomarkers can give information for diagnosis, pathogenesis, prognosis, disease progression and treatment response BIOMARKERS FOR DEGENERATION • Cerebrospinal TAU • STRUCTURAL MRI • FDG-PET BIOMARKERS FOR AMYLOID DEPOSITION • Cerebrospinal Aβ1-42 • PET Aβ IMAGING Biomarkers are parameters that can be reliably measured in vivo and reflect specific features of disease-related pathophysiological processes Pathological processes that begin prior to the stage of clinical AD Indicate the presence, absence or risk of later developing a disease. Characteristics of an ideal biomarker for AD glucose uptake in bilateral temporo- parietal regions + PCC Fig. 6 FDG-PET data from a CN (top) subject and a patient with ‘probable AD’ (bottom) illustrating prominent temporoparietal hypometabolism. 6 FDG-PET allow the in vivo quantification of local cerebral metabolic rate of glucose, which is tighly associated with synaptic activity. AD vs non-AD (84% S; 93% SP) Conversion MCI AD (80% accuracy) AD patients present a specific pattern of hipometabolism that has become a diagnostic tool for supporting clinical diagnosis MCI and at risk patients show less severe hypometabolism but match pattern seen in AD. Evidences points to EC as 1st affected region. • Extremly high accuracy in binding β-amyloid deposits • Good correlation with validated techniques • More accuracy and precision than FDG-PET Technical features • PIB retention matches the amyloid pattern of cortical distribution • Overlap between regional amyloid deposition and ‘default mode network’ (DMN) Findings in AD Findings in earlier stages High PIB retention observed in 50% of MCI patients, CN subjects at risk (ApoE*E4 carriers) and some older CN Some longitudinal studies suggest that those with PIB+ scans are much more likely to convert to AD, but more research is needed ! Does some brain activity pattern lead to amyloid deposition very early in the disease? MTL – Medial temporal lobe PCC – Posterior cingulate cortex PET – Possitron Emission Tomography PIB – 11 C-labelled Pittsburgh compound B ROI – Regions of interest S and SP – Sensibility and specificity Imaging Biomarkers For Alzheimer’s Disease Carmen María Menacho Pando – Biomedical Sciences Degree, Autonomous University of Barcelona (UAB)
Transcript of Imaging Biomarkers For Alzheimer’s Disease...Imaging techniques have proven to be promising...
ALZHEIMER’S DISEASE
MEASURE OF BRAIN ATROPHY
BIOMARKERS FOR AD
MUST REFLECT NEUROPATHOLOGIC CHARACTERISTICS
ACCURATE(>80% S and SP)
REFLECT DISEASE PROGRESSION AND
TREATMENT EFFICACY
MUST BE EVALUATED BY 2 INDEPENDENT STUDIES
(reproducible)
EASY TO USE
INEXPENSIVE
NON -INVASIVE
There’s no parameter that fully met this criterion
• Meanwhile, the use of biomarkers helps to exclude otherdementia or conditions with AD-like symptoms.
• The new diagnostic guidelines classifies them as biomarkers for neurodegeneration and for β-amyloid abnormalities.
• Although these abnormalities can occur during normal aging or in other dementias, they have specific patterns of changes for AD.
• Combinations of biomarkers are being investigated toimprove diagnosis accuracy for AD.
Biomarkers recommend by the new guidelines for diagnosis:
STRUCTURAL IMAGING - CT and MRI techniques Provide detailed images of the brain structure in vivo with high resolution
FUNCTIONAL IMAGING - fMRI and FDG-PET techniques Detect alterations in brain blood flow and glucose metabolism
Fig. 3 Voxed-based assessment of gray matterdifferences between AD and MCI subjects. Brain areas indicated have decreased gray mattervolume in AD when compared with MCI. 3
CT and MRI are applied as standard workup for AD diagnosis and drug trials to:
• Rule out other conditions, such as tumours orstrokes. • Calculate the rate of brain atrophy
Brain atrophy is related to the magnitude of neuronal loss, extent of NFT and disease progression.
2 different approaches:
Whole-brain volume
ROI measures
Whole-brain volume ROI measure: hippocampal atrophy
Fig. 4 Ten-year time serie demonstrating hippocampal, EC and ventricular changes on MRI in association with clinicaldecline from CN to MCI to AD. 4
fMRI is a non-invasive technique (no radiation is used) that detectchanges in blood flow associated to brain activity.Data can be obtained by task-free and task-based fMRI.
Findings:
•Decrease in neural activity in prefrontal regions, supramarginal gyrus and MTL in AD; in MCI subjects findingsare less consistent.
•Abnormalities in functionalconnectivity between brainnetworks in both MCI and AD.
Fig. 5 Group statistical comparison showingregions with decreased activation in AD patients compared to age-matched NC usingtask-based fMRI 5
MOLECULAR IMAGING - PIB-PET technique Use of radiotracers for the in vivo detection and quantification of β-amyloid plaques
• Earlier affectation• Hyppocampal atrophy is the gold estandard but also MTL, EC and other structures are affected• No automated methods available
BIOMARKERS IMAGING BIOMARKERS
Fig. 7 PIB-PET scans from a CN negative(left), a CN positive (middle) and from AD patient (right). PIB + show high retention in frontal, temporal and occipital cortices. 7
Deposition in frontal, temporoparietal and occipital cortices + PCC + striatum
CO
NC
LUSI
ON
S Imaging techniques have proven to be promising biomarkers for detecting Alzheimer’s disease pathological processes, but still moreresearch is needed to address some aspects:
• General validation and standardization of methods.• Hippocampal atrophy is gold-standard approach for structural imaging but automated methods are required.• Functional abnormalities must be further investigated in MCI patients with both fMRI and FDG-PET for assess if some variables(such as cognitive reserve) could be responsible for the variability of the results. Further research is also needed to study theanomalies seen between brain networks.• Molecular imaging is a new field still developing new and better tracers for tau and activated microglia. As for amyloid tracers,more longitudinal studies should be done to evaluate whether or not amyloid deposition will invariable lead to clinical dementia.
1. © 2000 BrightFocus Foundation2. © 2005 LECMA Vaincre Alzheimer
3. Hampel H, Bürger K, Teipel SJ, Bokde ALW, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers ofAlzheimer’s disease. Alzheimers Dement [Internet]. 2008 Jan [cited 2015 Jan 4];4(1):38–48.
4. Cohen AD, Klunk WE. Early detection of Alzheimer’s disease using PiB and FDG PET. Neurobiol Dis [Internet]. Elsevier Inc.; 2014Dec [cited 2015 Apr 6];72:117–22.
5-6. Dickerson BC, Sperling RA. Neuroimaging Biomarkers for Clinical Trials of Disease- Modifying Therapies in Alzheimer ’ sDisease. 2005;2(April):348–60.
7. Sperling R, Mormino E, Johnson K. The Evolution of Preclinical Alzheimer’s Disease: Implications for Prevention Trials. Neuron[Internet]. Elsevier Inc.; 2014 Nov [cited 2014 Nov 6];84(3):608–22.
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BIO
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MATERIAL AND METHODS
Scientific literature search on Pubmed database: papers andreviews selected by relevance journal and publication date. Articlescited in other publications were also consulted.
Official websites of Alzheimer’s disease organizations
Key words: Alzheimer’s disease, diagnosis, biomarkers, imaging biomarkers, structural imaging, functional imaging, FDG-PET, PIB-PET and similar combinations.
Fig. 2 Neurofibrillary tangle and senile (β-amyloid) plaque2
Dementia is a growing epidemic andAlzheimer’s disease (AD) represents60-80% of cases
Fig. 1 Dementia prevalence worldwide1
Antemortem diagnosis is a clinical diagnosis only for‘PROBABLE/POSSIBLE AD’
NO CURENO PATHOGENESIS NO DIAGNOSIS
Definitive diagnosis is madepostmorem by thedemonstration of sufficientamount of AD molecular hallmarks of pathology
New revised diagnostic guidelinespropose the introduction of biomarkers to support AD clinicaldiagnosis
β-AMYLOID PLAQUES – extracellular deposits of fibrillar β-amyloid proteolytic fragment (Aβ42), first generated in the frontal cortex
NEUROFIBRILLARY TANGLES (NFT) – intracellular microtubule-associated tau protein misfolded caused by an aberranthyperphosphorylation. First originate in MTL and spread in a centrifugal manner.
NEURODEGENERATION – progressive loss of neurons and synapsesresulting in brain atrophy. Correlates with NFT development and cognitive decline.
Disease-changing treatments are likely to be moreeffective before this phase, when the damage caused bythe neurodegeneration can be reversible
ABBREVIATIONS AND ACRONYMS
CN – Cognitive normal
CT – Computed Tomography
FDG – Fluorodeoxyglucose
EC – Entorhinal cortex
MCI – Mild cognitiveimpairment
(f)MRI – (functional) MagneticResonance Imaging
Biomarkers can give information for diagnosis, pathogenesis, prognosis, disease progression
and treatment response
BIOMARKERS FOR DEGENERATION
• Cerebrospinal TAU
• STRUCTURAL MRI
• FDG-PET
BIOMARKERS FOR AMYLOID DEPOSITION
• Cerebrospinal Aβ1-42
• PET Aβ IMAGING
Biomarkers are parameters that can be reliably measured in vivo and reflect specific features of disease-related pathophysiological processes
Pathological processes that begin prior to the stage of clinical AD
Indicate the presence, absence or risk of later developing a disease.
Characteristics of an ideal biomarker for AD
glucose uptake in bilateral temporo-parietal regions + PCC
Fig. 6 FDG-PET data from a CN (top) subject and a patient with ‘probable AD’ (bottom) illustrating prominenttemporoparietal hypometabolism. 6
FDG-PET allow the in vivo quantification of local cerebral metabolicrate of glucose, which is tighly associated with synaptic activity.
AD vs non-AD (84% S; 93% SP)Conversion MCI AD (80% accuracy)
AD patients present a specificpattern of hipometabolismthat has become a diagnostictool for supporting clinicaldiagnosis
MCI and at risk patients show less severehypometabolism but match pattern seen in AD.Evidences points to EC as 1st affected region.
• Extremly high accuracy in binding β-amyloid deposits
• Good correlation with validated techniques
• More accuracy and precision than FDG-PET
Technicalfeatures
• PIB retention matches the amyloid pattern of cortical distribution
• Overlap between regional amyloid depositionand ‘default mode network’ (DMN)
Findings in AD
Findings in earlier stages
High PIB retention observed in 50% of MCI patients, CN subjects at risk(ApoE*E4 carriers) and some older CN
Some longitudinal studiessuggest that those with PIB+ scans are much more likely toconvert to AD, but more research is needed!
Does some brain activitypattern lead to amyloid deposition very early in the disease?
MTL – Medial temporal lobePCC – Posterior cingulate cortexPET – Possitron EmissionTomographyPIB – 11C-labelled Pittsburgh compound BROI – Regions of interestS and SP – Sensibility and specificity
Imaging Biomarkers For Alzheimer’s DiseaseCarmen María Menacho Pando – Biomedical Sciences Degree, Autonomous University of Barcelona (UAB)
