The search for imaging biomarkers in psychiatric disorders Flashcards
what is the definition of biomarkers?
objective biological measures that can predict clinical outcomes
What is the precision medicine initiative?
Treatment and prevention for each person is carried out by taking into account:
- the individual’s genes
- environment and lifestyle
- relies heavily on biomarkers.
What authoritative state did the precision medicine initiative gain and when?
it gained official support from the White house in January 2015
Which disease group has the precision medicine technique been influential in?
Cancer treatment
- drugs that target specific molecular-signalling pathways related to genetic mutations
What does the precision medicine initiative allow?
Treatments are therefore tailored to a patient’s genomic profile
What disease treatment is the precision medicine initiative application the most challenging and why?
In psychiatry due to the unknown complex interactive links from genes to behaviour
What are psychiatric disorders responsible for in the population?
Personal, social and financial burden
What was the estimated cost for psychiatric disorders in the USA in 2006?
57 billion dollars
What is the total indirect annual cost of mental illnesses in the USA?
193 billion dollars
How can biomarkers help reduce costs of mental illness (treatment)?
By enabling better and earlier detection and improved treatments.
What are the two types of biomarkers?
Diagnostic biomarkers- index a biological process associated with health or disease
Predicitive biomarkers- reflect a process associated with the therapeutic response and are used in clinical stratification
What does neuroimaging allow?
Identification of process associated with the therapeutic response and indexing a biological process associated with health or disease
What can PET measure?
The phenotypic variations in molecular and cellular disease targets
What can structural or fMRI measure?
Phenotypic variations in specific brain circuits that are a unique representation of the interaction between genes and environment and are associated with specific alterations in behaviour
What factor determines whether specific neuroimaging techniques can become imaging biomarkers for psychiatric disorders?
If these measures can demonstrate sufficient precision and reliability and can predict a clinical diagnosis or outcome
What is this review about?
Discusses the main challenges of developing imaging biomarkers for psychiatric disorders and outline crucial benchmarks for the translation of neuroimaging findings into clinically useful biomarkers.
What is the main challenge of developing imaging biomarkers for psychiatric disorders?
The definition of psychiatric disorders according to the DSM and ICD is based on combinations of symptoms alone.
What do ICD and DSM stand for?
International Classification of Diseases
Diagnostic Statistical Manual
What other non imaging modalities collaboratively with neuroimaging techniques in the diagnosis of psychiatric disorders?
Genetic
Peripheral Blood based tests
Cognitive based tests
What do NIH and NIHM stand for?
National Institute Health and National Institute of Mental Health
What was the new classification system developed by the NIHM?
It was based on the RDoC the research domain criteria
What does the RDoC approach entail?
New way of classifying mental disorders based on dimensions of observable behaviour and neurological measures
Which elements does the RDoC approach aim to identify?
Genes, molecules, cells, circuits, physiological measures and behaviours associated with specific cognitive constructs across different systems
What does SPECT stand for?
Single photon emission computer tomography
What does MRS stand for?
Magnetic resonance spectroscopy
What does PET stand for?
Positron Emission Tomography
Which neuroimaging techniques fit well with the RDoC approach? Why?
PET, SPECT, MRS
They can identify biomarkers related to the cells and circuits
What does DTI stand for?
Diffusion tensor imaging
What does DTI do?
Can produce images of anatomical pathways and circuits
What does fMRI do?
During rest and task performance affords characterisation of functional circuits
Will the RDoC replace current categorical methods?
Unlikely but it can aid in the search for biomarkers
What type of biomarkers can be identified with the RDoC approach?
Neuroimaging markers of cognitive functions such as reward learning or working memory impaired aross psychiatric conditions.
What characteristic was identified in schizophrenic patients during a working memory task?
Disrupted activation of a distinct neural pattern in the dorsolateral and medial prefrontal cortex that correlated with reductions in working memory capacity
What is the second challenge to biomarker identification in psychiatric disorders?
The pathological features of psychiatric diseases may be subtle and elusive to neuroimaging.
What is a way to deepen the insight biomarker analysis using neuroimaging techniques?
By Using task-based assessments or other challenge paradigms that reveal ‘at work’ pathological phenotypes
Name one way to improve biomarker identification with regards to imaging tools?
Develop novel tracers for uncharted molecular targets, example: neuroinflammation imaging tracers (identified changes in those tracers seen in MDD in schizophrenia)
Can the results from imaging studies be 100% reliable?
No because replication is less valued than novelty.
Which phase is the neuroimaging field in, and what does that phase entail?
In the mechanistic discovery phase, more effort is focused on uncovering alterations in imaging measures than pursuit of promising biomarkers.
What is necessary in order to produce a larger pool of biomarkers?
The need for replication using identical paradigms in well-powered studies be accepted as the norm.
What strategy could spur the search and development of imaging biomarkers in DSM diagnosed psychiatric disorders?
Precision-medicine like study involving 1000 volunteers with a specific DSM diagnosis with several imaging modalities.
What does validation of biomarkers entail?
The comparison of a prediction with an actual outcome
What type of predictions and outcomes does biomarker validation consider?
Diagnostic
Histologic
therapeutic
What does validation require?
Correlative analysis of in vivo imaging measures against in vitro i.e. postmortem histological examinations of brain tissue (unavailable for psychiatric disorders).
What is needed to establish a clinical diagnosis or observed clinical outcome that can be compared to the biomarker prediction?
Longitudinal follow-up
What is a characteristic a biomarker must possess in order to be used for clinical practise?
An acceptable level of sensitivity, specificity and predictive value to be easily acceptable, practically feasible, easily quantifiable and cost effective.
What are the challenges with the search for neuroimaging biomarkers in psychiatric disorders?
- Lacking gold standards for psychiatric diagnosis
- Identification of pathological features
- Validation of biomarkers
What qualities must the methods adopted to advance the discovery and validation of biomarker research possess?
simple, reliable and easy to implement.
What type of data must be collected to assign a likelihood of a diagnosis or outcome?
Database of healthy individuals collected from each scanner to provide normative values and derive thresholds that separate health from illness
What strategy can be implemented to assure standardized procedures?
- A required protocol that includes performance of quality-assurance tests before data acquisition
- A specific analysis software for data processing
What does ADNI stand for?
Alzheimer’s Disease Neuroimaging Initiative
What does a priori mean?
Something can be known without experience or sense data
What type of study design does biomarker development require?
A priori large scale, multi site studies with a coordinated analysis plan that includes independent validation
Define sensitivity
The proportion of individuals who test positive among those who have the outcome of interest
Define specificity
The proportion of individuals who test negative among those who do not have the outcome of interest
What is PPV?
Positive product value is the proportion of individuals who have the outcome of interest among those who tested positive
What is NPV?
Negative predictive value is the proportion of individuals who do not have the outcome of interest among those who tested negative
What is internal validity?
The ability to claim that the measure of interest in a study measures the intended feature in an unbiased way and without the influence of confound third variables.
What is external validity?
The ability to extrapolate the results of a study to the general population of interest (Real life clinical situations) demonstrating this requires the replication of study results in naturalistic samples independent from the original study.
Define reliability
Refers to the consistency of a measure
What are the types of reliability
1.Test-retest reliability
The consistency of a measure with itself when administered in several occasions
2. Inter-rater reliability
In the appraisals of this measure across several raters
What does molecular PET imaging consist of?
The administration of radio tracers to image specific targets in the brain and collection of radioactive signals produced by the radio-tracers with a PET scanner
What are the mechanism of radiotracer function?
They bind to target molecules or act as substrates for the metabolic pathways of endogenous substances
How are radiotracers administered?
Injected into the subject lying in the PET scanner
Define and give examples of types of target molecules
Those are molecules of interest, potential biomarkers:
- neuroreceptors
- re-uptake transporters
- intracellular enzymes
How long do PET scans last?
10-20 minutes of single or static snapshots of the tracer distribution and then hours of kinetic profile recording from sequential dynamic images
What type of model of data imaging requires blood sample and why?
- Comprehensive model
Uses blood samples to estimate the radioactivity that relates only to the parent tracer crossing the BBB
What is the BBB
Blood Brain Barrier
What are the advantages of bloodless imaging technique methods?
- Many error sources are bypassed
- Noise related to plasma and metabolite analysis is excluded
What is the prerequisite to bloodless radiotracer methods?
The presence of a reference brain region devoid of receptors or other targets of interest which serves a ‘surrogate measure’ of radiotracer availability
What does the MRI refer to?
A family of imaging techniques that use the magnetic fields and radio waves to excite protons in water containing brain tissue and read out signals that these atoms emit back
What are MRIs dependent on?
The magnetic property of the tissue
What do the changes in the signal signify?
These changes are a result of the tissue proton density,
What causes the changes in magnetic susceptibility and what do these changes allow?
Changes in magnetic susceptibility (that result from changes in blood oxygenation) and these changes allow the interpretation of brain morphology, integrity and neural activity.
Fill in the blanks
MRI techniques are ………………… and do not involve …………………
- non invasive
2. radioactivity
What type of scan does the structural MRI provide?
An anatomical image that delineates different tissues and brain structures
What type of scan does the functional MRI provide?
Measures fluctuations in blood flow or oxygen levels at rest or during a challenge be it cognitive (like a memory test) or otherwise
Give examples of some validation steps to ensure MRI techniques measure the intended anatomical and functional features
- Prediction of neuronal counts from structural techniques
- Capturing of individual performance
- Preferences from a task-based functional technique
Fill in the blank
Reliability is crucial for ……………….
standardisation
What is the NEWMEDS Consortium?
Is a novel initiative of collaboration across academia and the pharmaceutical industry to accelerate the development pf new therapeutics for severe mental illness.
What are the advantages of fully automated standardised methods?
Since they use a unified software platform and are easier to implement across different sites.
What are the advantages of manual methods?
They might be better for certain purposes
Fill in the blanks
Although standardised pipelines for ………………….. of MRI data exist and continue to become increasingly ……………….. as improved sequences are developed (for example, the recent advances linked to the ……………. ………….. …………..), no single pipeline is likely to become a one-size-fits-all approach that covers all needs for ………………… ………………….
- preprocessing
- sophisticated
- Human Connectome Project
- biomarker development
What should any given biomarker include?
A detailed protocol that specifies everything from sequencing parameters and data collection protocol to preprocessing protocol and analysis to derive robust outcome measures.
What are are post processing methods and when are they especially crucial?
They are used to minimise motion artefacts and are crucial for resting phase fMRIs (whereby design-predicted time courses associated with task manipulators are not available for explicitly modelling signal dynamics).
What is the cost of an MRI scan in the States?
From $600 in an academic centre and up to $1000 in commercial centres
What is the cost of an PET scan in the States?
From $3000 to $5000 per scan (including radiotracer production and scanning costs)
Provide evidence that indicates that price for neuroimaging might decrease in the future
- MRI technologies are becoming accessible at most medical centres
- Automated analysis methods may be available through internet based long site systems
What should be the main focus on the field?
The development of robust biomarkers and cost effectiveness
How is cost effectiveness determined?
By the clinical usefulness of the biomarker in avoiding additional expenses related to misdiagnosis, unnecessary procedures, hospitalisations and other disease related burdens.
When can a neural finding related to a mental pathology be considered a biomarker?
Only if it has sufficient clinical predictive value and can become an accurate proxy for some clinically relevant outcome such as: diagnosis, prognosis or treatment response.
Why do only few, of the many reported clinical abnormalities, in mental disorders considered true biomarkers?
The majority of clinical neuroimaging reports of neural abnormalities do not assess predictive value.
What neural abnormality was found in patients with MDD?
Average thinning of the cortical mantle of the prefrontal cortex
What neural abnormalities were found in patients with schizophrenia?
- A pathological increase of dopamine storage and release capacity in presynaptic dopamine neurons.
- Increase in blood volume in the CA1 region of the hippocampus
- Deficient increases in haemodynamic responses during reward anticipation in the ventral striatum
What neural abnormalities were found in patients with OCD?
- Increased volume of the striatum
What neural abnormalities were found in patients with anxiety disorders?
- Increased haemodynamic responsiveness of the amygdala to negative emotional stimuli
What neural abnormalities were found in patients with PTSD?
- A specific decrease of activity in various prefrontal regions associated with the regulation of emotion
What is the first step into the development of clinically useful biomarkers in psychiatry?
Define a clinically relevant questions that could potentially lead to improvements in patients’ long-term functioning and quality of life.
What will relevant questions be related to?
- Clinical outcome
- Differential diagnosis
- Treatment selection
Describe the landmark MRI study in patients at high clinical risk of psychosis
A machine-learning algorithm using morphometric gray matter features from a structural MRI scan was able to predict conversion to psychotic disorders with positive
and negative predictive values over 80%.
What was the ADHD-200 competition?
Aimed to develop imaging biomarkers for diagnostic classification of attention-deficit hyperactivity disorder (ADHD) using a large functional and structural MRI data set, the best classification approach used solely personal
characteristics (such as age, sex, handedness and IQ) and none of the available imaging data
What are the steps into developing neuroimaging biomarkers in psychiatry?
- Identifying a clinically relevant question
- Ensuring the biomarker measures the intended biological processes
- Demonstrating the biomarker’s predictive value
- Demonstration of clinical utility
What is the second step into the development of clinically useful biomarkers in psychiatry?
Ensuring the biomarker is operating on brain -based phenotypes directly associated with the physiological mechanisms of interest rather than epiphenomenal consequences of the illness and its treatment.
What is the third step into the development of clinically useful biomarkers in psychiatry?
Show that it has a sufficiently high predictive value to be clinically useful beyond simple demonstration of statistically relevant results
What does the third step involve?
External cross-validation in an independent clinical sample of adequate size.
What is the fourth step into the development of clinically useful biomarkers in psychiatry?
Longitudinal designs in which biomarkers are put to a definitive test to establish the clinical utility.
What is an advantage of longitudinal studies?
they allow for the establishment of a final diagnosis for patients with unclear presentation to confirm biomarker-based diagnosis
What does RCT stand for?
Randomised control trial
What does NNT stand for?
Number needed to treat
What does NNA stand for?
Number needed to assess, the number of individuals who would have to undergo a specific procedure to benefit said individual.
Fill in the blanks
demonstrating that biomarker use is associated with a reduction in ………….. and …………….. in
quality of life for the general population.
- morbidity
2. improvement
What does FDA stand for?
Food and Drug Administration
What does EMA stand for?
European Medical Agency
What does NAPLS stand for?
North American Prodrome Longitudinal Studies
