Adult AD/HD (Attention Deficit/Hyperactivity disorder) in Norway From clinical characterization to molecular mechanisms

Project staff

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Jan Haavik: prof. of biochemistry / mol. biology; adult psychiatrist Christopher Gillberg: professor of child & adolescent psychiatry Per M. Knappskog: professor, molecular genetics Stefan Johansson: research scientist in genetics Anne Halmøy: MD: adult psychiatrist, PhD student Kenneth Hugdahl: professor of neuropsychology Per Bergsholm: ass. professor of adult psychiatry, Førde Ole Bernt Fasmer: ass. professor of adult psychiatry, Bergen Astri Lundervold: ass. professor of psychology Helene Halleland: psychologist, PhD student Margaretha Dramsdahl: MD, adult psychiatrist Elisabeth Landaas: medical student Kaya Jacobsen: medical student International ADHD genetics network/ Stephen V. Faraone, professor, SUNY Upstate Medical University

Financial support: Research Council of Norway Helse-Vest / University of Bergen/ Lundbeckprisen/Dobbeltkompetanseprosjektet

Plan for this presentation

 Background/aims  The research questions in my project  How can this contribute to our understanding of ADHD in adults?

The AD/HD diagnosis  Core symptoms: 

Attention deficit



Hyperactivity



Impulsivity

 A common, often disabling condition, but still poorly understood   Reserved for children?

No specific test – imprecise diagnostic criteria

Why study AD/HD in Norway?

    Most studies from the USA The registry of ”expert teams”; unique source of ”real” patients 5000 patients from 1997-2005!

The Norwegian population; ethnically homogeneous - suitable for genetic studies

Why study AD/HD in adults?

 World wide prevalence in children 3-7%    ~50 % will persist into adulthood Little knowledge from adults Treatment with stimulants equally efficient as in children  Diagnosing ADHD in adults; an everyday-clinical challenge  Heterogeneity in clinical aspects and therapeutical response 

Subgroups with different etiologies and treatment needed?

 Persistence into adulthood; 

The most severe cases? Subgroup with a stronger genetic component?

Phase I (2004-2006) Recruitment of 500 already diagnosed patients from expert teams + 500 controls Screening questions (for doctors and for patients + controls) Rating scales: Adult ADHD Self Report Scale (ASRS-18) Wender Utah Rating Scale (WURS-25 ) TEMPS-A, 21 questions MDQ (16 questions) Blood/spit samples for DNA extraction and protein analysis

Phase II (2005-2007) Selection of patients for further diagnosis & testing (n=100) Clinical psychiatric interviews: MINI+, K-SADS (patients & controls) Questionnaires: TCI, migraine (HUNT) •Neuropsychological tests: •sMRI •fMRI

Summary of tests:

D-KEFS (45 min) –Verbal Fluency Test –Design Fluency Test –Colour-word Interference Test –Sorting Test –Tower Test PASAT (10 min) Attentional Network Test (30 min) Word recognition and matrices from WASI (20 min) California Verbal Learning Test – II (20 min) Benton’s Visual Memory Test (5 min)

Subclassification of ”endophenotypes” for further study

Phase III (2006-2012) Defined ”endophenotypes” •Association studies against known candidate genes •Linkage studies in affected families •Proteomic studies Input from collaborating groups New candidate proteins/mutations/mechanisms Further validation: Functional studies on isolated proteins, in cell culture and animals Diagnostic & therapeutic implications

What is ”ADHD”?

CD/ODD ADD ?

ADHD HD HD Bipolar I Bipolar II DAMP?

Endophenotyping



Phenotype;

 (often imperfect) indicator of the genotype 

Endophenotype;

 A measurable component unseen by the unaided eye along the pathway between disease and distal genotype ( Gottesman et al, Am J Psych 2003) 

A simpler clue to genetic underpinnings than the disease syndrome itself



Can clarify classification and diagnosis and foster the development of animal models

Criteria for endophenotypes Criterion Complications / Comments Required Criteria Reliable Quantitative Trait Covariance with ADHD Familial and co-familial with ADHD Present in unaffected relat.

Heritable and co-herit. w/ ADHD Latent traits / composites may help.

Modest effects, heterogeneity.

Power issues due to small effect sizes.

Difficult if not in ongoing twin studies.

Criteria that are useful but not required (in all cases) Developmental stability.

Grounded in neuroscience.

Required for parent-offspring designs.

Could we miss useful endophenotypes?

Simpler etiology than ADHD.

More heritable than ADHD.

Difficult to test, but should be considered.

Ideal, but not likely.

Not Required Necessary and sufficient cause.

Very unlikely.

Specific to ADHD.

But impact of comorbidity is a key issue.

Willcutt, 2006

How do we get to these endophenotypes

?

 ”Decompose” AD/HD in subgroups by different parameters:      Symptom profile Comorbidity Environmental (pre-and perinatal) risk-factors fMRI

Neuropsychology

 Then compare subgroups with the genetic characteristics

Can neuropsychological measures be valuable for endophenotyping?

 Neuropsychological endophenotypes are valuable in our search for genetic correlates of ADHD  Few studies on cognitive endophenotyping in ADHD  Most have focused on aspects of executive functioning

Which neuropsychological measures can be used for endophenotyping?

 Some candidate endophenotypes:  Working memory           Spatial Verbal Inhibition Processing speed Organization Planning Set shifting Respons variability Reaction time

Attention

Attention as an endophenotype for ADHD

 Attention Network Test  Attention as an organ system  Look at subcomponents of attention

How can this knowledge contribute to our understanding of ADHD?

 Decide level of functioning on different areas  Divide into more appropriate subgroups  More precise diagnostic criteria  More specific treatment

Bridging the gap between basic science and clinical medicine

Clinical practice Clinical research

Bergen University/ hospital campus

Basic research