Co-sponsored by

September 26 – 28, 2013 | Westin Tampa Harbour Island

Lunch Symposium: Future Leader Presentation on Schizophrenia

Nithin Krishna, MD University of Maryland School of Medicine Baltimore, MD

Variation in Succinic Semialdehyde Dehydrogenase (ALDH5A1) Gene Is Associated With Eye Tracking and Early Visual-Processing Deficits in Schizophrenia

Nithin Krishna, MD University of Maryland School of Medicine Department of Psychiatry Baltimore, MD

Nithin Krishna, MD

● Dr. Krishna has no disclosures to report.

Disclosures

Learning Objective

Describe the genetics of smooth-pursuit eye-movement deficits in individuals diagnosed with schizophrenia

1

Overview

● Schizophrenia historical perspective ● Endophenotypes (or viability markers) ● Genetic finding and treatment implications

●  In1893, Emil Kraepelin, in his seminal work, described dementia praecox (DP) based on longitudinal observations of a large number of clinical cases

●  Kraepelin considered that DP was caused by heredity and as a “tangible affection of the brain, probably damage or destruction of cortical cells . . . which was the result of chemical disturbances”

●  Three categories of psychosis: organic, affective, and poor outcome

Kraepelin

Kraepelin E. Psychiatrie: ein lehrbuch fur studierende und aerzte. Leipzig, Germany: JA Barth; 1899. Lehmann HE, et al. Can J Psychiatry. 1997;42(4):152–162. PMID: 9067064 Picture: Wikimedia Commons. http://commons.wikimedia.org/wiki/File:Emil_Kraepelin_1926.jpg

Kraepelin

●  Kraepelin’s work integrated experimental psychology in clinical trials (cocaine, opium, caffeine, tea, and fatigue). He set up experimental protocols for the measurement of “mental reactions and mental effects.”

●  He spent many of his latter years at the German Institute for Psychiatric Research, which he founded, where he worked on neuropathology, anatomy, histology of the cerebral cortex, brain localization, genetics, serology, metabolism, and experimental psychology.

●  Both Kraepelin and Morel suggested psychosis with poor outcome (dementia praecox) as being distinct from organic dementia and affective psychosis.

Engstrom, E, et al. Krepelin, social section. In Berrios GE, Porter R. (eds), A History of Clinical Psychiatry: The Origin and History of Psychiatric Disorders. 1999.

●  In 1908, Eugen Bleuler termed the disorder schizophrenia, which has its origins in the Greek, translating roughly to shattered mind.

● Bleuler defined schizophrenia (affective flattening, autism, ambivalence, and loose associations).

Bleuer

1.  Bleuler E. Physisch und psychisch in der pathologie. Zeitschrift für die Gesamte Neurologie und Psychiatrie 1915;30:426–475.

2.  Lehmann HE, Ban TA. Can J Psychiatry. 1997;42:152–162. PMID: 9067064 3.  Picture: Wikimedia Commons. http://commons.wikimedia.org/wiki/File:Eugen_bleuler.jpg

History: Psychiatry and Schizophrenia

●  During the 1940s – 1970s, American psychiatry turned away from Kraepelin’s biological approach to one that was environmental and psychological.

●  The National Institute of Mental Health (NIMH) was created in 1949 with its initial goal to support research that reached the social bases of mental disorders. Biological research was not a priority.

●  Harvard psychiatrist Gerald Klerman named 1978 the “Year of Kraepelinian Revival” because of Feighner and colleagues’ landmark 1972 publication: Diagnostic Criteria for Use in Psychiatric Research

Decker HS. Hist Psychiatry. 2007;18(71 Pt 3): 337-360. PMID: 18175636. Feighner JP, et al. Arch Gen Psychiatry. 1972;26(1):57-63. PMID: 5009428.

History: Psychiatry and Schizophrenia

●  Robert Spitzer was inspired by Feighner and colleagues’ work in the development of research diagnostic criteria; in that context, many consider both DSM-III and DSM-III-R to be, to some extent, neo-Kraepelinian documents.

●  Around the same time, Samuel B. Guze, a coauthor of Feighner’s report, conducted the first genetic (twin) study in psychiatry.

●  The trajectory for the 20th century’s leap in research activity in schizophrenia was set in the 1970s.

Decker HS. Hist Psychiatry. 2007;18(71 Pt 3): 337–360. PMID: 18175636. Feighner JP, et al. Arch Gen Psychiatry. 1972;26(1):57-63. PMID: 5009428.

Clinical Features of Schizophrenia

● ~1% lifetime prevalence rate ● Reality distortion with variable course ● Reduced drive (social, motivation,

pleasure) ● Disorganization ● Cognitive impairment ● Familial/genetic

McGrath JJ, et al. Schizophr Bull. 2013;39(5):955-959. PMID: 23907349.

Genetic Studies: Risk of Schizophrenia vs. Degree of Kinship Search for Disease Genes: The Process  

Level of Kinship Shared Genes Risk of SCZ

None Minimal 0.8%

2nd degree 25% 3%-5%

1st degree 50% 9%-12%

Dizygotic twins 50% 12%-15%

Monozygotic twins 100% 40%-50%

Both parents SCZ 40%-45%

SCZ = schizophrenia. Baron, M, et al, Am J Psychiatry. 1985;142(4):447-455. PMID: 3976917 Kendler KS, et al. Psychol Med. 1997;27(2):411–419. PMID: 9089833

Picture modified from Darling D. Sickle cell disease. Encyclopedia of Science Website. http://www.daviddarling.info/encyclopedia/S/sickle_cell_disease.html 2008.

Disease Families

Picture modified from www.yalemedicalgroup.org , http://health.howstuffworks.com & U.S. Department of Energy Human Genome Program

Source: Maryland Psychiatric Research Center Molecular Genetic lab

Exon 6 Exon 8 Exon 7

Linkage Analysis Fine Mapping & Association Cloning Gene Characterization Rx Targets

Causes of Schizophrenia: Summary of Findings From Linkage Studies ● Several potential candidate regions on

chromosome 1q, 5q, 6p, 8p, 10p, 13q, 15q, and 22 are identified ● Problems remain: Failure to replicate in

some samples and even when “replication” occurs, LOD scores are low in 1 – 2 range

Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 18502737.

Causes of Schizophrenia: Likely Reasons for Failures

●  Undefined boundary of the illness (e.g., schizotypal symptoms)

●  Disease is multifactorial, with several contributing genetic and environmental factors !  Prenatal stress, infection, and other environmental insults !  Nonspecific genetic factors affecting brain development

●  Each etiologic factor has only a small effect, and various combinations of genes and/or environmental insults are required for the disease expression

Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 18502737.

Causes of Schizophrenia: Failures of Linkage Studies and Possible Solution ● Reduction of phenotypic heterogeneity ● Better define the boundary

! Subtyping schizophrenia: e.g., deficit phenotype, psychosis phenotype,

! Neurophysiologic and cognitive markers !  Identify biological subtypes ! Nearer to the physiologic effects of genes ! Animal models are available ! Different physiologic/cognitive markers may be

indexing the small effects of different individual genes

Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 18502737.

Working Model

Source: Maryland Psychiatric Research Center Molecular Genetic lab resource, slide modified from Dr.Thakers Grand round talk.

Genotype1

Genotype2

Genotype3

Environmental Insult

Genetic Liability

Schizophrenia

Subtle symptoms but no schizophrenia

or

or

What Makes a Good Endophenotype?

● Stable over time and unaffected by symptoms or related factors

● Easy to measure ● Measures a specific physiologic deficit, or an “elemental” neuronal process

● Unaffected by demographic or other environmental variables

●  Is heritable ● Has a known neurobiology

Gottesman, II, et al.. Br J Psychiatry. 1973;122(566):15–30. PMID: 4683020 Gottesman, II, et al.. Am J Psychiatry: 2003;160(4):636–645. PMID: 12668349

Heritability Estimates

SCZ = schizophrenia. Source: Maryland Psychiatric Research Center Molecular Genetic lab resource, slide modified from Dr.Thakers Grand round talk.

Endophenotype

SCZ

Heritability Estimates

Genes Clinical Relevance

800

600

400

200

0

322.9322.8322.7322.6322.5322.4sec

PPI  

PPI deficits reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation1

Search for Disease Genes: Endophenotype Approaches

PPI = prepulse inhibition. Swerdlow NR, et al. Arch Gen Psychiatry. 1994;51(2):139-154. PMID: 8297213 Images/graphs source: Maryland Psychiatric Research Center, PPI lab Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 18502737

Rx to correct PPI deficits

Eye tracking abnormality

Eye tracking measures maps onto working memory and mnemonic function1  

Novel Rx

Eye-Tracking Measures as an Endophenotype or a Liability Marker for Schizophrenia

MPRC, Eyetracking lab resource Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 1850273

The inhibition of the P50/300 auditory event-evoked potential, is related to measures of impaired early sensory processing as well as attentional deficits in

Rx  

P50/P300

Brain Wave or EEG Measures as Liability Marker

MPRC = Eyetracking lab resource; EEG = electroencephalogram. Goldberg TE, et al. Am J Psychiatry. 1991;148(1):78-84. PMID: 1984711 Qlincy A, et al. Biol Psychiatry. 2000;47(11):969-977. Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 1850273

SPEM: Refining the Phenotype

SPEM = smooth pursuit eye movement. Thaker, GK, et al. Arch Gen Psychiatry. 1998;55(9):830-836. PMID: 9736010. Hong LE, et al. Arch Gen Psychiatry. 2006;63(3):259-264. PMID: 16520430.

Targ

et a

nd e

ye

posi

tions

, deg

ree

-10

-5

0

5

10Maintenance

pursuitPredictive

pursuit

MaskPursuit initiation

500 ms

●  Pursuit measure: eye velocity/target velocity → Maintenance pursuit: heritability 30% → Predictive pursuit gain: heritability 90%

Smooth Pursuit Eye Movement Abnormality

MPRC = Eyetracking lab resource Thaker GK. Schizophr Bull. 2008;34(4):760-773. PMID: 1850273.

●  Abnormal in patients with schizophrenia and their relatives ●  Heritability ~ 0.90 ●  Linked to 6p23-21 locus ●  Same region implicated in dyslexia  

Eye Tracking - Gene Screening Study

● Genome-wide association study ! 50 cases and 50 healthy control subjects ! Focus on 6p region (2 studies showed linkage

to 6p23-21 locus) ! Genome wide

Maryland Psychiatric Research Center Molecular Genetic lab resource, slide modified from Dr.Thakers Grand round talk

Eye Tracking

● In 6p region: TTRAP (dyslexia gene) ! ALDH5A1 (codes for an enzyme that degrades

GABA)

Predictive Pursuit

TTRAP = tyrosyl-DNA phosphodiesterase 2; ALDH5A1 = aldehyde dehydrogenase 5 family, member A1; GABA = gamma-aminobutyric acid.

Maryland Psychiatric Research Center Molecular Genetic lab resource, slide modified from Dr.Thakers Grand round talk

Robust Association With Smooth Pursuit Initiation

●  Study 1 sample (N = 351) ●  Robust effect of rs

3765310 (corrected p < .0005 explaining ~12% of the variance)

●  This is a single point mutation (C > T) converts proline at amino acid 182 to leucine

●  The mutation reduces SSADH enzyme activity by 54%

SSADH = aldehyde dehydrogenase 5 family, member A1. Maryland Psychiatric Research Center Molecular Genetic lab unpublished data.

40

45

50

55

60

65

70

75

80

85

TT CT CC

Deg

/sec

/sec

Study 2 Sample (ALDH5A1 rs3765310)

Control (n=140)

Psychosis (n=243)

p < .007

GABA plays an important role in motion perception by mediating surround-center interaction

GABA GABA receptor sensitivity

ALDH5A1 Gene: Codes SSADH

ALDH5A1 = aldehyde dehydrogenase 5 family, member A1 GABA = gamma-aminobutyric acid. SSADH = Succinic semialdehyde dehydrogenase Blasi P,et al. Mol Genet Metab. 2002;76(4):348-362. PMID: 12208142.  

Study 3. Early Visual Processing in a Small Sample

Maryland Psychiatric Research Center Molecular Genetic lab unpublished data.

Abnormality in early visual processing (specifically longer P1 latency and smaller P1 amplitude following visual flash)

N = 35 Significant effect of the genotype (p < .05)

Summary of Our Study

● Functional variation in ALDH5A1 gene, that reduces SSADH enzyme, is associated with early visual-processing impairments in schizophrenia ● Abnormality in GABA neurotransmission

affecting center-surround inhibition is a plausible mechanism

ALDH5A1 = aldehyde dehydrogenase 5 family, member A1; SSADH = succinic semialdehyde dehydrogenase; GABA = gamma-aminobutyric acid.

Eye Tracking Abnormality

● May index abnormality in adjusting for our own actions, leading to perceptual distortions. ● Reading ability ● Association of motion-processing deficit

with negative symptoms

Clinical Correlate

Maryland Psychiatric Research Center Molecular Genetic lab unpublished data

Endophenotype

SCZ

Heritability Estimates

Genes Clinical Correlates

ALDH5A1

Perceptual Distortions

Reading Disability

Reading Dynamic Facial Expression

Clinical Correlates

SCZ = schizophrenia. Maryland Psychiatric Research Center Molecular Genetic lab unpublished data.

Acknowledgment

● Mentors ! Gunvanth Thaker, MD ! Elliot Hong, MD ! Ikwunga Wonodi, MD ! Ann Summerfelt, MA

● Multiple sites: Chicago, Dallas, Detroit, and Hartford

● Thanks to the families of our patients ● Supported by NIMH, MIRECC (PI: Thaker GK,

Hong LE)

NIMH = National Institute of Mental Health; MIRECC = Mental Illness Research Education and Clinical Centers

Questions & Answers

Co-sponsored by