Transcript Slides - Yale School of Medicine

National Institute on
Alcohol Abuse and Alcoholism
1-04
NIAAA Perspective on the Role of
Neuroimaging in Alcohol Research
Ting-Kai Li, M.D.
Director
National Institute on Alcohol Abuse
and Alcoholism
National Institutes of Health
Department of Health and Human Services
International Conference on Applications of Neuroimaging to
Alcoholism
Yale Center for the Translational
Neuroscience of Alcoholism
January 17, 2004
In the United States:
 14 million Americans suffer from alcohol
abuse or dependence – 100,000 die annually
 One in four children under age 18 is exposed
to family alcohol problems
 Between 20%-40% of hospital admissions are
alcohol-related
 Alcohol problems cost U.S. society an
estimated $185 billion annually
Disease Burden by Illness - DALY United States,
Canada and Western Europe, 2000
15 - 44 year olds
Unipolar
depressive disorders
Alcohol use disorders
Road traffic accidents
Drug use disorders
Self inflicted injuries
Bipolar disorder
Migraine
Schizophrenia
Hearing Loss, adult
onset
HIV/AIDS
0
2
Source: WHO – Burden of Disease Statistics, 2001
4
6
8
10
Percent of Total
12
14
16
18
NIAAA’s Contemporary Mission
To create a knowledge base that will yield
the greatest good for the largest proportion
of the population by:
 Increasing understanding of normal and
abnormal biological functions and behavior
relating to alcohol use
 Improving the diagnosis, prevention, and
treatment of alcohol-related problems and
alcoholism
 Enhancing the access to quality health care
Cumulative Distribution of Alcohol
Consumption
Percent of Consumption
100
80
60
40
20
0
0
10
20
30
40
50
60
70
80
Percentile Group
Source: Greenfield and Rogers; J. Stud. Alcohol 60:; 79-89, 1999
90 100
Alcohol Abuse
Alcohol abuse is a pattern of high-risk* drinking
that results in several complex outcomes,
including:
Personal problems such as illegal underage drinking;
drinking-related injuries and death; impact on memory
and cognition; loss of employment, family, friends,
and other significant relationships; and increased risk
for health problems and organ damage…
*High-risk drinking: for Men: more than 14 drinks/week or 5 or more
drinks per occasion; for Women: more than 7 drinks/week or 4 or
more drinks per occasion (Helping Patients With Alcohol Problems - A Health Practitioner's Guide, NIAAA, 2003)
Alcohol Abuse
…Problems to others, including homicides,
sexual assault and other forms of
interpersonal crime and violence, property
damage, and risk for injury and death
Problems for society, including increased
health care costs, loss of economic
productivity, and balancing economic, health,
and social benefits of alcohol with the
significant adverse consequences of highrisk drinking
Alcohol Dependence
Alcohol Dependence (Alcoholism) is a
common complex disease characterized by a
persistent and progressive pattern of
abnormally intense alcohol-seeking behavior
that, over time, results in the
 loss of control over drinking
 a preoccupation with drinking
 the development of tolerance and
dependence
Multidisciplinary and Transdisciplinary
Research
 Epidemiology
 Genetics
 Prevention
 Neuroscience
 Treatment and
Recovery
 Pharmacokinetics
and Metabolism
 Translational Research
- animal models to humans
- medications development
Alcohol-related health, personal,
and social problems arise from
drinking:
 too much too fast
 too much too often
Prevalence of Lifetime Alcohol Dependence by
Age of First Alcohol Use and Family History of
Alcoholism
60
% Prevalence
50
FHP
Total
FHN
40
30
20
10
0
13
14
15
16
17
18
19
Age at First Alcohol Use
20
21
Percentage in each age group who
develop first-time alcohol dependence
Age at Onset of DSM-IV Alcohol Dependence
1.8
*
1.6
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0.0
5
10
15 18 21
25
30
35
40
Age
Source: NIAAA National Epidemiologic Survey on Alcohol and Related
Conditions, 2003
45
50
Basic Questions in Alcohol
Abuse and Dependence
 Why people drink
 Why some drink more than
others
 Why some drink despite
negative consequences
Between Individual Variations in
Responses to Alcohol
 Pharmacokinetics: absorption,
distribution, and metabolism of
alcohol
3-4 fold
 Pharmacodynamics: subjective
and objective responses to
alcohol
2-3 fold
Variation in Brain Exposure to Alcohol
Ethanol Elimination Rates in Monozygotic (MS) and
Dizygotic (DZ) Twins: Evidence for Genetic
Influence
Ethanol Elimination Rate (mg/kg/h)
Range (80 subjects)
Mean - ±SD
59 -148
102 ± 22
Intraclass Correlation Coefficient (r)
for MZ Twins (19 pairs)
0.76
for DZ Twins (21 pairs)
0.28
Heritability
h2=0.5 [MZ+DZ]
0.66
Metabolism of Ethanol and
Acetaldehyde in Liver Cells
Ethanol
 stimulant
 depressant
acetaldehyde
Acetate
 stimulant (CNS)
 aversive (systemic)
 depressant
Addiction:
Ethanol
salsolinol?
adenosine?
Biphasic Properties of Alcohol
Molecular
Approaches
Physiological
Approaches
 Genomics
 Neuroimaging
 Proteomics
 Electrophysiology
 Metabolomics
 Drug selfadministration (oral,
iv, intracranial)
Selectively Bred Alcohol-Preferring Rats as
Animal Model to Study Alcoholism
 Voluntarily consume 6-8g ethanol/kg/day
 Attain BACs of 0.05 – 0.25 g%
 Work to obtain the ethanol
 Consume ethanol for its pharmacological effects
(not taste, smell, or calories)
 Develop tolerance with chronic drinking
 Develop physical dependence with chronic
drinking
Alcohol Deprivation Effect
(ADE)
 Temporary increase in alcohol
consumption following a period of
alcohol deprivation
 Observed in rats, mice, monkeys, and
humans
 Animal model for studying relapse
Repeated Deprivations – Concurrent
EtOH Concentrations
Neuroimaging is a Critical
Technology for Translational Alcohol
Research
 Animal models to human
populations
 Metabolites and receptors to
medications development
Workshop on International Collaborative
Research
 Co-sponsored by NIAAA and the German
Ministry on Education and Research
 Information on funding mechanisms and
opportunities
 Monday, January 19, Yale TAC Building,
auditorium, 1:00 – 4:00 PM
Acknowledgement
Brenda G. Hewitt