neuropsychology and neuroimaging of alcohol use disorder ... · korsakoff’s syndrome kopelman et...
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NEUROPSYCHOLOGY AND NEUROIMAGING OF ALCOHOL USE DISORDER WITH AND WITHOUT KORSAKOFF’S SYNDROME:
A BETTER UNDERSTANDING FOR A BETTER TREATMENT
Anne Lise PITEL
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CONFLICT OF INTEREST
No conflict of interest to declare.
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ALCOHOL USE DISORDER (AUD): EPIDEMIOLOGY
10% of French population with disastrous health, psychological, social and professional consequences (Rehm et al. 2011).
Alcohol is the cause of 49 000 deaths per year and 18% of the premature deaths in the 35-64 year-old people in France (Guerin et al. 2013).
17% of the admissions in the emergency department in France.
Worldwide, alcohol is the third risk factor for morbidity after high blood pressure and tobacco (Moller 2013).
Alcohol is the cause of more than 60 diseases (dependence, cirrhosis, psychosis, fetal alcohol syndrome, …) (World Health Organization 2014).
Alcohol contributes to the development of more than 200 diseases (cancer, heart disease, pancreatitis, liver disease, …) (Moller 2013).
The life expectancy is reduced of 20 years in a man with alcohol dependence (John et al. 2013).
The cost related to alcohol or tobacco use disorders is 349 billion euros for Europe, knowing that it is 105 for dementia and 64 for strokes (Effertz et Mann 2013).
Tremendous social cost: first cause of hospital admission, sick leave and premature death.
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ALCOHOL USE DISORDER (AUD): DSM-5 CRITERIA
Changes in the concepts:
Alcoholism
Alcohol dependence (DSM IV)
Alcohol Use Disorder (DSM V)
A problem pattern of alcohol use, leading to clinically significant impairment or distress, manifested by 2 or more of the following in a 12-month period:
Alcohol drunk in larger amounts or for longer time
Persistent desire or unsuccessful efforts to cut down
Inordinate time spent obtaining alcohol
Craving (strong desire to use alcohol)
Failure to fulfill work, school, home obligations
Continued use despite social or interpersonal problems
Societal, occupational, recreational activities reduced
Recurrent use when physically hazardous
Continued use despite physiological or psychological problems
Tolerance
Withdrawal
WHY?
Because alcohol changes the brain…
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Acute alcohol intoxication reversibly affects brain function.
Chronic alcohol abuse affects the brain in enduring ways, and these effects themselves may contribute to the loss of control.
HOW DOES ALCOHOL CHANGE THE BRAIN?
Self-perpetuating
disorder
From Pr E.V. Sullivan
AUD = BRAIN DISEASE
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KORSAKOFF’S SYNDROME
Kopelman et al. 2009
Arts et al. 2017
Sergei Korsakoff (1887, 1889, 1891): « polyneuritic psychosis » observed in 30
cases of chronic and excessive alcohol consumption and 16 patients in whom alcohol
had not played a role. Main feature: severe and enduring memory disoders.
Korsakoff’s syndrome (KS)
+ = KS
+ = KS + Thiamine
(Vit B1)
deficiency
50’s
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QUESTIONS
❶ Are there neuropsychological deficits in AUD before the development of KS?
❷ What are the clinical consequences of neuropsychological deficits observed in AUD?
❸ What are the differences between altered brain structure and function in AUD and KS?
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ARE THERE BRAIN ABNORMALITIES AND COGNITIVE DEFICITS IN AUD BEFORE
THE DEVELOPMENT OF KS? Question 1
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NEUROPSYCHOLOGICAL PROFILE IN AUD
Sullivan et al. 2000
* *
*
Oscar-Berman et al. 2014 (review)
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EXECUTIVE FUNCTIONS IN AUD
Pitel et al. 2007
Ihara et al. 2000
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EPISODIC MEMORY IN AUD
Pitel et al. 2007
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METAMEMORY IN AUD
Le Berre et al. 2010
Objective measure:
Recognition task/FOK
Subjective measure: MIA
questionnaire No difference on the Strategy, Tasks,
Capacity, or Achievement subscores
• AUD group less accurate than the control group
• Tendency to overestimate their memory capacities,
believing themselves capable of recog- nizing the correct
word when in fact they subsequently fail to do so. Le Berre and Sullivan, 2016
Limited awareness of memory deficits
Mild form of mnemonic anosognosia?
Denial?
Not only for memory.
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SOCIAL COGNITION IN AUD
Decoding emotions in facial expression,
body postures and prosody Theory of Mind
D’Hondt et al. 2014; Maurage 2008; Maurage et al. 2013; Rupp et al. 2017
Thoma et al. 2013; Uekermann et al. 2007; Bosco et al. 2014;
Nandrino et al. 2014; Schmidt et al. 2016
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NEW SEMANTIC LEARNING IN AUD
Day 2: Learning session 1
Day 9 : Learning session 8
Day 3: Learning session 2
“ What is this? Does the ratel belong to the family of insectivorous,
carnivorous or herbivorous animals? Does the ratel attack buffaloes, gazelles or rodents?...”
“ What is this?
Which family of animal does the ratel belong to? Which type of animal does it attack?...”
Day 1: Pre-learning assessment
Concept presentation
“ This animal is a ratel,
It belongs to the family of carnivorous animals, It attacks buffaloes…”
time
Pitel et al. 2007
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NEW PROCEDURAL LEARNING IN AUD
time
Day 1/Session 1:
Day 2/Session 2:
Day 3/Session 3:
Day 4/Session 4:
10 trials of the Tower of Toronto
10 trials of the Tower of Toronto
10 trials of the Tower of Toronto
10 trials of the Tower of Toronto
Pitel et al. 2007
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DECISION-MAKING IN AUD (1)
Iowa Gambling task
Le Berre et al. 2014
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DECISION-MAKING IN AUD (2)
Le Berre et al. 2014
Emotionally and cognitively
unable to anticipate risky
situations
les situations à risques
Ventromedial cortex: emotional and social
components
Cingulate cortex: cognitive component
Hippocampus: memory and learning
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QUESTIONS
❶ Are there neuropsychological deficits in AUD before the development of KS?
YES!!!
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WHAT ARE THE CLINICAL CONSEQUENCES OF ALTERED BRAIN STRUCTURE AND
FUNCTION OBSERVED IN AUD? Question 2
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MOTIVATION
Prochaska and Di Clemente Le Berre et al. 2013
Awareness
Decisional balance
LOW EPISODIC
MEMORY ABILITIES
LOW EXECUTIVE
ABILITIES
HIGH DECISION-
MAKING ABILITIES
RTC questionnaire, neuropsychological
performance and brain structure
(p<0.005 FDR; k>150)
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= =
ALCOHOL TREATMENT
Semantic learning
Procedural learning
Metamemory
Metacognition
Motivation Decision-making
Executive functions
Episodic memory
?
Denial?
Inhibition Flexibility
NEUROPSYCHOLOGICAL DEFICITS = HIGH RISK OF RELAPSE!!!
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A systematic assessment of cognitive abilities is required in recently
detoxified AUD patients
All AUD patients may not be cognitively able to benefit fully
from treatment
To assess
(ideal!)
To detect
(pragmatic…)
To identify risk factors
-subclinical signs of WE
-thiamine deficiency
-liver dysfunction
-denutrition
To adjust
treatment
To favor
spontaneous
recovery
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SCREENING TOOLS
MMSE (Folstein, 1975) BEARNI MOCA (Nasreddine et al. 2005
Not sensitive
Not specific
Sensitive
Not specific
Useful for differential diagnosis
Only in French
Sensitive (too much?)
Specific
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SUBCLINICAL SIGNS OF WERNICKE ENCEPHALOPATHY (WE)
Pitel et al. 2011
Cf post mortem: Harper et al. 1986, 1989 1 criterion = risk for WE
Clinical criteria of Caine et al. 1997:
• Dietary deficiency: > 30 missed-meals over lifetime
• Oculomotor abnormalities: nystagmus
• Cerebellar dysfunction: lower limb ataxia
• Altered mental state: DRS<123
2 criteria = signs of WE
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* * * *
*
* *
* *
*
*
*
†
†
† †
†
†
†
†
‡
†
Pitel et al. 2011
SUBCLINICAL SIGNS OF WERNICKE ENCEPHALOPATHY (WE)
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BIOLOGICAL FACTORS
Ritz et al. 2016
Correlation between poorer memory
scores and lower TDP levels
TDP (active form of thiamine)
Pitel et al. 2011
alcoholics=controls
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RECOVERY OF BRAIN FUNCTION
Pitel et al. 2009
6 months of sobriety
Relapse within 6 months (>1 drink)
Improvement Return to normal
No improvement Deterioration
Oscar-Berman et al. 2014 (review)
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TREATMENT ADJUSTMENTS
Treatment delay
Screening and neuropsychological assessment
Preserved NP abilities Mild-to-moderate NP
deficits
Reassessment
Persistent NP deficits Neuropsychological
recovery
Regular alcohol treatment
Severe NP deficits
« Mid-term » care unit
Nursing home
Specialized unit (when available…)
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TREATMENT ADJUSTMENTS
Cognitive remediation/rehabilitation Bates et al. 2013
Rupp et al. 2012
Treatment delay Modification of attentional bias toward alcohol
Wiers et al. 2006
Schoenmakers et al. 2007, 2010
Boffo et al. 2015, 2017
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QUESTIONS
❶ Are there neuropsychological deficits in AUD before the development of KS?
❷ What are the clinical consequences of neuropsychological deficits observed in AUD?
Evaluate Identify risk
factors
Adjust
treatment
Favor
recovery
Limit the
benefit of
treatment
Increase the
risk of
relaspe
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WHAT ARE THE DIFFERENCES BETWEEN ALTERED BRAIN STRUCTURE AND FUNCTION
IN AUD AND KS? Question 3
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GRAY MATTER (GM) ABNORMALITIES
FDR p<0.05
Pitel et al. 2009
KS: variability in the individual pattern Pitel et al. 2012
AUD<CS KS<CS Conjunction
KS<CS and AUD<CS
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GM: SPECIFICITY OF KS COMPARED WITH AUD
KS<AUD
P<0.001 unc.
Pitel et al. 2012
Le Berre et al. 2015 KS<AUD and France vs US
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WHITE MATTER (WM) ABNORMALITIES
Pitel et al. 2009
KS: variability in the individual pattern
AUD<CS KS<CS Conjunction
KS<CS and AUD<CS
Pitel et al. 2012 FDR p<0.05
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†
KS<AUD
*: significant difference compared to controls
†: significant difference compared to alcoholics
P<0.001 unc.
WM: SPECIFICITY OF KS COMPARED WITH AUD
Pitel et al. 2012 Le Berre et al. 2015
KS<AUD and France vs US
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WM MICROSTRUCTURE (1)
Segobin et al. 2015
Voxel-by-voxel comparisons of FA values (TBSS)
HC vs UAp-value
Anterior limb of Internal capsule
Anterior corona radiata
fornix CingulumCorpus callosum
HC vs KS
UA vs SK
Corpus callosum
middle and superior cerebellar peduncles
5,000 permutations,
FWE P<0.05
TFCE for cluster-wise correction
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WM MICROSTRUCTURE (2)
Fronto-cerebellar circuit Papez circuitFronto-cerebellar circuit
Papez circuit
Fornix Cingulum
Cluster analysis on certain fiber tracts Between-group comparisons of episodic memory results
Cingulum Fornix
* sig different from HC (p<0.05) ** sig different from HC (p<0.001) § sig different from UA_LOW(p<0.05) § § sig different from UA_LOW(p<0.001) ¥ sig different from UA_HIGH(p<0.001)
Mid cerebellar peduncles
Sup cerebellar peduncles Segobin et al. 2015
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Pitel et al. 2008
Similar profils
AUD patients at risk for KS
MEMORY DISORDERS (1)
* *
* *
* * *
* * *
* *
*
* *
*
*
Continuity between AUD and KS
* *
*
* * * *
*
EPISODIC MEMORY
WORKING MEMORY
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MEMORY DISORDERS (2)
SOURCE MEMORY: temporal confusion
Continuous recognition task
Brion et al. 2017
* *
Temporal confusion in KS only
Confabulations?
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QUESTIONS
❶ Are there neuropsychological deficits in AUD before the development of KS?
❷ What are the clinical consequences of neuropsychological deficits observed in AUD?
❸ What are the differences between altered brain structure and function in AUD and KS?
Papez circuit Episodic memory Temporal
confusion/confabulation Recovery
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DISCUSSION
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QUESTIONS
Evaluate Identify risk
factors
Adjust
treatment
Favor
recovery
Limit the
benefit of
treatment
Increase the
risk of
relaspe
YES!!!!
❶ Are there neuropsychological deficits in AUD before the development of KS?
❷ What are the clinical consequences of neuropsychological deficits observed in AUD?
❸ What are the differences between altered brain structure and function in AUD and KS?
Papez circuit Episodic memory Temporal
confusion/confabulation Recovery
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TWO BRAIN CIRCUITS PREDOMINANTLY AFFECTED
Working memory
Executive functions
Motor abilities
Episodic
memory
Pitel et al. 2014
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THALAMIC SEGMENTATION IN AUD AND KS
Segobin et al. In preparation
Frontal executive: BA9, BA46
Cerebellar executive: Crus I et II
Frontal motor: precentral gyrus
Cerebellar motor: Lobs IV-VI
Hippocampus Morel Atlas
70% of MD
Hippocampus
target
Morel Atlas
84% of ANT nucleus
Frontal executive
target
Vo
lum
e
DTI sa
mp
les
Atrophy MD:
AUD=KS
No disconnexion
between MD and
frontal
Atrophy ANT in
KS only
Disconnexion
between ANT and
hippocampus in
both groups
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Mild-to-moderate
atrophy
AUD Mild-to-moderate
disconnexion
Mild-to-moderate
dysfunction of the PC
Mild-to-moderate
WM and executive
deficits
Mild-to-moderate
episodic memory
deficits
MEDIO-DORSAL
NUCLEAR GROUP
ANTERIOR
NUCLEAR GROUP
Mild-to-moderate
dysfunction of the FCC
Reversible
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Mild-to-moderate
disconnexion
Mild-to-moderate
dysfunction of the PC
Mild-to-moderate
WM and executive
deficits
Mild-to-moderate
episodic memory
deficits
MEDIO-DORSAL
NUCLEAR GROUP
ANTERIOR
NUCLEAR GROUP
Mild-to-moderate
atrophy
Mild-to-moderate
dysfunction of the FCC
Severe atrophy
+ altered thiamine metabolism
or thiamine deficiency
ANTERIOR
NUCLEAR GROUP
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Mild-to-moderate
disconnexion
Mild-to-moderate
WM and executive
deficits
MEDIO-DORSAL
NUCLEAR GROUP
ANTERIOR
NUCLEAR GROUP
Mild-to-moderate
atrophy
Mild-to-moderate
dysfunction of the FCC
Severe atrophy
+ altered thiamine metabolism
or thiamine deficiency
ANTERIOR
NUCLEAR GROUP
Severe dysfunction of the PC
Amnesia
KORSAKOFF
SYNDROME Persistent
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CONCLUSION
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ALCOHOL-INDUCED NEUROCOGNITIVE DISORDER (DSM-5 CRITERIA)
Amnestic-confabulatory type
Persistent: Neurocognitive impairment continues to be significant after an extended period of abstinence
A. Clinical criteria for major neurocognitive disorder
B. Does not occur exclusively during the course of a delirium an persists beyong the usual duration of intoxication and acute withdrawal
C. Duration and extent of use are capable of producing the neurocognitive impairment
D. The temporal course of the neurocognitive deficits is consistent with the timing of alcohol use and abstinence
E. The neurocognitive disorder is not attributable to anther medical condition or is not better explained by another mental disorder
A. Clinical criteria for mild neurocognitive disorder
B. Does not occur exclusively during the course of a delirium an persists beyong the usual duration of intoxication and acute withdrawal
C. Duration and extent of use are capable of producing the neurocognitive impairment
D. The temporal course of the neurocognitive deficits is consistent with the timing of alcohol use and abstinence
E. The neurocognitive disorder is not attributable to anther medical condition or is not better explained by another mental disorder
ACKNOWLEDGEMENT OF ALCOHOL-RELATED NP DEFICITS
CONTINUUM BETWEEN ALCOHOLICS AND KORSAKOFF PATIENTS
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AUD is a major health issue worldwide!
The detection of alcohol-related NP deficits is clinically relevant
for the treatment of alcohol addiction
to prevent neurological complications such as KS
The comparison between AUD and KS gives insight on the physiopathology of these diseases
Interesting model to examine:
neuropsychological/brain recovery
the role of the thalamus in memory (ANT versus MD)
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François
Vabret
Anne Lise
Pitel
Céline
Boudehent
Ludivine
Ritz
Hélène
Beaunieux
Shailendra
Segobin
Alice
Laniepce
Nicolas
Cabé
Angéline
Maillard
Anne-Pascale
Le Berre Edith V.
Sullivan
Adolph
Pfefferbaum