Christian Bocti, MD, FRCP(C)Professeur agrégé, Neurologie, Département de médecine,

FMSS, Université de Sherbrooke

Service de Neurologie, Clinique de Mémoire et

Centre de recherche sur le vieillissement

CIUSSS de l’ Estrie - CHUS

10th Canadian Conference on Dementia, 2019

Major Neurocognitive DisordersAssociated with Alcohol Abuse

Conflicts of interest

Christian Bocti holds

convertible debentures in

I do enjoy a glass of wine

This presentation will provide an overview of the often

under-recognized contribution of alcohol use on cognitive

functions.

Objectives:

Differentiate the neurocognitive disorders that can be

linked to alcohol

Explain the pathophysiology of NCDs induced by

alcohol

Discuss the management of NCDs induced by alcohol

Case presentation 1

Case presentation 2

Questions

Key message

If you drink,

your brain will shrink.

The Alcohol Paradox

Claim: This substance, at low dose,

prevents dementia!

However, at higher doses, it increases

the risk of dementia, cancer and

death…

Plan

Introduction: statistics, diet, mortality

Drinking, the brain and cognition

Clinical

Imaging

Pathophysiology

Treatment

Introduction: what is a « drink »?

1 drink = 17 ml of pure alcohol (13g)

Public Health Agency of Canada 2015

« At-risk » use = More than 3 (women) or 4 (men) drinks on one occasion, every month.

About 80 % of adults use alcohol in Canada

People under-report the quantity of

alcohol they use...by how much???

PHAC 2015

Alcohol for dementia prevention?

1. Vascular prevention: treat hypertension!

2. Physical exercise: at least 3 x 30 min. / week

3. Mediterranean diet (including wine)

4. Cognitive activities: challenge yourself !

5. Social activities: interact with family & friends!

Medit

err

anean d

iet

EP

IC /

MH

I

Mediterranean diet :

observational study(NYC)

Scarmeas 2009

Strength of evidence ?

Daffner 2011

Estruch et al. NEJM 2013, Martinez-Lapiscina et al. JNNP 2013

PREDIMED: a randomized controlled

trial on the mediterranean diet

After 6 years: + 0,6 MMSE and + 0,5 CDT (score on 7)

Among participants with high genetic risk, 1.13% (95% CI, 1.01%-1.26%) of those with

a favorable lifestyle developed dementia compared with 1.78% (95% CI, 1.38%-2.28%)

with an unfavorable lifestyle (hazard ratio, 0.68 [95% CI, 0.51-0.90]).

JAMA. 2019;322(5):430-437.

doi:10.1001/jama.2019.9879

Published online July 14,

2019

UK BioBank n=200 000

Do you recommend

moderate drinking

to prevent cognitive decline?

Wow! These studies really provide Level 1

evidence that alcohol is good for your brain!(as part of MeDi or healthy lifestyle)

…

Only one glass a day!

WHAT IS THE EFFECT OF ALCOHOL

ON THE BRAIN ?

A new analysis from a large scale prospective long

term study: Whitehall II (observational)

527 participants followed for 30 years; no

beneficial effect of alcohol on hippocampal

volumes measured on MRI

This was also noted in the Framingham Study (Paul et

al. Arch Neurol 2008)

Even minimal use (1-7 drinks/week) associated

with declining cognitive performance compared

with no use (verbal fluency - 6 )

Topiwala et al. BMJ 2017

Topiwala et al. BMJ 2017

Catégories :

0 / semaine

1-7

7-14

14-21

21+

Conclusion from that study

« There was no evidence of a protective effect of light drinking over abstinence on brain structure or function. »

- Topiwala et al, 2017

But at least, alcohol is

good for your heart, right?

Wood et al. Risk threshold… Lancet 2018

Wait? What? The same study now

shows the opposite result???

Contribution of alcohol to early-

onset dementia (France)

This graph shows that alcohol is the main etiology in 39 % of early-onset dementias

and contributes to another 18% - from a nationwide hospital discharge database

Schwarzinger 2018

HR for AUD

= 3.36

What is alcohol-related

dementia? Terminology

“KS is a largely irreversible residual syndrome, caused by severe

thiamine deficiency and occurring after incomplete recovery from

a Wernicke encephalopathy, predominantly in the context of

alcohol abuse and malnutrition, characterized by an abnormal

mental state in which episodic memory is affected out of all

proportion to other cognitive functions in an otherwise alert and

responsive patient, whose psychological make-up may be further

distinguished by executive dysfunction, flattened affect, apathy,

lack of illness insight, and possibly by fantastic confabulations in

the early stage.”

« Polyneuritic psychosis » Original publications from 1887-1891

Sergei Korsakoff

Aarts, Walvoort, Kessels. Korsakoff’s syndrome: a critical review, 2017

Korsakoff’s syndrome

Severe anterograde amnesia*

Retrograde amnesia(many years)

Executive dysfunction

Apathy

Flat affect

Lack of insight

Confabulation possible

Often follows Wernicke’s (= WKS)

* See next slide

Is it justified to distinguish between

WKS and other alcohol-related

cognitive problems ?

The common research strategy to define WKS

by critieria that emphasize severe anterograde

amnesia might have created a

neuropsychological stereotype that is NOT

representative of the whole clinical picture.

(circular reasoning)

Bowden 1990

Wernicke’s Encephalopathy

Classical definition :

CONFUSION

ATAXIA

NYSTAGMUS

??? How many have the classic triad ???

16 %Harper et al. 1998

Poor sensitivity of the clinical

diagnosis of WE

Population-based autopsy stuydy in Australia

1996-97: 25 cases WKS out of 2200 (1.1%)

Only 16 % (4 cases) had WKS in their chart

2 others had a diagnosis of « alcoholic dementia »

And 5 others had unspecified memory problems

documented

Suggests that the majority of acute cases are

missed, and/or repeated acute low grade injuries?

Harper et al. 1998

1. Dietary deficiencies

– Undernutrition (BMI <2 SD below normal)

– A history of grossly impaired dietary intake

– An abnormal thiamine status

2. Oculomotor abnormalities

– Ophthalmoplegia

– Nystagmus

– Gaze palsy

3. Cerebellar dysfunction

– Unsteadiness or ataxia

– Abnormalities of past pointing

– Dysdiadokokinesia

– Impaired heel-shin testing

Improving the diagnosis of WE

You need 2 out of 4:4. Altered mental state

– Disorientation in two of three fields

– Confused

– An abnormal digit span

– Comatose

or

Mild memory impairment

– Failure to remember two or more words

in the four-item memory test

– Impairment on more elaborate

neuropsychological tests of memory

function

Caine et al 1997

excellent sensitivity

excellent specificity if no HE

Comparison of WKS alcoholics and

« uncomplicated » alcoholics

1. On neuroimaging structural substrates of amnesia are

similar but volume loss is less severe

2. On neuropsychological assessment, non-memory

domains are as similarly affected

3. Amnesia is present but less severe than observed in WKS

(but is it by definition?)

In summary: quantitative rather than qualitative differences

Fama et al. Neuropsychol review 2012

Ove

rlap Z

ones W

KS

vs W

KS

am

ong a

lcoholic p

ati

ents

Pitel 2012

Gray matter

atrophy

on MRI:

More

similarities

than

differences

KS Korsakoff

CS Controls

AL: alcohol users

Structures of the Human Memory System

hippocampus (1) > fornix (2; loop around the thalamus), with one branch (3) to the anterior

thalamic nuclei (7), another (4) to the mammillary bodies > mammillary bodies (5) >

mammillothalamic tract (6) > anterior thalamic nuclei (7); projections to the cingulate cortex

(8) > cingulate cortex (9) > retrosplenial cortex (10) > parahippocampal gyrus (11)

Aarts, Walvoort, Kessels. Korsakoff’s syndrome: a critical review, 2017

Control

subject

AL w/o

WKS

AL w

WKS

Age=63 for all

T1 MRI Pitel 2012

Volume of mamillary bodies, thalamus and

cerebellum in Controls, AL, WKS

Alcohol users without WKS are right in

between Controls and WKS, suggesting

a « dose–response curve »Sullivan 2009

Reduced cortical thickness and

glucose metabolism in AUD

19 AUD (12 drinks/d)vs 20 controls (0-2 drinks/d); cognitive measures

not different ( CANTAB); dose-response relationship of total lifetime

alcohol with both CT and rCMRGlu = evidence of neurotoxicity

Tomasi et al. 2019

Non-WKS alcoholics Striking similarity in patterns of atrophy for WKS and non-

WKS alcoholics

Supports a continuity hypothesis

Diencephalic structures are more severely affected in WKS,

but essentially the same structures are reduced in volume

Either we miss many (most) cases of acute WE

Maybe there was no acute WE

Maybe alcohol has direct neurotoxicity

Pitel 2012

The most important

difference…on neuropathology

Neuronal counts in the anterior thalamic

nuclei best discriminate between WKS and

non WKS alcoholics. All other regions are

affected to a similar degree!

Harding 2000

Korsakoff Syndrome

Ethanol neurotoxicity vs nutritional deficiency

Wernicke’s Encephalopathy

B1 (thiamine) deficit, associated or not to excessive

alcohol use (bariatric surgery, hypermesis

gravidarum…).

Upwards of 20 % mortality if untreated

Korsakoff Syndrome

Theoretically follows WE but « de novo » quite often

probably due to the fact that WE diagnosis is difficult

Occasionally same clinical picture after trauma,

hemorrhage to diencephalic structures

Exact etiology ? Controversy

Many pitfalls in this discussion

Effect of alcohol on absorption of thiamine and metabolism of

thimaine

Lifestyle of heavy alcohol drinkers often does not include

optimal nutrition, management of health and chronic conditions

Indirect effects vis hepatic encephalopathy

Comorbidities such as other substance abuse, psychiatric, TBI

Deficiency of thiamine or direct alcohol toxicity?

In an animal model, alcohol aggravates

damages due to thiamine deificiency in the

thalamus and maillary bodies

= detrimental synergy

Pfefferbaum et al. 2007

Pereira et al. 2015

Many ways in which

alcohol may be toxic for

neurons

Deficiency of thiamine or direct alcohol toxicity?

Nutritional deficiency or

biochemical predisposition?

There clearly is a genetic predisposition to WE

Genetic variants of « transketolase » have been associated

with susceptibility to WE

Other genetic variants implicated as well (thiamine

transporters)

ApoE4 (here too!!!)

Multiple metabolic roles of thimaine pyrophosphate (co-

enzyme) in the brain

Body reserves are about 3 weeks for thiamine

Wernicke’s: role of MRI

T2 / FLAIR Hyperintensities T2 around the

3rd ventricle (thalamus), mamillairy bodies,

periaqueductal grey matter and tectal plate

(mesencephalon)

Example MRI: Wernicke

Sullivan & Pfefferbaum 2009

Example MRI/neuropathology:

Wernicke

Liu 2005

Haemorragic necrosis of mamillary bodies

TREATMENT

James Prochaska et Carlo DiClemente (1982)

Arrêt de l’abus d’alcool: amélioration de « l’atrophie » octobre 2012 - MoCA 28

Troubles cognitifs -

abus d’alcool, atrophie cérébrale:

mars 2012 - MoCA 21

La modification du comportement, ça marche (parfois)

Wernicke: medical emergency

High Dose I.V. Thiamine

Various suggestions : 100 mg IV daily for a week

Guidelines from EFNS. 200 mg I.V. tid

According to review in Lancet Neurology (Secchi & Serra

2007): doses as high as 500 mg IV for 3 days

Usual daily needs = 1.5 mg

For various reasons heavy alcohol use impairs the body’s

ability to absorb and metabolize thiamine

Sechi 2007

Conclusions• There is no minimal intake of alcohol that is beneficial, or

even safe, for the brain.

• Chronic use has a dose-response relationship with some

cognitive decline and colume loss of the hippocampus

• Some positive prevention results from observational studies

are likely explained by confounders.

• Lower your threshold for diagnosis of WE and use high dose

I.V. Thiamine liberally

Conclusions -2If you drink

Your brain will shrink

Cardiac benefits appear trivial in the face

of increased overall mortality, above a

certain threshold

Nutritional advice and national guidelines, should

be revised downwards to reflect this.

5e Congrès Québécois sur la

maladie d’Alzheimer!

4-6 Novembre 2020

Centre des Congrès de Québec

Le futur de la maladie d’Alzheimer

*** Save the date ***