Vascular dementia

Vascular cognitive impairment

Ingmar Skoog, M.D., Ph.D.

Director of the Centre for Ageing and Health (AGECAP)
Institute of Neuroscience and Physiology
Unit of Neuropsychiatric Epidemiology
Sahlgrenska Academy at Gteborg University
Gteborg, Sweden

www.gu.se

Neuropsychiatric
Epidemiology
(Epinep)
Institute of Neuroscience and
Physiology Department of
Psychiatry and Neurochemistry
Sahlgrenska Academy at University
of Gothenburg, Sweden
www.epinep.gu.se

Senior researchers
Ingmar Skoog
Margda Waern
Tore Hllstrm
Svante stling
Pia Gudmundsson
Hanna Falk
Kerstin Frndin
Xinxin Guo
Anne Brjesson-Hanson
Silke Kern
Helena Hrder
Simona Sacuu
Lena Johansson
Anna Zetterberg
Jrgen Kern
Madeleine Mellqvist Fssberg
Eva Billstedt
Deborah Gustafson
Bjrn Karlsson
Stefan Wiktorsson
Nils Beckman
PhD students
Thorsteinn Gislasson
Johan Nilsson
Robert Sigstrm
Daniel Jaraj
Mats Ribbe

Scientific Coordinator
Pia Gudmundsson
Administrative Coordinator
Tina Jacobsson
Administrativ Assistant
Cecilia Mellqvist
Felicia Nord
Statisticians
Kristoffer Bckman
Erik Joas
Thomas Marlow
Valter Sundh
Research nurses
Carina Alklid
Fredrika Jnsson
Rebecca Ibstedt
Margareta Lewander
Helen Lidn
Birgitta Tengelin Widepalm
Malin Thorell
Bosse Svenningsson
Research trainees
Isak Fredn Klenfeldt
Therese Rydberg
Johan Skoog
Jenna Al-Najjar

Sahlgrenska akademin

Neuropsychiatric Epidemiology
EPINEP
Forskningsledare: Ingmar Skoog

www.gu.se

BASIC CONCEPT OF VASCULAR

DEMENTIA
Cerebrovascular disease causing
dementia

I. Skoog 2010

BASIC CONCEPT OF VASCULAR

DEMENTIA
Cerebrovascular disease causing
dementia

I. Skoog 2010

Dementia (DSM-IV)

A) Memory impairment
AND
B) One or more of the following.
a) aphasia
b) apraxia
c) agnosia
d) disturbance in executive function
C) Disturbance in social or occupational functioning

Prevalence of dementia
according to old criteria
(memory mandatory)

6-10% above age 65

20% above age 80
50% above age 95

PROPORTION OF DIFFERENT
TYPES OF DEMENTIA
Alzheimers Disease
55-75%
Vascular Dementia
20-30%
Other dementias
10-20%

VASCULAR COGNITIVE
IMPAIRMENT
Cardiovascular and cerebrovascular
diseases causing cognitive
impairment
Includes both vascular dementia and
mild cognitive impairment
I. Skoog 2010

VASCULAR COGNITIVE IMPAIRMENT (VCI)

Old criteria for dementia and MCI

based on Alzheimer disease (memory
dysfunction mandatory)
BUT
cognitive dysfunction in VCI may
have a variable picture
I. Skoog 2010

Major Neurocognitive Disorder or Dementia

(DSM-5)
A) At least one of
B) 6 cognitive dysfunctions including memory
Complex attention
Learning and memory
Executive ability
Language
Perceptual ability
Social cognition
C) Memory not mandatory
D) Significantly interfere with daily activities

APA 2013

VASCULAR COGNITIVE
IMPAIRMENT
Cardiovascular and cerebrovascular
diseases causing cognitive
impairment
Includes both vascular dementia and
mild cognitive impairment
I. Skoog 2010

Many different cerebrovascular

diseases may cause dementia

The vascular burden of the brain

Kalaria 2013

Two Major Forms of CVD leading to

dementia
Large-vessel disease
Cardiac embolic events
Atherosclerosis, plaque rupture,
intraplaque hemorrhage,
thrombotic occlusion, and
embolism, dissection,
dolichoectasia.

Small-vessel disease
Arteriolosclerosis, Fibrinoid necrosis.
Microaneurysm. Fibrohyalinosis.
Lipohyalinosis. Microatheroma.
Cerebral amyloid angiopathy,
Segmental arterial disorganization

Large cortical and

subcortical infarcts

Small subcortical
infarcts
Diffuse white matter
lesions
From Kalaria 2013

Vascular causes of dementia

Vascular
brain disorders

Stroke
Silent cerebral infarcts
Lacunar infarcts
Microbleeds
Ischemic white matter
lesions
Vessel wall pathology

Vascular
risk factors

Hypertension
Overweight
ApoE e4
Hypercholesterolemia
Diabetes mellitus
Atherosclerosis
Coronary heart disease
Smoking

Large cortical infarcts

Permission from Leonardo Pantoni

Small infarcts in the basala ganglia

Permission from Leonardo Pantoni

STROKE IS PART OF THE

DIAGNOSTIC CRITERIA FOR
VASCULAR DEMENTIA
BUT

STROKE IS PART OF THE

DIAGNOSTIC CRITERIA FOR
VASCULAR DEMENTIA
BUT
IS STROKE RELATED TO
DEMENTIA?

Prevalence of dementia in relation to

stroke between age 70 and 97
Stroke

OR (95%-CI

No (%)

Yes (%)

70-80-year-olds

18

85-year-olds
(N=492)

24

57

4.3 ( 2.7-6.9)

97-year-olds
(N=592)

51

60

1.5 (1.0-2.3)

Lindn, Skoog et al Neuroepidemiology 2004

Liebetrau & Skoog. Stroke 2003,
Andersson & Skoog. Age Ageing 2012

6.7 (2.6-17.6)

The risk of dementia in relation to stroke

in women followed over 40 years
***
***
**

***

**

Guo, stling, Skoog 2014

The risk for stroke in relation to dementia

in women followed over 40 years

***
**

**

**

Guo, stling, Skoog 2014

Increased risk for dementia

before stroke shows the
importance of silent vascular
burden

Silent infarcts
Ischemic white matter lesions
Co-occurrence of many different
cerebrovascular disorders in the same
individual (mixed cerebrovascular disorders)
Shared risk factors

The role of Silent

cerebrovascular disease

Silent infarcts
Lacunar infarcts
Microbleeds
White matter lesions

The incidental finding on brain

imaging

Vascular causes of dementia

Vascular
brain disorders

Stroke
Silent cerebral
infarcts
Lacunar infarcts
Microbleeds
Ischemic white matter
lesions
Vessel wall pathology

Vascular
risk factors

Hypertension
Overweight
ApoE e4
Hypercholesterolemia
Diabetes mellitus
Atherosclerosis
Coronary heart disease
Smoking

Are silent infarcts related to

dementia?

RISK OF DEMENTIA IN RELATION TO

INFARCTS ON CT AND HISTORY OF STROKE
AT AGE 85
H-70 STUDY, GTEBORG, SWEDEN

OR
No infarcts/No history

1.0

Infarcts/No history

2.5*

(silent infarcts)
No infarcts/History

4.4*

Infarcts + History

5.2*
Liebetrau & Skoog. Stroke 2004

SILENT INFARCTS ON MRI

The frequency of silent infarcts on MRI

increases with age
(Vermeer et al, Stroke 2003)

Increases the incidence of dementia (HR 2.3

(95-% CI 1.1-4.7) during 3.6 years follow-up
(Vermeer et al. N Engl J Med 2003)

Vascular causes of dementia

Vascular
brain disorders

Stroke
Silent cerebral infarcts
Lacunar infarcts
Microbleeds
Ischemic white matter
lesions
Vessel wall pathology

Vascular
risk factors

Hypertension
Overweight
ApoE e4
Hypercholesterolemia
Diabetes mellitus
Atherosclerosis
Coronary heart disease
Smoking

Lacunes and
Lacunar infarcts

Lacunes
complete or cavitating infarcts; up
to 15 mm; common in subcortical
structures

Courtesy from Raj Kalaria

Lacunar syndromes

Pure one-sided sensory stroke

Pure motor hemiparesis
Homolateral ataxia
Clumsy hand syndrome
More than 40 syndromes described
Sometimes associated with dementia

Skoog 2013

Vascular causes of dementia

Vascular
brain disorders

Stroke
Silent cerebral infarcts
Lacunar infarcts
Microbleeds
Ischemic white matter
lesions
Vessel wall pathology

Vascular
risk factors

Hypertension
Overweight
ApoE e4
Hypercholesterolemia
Diabetes mellitus
Atherosclerosis
Coronary heart disease
Smoking

Cerebral microbleeds

Greenberg et al. Lancet Neurology 2009

Cerebral microbleeds

Small (5-10 mm) perivascular well-demarcated,

hypointense, rounded foci on MRI
Thought to be products of hemorrhage,
especially hemosiderin
Neuropathology debated
Increases with age
Normal elderly 25% (above age 80 years 40%)
More common in persons with CVD
Lobar microbleeds related to ApoE e4
Related to hypertension, diabetes mellitus and
low cholesterol

Skoog 2013

Cerebral microbleeds

Cortical lobar microbleeds supposed to be

related to AD and caused by CAA
Subcortical microbleeds supposed to be related
to WMLs, lacunar infarcts and vascular risk
factors and caused by lipohyalinosis
Number of microbleeds related to dementia
Number of lobar microbleeds related to worse
cognitive performance
Microbleeds related to increased risk of stroke
Related to use of antithrombotic drugs??
Skoog 2013

Vascular causes of dementia

Vascular
brain disorders

Stroke
Silent cerebral infarcts
Lacunar infarcts
Microbleeds
Ischemic white matter
lesions
Vessel wall pathology

Vascular
risk factors

Hypertension
Overweight
ApoE e4
Hypercholesterolemia
Diabetes mellitus
Atherosclerosis
Coronary heart disease
Smoking

Permission from Philip Scheltens

WHITE MATTER LESIONS ON CT

Demented
(N) %
Men (N=75)

37

Women (N=263)

56 *

Permission from Arne Brun

Permission from Arne Brun

Prevalence of WMLs in the

elderly

MRI: 50-100% depending on age and scale

CT: 55-70% depending on age and scale

Consequences of subcortical ischemic

vascular disease (white matter lesions)

Dementia
Mild cognitive symptoms
Depression
Functional disability
Gait disturbance and falls
Hip fracture
Urinary incontinence
Brain atrophy
Stroke and other vascular disease
High mortality rate

WHITE MATTER LESIONS IN

RELATION TO DEMENTIA IN 85YEAR-OLDS
%
No dementia
34
Alzheimers disease 64**
Vascular dementia 70***
Other dementias 80*
Skoog et al J Geriatr Psychiatry Neurol 1994

White matter lesions severity on MRI

and the development of
dementia
during 5 year follow-up
OR

(95%-CI)

(per 1 SD increase
in WML score)
Dementia

1.67

(1.3-7.2)

Prins et al Arch Neurol 2004

White matter lesions in 2000 and

the development of
dementia and depression
during a 5 year follow-up
OR

(95%CI)

3.0

(1.3-7.2)

Depression 3.0

(1.0-9.2)

Dementia

Olesen P et al. Neuropsychopharmacology 2010

Consequences of subcortical ischemic

vascular disease (white matter lesions)

Dementia
Mild cognitive symptoms
Depression
Functional disability
Gait disturbance and falls
Hip fracture
Urinary incontinence
Brain atrophy
Stroke and other vascular disease
High mortality rate

Cognitive function in nondemented 85-year-olds in relation

to CT white matter lesions
No WMLs
(N)

WMLs

Mean (N)

mean

Verbal ability

(76) 19

(36) 17

Visuospatial ability

(81) 13

(42)

Perceptual speed

(78) 14

(38) 12 *

Skoog et al. Acta Neurol Scand 1996

9 **

Cognitive function in nondisabled elderly (LADIS)

Subcortical ischemic vascular disease on MRI

related to worse performance in:
Global cognitive function
Psychomotor speed
Attention
Executive functions
Verbal fluency
Working memnory
Jokinen et al . Cerebrovasc Dis 2009

Consequences of subcortical ischemic

vascular disease (white matter lesions)

Dementia
Mild cognitive symptoms
Depression
Functional disability
Gait disturbance and falls
Hip fracture
Urinary incontinence
Brain atrophy
Stroke and other vascular disease
High mortality rate

White matter lesions at baseline

and risk of stroke during 4 years
of follow-up.
The Rotterdam Study
RR

95%-CI

Periventricular
lesions

4.7

(2.0 to 11.2)

Subcortical lesions

3.6

(1.4 to 9.2)

RR= upper tertile versus lowest tertile of WML severity

(Vermeer et al. Stroke 2003)

The incidental finding of silent

CVD on brain imaging

Treatment implications?
Treat vascular risk factors
Antithrombotics? Aspirin?
The implication of microbleeds in a person with
stroke or TIA?

THE CONCEPT OF
MIXED DEMENTIA/
MIXED MCI

DEMENTIA IN INDIVIDUALS
WITH ALZHEIMER NEUROPATHOLGY
THE NUN STUDY

%
No infarcts
57
1-2 lacunar 93
Large infarct
75
Snowdon et al JAMA 1997

Alzheimers disease

?
Dementia

?
Mild cognitive
impairment

?
No dementia

Cerebrovascular disease

MIXED DEMENTIA/MCI

Most often Alzheimers disease and

cerebrovascular disease (vascular dementia,
VCI)
Impossible to know which disorder contributed
most
Artificial to try to decide on one diagnosis
Each disorder should be diagnosed
independently of the other
Treatment should be directed to each disorder
separately
Mixed dementia/MCI probable underdiagnosed

MIXED DEMENTIA

ALZHEIMERS DISEASE
CEREBROVASCULAR
DISEASE
OTHER TYPES

A Brjesson Hanson

MIXED DEMENTIA

ALZHEIMERS DISEASE
CEREBROVASCULAR
DISEASE
OTHER TYPES

A Brjesson Hanson

The concept of mixed dementia is

good news for AD prevention

If we prevent cerebrovascular disease, less

persons with Alzheimers disease in the brain
will develop the clinical symptoms of dementia

RISK FACTORS FOR VASCULAR

DEMENTIA

RISK FACTORS FOR

STROKE
Advancing age
Hypertension
Diabetes mellitus
Atrial fibrillation
Previous myocardial infarction
Hyperlipidemia
Low-density lipoprotein cholesterol
Smoking
Overweight
Depression

Depression at age 85 in relation to

first-ever stroke from age 85 to 88
Current
depression at age
85

Incidence of stroke from age 85-88

RR (95%-CI)
Non-demented
(N=307)

2.4 (1.2-4.6)

Demented (N=94)

3.8 (1.2-9.8)
Liebetrau & Skoog. Stroke 2008

RISK FACTORS FOR

WHITE-MATTER LESIONS
Age
Hypertension
Atherosclerosis
Endothelial dysfunction
Diabetes mellitus
Stroke
Cardiovascular disorders
Atrial fibrillation
Overweight
Cardiovascular risk factors
Poor lung function
Stress

Blood pressure in relation to white matter

lesions on CT in 2000. The Prospective
Population Study on Women in Gteborg.
OR per 10 mmHg increase in blood pressure
SBP

DBP

OR

OR

1968

0.9 (0.8-1.1)

1.4 (1.1-1.8)

1974

0.9 (0.8-1.1)

1.3 (1.0-1.7)

1980

0.9 (0.8-1.0)

1.4 (1.1-1.8)

1992

1.0 (0.9-1.1)

1.3 (1.0-1.6)

Guo et al Hypertension 2009

Alzheimer disease

Are vascular risk factors related to

Alzheimers disease?

Is Alzheimers disease a vascular disorder?

Vascular risk factors for AD

ApoE e4 (1993)
Hypertension (1996)
Hypercholesterolemia (1997)
Diabetes mellitus (1997)
Atherosclerosis (1997)
Overweight (2003)

Vascular risk factors for AD

ApoE e4 (1993)

Hypertension (1996)

Hypercholesterolemia (1997)
Diabetes mellitus (1997)
Atherosclerosis (1997)
Overweight (2003)

The role of blood pressure

A 15-year follow-up of
blood pressure and Alzheimers disease
Demented
(N) %
Men (N=75)

37

Women (N=263)

56 *

Skoog et al. Lancet 1996

LONGITUDINAL STUDIES ON BLOOD

PRESSURE AND ALZHEIMERS DISEASE
Previous high blood pressure
5-15 years
Alzheimers disease in late life
The H70-study in Gothenburg
Skoog et al. Lancet 1996
The Honolulu-Asia Aging Study
Launer et al. Neurobiol Aging 2000
The Rotterdam Study
Ruitenberg et al. Dissertation 2000

Kuopio, Finland
Kivipelto et al. BMJ 2001
Kungsholmen Study
Qiu et al Arch Neurol 2003
Chinese Study
Wu et al Life Science 2003

Blood pressure trajectories in relation to

late life dementia in women followed for 38 years

Joas et al. Hypertension 2012

The role of antihypertensive

treatment

HONOLULU-ASIA AGING STUDY

High midlife blood pressure
in men not treated for hypertension
Alzheimers disease in old age
Vascular dementia in old age

Launer et al. Neurobiology of Aging 2000

ANTIHYPERTENSIVE DRUGS
AND RISK OF DEMENTIA
Kungsholmen (incidence) RR (95%-CI)
Dementia
0.7 (0.6-1.0)
(Guo et al. Arch Neurol 1999;56:991-996
Rotterdam (incidence)
RR (95%-CI)
Dementia
0.76 (0.52-1.12)
Vascular dementia
0.30 (0.11-0.99)
(In`t Veld et al. Neurobiol Aging. 2001;22:407-12 )
Cashe County (incidence) RR (95%-CI)
Alzheimers Disease 0.64 (0.41-0.98)
(Khachaturian et al. Arch Neurol 2006;63:686-92

Vascular risk factors for AD

ApoE e4 (1993)
Hypertension (1996)
Hypercholesterolemia (1997)
Diabetes mellitus (1997)
Atherosclerosis (1997)
Overweight (2003)

But the world is changing

And so is the prevalence of
vascular risk factors

The future is already here

Vascular factors in 75-year-olds

Men

Women

1976-77

2005-06

1976-77

2000-01

Any cardiovascular disease

83

74**

91

67***

Myocardial infarction

16

12

15*

Angina pectoris

12

6*

10

Stroke

12*

6*

TIA

Current smokers

32

11*

11*

Life-time smokers

64

65

10

42*

Zhi et al Aging Clin Exp Res. 2013

Vascular factors in 75-year-olds

Men

Women

1976-77

2005-06

1976-77

2000-01

Diabetes mellitus

11

16

11*

Overweight

47

67**

55

62

Obesity

17**

16

21*

Hypertension

76

61**

91

61**

Hypercholesterolemia

66

50**

85

74**

Zhi et al Aging Clin Exp Res. 2013

Systolic blood pressure from

age 70 to 79 in two birth cohorts

Joas et al 2013

PREVALENCE WITH HIGHER

EDUCATION
1986-87

2008-10

N=494

N=571

25

58 ***

1986-87: Skoog et al. N Engl J Med 1993

How does this influence the

prevalence of dementia?

PREVALENCE OF DEMENTIA IN
85-YEAR-OLDS 1986-87 AND
2008-10
1986-87

2008-10

N=494

N=571

31

24 *

1986-87: Skoog et al. N Engl J Med 1993

Type of dementia in 85-year-olds

examined in 1986-87 and 2008-9

1986-87

2008-9

Alzheimer

13

11

Vascular

14

Other

NEJM 1993

p<0.05

PREVALENCE OF STROKE IN
85-YEAR-OLDS 1986-87 AND
2008-10
1986-87

2008-10

N=494

N=571

16

30 **

1986-87: Liebetrau, et al. Stroke 2003

The risk for dementia after

stroke 1986-87 and 2008-9

1986-87

2008-9

No Stroke (%)

23

19

Stroke (%)

57

30

4.3 (2.7-6.9)

1.8 (1.2-2.7)

OR (95%-CI)

1986-87: Liebetrau, et al. Stroke 2003

Reasons for the lower

prevalence of dementia

Larger cognitive and physical reserve in new

cohorts of elderly
New cohorts less vulnerable to different insults,
e.g. stroke
THE HEALTH PARADOX: New generations of
elderly have more disorders, but are healthier
with their disorders

Work-up in vascular dementia

Brain imaging
ECG
Carotid ultrasonography
Blood screen (trombocytes, lipids, glucose etc)
Blood pressure

Therapeutic approach

Secondary prevention targeting vascular targets

Optimum acute stroke care
Cognition improving strategies

Treatment and preventive

strategies

Treat vascular risk factors (hypertension,

diabetes mellitus, hypercholesterolemia,
smoking, obesity)
Low dose acetylsalicylates
Atrial fibrillation
Treat medical and psychiatric illnesses early

Other putative preventive strategies

Decrease stress
Good sleep
Physical activity, good lung function
Leisure time activity
Mentally stimulating activity
Social networking
Mediterrean diet
Healthy diet (cold water fatty fish, green leafy vegetables,
multivitamines)
Omega 3 fatty acids
(High sexual activity)
Red wine?

SYMPTOMATIC TREATMENT WITH

ALZHEIMERS DISEASE DRUGS IN
MIXED DEMENTIA

Acetylcholinesterase inhibitors
Donepezil
Rivastigmine
Galantamine

Prevents the breakdown of acetylcholine

Moderate effect on cognitive function
Maybe effective in 1 out of 5 patients

AD drug trials borderline in VaD

Black S et al. Stroke 2003;34:2323-30; Wilkinson D et al. Neurology 2003;61:479-86; Ogrogozo JM et al. Stroke 2002;33:1834-9; Erkinjuntti T et al. Lancet
2002;359:1283-90; Wilcock G, et al. Int Clin Psychopharmacol 2002;17:297-305; Auchus AP et al. Neurology 2007;69:448-58; Romn GC et al. Stroke
2010;41:1213-21.

But..both risk factors and

dementia needs to be detected..

Many people have hypertension, diabetes

mellitus and hypercholesterolemia without
knowing it
Many people have dementia or cognitive
impairment which is not detected
The latter may have implications for adherence
to medications for physical disorders

WHAT IS GOOD FOR YOUR HEART

IS GOOD FOR YOUR BRAIN
AND
WHAT IS GOOD FOR YOUR BRAIN
IS GOOD FOR YOUR HEART