Stroke and Cognition: VaD, AD and Mixed Dementia

1
Stroke and CognitionVaD, AD and Mixed Dementia

• Dr. Nicole Didyk
• MD, FRCP(C)
• Geriatrician,
• Secondary Stroke Prevention Clinic
• Kitchener, ON

2
Case Presentation

• 67 yo man of Laotian heritage
• Referred for angry outbursts, aggressive
  behaviour
• Currently lives with wife, daughter and her
  family
• Family doing medication, finances, cooking since
  2005
• No driving since MVC in 2004
• Suspicious about money, strange people breaking
  into house

3
Case Presentation

• Grade 4 education in Laos
• In Canada for 30 years
• Worked as labourer, retired 1997
• Requires translation from family to complete
  cognitive assessment

4
Case Presentation

• PMH
• MVC 2004 with significant limb injury, no
  documented brain injury but family feel he has
  had memory and behaviour change since then, and
  has been gradually progressive
• Ischemic left thalamic stroke 2005
• Hemorrhagic right thalamic stroke 2006
• Hypertension noted in last hospital admission
• No residual physical deficits
• MEDS calcium and Vitamin D, glucosamine
  chondroitin

5
Case Presentation

• Physical and cognitive exam
• MMSE 15/28
• Pentagons OK
• Impaired clock
• Normal neuro exam
• Not depressed
• Normotensive (130/58)
• Heart rhythm regular

6
Case Presentation

• Cholesterol
• Total cholesterol 6.30
• HDL1.4
• LDL 4.9
• CT head(2006) chronic changes, old infarcts
• Carotid dopplers (2004) No significant stenosis
• ECHO LVH, no LV systolic dysfunction

7
What is Diagnosis?

• Acquired brain injury?
• Alzheimers disease?
• Vascular dementia?
• Mixed dementia?
• Psychiatric issue?
• Something else?

8
What is Treatment?

• Cholinesterase inhibitor? Which one?
• Platelet inhibitor? Which one?
• Statin?
• Psychotropic?
• Placement?
• Something else?

9
Stroke and Cognition

• Alzheimers Disease
• Vascular Dementia
• Mixed Dementia

10
Educational Objectives

• Recognize the prevalence and impact of vascular
  dementia (VaD)
• Understand causes and characteristics of Vascular
  Dementia
• Identify patients at risk for VaD
• Differentiate VaD from Alzheimers disease (AD)
  and Mixed dementia (AD and VaD)
• Evaluate the usefulness of cholinesterase
  inhibitors (ChEIs) in VaD
• Discuss concept of triple therapy in dementia
  care

11
Overview of Dementia
12
Dementia is

• Common
• 8 of people aged 65 and over (Canada)
• 11 of people aged 75 and over
• 35 of people aged 85 and over
• 25 of Canadians have someone in their family
  with AD
• 52 of Canadians know someone with AD
• Increasing (TRIPLE IN 30 YEARS).
• Expensive (6 B)
• Treatable (HOPE).

13
Dementia is (DSM IV Definition)

• Memory impairment plus one other cognitive domain
  (the As)
• Change from previous
• Affects function
• Not due to general medical condition
• Not diagnosed solely in the midst of a delirium

14
Symptomatic Domains of AD Over Time
Deterioration
Time
Adapted from Gauthier et al. Clinical Diagnosis
and Management of Alzheimers Disease, 1999.
15
Clinical Features of Dementia ABC

• A ADLs
• Finances
• Shopping
• Driving
• Cooking
• Travel
• Laundry

• B Behaviour
• Anger
• Irritability
• Apathy
• Depression
• Agitation

• C Cognition
• Forgetfulness
• Repetitive questions/stories
• Word finding problems
• Planning meals/shopping
• Misplacing objects/getting lost

16
The Greatest Risk Factor for Dementia is Age

• Risk doubles every 5 years.

But each additional risk factor approximately
doubles the risk

• ve family history
• doubles the risk.

17
Dementia Prevalence Related to Age
Canadian Study of Health and Aging, 1994
18
Dementia Risk Factors

• Genetics
• Apolipoprotein E4 status
• Gender (female)
• Head trauma

19
Dementia Risk Factors

• Vascular disease
• Coronary artery disease
• Cerebrovascular disease (CVD)
• Vascular risk factors
• Hypertension
• Type 2 Diabetes
• Atrial fibrillation

20
From the Nun Study

• The presence of 12 lacunar infarcts in basal
  ganglia, thalamus or deep white matter increased
  odds ratio by 20.7 for those with AD lesions
  within neocortex
• Fewer neuropathological lesions of AD appear to
  be needed to result in clinical dementia in
  those with lacunar infarcts or deep white matter
  infarcts than those without infarcts.
• (Snowdon JAMA 1997 277 813-7)

21
Stroke and Cognition Vascular Dementia
22
Evolution of the Concept and Treatment of
Vascular Dementia (VaD)
1860s 1890s 1970s 1970s 1990s 2000s

• Senile dementia normal aging No need to treat
• Senile dementia abnormal Treat with
  vasodilators process due to arteriosclerosis
• Senile dementia AD Cholinergic hypothesis ?
  cholinomimetics in AD
• Arteriosclerotic dementia MID Treat by
  preventing further cerebrovascular damage
• VaD is more than MID Prevent/treat risk factors
• Cholinergic hypothesis of VaD Rationale for the
  use of cholinomimetics in VaD

Francis PT et al. J Neurol Neurosurg Psychiatry,
1999.
Román GC. Alzheimer Dis Assoc Disord, 1999.
23
Vascular Disease and End-Organ Damage
Stroke, Transient Ischemic Attack, DEMENTIA
Adapted from Nyenhuis DL et al. J Am Geriatr Soc,
1998.
24
The brain as a cognitive organ is a major target
for vascular risk factors
25
VaD Risk Factors

• Demographic
• Age
• Sex
• Ethnicity

• Stroke factors
• Previous/recurrent
• cerebrovascular accident (CVA)/TIA

• Vascular risk factors
• Hypertension Cigarette smoking
• Atherosclerosis Hypercholesterolemia
• Diabetes mellitus Ischemic heart disease
• Low blood pressure Atrial fibrillation
• Coagulopathies Elevated homocysteine
• Peripheral vascular disease Myocardial
  infarction (MI)/angina
• CHF
• CABG

Pratt RD. J Neurol Sci, 2002. Skoog I.
Neuroepidemiology, 1998.
26
Diagnosis of VaDThe NINDS-AIREN Criteria

• Diagnosis of dementia
• Cognitive decline (memory and two other domains)
• Impaired functional abilities as a result of
  cognitive decline
• Evidence of cerebrovascular disease (CVD)
• Focal neurological signs consistent with stroke
• Brain CT or MRI required
• Relationship between dementia and CVD
• Temporal association between the two abrupt
  onset of dementia after CVD event
• Sudden stepwise cognitive deterioration

Román GC et al. Neurology, 1993.
27
Diagnosis of VaDThe Hachinski Ischemia Score

• Feature Score
• Abrupt onset 2
• Stepwise deterioration 1
• Fluctuating course 2
• Nocturnal confusion 1
• Relative preservation of personality 1
• Depression 1
• Somatic complaints 1
• Emotional incontinence 1
• History of hypertension 1
• History of strokes 2
• Evidence of associated atherosclerosis 1
• Focal neurological symptoms 2
• Focal neurological signs 2

Score 7 - VaD Score 4 AD
Pantoni L, Inzitari D. Ital J Neurol Sci, 1993.
28
Distribution of Dementia
Alzheimers disease (AD) 64
VaD
19
Other dementias
17

• VaD is the second most common cause of dementia
  in western countries,
• and may be the most common elsewhere (e.g.,
  Asia)

Canadian Study of Health and Aging. CMAJ, 1994.
29
Prevalence and Epidemiology of VaD

• The prevalence of VaD increases with age

• Worldwide elderly population is expected to reach
  2 billion by 2050

Canadian Study of Health and Aging. CMAJ,
1994. World Population Ageing 1950-2050,
Executive Summary. Population Division, DESA,
United Nations.
30
Prevalence and Epidemiology of VaD

• Populations at risk for VaD
• Post-stroke and TIA
• CHF
• Post-CABG
• Post-MI
• Secondary Stroke Prevention Clinic vs. Memory
  Clinic

31
VaD A Heterogeneous Disorder
Cardiovascular Risk Factors
Hypertension Diabetes Genetics
Hypercholesterolemia Heart Disease
Ischemic Damage to Cerebral Vasculature
Multiple Distinct Pathologies
Small Vessel Infarcts
Hemorrhage
Hypoperfusion
Large Vessel Infarcts

• Multiple Lacunae
• Binswangers Disease
• CADASIL

• Global (e.g., cardiac arrest)
• Hypotension

• Chronic SDH
• SAH
• ICH

• Strategic Single Infarcts
• Multi-infarct Dementia

Final Common Pathway
Damage/interruption of subcortical circuits and
projections
Damage to critical cortical and subcortical
structures
? Cholinergic transmission
VaD
Erkinjuntti T. CNS Drugs, 1999.
32
Stroke and Dementia

• Typical cerebrovascular causes of vascular
  dementia
• Thrombosis
• Embolism
• Small-vessel disease
• 25 of patients may develop dementia within 6
  months of a stroke
• Location and volume of infarct will influence
  outcome

Sachdev PS, et al. Med J Aust, 1999. Hénon H, et
al. Neurology, 2001. Kurz AF. Int J Clin Pract,
2001.
33
Stroke and Dementia

• However, approximately 50 of all post-stroke
  dementia is due to AD
• and, dementia can occur in patients with
  extensive white matter lesions in the absence of
  strokes

Sachdev PS, et al. Med J Aust, 1999. Hénon H, et
al. Neurology, 2001. Kurz AF. Int J Clin Pract,
2001.
34
Brain Imaging of VaD
3 Types of VaD
Multiple large vessel infarcts
Bilateral strategic thalamic infarcts
Binswangers disease
Source Stephen Salloway, MD
35
VaD Pathology and Clinical Presentation
Small vessel disease
Large vessel disease
Pathology
Subcortical infarcts in strategic locations
(e.g., thalamus)
Large cortico-subcortical infarcts
Lesion location
40 No focal signs or mild UMN signs (e.g., arm
drift, etc.)
Focal
Neurological signs and symptoms
Dementia-related changes
Memory impairment cortical dysfunction (aphasia,
apraxia,agnosia, visuospatial dysfunction)
Memory impairment
Cognition
Executive dysfunction (slowing, initiation,
planning, organizing, sequencing, monitoring, set
shifting, abstraction, judgement)
Classic
Common
Preserved until late
Personality
Change
Insight
Retained until late
Can be impaired
Less common (although some depression)
Depression, apathy, anxiety, emotional lability
Affective/mood disturbances
Cummings JL. Dementia, 1994.
36
AD vs. VaD Classical Clinical Features
VaD
AD
Abrupt Stepwise Present Present Present
(CADASIL, autosomal dominant 19q12)
Spotty deficits, executive dysfunction often
prominent
Insidious Slow, gradual Usually absent May be
present Present (linked to genes on various
chromosomes)
Memory, naming - with typical progression
Onset Progression Focal neurological signs or
symptoms Vascular risk factors(e.g.,
hypertension, diabetes, TIA/CVA,
CAD) Genetics Cognitive profile
Román G. Int J Clin Pract, 2001.
37
Overlap Between Alzheimers Disease (AD) and VaD
Cholinergic deficit
VaD
AD
Mixed AD/VaD Amyloid plaques Genetic
factors Neurofibrillary tangles Stroke/TIA Hyperte
nsion Diabetes Hypercholesterolemia Heart disease
Amyloid plaques Genetic factors Neurofibrillary
tangles
Stroke/TIA Hypertension Diabetes Hypercholesterole
mia Heart disease
Kalaria RN, Ballard C. Alzheimer Dis Assoc
Disord, 1999.
38
The continuum of Vascular Dementia (VaD) and
Alzheimers disease (AD)
39
Emerging view of VaD and AD

AD w/CVD
AD
VaD
40
Cholinergic Hypothesis of VaD
A cholinergic deficit in VaD may arise from

• Alterations in the soma of nucleus basalis of
  Meynert cholinergic neurons - found in some cases
  of VaD at autopsy
• Vascular lesion involvement of cholinergic
  pathways
• Not present in controls
• Moderate to severe in 66 of VaD patients
• Other cholinergic markers also decreased in VaD
  patients, including decreased acetylcholine in
  the cerebrospinal fluid of patients with VaD of
  the Binswangers type and small vessel disease

Amenta F et al. Clin Exp Hypertens, 2002. Swartz
RH et al. J Stroke Cerebrovasc Dis, 2003.
41
Cholinergic Deficit in VaD

• Involvement of cholinergic pathways in VaD
  patients

With permission from Oxford University Press.
Cholinergic pathways in healthy brain
White matter hyperintensities in VaD
Selden NR, et al. Brain, 1998. Swartz RH, Black
SE. J Neurol Sci, 2002.
42
Stroke and Cognition Screening for Dementia
43
Dementia Screening

• High risk asymptomatic elderly
• Age over 80 (prevalence of dementia gt 25) by age
  alone
• Age over 65 and clinical factors
• Post CVA
• Vascular risk factors
• Delirium,
• Depression (1st onset over age 65)
• Warning signs / behavioral flags
• Family history

44

• Behavioral Flags for Professionals
• 1. Frequent phone calls.
• 2. Poor historian, vague.
• 3. Poor compliance meds/instructions.
• 4. Appearance / mood / personality.
• 5. Word finding / decreased interaction.
• 6. Appointments - missing / wrong day.
• 7. Confusion surgery, illness, meds.
• 8. Weight loss / dwindles.
• 9. Driving accident / problems.
• 10. Head turning sign. (Turning to caregiver for
  answer).

45
Any Memory Concerns Expressed by the Caregivers
Should be Comprehensively Evaluated

• Canadian Consensus Conference on Dementia
• Memory Complaints should be evaluated and the
  individual followed to assess progression (B)
• Complaints should be considered very seriously if
  confirmed by caregivers / informants. Cognitive
  assessment and careful follow-up is recommended
  (A).
• (Patterson Can J. Neuro Sci 2001 28 (Suppl. 1)
  S 3-16).

46
Screening for VaD

• Dementia screening tools (AD)
• MMSE
• MOCA
• Clock drawing
• Trails B
• Luria kinetic melody (hand test)
• Questioning of patient/caregiver about activities
  of daily living
• Identification of symptoms of executive
  dysfunction

47
Dementia Quick Screen 2 Minutes

• 3 item recall (0-1 correct OR 3.1)
• 4-legged animals in 1 minute (lt15 OR 20.2)
• Clock drawing (abnormal OR 24)
• Year (OR 37)

48
MMSE (cut off lt 24)

• Focus on memory/orientation 16/30 points (good
  for AD, poor for non-Alzheimers dementias)
• Poor at upper end at discrimination between
  normal (especially highly educated) and MCI
• Poor with those lt grade 5 education (cut off 20
  for 80 yo, 19 for 85 yo)

49
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50
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51
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52
MOCA (www.mocatest.org)

• Comprehensive Many more domains than MMSE (good
  for AD and non AD)
• Minor adjustment for education (add 1 point if
  grade 12)
• Much better discrimination
• Normal vs MCI and Dementia
• 26 lt 26 lt 26
• (usually 21-25) (usually lt 20)
• (function OK) (function affected)

53
Is Function Affected / Activities of Daily
Living?

• Instrumental ADL Affected (SHAFT)
• Shopping
• Housework/Hobbies
• Accounting Bank
• Food Preparation
• Transportation
• and Medication Management
• Basic ADL Affected (DEATH)
• Dressing
• Eating
• Ambulation
• Toilet
• Hygiene

54
Management of Dementia

• AD, VaD, and Mixed

55
Concept of Triple Therapy

Vascular risk factors
Caregiver education and support
A trial of cholinesterase inhibitor (CI)
56
Triple Therapy

• Treatment goals
• Prevent further cerebrovascular events
• Minimize symptoms of dementia syndrome
• Support caregiver
• The presence of CVD in dementia should not deter
  from treatment of cognitive, functional, or
  behavioural impairment due to dementia disorder
• The presence of CVD may impact the underlying
  dementia

57

• It is now increasingly clear that risk factors
  should be treated in dementia whether the
  diagnosis is AD, VAD or mixed AD / VAD 80 of
  dementia
• STROKE PREVENTION DEMENTIA PREVENTION
• Atrial fibrillation
• Hypertension especially systolic
• Smoking
• Diabetes
• Hyperlipidemia

58
Management of VaD

• Risk assessment
• Age, hypertension, smoking, diabetes, history of
  stroke/TIA
• Reduction of risk of further damage
• Management of stroke and risk factors (e.g.,
  hypertension, hypercholesterolemia)
• Treatment of dementia symptoms
• Cognition, global function, activities of daily
  living
• Treatment of comorbid conditions
• Depression, anxiety, agitation

Erkinjuntti T. CNS Drugs, 1999. Gupta A et al.
Int J Clin Pract, 2002.
59
Prevention of VaD Control of Risk Factors
Identify patients at risk

Erkinjuntti T. CNS Drugs, 1999.
60
Treat Vascular Risk Factors

• From NUN Study INFARCTS ? risk for dementia
  (Odds ratio 20 times)
• CCG level 1/Grade A
• Good evidence to treat systolic hypertension
  (goal 140)

61
Treat Cholinergic Deficit

• A TRIAL with a cholinesterase inhibitor should be
  given to all APPROPRIATE patients.
• CCG Level 1/Grade A
• All 3 CIs are efficacious for mild to moderate AD

62
Cholinesterase Inhibitors (CI)
63
Randomized, controlled trials with AChEIs in AD
w/CVD and VaD

• Cholinergic deficits in AD w/CVD and VaD suggest
  a role for AChEIs
• Large, randomized, placebo-controlled trials have
  tested AChEIs in AD w/CVD and VaD
• GAL-INT-6 AD w/CVD or VaD
• Donepezil 307 and 308 Possible or probable VaD
• GAL-INT-26 Probable VaD with expert reader

Erkinjuntti T et al. Lancet 2002 359 128390.
Black S et al. Stroke 2003 34 232330.
Wilkinson D et al. Neurology 2003 61 47986.
Auchus AP et al. Poster presented at the 56th
Annual Meeting of the American Academy of
Neurology (AAN) 2004 April 24 May 1 San
Francisco, California, USA.
AChEIs acetyl-cholinesterase inhibitors
64

• The individual response is approximately
• ¼ are super responders with obvious significant
  improvement usually within 6 weeks.
• ½ are mild responders with modest improvement or
  maintenance at the same level.
• ¼ are non-responders with continued
  deterioration at the previous rate of decline.

65
Evaluating Therapy

• The major aspects of determining if a patient is
  responding to an AChEI are
• Caregiver impression target symptoms
• Cognitive assessment (MMSE / Clock)
• Global impression
• An adequate trial to determine response is
• 3 6 months

66
Caregiver Support

• Referral to Alzheimers Society
• Referral to CCAC
• Day Programs
• Day Hospital

67
Overall Summary

• VaD should be considered in patients with risk
  factors such as hypertension, diabetes,
  ?cholesterol and history of stroke/TIA
• Triple therapy approach stroke prevention,
  cholinesterase inhibitor, caregiver support
• Cholinesterase inhibitors have been shown to be
  effective, safe and well tolerated in studies
  with VaD patients

68
Rivastigmine in VaD Study Design

• Design
• 12-month, randomized, controlled, open study
• Subjects
• 208 patients who met the NINDS-AIREN criteria for
  mild to moderate probable subcortical VaD, with
  an MMSE and DSM-IV for dementia were randomized
  to
• Rivastigmine 3-6 mg/day (Group A) or
  Cardioaspirin 100 mg/day (Group B)
• Outcome measures
• MMSE (cognition)
• Ten-Point Clock-Drawing (TPC) test (executive
  function)
• WF-phonol. (word fluency)
• Behavioural Pathology in AD Rating Scale
  (BEHAVE-AD, behaviour)
• Geriatric-Depression Scale (GDS, depression)
• Cumulative Illness Rating Scale (CIRS, global
  health)

Moretti R, et al. Am J Alzheimers Dis Other
Demen, 2003.
69
Rivastigmine in VaD Cognition
MMSE
pNS
Moretti R, et al. Am J Alzheimers Dis Other
Demen, 2003.
70
Rivastigmine in VaD Behaviour
BEHAVE-AD




plt0.01


Moretti R, et al. Am J Alzheimers Dis Other
Demen, 2003.
71
Rivastigmine in VaD Executive Function
TPC test
plt0.05

Moretti R, et al. Am J Alzheimers Dis Other
Demen, 2003.
72
Rivastigmine in VaD Summary

• Rivastigmine-treated patients demonstrated
  benefits in
• Executive function, as shown by less decline on
  the TPC scale versus placebo
• Behaviour, with improvement on several items on
  the BEHAVE-AD scale versus placebo
• Global function, as shown by improved GDS scores
  versus placebo
• Rivastigmine treatment was well tolerated
  throughout the trial

Moretti R, et al. Am J Alzheimers Dis Other
Demen, 2003.
73
Galantamine in VaD and Mixed Study Design

• Design
• 24-week, randomized, placebo-controlled,
  multicenter, multinational trial
• Subjects
• 592 patients (21 randomization) 4 mg/day for 1
  week, escalated to 24 mg/day by week 6
• Modified NINDS-AIREN criteria confirmed
  radiographic lesions
• 49 AD with cerebrovascular disease
• 42 probable VaD
• 9 undecided (either VaD or AD with
  cerebrovascular disease)
• Outcome measures
• ADAS-cog (cognition)
• CIBIC-plus (global function)
• Disability Assessment in Dementia (DAD,
  activities of daily living)
• Neuropsychiatric Inventory (NPI, behaviour)

Erkinjuntti T et al. Lancet, 2002.
74
Galantamine Study Cognition
plt0.001
-4
-3
-2
-1
LS mean ( SE) change from
baseline score
0
1
Galantamine (24 mg/day)
2
Placebo
3
Study week
Erkinjuntti T et al. Lancet, 2002.
75
Galantamine Study Behaviour
plt0.05
NPI


ITT LOCF
Erkinjuntti T et al. Lancet, 2002.
76
Galantamine Study ADLs
plt0.01
DAD


ITT LOCF
Erkinjuntti T et al. Lancet, 2002.
77
Galantamine Short-term studiesCochrane review
at 6 months
Galantamine ITT analysis
CognitionADAS-Cog
FunctionADCS-ADL
BehaviourNPI
Global scoresCIBIC-plus
Favours treatment
Favours placebo
OR odds ratio WMD weighted mean difference
(fixed)
78
GAL-INT-6 Galantamine in AD w/CVD or probable
VaD at 6 months
Cognition/ADAS-Cog
Function/DAD


p lt 0.001 vs baseline and placebo
p lt 0.01 vs placebo
Behaviour/NPI
Global performance


p lt 0.05 vs placebo
p 0.0011 vs placebo
Erkinjuntti T et al. Lancet 2002 359 128390
Reprinted with permission from Elsevier (The
Lancet, 2002, 359, 12831290).
79
Cognition in Patients with ADCVD
Double Blind n285
Open Label n238
Galantamine24 mg/day


Placebo
Improvement
Mean change from baseline in ADAS-Cog score
p lt 0.05 vs. baseline p lt 0.01 vs. baseline
p lt 0.001 vs. baseline p0.001 GAL vs. PLACEBO

Time (months)
Bullock et al. Dement Geriatr Cogn Disord, 2004
80
Mean Change in Daily Time Spent by Caregiver
Assisting With ADL at 6 Months
30
Galantamine 24 mg/d (n 165)

20
10
Placebo (n 160)
Change From Baseline in Daily Time Spent
Assisting With ADL (min)
0
10
20
30
40
50
p lt 0.05 vs baseline
Wilcock GK et al (poster WAC 2000) Blessa R.
Dement Geriatr Discord 2000 1128-34.
81
Galantamine Study Summary

• Galantamine-treated patients demonstrated
  benefits in
• Cognition, as shown by improvement in scores on
  the ADAS-cog scale versus placebo
• Global function, as shown by a clinicians
  assessment of change reflected by improved
  CIBIC-plus scores versus placebo
• Activities of daily living, as shown by less
  decline on the DAD scale than placebo
• Behaviour, as shown by improvement on the NPI
  scale versus placebo
• Galantamine was well tolerated throughout the
  trial

Erkinjuntti T et al. Lancet, 2002.
82
Summary of Galantamine in ADCVD

• Demonstrated efficacy in maintenance of ADL and
  behaviour
• Longer term trials (up to 2 years) have shown
  positive effects in maintaining cognition

Erkinjuntti et al. The Lancet, 2002 Kurz et al.
Eur J Neurol, 2003
83
Donepezil in VaD Cognition
MMSE









plt0.01, plt0.001 versus placebo
ITT LOCF
Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
84
Donepezil in VaD Cognition
ADAS-cog










plt0.001 versus placebo
ITT LOCF
Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
85
Donepezil in VaD Global Function
CIBIC-plus at endpoint (week 24 LOCF)
Clinical decline
Clinical improvement
45
Donepezil 10 mg/day
40
Overall treatment plt0.01 plt0.001 Donepezil 5
mg/day vs. placebo p0.06 Donepezil 10 mg/day
vs. placebo
(n398)
Donepezil 5 mg/day
35
(n399)
Placebo
30
(n383)
25
of patients
20
15
10
5
0
Marked
Moderate
Minimal
No change
Minimal
Moderate
Marked
improvement
improvement
improvement
worsening
worsening
worsening
Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
86
Donepezil in VaD Global Function
CDR-SB




plt0.05, plt0.01 versus placebo
ITT LOCF
Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
87
Donepezil in VaD Instrumental ADLs
IADLs (ADFACS)






plt0.05, plt0.01 versus placebo
ITT LOCF
Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
88
Donepezil in VaD Summary

• Donepezil-treated patients demonstrated benefits
  in
• Cognition, as shown by improvement in scores on
  the ADAS-cog and MMSE scales versus placebo
• Global function, as shown by a clinicians
  assessment of change reflected by improved
  CIBIC-plus scores, and CDR-SB scores, versus
  placebo
• Activities of daily living, as shown by
  improvement on the IADLs of the ADFACS scale
  versus placebo
• Donepezil treatment was well tolerated in VaD
  patients
• The types of AEs were similar to those observed
  in AD patients (i.e., cholinomimetic effects)

Black S et al. Stroke, 2003. Wilkinson D et al.
Neurology, 2003. .
89
Summary of Galantamine in ADCVD

• Demonstrated efficacy in maintenance of ADL and
  behaviour
• Longer term trials (up to 2 years) have shown
  positive effects in maintaining cognition

Erkinjuntti et al. The Lancet, 2002 Kurz et al.
Eur J Neurol, 2003
90
Canadian Consensus Guidelines in Mixed Dementia
(AD with CVD/AD and VAD)

• Level 1 Grade B
• Galantamine can be considered a treatment option
  for mixed Alzheimers with cerebrovascular disease

91
Galantamine Summary

• Consistently positive results on all trials
• Maintains cognition for 12 months
• Delays emergence of behavioural symptoms
• Maintains activities of daily living
• Efficacy not compromised by tolerability concerns
• Lessens caregiver burden delays nursing home
  placement
• Convenient, once daily formulation

92
Recommendations for treatment

• Galantamine is the only AD agent evaluated in a
  randomized, double-blind study of patients
  diagnosed as having AD w/CVD
• only agent with AD w/CVD data included in the
  product label
• Galantamine has shown robust and lasting efficacy
  in the AD w/CVD population
• Galantamine is safe in AD w/CVD
• does not increase risk of additional
  cardiovascular or cerebrovascular events, even in
  the high cardiovascular-risk populations studied

93
Triple Therapy

• Screen for and control vascular risk factors
• Consider CI
• Support caregiver