1. Vascular Dementia
Moises Gaviria MD
Distinguished Professor of Psychiatry University of Illinois at Chicago
Director of Neuropsychiatry at Christ /Advocate Medical Center

2. HISTORICALHISTORICAL
PERSPECTIVEPERSPECTIVE

3. Historical Overview
Perhaps the earliest clinical description of
vascular dementia comes from Thomas
Willis, whose careful attention to the
cerebral vasculature led to his description
of the circle of Willis in 1684.
Under the heading “A palsie often
succeeds stupidity, or becoming foolish,”
he relates the following:
I have observed in many, that when, the Brain
being first indisposed, they have been
distempered with a dullness of mind, and
forgetfulness, and afterwards with a stupidity
and foolishness, after that, have fallen into a
palsie, which I often did predict.

4. and Alzheimer (1895)
Historical Overview
proposed a concept of “arteriosclerotic brain degeneration”
Binswanger (1894)

5. Historical Overview
Otto Binswanger and Alois Alzheimer
separated the dementia paralytica
(neurosyphilis), a common disease
at that time, from vascular dementia
Based on this classification Kraepelin
concluded that cerebral arteriosclerosis or
arteriosclerotic insanity was the most
frequent form of senile dementia
Emil Kraeplin (1856-1926)

6. Historical Overview
DSM-II (1968), the term “arteriosclerotic brain
degeneration” was modified to “ psychosis with
cerebral arteriosclerosis “
Hachinski (1974) proposed the term
multi-infarct dementia (MID),
and the original
Hachinski Ischemic Score (HIS)
providing criteria for diagnosis of
vascular dementia.

7. In 1991 Neuroepidemiology Branch of the
National Institute of Neurological Disorders and
Stroke (NINDS) convened an International
Workshop with support from the Association
Internationale pour la Recherche et
l'Enseignement en Neurosciences (AIREN),
resulting in research criteria for the diagnosis of
vascular dementia
Historical Overview
Neurology 1993; 43: 250-260

8. VaD Classifications
All existing classifications identify patients
with VaD, but their sensitivity and specificity
vary.
Diagnostic and Statistical Manual of Mental
Disorders, Fourth Edition [DSM-IV],
National Institute of Neurological Disorders and
Stroke–Association Internationale pour la
Recherche et l’Enseignement en Neurosciences
[NINDS-AIREN],
International Statistical Classification of Diseases,
10th Revision [ICD-10]
California Alzheimer’s Disease Diagnostic and
Treatment Centers [CAD-DTC]

9. VaD Classifications
The criteria of the CAD-DTC apply exclusively to VaD caused
by ischemic CVD
NINDS-AIREN criteria recognize that VaD may result from
complete or incomplete brain ischemia, cerebral hemorrhage,
and other vascular or circulatory injuries to the brain.
Both evolved from the Hachinski Ischemic Scale [HIS].
Both sets of VaD criteria rely on neuroimaging by CT or MRI
for confirmation of cerebrovascular lesions .
Lesions include both large and small vessel ischemia.
Erkinjuntti, Timo MD; Roman, Gustavo et al.
Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment.
Stroke. 35(4):1010-1017, April 2004.

10. Large-vessel injuries are:
Multiple either cortical or cortico-subcortical infarcts
Single, strategically placed infarcts that occur in areas that are
crucial for cognition or behavior
Angular gyrus
Basal forebrain
Thalamus
Anterior or posterior cerebral artery strokes
Small-vessel injury is manifested as:
Multiple basal ganglia and white matter lacunae
Extensive white matter lesions
Combinations of both.
Patients can have evidence of either large-vessel or small-vessel
disease or both.
Erkinjuntti, Timo MD; Roman, Gustavo et al.
Emerging Therapies for Vascular Dementia and Vascular Cognitive Impairment.
Stroke. 35(4):1010-1017, April 2004.
VaD Classifications

11. The NINDS-AIREN criteria are currently most widely
used in clinical drug trials on VaD.
Based on neuropathological series
sensitivity was 58%,
specificity was 80%,
successfully excluded AD in 91% of cases,
proportion of combined cases misclassified as
probable VaD was 29%.
Compared to the CADDTC criteria, the NINDS-AIREN
criteria were more specific, and they better excluded
combined cases (54% vs. 29%)
Gold, G., P. et al.. Sensitivity and specificity of newly proposed clinical
criteria for possible vascular dementia. Neurology 49 1997, : 690-694
VaD Classifications

12. PATHOGENESISPATHOGENESIS

13. Pathogenetic mechanisms
Regional cerebral blood flow is reduced
Oxidative stress including free radicals
Damage of endothelial cells
Chronic hypoperfusion
Polioararoisis and leukoaroiosis
Changes in the small penetrating arteries and arterioles in
the white matter

14. A
P
EC
NORMAL CAPILLARY
A
P
EC
SVaD CAPILLARY
BL BL
L
L
A= astrocyte
P=perycite
EC= endothelial cell
BL= basal lamina
L=lumen
Thickened basal lamina
Endothelial cell shape distorsion
Degenerating perycite
Severe luminal blocking

15. NFkb
iNOS receptor
Regulation protein
transcripton
IkBa
eNOS
EndotheliumEndothelium
Endothelial changes Cytokines
activation
NO
H2O2
O-2
NOO-2
H2O2
H2O2
•Citosolic Superoxide Dysmutase

16. endothelium
PPARj
CuZn-
SODNFkb
Angiotensin II receptor
ANGIOTENSIN II
Kidney
Arteriolar
vasoconstriction
INCREASED BLOOD PRESSURE
Peroxisome Proligerator Activated Receptor
CuZn Superoxide Dysmutase

17. IMAGINGIMAGING
ININ
VaDVaD

18. Increased sophistication of imaging
in VaD
Initially CT scanning demonstrated lacunar infarcts as well as
patches of white matter disease (leukoariosis).
Then the MRI scan, particularly with the fluid-attenuated inversion
recovery (FLAIR) sequences dramatically demonstrated not only
the extent of the white matter disease, the hallmark of small vessel
disease, but also the small cortical lesions that were not identified
on the old T1 and T2 sequences.
In addition to localizing lesions in the brain, it is now possible to
quantitate the extent of the white matter change using an
automated magnetic resonance tissue class segmentation
technique.
Wei X, et al. Quantitative analysis of MRI white matter signal abnormalities with high
reproducibility and accuracy. J Magn Reson Imaging 2002; 15: 203–209

19. In addition to the morphologic imaging
techniques, functional scans; PET and SPECT
are able to image perfusion and, in the case of
PET, oxygen or glucose use of the cortical
gray and subcortical white matter tissue.
This is useful in differentiating VaD from
Alzheimer's disease, where there is a temporal
and parietal decrease in uptake, from the
scattered perfusion defects seen in vascular
dementia.
Increased sophistication of imaging
in VaD

20. MRI Procedures with Clinical
Significance
Diffussion and perfusion MRI are being
used increasingly in neurovascular
clinical applications.
DTI is being found to be a helpful
technique in the studies of the white
matter disease and in correlating it with
cognitive impairment

21. Anisotropy in White Matter
Isotropic diffusion.
No barriers to motion of hydrogen
Diffusion in CSF Diffusion in White Matter
Anisotropic diffusion.
Hydrogen flows along the axis of
the white matter tract
Fractional Anisotropy = 0.05 FA = 0.75
Myelin
barrier
Courtesy of G. Stebbins

22. Diffusion Tensor Imaging

23. White matter hyperintensities
White matter hyperintensities (WMHs)
are areas of increased signal on T2-
weighted and fluid-attenuated inversion
recovery MRI sequences of the brain.
These phenomena may not be benign
because they are seen in up to 70% of
persons with vascular dementia and
Alzheimer’s disease.
Stroke Risk Profile Predicts White Matter Hyperintensity Volume
The Framingham Study Tom Jeerakathil et al.
(Stroke. 2004;35:1857-1861.)

24. White matter hyperintensities

25. Multiple studies have found adverse
associations between WMH and
neuropsychological function, gait and
balance, lower extremity function,
depression, and recurrent stroke and
death.
Stroke Risk Profile Predicts White Matter Hyperintensity Volume
The Framingham Study Tom Jeerakathil et al.
(Stroke. 2004;35:1857-1861.)
White matter hyperintensities

26. Stroke Risk Profile Predicts White Matter
Hyperintensity Volume
Offspring subjects obtained from the
Framingham Cohort were invited to undergo
a brain MRI using a standard protocol to
assess the relationship between WMHV and
10 year probability of stroke events.
The contribution of individual risk factors to
the 10-year probability of stroke events was
determined using sex-specific Cox
proportional hazard models.
Stroke Risk Profile Predicts White Matter Hyperintensity Volume
The Framingham Study Tom Jeerakathil et al.
(Stroke. 2004;35:1857-1861.)

27. Stroke Risk Profile Predicts White Matter
Hyperintensity Volume
Component risk factors included:
Age in years
Systolic blood pressure (SBP) in mm Hg
Use of antihypertensive medication
Diabetes
Number of cigarettes smoked per day
CVD
Atrial fibrillation
Left ventricular hypertrophy (LVH) by
electrocardiogram (EKG).
Stroke Risk Profile Predicts White Matter Hyperintensity Volume
The Framingham Study Tom Jeerakathil et al.
(Stroke. 2004;35:1857-1861.)

28. MRI study in elderly people
If the MRI findings are markers for early
cognitive and gait impairments,
identification and control of causal
factors could reduce the risk of these
common problems of the elderly.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

29. MRI study in elderly people
Correlates of white matter findings were
sought among 3301 elderly people who
underwent MRI scanning and denied history
of stroke or transient ischemic attacks.
Participants underwent extensive
standardized evaluations at baseline and on
follow up, including standard questionnaires,
physical examination, multiple blood tests,
ECG, PFT’s etc.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

30. MRI study in elderly people
Many potential risk were related to the white
matter grade, but in the multivariate model
the factors significantly (all P< .01) and
independently associated with increased
grade were:
Greater age
Clinically silent stroke on MRI
Higher systolic blood pressure
Lower forced expiratory volume in 1 second
(FEV1)
Income less than $ 50,000 per year
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

31. Descriptive term introduced in 1987 by Hachinski and
colleagues to indicate the periventricular white matter
MR hyperintensities frequently found in elderly people
Leukoaraiosis

32. Leukaraiosis
Demyelinization in brain subcortical
structures
Loss of glia cells
Spongy appearance and occlusion of
veins and venules by collagenous
thickening of vessels walls
Changes in the small penetrating
arteriolae in the white matter
Leukoaraiosis could be graded

33. Diagnosis of Acute Stroke
65 y.o. male Hx HTN, c/o feeling of LE weakness
Courtesy of K. Thoulborn

34. Diagnosis: Early Subacute Stroke
65 y.o. male Hx HTN, c/o feeling of
weakness
DWI
ADC
Courtesy of K. Thoulborn

35. High Risk Patients
Patient s/p stroke and occlusion of
left ICA
Pre Gd post Gd
FLAIR GRE DTI (FA)
Left ICA
Occlusion
Courtesy of K. Thoulborn

36. Perfusion for Hemodynamic Reserve
1 10 20 30
40
8000
6000
4000
2000
0
Vasodilation
(acetozolamide)
1 10 20 30
40
8000
6000
4000
2000
0
Courtesy of K. Thoulborn

37. Tissue Perfusion
Relative CBV Tissue Transit Time
Courtesy of K. Thoulborn

38. Hemodynamic Reserve
Hand Clasping
Paradigm fMRI -
cognitive stress test
for hemodynamic
reserve
17
-17
4.0
Courtesy of K. Thoulborn

39. Diffusion-weighted MRI
for the details
of acute cerebral ischemia

40. DWI in stroke

41. DWI in VaD
Diffusion-weighted MRI (DWI) has
already had a substantial affect on the
diagnosis of patients with ischemic
stroke. It provides in vivo pathological
information and allows the
differentiation of acute stroke from
chronic stroke and from non-specific
white matter lesions.
Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.
The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45)

42. DWI in VaD
The high contrast of the acute DWI
lesion against the dark background
facilitates the detection of lesions even
when they are 1mm or less in diameter.
Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.
The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45

43. DWI in VaD
Small lesions. Which are undetectable
by other means, include small lacunar
infarcts, punctate cortical infarcts, and
DWI bright dots in patients with
transient ischemic attacks (TIA).
The latter constitute remnants or
“footprints” of recent ischemia and
confirm the clinical TIA syndrome as
ischemic.
Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.
The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45

44. DWI in VaD
Because of these attributes, DWI not
only confirms the clinical diagnosis,
but also facilitates the recognition of
certain patterns of ischemia, thereby
providing clues to the underlying
aetiology.
DWI is becoming an important
technique for optimum management of
patients.
Achim Gass, Hakan Ay, Kristina Szabo, Walter J Koroshetz.
The Lancet Neurology. Vol-3 Jan 2004; 3: 39-45

45. DWI in VaD
Gerraty and colleagues confirmed that infarct
pathogenesis can be better revealed with DWI than
with conventional MRI in patients with lacunar stroke
syndromes.
They used DWI and perfusion-weighted MRI (PWI)
within 24 hrs. of stroke in a prospective series of 106
patients, including 19 with lacunar syndrome.
With use of DWI and PWI, the final diagnosis of
infarct pathogenesis was changed from occlusion of
small perforating artery to large-artery embolism in
13 of the 19 patients who presented with lacunar
syndromes.
Oliveira-Filho j, Ay Koroshetz WJ, et al.
Localization of clinical syndromes using DWI:
two examples of the “capsular” warning syndrome.
J Neuroimaging 2001; 11: 44-47

46. Hypertension and VaD

47. Hypertension and VaD
Dementia and a decline in cognitive
function have been added to the
consequences of hypertension.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

48. Hypertension and VaD
Hypertension is an established risk
factor both for stroke and coronary
heart disease. And the fact that the
prevalence of hypertension increase
with age provides one explanation for
the expected rise in stroke and
coronary heart morbidity in the future
as the population in industrialized
countries ages.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

49. Hypertension and VaD
The SCOPE trial was initiated as a
placebo-controlled study with the aim
of assessing the effects of
antihypertensive treatment with the
angiotensin II type 1 (AT 1) receptor
blocker candesartan cilexetil
(canderartan) in elderly (70-89 years)
patients with SBP 160-179mmHg and
/or diastolic blood pressure (DBP) 90-
99mmHg.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

50. Hypertension and VaD
The benefits of antihypertensive
treatment in the elderly are well
established.
Several large intervention trials have
shown a significant reduction in the
incidence of stroke and cardiovascular
morbidity in treated elderly with
hypertension.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

51. Hypertension and VaD
Because changed in the treatment guidelines
and for ethical reasons it became necessary
during the recruitment period to recommend
open-label active antihypertensive therapy in
both treatment groups for patients whose
blood pressure remained high.
As a result, the trial actually compared a
candesartan-based regimen with a usual
treatment not containing candersartan.
WT Lonstreth, Teri Manolio, Alice Arnold et al.
Clinical correlates of White Matter Findings on Cranial Magnetic Resonance
Imaging of 3301 Elderly People. Stroke, 1996; 27: 1274-1282

52. TreatmentTreatment
OptionsOptions

53. Treatment of VaD
Primary and secondary stroke prevention
can decrease VaD incidence.
Treatment can be divided in:
improvement of core symptoms
(cognition, function and behavior)
slowing progression
neuropsychiatric symptoms (depression,
agitation, anxiety)

54. Primary prevention
Treatment of vascular risk factors
(HTN, lipid abnormalities, atrial
fibrillation, MI, CAD, DM, smoking,
hyperhomocysteinemia)
Treatment of isolated systolic HTN in
elderly decreased incidence of
dementia significantly
Forette et al “ The prevention of dementia with antihypertensive treatment
New evidence from the Systolic Hypertentsion in Europe”
Arch Int Med 162, 2002

55. Secondary prevention
Early diagnosis and treatment of acute
stroke.
Prevention of stroke recurance:
Statins shown to prevent dementia in animal studies
Perindopril (ACE inhibitor) showed strikingly beneficial
effects in reducing the risk of dementia and cognitive
impairment in pts with recurrent stroke
Fassbender et al Proc. Natl. Acad.Sci. 2001
The PROGRESS collaborative group Arch. Int. Med. 2003

56. Secondary prevention cont’d.
Intensive management of existing
risk factors
Fasting total homocysteine is an independent
predictor of cognitive decline
Elevated homocysteine is a marker of folate/B12
deficiency
Significant improvement in cognition shown after
supplementation in pts with mild to moderate
dementia
Nilsson et al. “Improvement of cognitive functions after cobalamin/folate supplementation
in elderly patients with dementia and elevated plasma homocysteine.”
International Journal of Geriatric Psychiatry. 2001.

57. Numerous compounds purported to be useful in the
symptomatic treatment of VaD include:
Antithrombotics
Ergot alkaloids
Nootropics
Thyrotropin-releasing hormone analogue
Ginkgo biloba extracts
Plasma viscosity drugs
Hyperbaric oxygen
Antioxidants
Calcium antagonists.
These studies had mostly negative results, were based
on small numbers and short treatment periods, and often
included mixed populations and various diagnostic
criteria, evaluation tools, and clinical end points.
Pharmacotherapy of of VaD
Erkinjuntti, Timo MD; Román, Gustavo MD et al. Emerging Therapies for Vascular
Dementia

58. Pharmacotherapy of of VaD
Cholinergic deficits are well documented in
VaD, independently of any concomitant AD
pathology.
Cholinergic structures are vulnerable to
ischemic damage; for instance, basal
forebrain cholinergic nuclei are irrigated by
penetrating arterioles susceptible to the
effects of arterial hypertension
Hippocampal CA1 neurons are particularly
vulnerable to experimental ischemia, and
hippocampal atrophy is common in patients
with VaD in the absence of AD.
Erkinjuntti, Timo MD; Román, Gustavo MD et al. Emerging Therapies for Vascular
Dementia

59. The safety and efficacy of donepezil have been
studied in the largest clinical trial of pure VaD to
date.
A total of 1219 subjects were recruited for a 24-week,
randomized, placebo-controlled, multicenter,
multinational study divided into 2 identical trials, 307
and 308.
The patients were randomized to 1 of 3 groups:
placebo, donepezil 5 mg/d, or donepezil 10 mg/d.
Most patients (73%) fulfilled diagnosis of probable
VaD according to the NINDS-AIREN criteria.
All had brain imaging before enrollment (CT or MRI)
with demonstration of cerebrovascular lesions.
Patients with preexisting AD and those with mixed
dementia (AD plus CVD) were excluded.
Donepezil (Aricept®)
Erkinjuntti, Timo MD; Román, Gustavo MD et al. Emerging Therapies for Vascular
Dementia

60. Donepezil treatment group showed
statistically significant improvement in
cognitive functioning measured with
the ADAS-cog; the mean changes from
baseline score were as follows:
Donepezil 5 mg/d, -1.90 (P =0.001)
Donepezil 10 mg/d, -2.33 (P <0.001).
Black S, Román GC, et al. Donepezil 307 Vascular Dementia Study Group.Efficacy and tolerability
of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized,
placebo-controlled clinical trial. Stroke. 2003; 34: 2323–2332
Study 307

61. The MMSE also showed statistically
significant improvement versus placebo.
CDR-SB showed nonsignificant benefit in the
5-mg/d group but was significant in the 10-
mg/d group (P =0.007).
ADL showed significant benefits in
donepezil-treated patients over placebo with
the use of the ADFACS in both treatment
groups (P >0.02).
Study 307
Black S, Román GC, et al. Donepezil 307 Vascular Dementia Study Group.Efficacy and tolerability
of donepezil in vascular dementia: positive results of a 24-week, multicenter, international, randomized,
placebo-controlled clinical trial. Stroke. 2003; 34: 2323–2332

62. Donepezil treatment group showed
statistically significant improvement in
cognitive functioning measured with
the ADAS-cog; the mean changes from
baseline score were as follows:
Donepezil 5 mg/d, -1.65 (P =0.003)
Donepezil 10 mg/d, -2.09 (P =0.0002).
The MMSE also showed statistically
significant improvement versus
placebo.
Wilkinson D, Doody R, et al. Donepezil 308 Study Group. Donepezil in vascular dementia: a
randomized, placebo-controlled study. Neurology. 2003; 61: 479–486
Study 308

63. Study 308
CDR-SB showed non-significant benefit
in the 5-mg/d group but was significant
in the 10-mg/d group (P =0.03).
ADL showed superiority in the
donepezil-treated patients over placebo
with the use of the ADFACS in both
treatment groups, which, however, did
not reach significance at the end of the
study compared with placebo.
Wilkinson D, Doody R, et al. Donepezil 308 Study Group. Donepezil in vascular dementia: a
randomized, placebo-controlled study. Neurology. 2003; 61: 479–486

64. In a randomized controlled clinical trial, patients diagnosed
with probable VaD or with AD combined with CVD received
galantamine 24 mg/d (n=396) or placebo (n=196) in a
multicenter, double-blind, 6-month trial.
Eligible patients met the clinical criteria of probable VaD by
NINDS-AIREN criteria .
They also showed significant radiological evidence of CVD on
CT or MRI.
Evidence of CVD on a recent (within 12 months) scan included
multiple large-vessel infarcts or a single, strategically placed
infarct (angular gyrus, thalamus, basal forebrain, territory of
the posterior or anterior cerebral artery), or at least 2 basal
ganglia and white matter lacunae, or white matter changes
involving at least 25% of the total white matter.
The MMSE score was 10 to 25,
ADAS-cog/11 score was >=12
Age ranged from 40 to 90 years.
Erkinjuntti T, et al.. Efficacy of galantamine in probable vascular dementia
and Alzheimer’s disease combined with cerebrovascular disease:
a randomised trial. Lancet. 2002; 359: 1283–1290
Galantamine (Reminyl®)

65. In analyses of both groups as a whole, galantamine demonstrated
efficacy on all outcome measures.
Galantamine showed greater efficacy than placebo on ADAS-cog (2.7
points; P <=0.001) and CIBIC-plus (74% versus 59% of patients
remained stable or improved; P <=0.001).
ADL and behavioral symptoms were also significantly improved
compared with placebo (both P <0.05). Galantamine was well
tolerated.
In an open-label extension, the original galantamine group of patients
with probable VaD or AD plus CVD showed similar sustained benefits
in terms of maintenance of or improvement in cognition (ADS-cog),
functional ability (DAD), and behavior (NPI) after 12 months.
Although not designed to detect differences between subgroups, the
subgroup of patients with AD plus CVD on galantamine (n=188; 48%)
showed greater efficacy than placebo
Erkinjuntti T, et al.. Efficacy of galantamine in probable vascular dementia
and Alzheimer’s disease combined with cerebrovascular disease:
a randomised trial. Lancet. 2002; 359: 1283–1290
Galantamine (Reminyl®)

66. Rivastigmine: (Exelon®)
Effectively inhibits
acetylcholinesterase and
butyrylcholinesterase (BuChE)
Clinical significance of BuChE is
unknown
Reduces degradation rate of
released acetylcholine, allowing
more to be available for the
postsynaptic receptor

67. Rivastigmine in VaD
In a small open-label study of patients
with subcortical VaD, rivastigmine
improved:
Caregiver stress
Activities of daily living
Behavior
Cognition
Demonstrated long-term efficacy
Clear dose response that can maximize efficacy
Needs efficacy assessment in larger, double-blind,
randomized, placebo-controlled studies
Moretti R et al.. Rivastigmine in subcortical vascular dementia:
an open 22-month study. J Neurol Sci. 2002; 203: 141–146

68. Memantine (Namenda®)
Memantine after years of use in Europe is
now approved by FDA in the US for use in
mild to moderate Alzheimer,s disease.
Drug that works differently from currently
available anti-cholinesterase inhibitors.
It is suggested that an overstimulation of the
N-methyl-D-aspartate (NMDA) receptor by
glutamate contributes to neurodegenerative
disorders.
Memantine blocks the overstimulation of the
glutamate by blocking NMDA receptor

69. Two randomized, placebo-controlled 6-
month trials (MMM 300/MMM 500)
studied memantine (20 mg/d) in mild to
moderate probable VaD by NINDS-
AIREN criteria.
Memantine (Namenda®)

70. In the MMM 300 study, 147 patients were
randomized to memantine and 141 to
placebo.
After 28 weeks, the mean ADAS-cog scores
were significantly improved relative to
placebo:
the memantine group mean score had gained
an average of 0.4 points, whereas the
placebo group mean score declined by 1.6,
ie, a difference of 2.0 points (P =0.0016).
Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind,
placebo-controlled multicentre study of memantine in mild to moderate vascular dementia
Internat Clin Psychopharmacol. 2002; 17: 297–305
Memantine (Namenda®)

71. MMM 300 study
The response rate for CIBIC-plus, defined as
improved or stable, was 60% with memantine
compared with 52% with placebo (P =0.227).
The Gottfries-Bråne-Steen (GBS) Scale and the
Nurses’ Observation Scale for Geriatric Patients
(NOSGER) total scores at week 28 did not differ
significantly between the 2 groups.
GBS Scale intellectual function subscore and the
NOSGER disturbing behavior dimension also
showed a difference favoring memantine (P =0.04
and P =0.07, respectively).
Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group. A double-blind,
placebo-controlled multicentre study of memantine in mild to moderate vascular dementia
Internat Clin Psychopharmacol. 2002; 17: 297–305

72. MMM 500 study
The MMM 500 study randomized 277 patients to memantine and
271 to placebo.
At 28 weeks, the active group had gained 0.53 points and the
placebo group declined by 2.28 points in ADAS-cog, a
significant difference of 1.75 ADAS-cog points between the
groups (P <0.05).
There were no differences in CGIC, Mini–Mental State
Examination (MMSE), GBS, or NOSGER scores between
groups.
Memantine was well tolerated in both studies. In a post hoc
pooled subgroup analysis of these 2 studies by baseline
severity as assessed by MMSE, the more advanced patients
obtained a larger cognitive benefit than did mildly affected
patients. Patients with MMSE score <15 at baseline showed an
ADAS-cog improvement of 3.2 points over placebo.
Wilcock G, Möbius HJ, Stöffler A, on behalf of the MMM 500 group
. A double-blind, placebo-controlled multicentre study of memantine
in mild to moderate vascular dementia (MMM500).
Internat Clin Psychopharmacol. 2002; 17: 297–305

73. Conclusions
Vascular Dementia is a preventable
disease
Progress has been made in the
diagnosis and treatment of this
condition
A public health approach should guide
future research