CNS Drugs

DOI 10.1007/s40263-017-0459-3

REVIEW ARTICLE

Pharmacotherapy for Vascular Cognitive Impairment

Muhammad U. Farooq1 • Jiangyong Min1 • Christopher Goshgarian1 •

Philip B. Gorelick1,2

Ó Springer International Publishing AG 2017

Abstract Vascular cognitive impairment (VCI) is the factor control are important in the management of VCI and
second most common type of dementia after Alzheimer’s should not be ignored. However, there is a need for more
disease (AD). Stroke and cardiovascular risk factors have robust clinical trials focusing on executive function and
been linked to both AD and VCI and potentially can affect other cognitive measures and incorporation of newer
cognitive function in mid and later life. Various pharma- imaging modalities to provide additional evidence about
cological agents, including donepezil, galantamine, and the utility of these strategies in patients with VCI.
memantine, approved for the treatment of AD have shown
modest cognitive benefits in patients with vascular
dementia (VaD). However, their functional and global
Key Points
benefits have been inconsistent. Donepezil has shown some
cognitive benefit in patients with VaD only, and galan-
Vascular cognitive impairment is the second most
tamine has shown some benefit in mixed dementia (AD/
common type of dementia.
VaD). The benefits of other drugs such as rivastigmine,
memantine, nimodipine, and piracetam are not clear. Some Various pharmacological agents, including donepezil
other supplements and herbal therapies, such as citicoline, and galantamine, have shown modest cognitive
actovegin, huperzine A, and vinpocetine, have also been benefits in patients with vascular dementia, but their
studied in patients with VaD, but their beneficial effects are functional and global benefits have been
not well established. Non-drug therapies and lifestyle inconsistent.
modifications such as diet, exercise, and vascular risk The benefits of other drugs, such as rivastigmine,
memantine, nimodipine, piracetam, and herbal
& Muhammad U. Farooq therapies, are not well established.
farooqmu@mercyhealth.com
Lifestyle modifications and vascular risk factor
Jiangyong Min
jiangyong.min@mercyhealth.com
control are important in the management of these
patients.
Christopher Goshgarian
christopher.goshgarian@mercyhealth.com
Philip B. Gorelick
pgorelic@mercyhealth.com
1 Introduction
1
Division of Stroke and Vascular Neurology, Mercy Health
Hauenstein Neurosciences, 200 Jefferson Street SE, Vascular cognitive impairment (VCI) has received signif-
Grand Rapids, MI 49503, USA
icant attention recently as a potentially preventable and
2
Department Translational Science and Molecular Medicine, treatable cause of cognitive impairment. In accordance
Michigan State University College of Human Medicine, 220
with this viewpoint, the World Stroke Day Proclamation
Cherry Street SE Room H 3037, Grand Rapids, MI 49503,
USA 2015 emphasized the following key points: (1) Stroke and

some dementias may be prevented; (2) Shared lifestyle and
other traditional cardiovascular disease (CVD) risk factors
underlie major world health problems, including major
dementias of later life; (3) These facts have been largely
ignored or not optimally applied; (4) Post-stroke dementia
should be an integral part of organized stroke and reha-
bilitative care; and (5) Prevention and management of
vascular risk factors should be encouraged [1, 2]. Alzhei-
mer disease (AD) and cerebrovascular diseases are the
number one and number two leading causes of cognitive
impairment, respectively, and account for about 80% of
cases, often as a mix of neuropathologies [3].
VCI may be defined as cognitive impairment associated
with clinical stroke or subclinical vascular brain injury and
ranges from mild cognitive impairment (MCI) to its most
severe form, vascular dementia (VaD) [3]. VCI encom-
passes all cognitive disorders associated with cerebrovas-
cular disease and represents cognitive impairment affecting
at least one cognitive domain. Additional VCI subcate-
gories exist and may include vascular MCI (VaMCI) (i.e.,
few impaired cognitive domains) and unstable VaMCI (i.e.,
in the recovery phase of a stroke, the patient may shift from
an impaired to an unimpaired cognitive state) [3, 4]. In
addition to the aforementioned criteria for VCI according
to the American Heart Association/American Stroke
Association (AHA/ASA) [3], there are other contemporary
criteria from the International Society of Vascular Behav-
ioral and Cognitive Disorders (VasCog) [5] and the Di-
agnostic and Statistical Manual of Mental Disorders, Fifth
Edition (DSM-5) [6].
In this review, we discuss the pharmacotherapy of VCI.
We include discussion of vascular contributions to cogni-
tive impairment, diagnostic criteria, clinical progression,
drug studies, and gaps in knowledge.
2 Vascular Contributions to Cognitive
Impairment
By the late 1990s, it became apparent that a number of
CVD and stroke risks were also risks for dementias of later
life, including AD [7]. A number of papers were published
in the ensuing years emphasizing the relationship between
these factors and AD, VCI, and stroke [8, 9]. It has been
estimated that the population attributable risk (PAR) of
stroke and CVD risks on AD is about 50% [10]. That is, up
to 50% of AD may be explained by preventable or modi-
fiable stroke and CVD risks. Specific stroke and CVD risks
that may play a role in the pathogenesis of cognitive
impairment and dementias of later life include hyperten-
sion, diabetes mellitus, hyperglycemia, insulin resistance,
hyperlipidemia, tobacco use, obesity, lack of physical
activity, poor diet, coronary artery disease, atrial
M. U. Farooq et al.
fibrillation, heart failure, and other such factors [11].
According to the results of large epidemiological studies,
over time it has been noted that the incidence or prevalence
of dementia or cognitive impairment has decreased
[12, 13]. Possible explanations for this compression of
incidence or prevalence of cognitive impairment include
better control of stroke and CVD risks and education [14].
Interestingly, the stroke and CVD risks linked to AD and
VCI may influence risk in both midlife and later life but
may play a role in conferring cognitive impairment as early
as middle adulthood [15]. Midlife and earlier time periods
may be a critical window for interventions to prevent or
modify existent stroke and CVD risks [16]. For example, in
a recent AHA/ASA scientific statement, hypertension was
found to have a deleterious effect in midlife for late-life
cognition; however, the impact of later-life hypertension on
cognition was less clear [16]. Whereas epidemiological
observational studies may support an association between
hypertension and cognition, especially in midlife, clinical
trials where cognition was not the primary outcome do not
consistently show that antihypertensive drug administration
improves cognition [16, 17].
An important scientific statement was released by the
Institute of Medicine (IOM) regarding actions to maintain
cognitive health. Specifically, the IOM recommends the
following practices: (1) Be physically active; (2) Prevent and
treat cardiovascular risk factors; and (3) Regularly review
medications and stroke and CVD risks that might influence
brain health with one’s healthcare provider [18]. In addition,
IOM recommends actions for which there is some scientific
evidence for maintenance of cognitive health: (1) Be socially
active and intellectually engaged (i.e., continue to learn); (2)
Achieve adequate sleep and have sleep disorders treated; and
(3) If hospitalized, avoid the risk of cognitive changes
associated with delirium [18]. The IOM report on mainte-
nance of cognitive health is a departure from previous
statement because, some years prior, a US National Institutes
of Health State-of-the-Science Conference addressed risks
and preventatives for AD and concluded evidence was
insufficient for any definitive modifiable risks for AD such as
stroke and CVD factors [19].
Sleep is an important biological function for memory
consolidation. Sleep apnea in patients with cognitive
impairment must be properly assessed and treated. The
HypnoLaus study assessing the association between sleep
structure and cognitive impairment in the general popula-
tion showed that participants aged [65 years with cogni-
tive impairment had higher sleepiness scores (p \ 0.05) as
compared to participants with no cognitive impairment.
Sleep disordered breathing was more severe in participants
with cognitive impairment with an apnea/hypopnea index
(AHI) of 18.0 (p \ 0.001). Their sleep was more disrupted,
and this was related to sleep disordered breathing and
Pharmacotherapy for VCI
intermittent hypoxia, which translated to higher oxygen
desaturation index (ODI) levels. AHI and ODI levels C4
and C6%, respectively, were independently associated with
cognitive impairment [20]. More study is needed to clarify
which factors are in the causal pathway linking sleep-re-
lated disturbances to cognitive impairment as the literature
is inconsistent. Other mechanisms by which select stroke
and CVD risks may have negative influences on cognitive
health are reviewed elsewhere [11].
3 Diagnostic Criteria for the Various Subtypes
of Vascular Cognitive Impairment (VCI)
Cerebral small vessel disease (CSVD) is a leading cause of
cognitive impairment and functional decline in the elderly
[21]. CSVD refers to pathological processes and a number of
etiologies that affect small arteries, arterioles, venules, and
capillaries of the brain. The most common forms of CSVD
are age related and hypertension related and cerebral amy-
loid angiopathy (CAA). The main neuroradiologic mani-
festations of CSVD are lacunar infarcts, white matter lesions,
cerebral micro-hemorrhages, and larger deep brain hemor-
rhages. Thus, because the cerebral small vessels are not
easily imaged by conventional neuroimaging techniques, the
parenchymal consequences of CSVD (e.g., lacunar infarcts,
white matter changes) are usually emphasized [21].
CSVD is the most common form of VCI. However,
other stroke mechanisms may occur to cause VCI,
including but not limited to large artery atherosclerosis of
intracranial or extracranial arteries, cardioembolism, sub-
arachnoid or superficial brain hemorrhage, and non-
atherosclerotic mechanisms [4].
Although VCI represents a heterogeneity of sporadic and
heterogeneous disorders of the large and small blood vessels,
for the most common form of VCI, CSVD, there is a common
mechanistic theme of hypoxic hypoperfusion, lacunar
infarcts, and inflammation that disrupts the blood–brain
barrier (BBB) and results in the loss of the integrity of brain
myelin [22]. At the microscopic level, the neurovascular
unit, which is composed of neurons, glia, and perivascular
and vascular cells, helps maintain the structural and func-
tional integrity of the cerebral micro-environment but is
thought to be disrupted by oxidative stress and inflammation,
which lead to neurovascular dysfunction and resultant
cerebral vascular brain injury and, clinically, to VCI [4].
Before we address diagnostic criteria for subtypes of
VCI, we emphasize the importance of prevention of VCI
and other dementias of later life. Hachinski [23] has been a
substantial proponent of an upstream approach to provide
preventive efforts for the at-risk stage rather than waiting
until the patient is too far along the severity continuum of
VCI. Hachinski and Sposato [24] proposed the application
of a simple and reliable tool to detect VCI, emphasized the
importance of screening and detection of the vascular
component and risks, and recommended providing the best
available prevention options and then verification of the
approach.
Here, we discuss contemporary diagnostic criteria for
VCI. Historic terms such as ‘hardening of the arteries’ and
arteriosclerotic psychosis are no longer used [25]. We
begin our review of contemporary VCI diagnostic criteria
in the early 1990s.
3.1 Early Contemporary VCI Diagnostic Criteria
(1990s)
The diagnostic criteria from the National Institute of Neu-
rological Disorders and Stroke-Association Internationale
pour la Recherche et l’Enseignement in Neurosciences
(NINDS-AIREN) emphasized dementia, the heterogeneity
of vascular dementia syndromes and pathologic subtypes,
the variability of clinical course (i.e., static, remitting, pro-
gressive), specific features early in the course (gait dys-
function, incontinence, mood or personality changes), and
temporal relationship between stroke and dementia [26]. In
addition, this criteria illustrated the importance of neu-
roimaging to establish a diagnosis, the usefulness of neu-
ropsychological testing and involvement of multiple
cognitive domains, and correlative neuropathological eval-
uation with neuroradiological, clinical, and neuropsycho-
logical results [26]. The criteria were designed to be a guide
for neuroepidemiological study and validation testing. Cases
were classified as being possible, probable, or definite.
The key components of the NINDS-AIREN definition of
VaD include (1) presence of dementia; (2) evidence of
cerebral vascular disease as demonstrated by either history,
clinical examination, or brain imaging; and (3) the two
disorders must be reasonably related [26]. The diagnosis of
dementia required memory impairment and loss of intel-
lectual abilities sufficient to cause impairment of function
of activities of daily living. Furthermore, loss of memory
and deficits in at least two other cognitive domains were
required to establish a diagnosis. The inclusion of memory
loss in the definition of VaD in this criteria system has been
a point of contention and viewed as a potential pathway
whereby AD cases would be included, resulting in a
diagnosis of AD or mixed neurodegenerative and VaD
diagnoses, and not pure VaD.
The NINDS-AIREN criteria have been the most widely
used in VaD clinical trials.
3.2 Criteria for Ischemic Vascular Dementia
The State of California Alzheimer Disease Diagnostic and
Treatment Centers (ADDTC) criteria emphasized the

distinction between AD and ischemic vascular dementia
(IVD), broadened the conceptualization of VaD, empha-
sized the importance of neuroimaging as a diagnostic tool,
and identified research gaps and the need for validation of
the research criteria [27]. Fundamental to the criteria was
the presence of dementia defined as deterioration from a
known or prior level of intellectual dysfunction sufficient
to interfere with one’s customary affairs of life, indepen-
dent of level of consciousness and supported by bedside
mental status testing or, ideally, formal neuropsychological
testing.
A diagnosis of probable IVD included dementia plus
evidence of one or more ischemic strokes by history, neu-
rological signs, and/or neuroimaging study, or presence of a
single stroke with a clear temporal relationship to dementia.
Finally, they included at least one brain infarct outside the
cerebellum as well as suggestive features (e.g., multiple
infarcts in brain regions known to be associated with cog-
nitive impairment, history of transient ischemic attack
[TIA], and other features) and supportive (early appearance
of gait disturbance) and neutral features (e.g., slowly pro-
gressive symptoms). Possible IVD included the presence of
dementia and single stroke, or Binswanger disease (BD).
Definite IVD required dementia to be present, multiple
brain infarcts on pathological exam with some outside the
cerebellum, and—if AD pathology was present—a diag-
nosis of mixed dementia could be established.
3.3 Recent Contemporary VCI Diagnostic Criteria
(2000s)
3.3.1 Consensus Statement for Diagnosis of Subcortical
Small Vessel Disease
This statement represents an expert consensus about sub-
cortical small vessel disease or CSVD and is mechanisti-
cally oriented. The statement recognizes multiple infarcts
of the cortex and white matter regions secondary to large
artery atherosclerotic thrombosis or cardiac source embo-
lism [22]. CSVD is defined as subcortical gray and white
matter lesions manifesting as lacunar infarcts or white
matter hyperintensities identified by neuroimaging study.
The mechanism of lacunes (e.g., lipohyalinosis, fibrinoid
change) may differ from that of extensive white matter
disease, which may be caused by leakage of the BBB.
BD is a progressive form of CSVD characterized by
extensive white matter ischemic changes, whereby lacunes
may or may not be present, and underlying arterioloscle-
rosis. Clinically, BD includes gait disturbance, executive
dysfunction, hyperreflexia, apathy, and depression. Finally,
inherited forms of CSVD exist, such as cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL), which is due to a
M. U. Farooq et al.
mutation of the notch 3 gene, age-related white matter
damage, leukoaraiosis, and mixed dementias.
3.3.2 American Heart Association/American Stroke
Association Criteria
Central to the AHA/ASA and other VCI criteria are
demonstration of a cognitive disorder meeting neuropsy-
chological test criteria and a history of clinical stroke or
evidence of cerebrovascular brain injury or disease by
neuroimaging with evidence of a link between the cogni-
tive dysfunction and vascular disease [3]. However,
memory impairment is not required to establish a diagnosis
of VCI or VaD with this criteria, and the presence of white
matter lesions may be of less diagnostic significance in the
elderly. As mentioned, VCI represents all forms of cogni-
tive deficits and severity (e.g., VaMCI, VaD) of vascular
origin and from any of the potential causes of stroke.
Furthermore, dementia is defined as a decline in cognitive
function from a prior level and includes impairment in two
or more cognitive domains that are sufficient to affect an
individual’s ability to carry out activities of daily living,
independent of motor or sensory sequelae associated with
stroke. To establish a diagnosis of dementia, a minimum of
four domains (executive/attention, memory, language,
visuospatial functions) must be tested.
Based on the temporal relationship between stroke and
cognitive impairment plus other features after a diagnosis
of dementia, according to this criteria the categorization
includes probable or possible VaD, VaMCI, probable
VaMCI, possible VaMCI, and unstable VaMCI [3]. VaMCI
may be subdivided into four additional categories:
amnestic, amnestic plus other domains, non-amnestic sin-
gle domain, and non-amnestic multiple domain.
3.3.3 International Society of Vascular Behavioral
and Cognitive Disorders Criteria
Based on limitations of the term VaD, new criteria to
define AD that include the pre-dementia and dementia
phases of cognitive impairment, and an opportunity to
harmonize with DSM-5 criteria, a workgroup of the Vas-
Cog Society provided a critical re-examination of VaD.
The workgroup concluded that it was preferable to use the
term vascular cognitive disorder (VCD) and establish
detailed criteria for this entity in light of the heterogeneity
of vascular disorders, pathologies, and clinical manifesta-
tions associated with stroke and cognitive impairment [5].
As with other major VCI criteria, the two key features to
establish a diagnosis of VCD are presence of cognitive
impairment and determination that vascular disease is the
dominant if not exclusive pathology accounting for cog-
nitive impairment.
Pharmacotherapy for VCI
The workgroup statement provided comprehensive
details about how to establish a diagnosis of mild cognitive
disorder (i.e., cognitive deficits that do not interfere with
independence) and dementia or major cognitive disorder
(i.e., cognitive deficits that do interfere with indepen-
dence). In addition, there is thoughtful and detailed infor-
mation about underlying pathologies of VCD, application
of neuroimaging results (e.g., evidence of either large
vessel brain infarction, strategic infarction, more than two
lacunar infarcts outside the brainstem or extensive and
confluent white matter disease), the role of stroke and CVD
risks, neuropathologic diagnosis, levels of diagnostic cer-
tainty, subtypes of VCD, and discussion of multiple
causality, psychiatric, and behavioral symptoms, and
biomarkers relative to VCD. In the absence of stroke or
TIA, cognitive decline in relation to speed of processing,
complex attentional or frontal executive dysfunction, and
presence of gait, urinary, or personality/mood changes are
required to establish a diagnosis. The reader is referred to
the VasCog Society statement for additional detailed
information about VCD criteria [5].
3.3.4 Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, Criteria
The DSM-5 criteria, similar to the others discussed in this
review, link cognitive impairment of various severity (mild
or major vascular neurocognitive disorder) temporally to
stroke or evidence of decline in complex attention and
frontal-executive function when there is cerebrovascular
disease based on history, physical exam, or neuroimaging.
In the case of genetic disease (e.g., CADASIL), the criteria
link clinical and genetic findings [6, 28].
3.3.5 Vascular Impairment of Cognition Classification
Consensus Study Criteria
The Vascular Impairment of Cognition Classification
Consensus Study (VICCCS) was designed by an interna-
tional group of researchers to provide clinicians and
researchers a criterion with broader consensus on the
conceptualization of cognitive impairment due to vascular
pathology and to create standard nomenclature and abbre-
viations to be utilized in practice. The work was completed
between 2010 and 2013, close to the time when DSM-5 and
VasCog criteria were being developed. Group participants
were given the opportunity to review and comment on the
draft DSM-5 proposal. VasCog criteria are somewhat
aligned with the DSM-5.
The VICCCS proposed classification includes post-
stroke dementia (PSD), mixed dementia, subcortical
ischemic vascular dementia (SIVaD), and multi-infarct
dementia (MID) [29]. Patients with PSD are characterized
as having immediate and/or delayed cognitive decline that
begins after but within 6 months of stroke and occurs
without recovery. A hallmark of this type of dementia is
acute presentation and appearance of decline within
6 months of having a stroke. Mixed dementia includes all
the phenotypes specified for each combination, such as
VCI-AD, AD-VCI, and VCI-dementia with Lewy body
(DLB). The order of terms indicates the relative contribu-
tion of underlying pathology. SIVaD is mostly related to
small vessel ischemic disease and lacunar infarcts. MID is
due to multiple large cortical infarcts [29].
3.4 Sensitivity and Specificity of Criteria for VCI
In the USA it is estimated that slightly more than 50% of
patients with dementia receive no clinical cognitive eval-
uation by a physician [30]. The likelihood of having such
an evaluation may be predicted by severity of cognitive
impairment and current marital status [30]. Lack of
screening for dementia may be at least partly explained by
the US Preventive Services Task Force position that there
is insufficient evidence to support such screening. In a
systematic review and meta-analysis, brief screening tests
for dementia [e.g., Mini-Mental State Examination
(MMSE), Montreal Cognitive Assessment (MoCA), and
others] have been shown to have a high pooled sensitivity
(76–92%) and specificity (81–91%) [30, 31].
We now review two studies that emphasize select con-
temporary VCI criteria in relation to sensitivity and
specificity. The first study emanates from a geriatric
department and used neuropathologic diagnosis as the gold
standard [32]. This study included 113 dementia patients
who had autopsy. The criteria for the VaD form of VCI that
were compared include NINDS-AIREN, ADDTC, and the
Hachinski Ischemic Score (HIS). Patients were neu-
ropathologically diagnosed as having VaD according to the
criteria set forth by the Consortium to Establish a Registry
for Alzheimer’s Disease (CERAD). Respectively, sensi-
tivity and specificity were 0.63 and 0.64 for ADDTC cri-
teria, 0.58 and 0.80 for NINDS-AIREN criteria, and 0.43
and 0.88 for the HIS [43]. Patients with AD were suc-
cessfully excluded (ADDTC 87%, NINDS-AIREN 91%,
and HIS 97% of the time). The proportion of mixed
dementia excluded by individual criteria varied (ADDTC
54%, NINDS-AIREN 29%, and HIS 18%). Overall, for the
VaD criteria tested, there was rather low sensitivity, and
mixed dementia was most consistently excluded by
NINDS-AIREN criteria.
A second study originated from the Canadian Study of
Health and Aging and included 1879 men and women. The
study explored the proportion given a diagnosis of
dementia according to six commonly used classification
systems at the time (DSM-III, DSM-IIIR, DSM-IV, World

Health Organization International Classification of Dis-
eases (ICD)-9, ICD-10, and the Cambridge Examination
for Mental Disorders of the Elderly (CAMDEX)] [33]. The
prevalence of dementia according to the six classification
systems ranged from 3.1% (ICD-10) to 29.1% (DSM-III),
and only 20 subjects were given a diagnosis of dementia
according to all six classification systems. Based on oper-
ational definitions in each classification system and multi-
variate logistical-regression analysis, the factors that most
commonly caused disagreement between DSM-III and
ICD-10 were long-term memory, executive function, social
activities, and duration of symptoms. Thus, dementia cri-
teria may differ by as much as a factor of about tenfold.
Such a discrepancy could have a substantial effect on
research in and treatment of patients as well as practical
management decisions for patients based on these classi-
fication schemes [33].
4 Survival and Clinical Progression from VCI
to Dementia
4.1 Survival
Older studies have shown that patients with VaD, AD, or
mixed dementia had relentless and progressive behavioral
symptoms and cognitive decline and increased mortality
rates [34–37]. Of the three aforementioned diagnostic
groups, survival was shortest for VaD and mixed
dementia.
More recently, we published hospital-based survival
data among African Americans with AD (n = 113
including 53 deaths), VaD (n = 79 including 31 deaths),
and stroke without dementia (SWD) (n = 56 including 14
deaths) who were followed for up to 7 years [38]. Survival
rates at 7 years were 28.7% for AD, 54.9% for VaD, and
72.6% for SWD. After adjustment of age and clinical
dementia rating, differences in survival across the three
groups were not significant. Predictors of death were as
follows:
1. For AD patients: older age, more years of education
(possibly explained by the cognitive reserve hypoth-
esis), and lower Barthel Activities of Daily Living
scores.
2. For VaD patients: antihypertensive medication admin-
istration placed patients at higher risk of death, but use
of antithrombotics and higher diastolic blood pressure
was protective from death. Our article about blood
pressure and the prevention of cognitive impairment
[39] highlights that relatively higher blood pressure in
the very old has been associated with better cognitive
outcomes. Moreover, once cognitive impairment is
M. U. Farooq et al.
present, one may need to relax blood pressure control
[39]. However, this hypothesis needs to be supported
by additional studies.
3. For SWD patients: older age, history of smoking, and
clinical dementia rating scale [38]. Several other more
recent studies support the contention that cognitive
decline or dementia reduces survival [40–44].
4.2 Clinical Progression
Guidance for assessment of cognition in patients with
suspected VCI is available in a publication from the VCI
Harmonization conference [45]. It should be noted that
tests of executive function are sensitive to cognitive deficits
in patients with stroke and suspected VCI, memory may be
impaired due to attention or focus problems, and depres-
sion is common post-stroke [11].
Now, we review a study of cognitive and functional
decline in African Americans with VaD, AD, and SWD
[46]. Additional information on cognitive progression in
VCI is discussed below in the section on review of drug
studies.
We followed African American hospital-based patients
for up to 7 years for cognitive decline with annual neu-
ropsychological and clinical exams and functional assess-
ment [46]. The cohort included 79 patients who were
diagnosed with VaD, 113 with AD, and 56 with SWD.
Overall, patients with VaD and AD showed significant
cognitive and functional decline during follow-up, though
patients with VaD had a slower rate of decline than those
with AD, whereas patients with SWD generally did not
show cognitive or functional decline. The rate of cognitive
decline in patients with VaD was slower than that of
patients with AD on 5 of 13 measures but was not signif-
icantly different on the remaining eight cognitive measures
[46]. Thus, VaD is a progressive cognitive disorder but
may not progress as quickly as AD.
In a subsequent study of 41 post-stroke patients with a
subtype of VCI, vascular cognitive impairment but no
dementia (VCIND), who were compared with 62 post-
stroke patients with no cognitive impairment (NCI), we
reported the following main results: (1) Multivariate
logistic regression analysis of cognitive domains identified
immediate recall and psychomotor domains to best predict
VCIND group membership; and (2) In separate modeling
for behavioral domains, depressed mood predicted VCIND
group membership [47]. Because the combination of
immediate memory deficits, psychomotor slowness, and
depression may be observed in VaD, we hypothesized that
the pattern of neuropsychological deficits in VCIND may
be similar to that in VaD and that VCIND is within the
continuum between NCI and VaD [47].
Pharmacotherapy for VCI
MCI has been reported as a prodromal state over an
approximate 3.72-year time period, similar to that for AD
in patients who eventually develop VaD (the small vessel
or subcortical type) [48]. In the Canadian Study of Health
and Aging, 149 individuals who had a mean age of
79.3 years had VCIND [49]. After 5 years, 77 had died and
58 (46%) had dementia; 32 had no dementia, seven of
which had cognitive deterioration and four improved. Half
of those with VCIND developed dementia within 5 years.
This study subsequently showed that low baseline scores
on tests of memory and category fluency were associated
with dementia in those with VCIND [50]. Thus, there is
evidence that patients with MCI and memory disturbance
can convert to either AD or VCI.
5 Critical Review of Drug Studies Assessing
Therapeutics in the Population
In this section, we discuss various clinical trials of potential
pharmacological therapies for the treatment of VCI. Defi-
ciency in cholinergic neurotransmission is well known in
patients with VCI, and vascular lesions may produce
cholinergic dysfunction similar to that seen in AD.
Therefore, various clinical trials of acetylcholinesterase
inhibitors have been conducted in patients with VCI.
Acetylcholinesterase inhibitors are believed to improve
cognition in patients with AD by increasing the availability
of acetylcholine in the synaptic cleft. There is also some
evidence that these medications increase cerebral blood
flow [3, 51–53]. Therefore, these drugs are considered as a
potential treatment option in patients with VCI. However,
in clinical trials, dose-response effects to acetyl-
cholinesterase inhibitors in VCI have not been consistent.
Moreover, no definite benefit is seen in patients with VaD
in global functioning when treated with acetyl-
cholinesterase inhibitors. Thus, no acetylcholinesterase
inhibitor has received US FDA approval for use in VaD.
Now, we discuss clinical trials assessing the efficacy of
three available acetylcholinesterase inhibitors in VCI.
These include donepezil, rivastigmine, and galantamine
(Table 1). These medications are approved for the treat-
ment of mild to moderate AD.
5.1 Donepezil
Donepezil is an acetylcholinesterase inhibitor. As with AD,
cholinergic deficits and disruption of cholinergic pathways
occur in some patients with VaD and may contribute to
cognitive impairment in these patients. In several trials
assessing the efficacy of donepezil on VCI, patients with
mild to moderate VaD showed efficacy on measures of
cognition at both the 5- and 10-mg doses. However, benefit
was inconsistent on measures of global function in these
studies [3, 54–57].
Wilkinson et al. [54] conducted a 24-week double-
blind randomized placebo-controlled trial to evaluate the
efficacy and tolerability of donepezil in patients with VaD
[54]. Patients received either placebo or donepezil 5 or
10 mg as a single daily dose. Patients in the donepezil
10 mg/day treatment group received donepezil 5 mg/day
for 4 weeks and then 10 mg/day after that and until week
24. The primary efficacy measures were the Alzheimer’s
Disease Assessment Scale—cognitive subscale (ADAS-
cog) and Clinician’s Interview-Based Impression of
Change plus (CIBIC-plus). A total of 887 patients were
screened and 616 entered the study. They were random-
ized to receive placebo (n = 193), donepezil 5 mg/day
(n = 208), or donepezil 10 mg/day (n = 215). Patients
treated with donepezil 5 and 10 mg/day demonstrated
significant improvements vs. placebo on the ADAS-cog;
donepezil 5 mg -1.65 (p = 0.003) and donepezil 10 mg,
-2.09 (p = 0.0002). Greater improvements on the
CIBIC-plus version were observed in both donepezil
treatment groups than in the placebo group; however,
statistical significance was borderline in the 10-mg/day
group (p = 0.047). Donepezil was well tolerated in this
trial, and most of the serious side effects included stroke,
skin cancer, and pathological fractures, whereas typical
side effects were nausea, diarrhea, arthralgia, and leg
cramps [54].
Black et al. [55] conducted a 24-week, randomized,
placebo-controlled study of donepezil in patients with
VaD. They designed this study to determine the efficacy
and tolerability of donepezil (5 and 10 mg/day) versus
placebo in patients with VaD only. They excluded patients
with AD and also AD-associated cerebrovascular lesions.
Patients were assigned to one of three treatment groups: a
single daily dose of donepezil 5 mg (n = 198), a single
daily dose of donepezil 10 mg (n = 206), or matching
placebo (n = 199). Patients in the donepezil 10-mg/day
treatment arm received donepezil 5 mg/day for the first
4 weeks and then the dose was increased to 10 mg/day
thereafter. The primary efficacy outcome measures were
the ADAS-cog and CIBIC-plus. Patients treated with
donepezil 5 and 10 mg/day demonstrated significant
improvements versus placebo on the ADAS-cog (mean
change from baseline score effect size: donepezil
5 mg/day, -1.90; p = 0.001; donepezil 10 mg/day, -2.33;
p \ 0.001). However, some items on the cognitive battery
did not improve. Improvement in global function was
observed in a greater proportion of donepezil- than pla-
cebo-treated patients those receiving 5 mg/day
(p = 0.014). However, there was no significant benefit in
the group receiving 10 mg/day (p = 0.27). The CIBIC-
plus was used to determine the improvement in global
 M. U. Farooq et al.

Table 1 Summary of the key trials of donepezil, rivastigmine, galantamine, and memantine in patients with vascular cognitive impairment
Clinical trials Study design Dose Primary Results Adverse events
outcomes/efficacy
measures

DON
Wilkinson 24-week, double-blind, DON 5 mg/day ADAS-cog; CIBIC- On ADAS-cog: DON Withdrawal rates, PL
et al. [54] randomized, pc, (n = 208), plus 5 mg/day -1.65, 8.8%, DON 5 mg/day
parallel-group study 10 mg/day p = 0.003; DON 10.1%, DON 10 mg/day
to evaluate efficacy (n = 215), PL 10 mg/day -2.09, 16.3%. Serious AEs
and tolerability of (n = 193), p = 0.0002. On CIBIC- included stroke, skin
DON in pts with VaD plus: 25% of PL, 39% of carcinoma, pathologic
5 mg, 32% of 10 mg fractures, pneumonia,
group showed confusion, TIA. Typical
improvement, DON AEs included diarrhea,
5 mg/day p = 0.004, nausea, arthralgia, leg
DON 10 mg/day cramps, anorexia, and
p = 0.047 headaches
Black et al. 24-week, double-blind, DON 5 mg/day ADAS-cog; CIBIC- On ADAS-cog: DON Serious AEs were
[55] randomized, pc, (n = 198), plus 5 mg/day -1.90, reported: PL 15.1%,
parallel-group study 10 mg/day p = 0.001; DON DON 5 mg 16.2%, DON
to assess efficacy and (n = 206), PL 10 mg/day -2.33, 10 mg 21.8%. Included
safety of DON in pts (n = 199) p \ 0.001. On CIBI- stroke, TIA, and
with VaD plus: DON 5 mg/day, hypertension
p = 0.014; DON
10 mg/day, p = 0.27
Román et al. 24-week, double-blind, Participants were V-ADAS-cog; On V-ADAS-cog: DON AEs were similar in DON
[57] randomized, pc study randomly CIBIC-plus 5 mg/day vs. PL, LSM (80.7%) and PL (77.6%).
to assess efficacy and assigned 2:1 to difference -1.156, Common AEs included
safety of DON in pts DON 5 mg/day p \ 0.01. On CIBIC- nausea, anorexia,
with VaD (n = 648) or PL plus, p = 0.23 abdominal pain,
(n = 326) once diarrhea, abnormal
daily dreams, leg cramps
Dichgans 18-week, double-blind, DON 10 mg/day V-ADAS-cog LSM change from baseline 10 DON and 7 PL treated
et al. [58] randomized, pc study (n = 86), PL was -0.85 (SE 0.57) in pts discontinued
to see whether DON (n = 82) DON and –0.81 (SE treatment due to AEs
improves cognition in 0.59) in PL; p = 0.956
pts with CADASIL
GAL
Erkinjuntti Multicenter, 6-month, GAL 24 mg/day ADAS-cog/11; On ADAS-cog/11: GAL, The main AEs included
et al. [61] double-blind, (n = 396) vs. CIBIC-plus treatment effect 2.7 nausea and vomiting.
randomized, pc study PL (n = 196) points; p B 0.0001 These side effects were
of pts with probable On CIBI-plus: GAL 74 vs. more common in GAL
VaD or with AD 59% of pts remained group than PL. The
combined with stable or improved, slower dose escalation
cerebrovascular p = 0.001 helped with better
disease tolerability
Auchus et al. Multinational, GAL maximum ADAS-cog/11 and On ADAS-cog/11: mean Most AEs mild to
[62] 26-week, double- dose 24 mg/day ADCS-ADL total endpoint changes from moderate severity and
blind, randomized, (n = 396) vs. score baseline were -0.3 included nausea,
pc, parallel-group PL (n = 390) points in the PL and - vomiting, diarrhea, falls,
study 1.8 in the GAL group; dizziness, and anorexia.
p \ 0.001. No difference GI AEs were the most
in two groups on ADCS- common reason for
ADL score (0.7 vs. 1.3; discontinuing treatment
p = 0.783) (6% GAL, 1% PL)
Pharmacotherapy for VCI

Table 1 continued
Clinical trials Study design Dose Primary Results Adverse events
outcomes/efficacy
measures

RIV
Narasimhalu 24-week, double-blind, RIV up to Mean change from RIV group showed AEs included nausea,
et al. [64] randomized, pc trial 9 mg/day baseline in the significant improvement sleeping difficulty,
of safety and efficacy (n = 25) vs. PL TPC and Color (1.70 vs. 0.13, p = 0.02) headache, GI upset,
of RIV on cognitive (n = 25) Trails 1 and 2 on the animal sub-task of difficulty in breathing,
function in pts with the verbal fluency dizziness, diarrhea,
CIND measure. There was a vomiting, chest pain,
trend but no significant blurry vision. No
improvement in Color significant differences
Trails between safety outcomes
in RIV and PL
Moretti et al. 22-month, open-label Group A: RIV Global cognitive On MMSE: Group A: Main AEs included
[65] study to assess the 3–6 mg/day function was 1.6 ± 4.3; Group B: - nausea, muscle
effect of RIV in VaD (n = 8); Group assessed on 0.4 ± 1.9. Group A contractions, anorexia,
B: cardioaspirin MMSE and TPC; showed significant syncope and postural
100 mg/day behavioral improvements in TPC hypotension. Side effects
(n = 8) symptoms were scores of 2.1 points over in both groups were
assessed using baseline (p \ 0.01) and tolerable. There were no
NPI 3 points over Group B study withdrawals
(p \ 0.001). NPI scores
were significantly
improved, by 3.3 points
over baseline (\0.05)
and 4.2 points over
Group B (p \ 0.01)
MEM
Orgogozo 28-week, double-blind, MEM 10 mg/day ADAS-cog; CIBIC- On ADAS-cog: MEM, MEM was well tolerated
et al. [69] parallel-group RCT (n = 165) vs. plus treatment effect 2.0 vs. PL (frequency of
to determine efficacy PL (n = 156) points; 95% CI reported AE; 76 vs. 74%
and tolerability of 0.49–3.60. On CIBI- respectively), and most
MEM in pts with plus: response rate frequent AEs included
mild to moderate defined as improved or agitation, confusion,
VaD stable, was 60% with dizziness
MEM and 52% with PL
(p = 0.227)
Wilcock 28-week, double-blind, MEM 20 mg/day ADAS-cog; CGI-C On ADAS-cog: two study MEM was well tolerated
et al. [70] parallel-group, RCT (n = 277) vs. groups differed by a overall; 75% of PL and
to study safety and PL (n = 271) mean of 1.75 points 77% of MEM pts
efficacy of MEM in (median = 2.00) from experienced AEs; the
mild to moderate baseline in favor of main AEs included
VaD MEM; p = 0.000505. dizziness, confusion, and
On CGI-C: no constipation
statistically significant
difference between
groups at the end of
28 weeks; p [ 0.0038
AD Alzheimer’s disease, ADAS-cog Alzheimer’s Disease Assessment Scale cognitive subscale, ADCS-ADL Alzheimer’s Disease Cooperative
Study-Activities of Daily Living Inventory, AE adverse event, CADASIL cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy, CGI-C Clinical Global Impression of Change, CIBIC-plus Clinician’s Interview Based Impression of Change plus, CIND
cognitive impairment no dementia, DON donepezil, GAL galantamine, GI gastrointestinal, LSM least squares mean, MEM memantine, MMSE
Mini Mental State Examination, NPI Neuro-Psychiatric Inventory, pc placebo-controlled, PL placebo, pt(s) patient(s), RCT randomized con-
trolled trial, RIV rivastigmine, SE standard error, TIA transient ischemic attack, TPC Ten Point Clock Drawing, VaD vascular dementia, V-ADAS-
cog vascular ADAS-cog subscale

function and as a measure of overall clinical response to serious adverse events included stroke, TIA, and,hyper-
treatment. Donepezil was well tolerated, and withdrawals tension and common side effects were nausea, diarrhea,
due to side effects were relatively low in this study. The and muscle cramps [55].

The combined analysis of the abovementioned random-
ized, double-blind, placebo-controlled studies showed that
patients treated with donepezil 5 and 10 mg/day had sig-
nificant improvements in their cognitive functions (ADAS-
cog) versus those receiving placebo (p \ 0.01) [56].
Román et al. [57] studied the exclusive use of low-dose
donepezil 5 mg/day in patients with VaD. They used the
low-dose donepezil to minimize the side effects from the
medication in an attempt to reduce study subject withdrawal.
Two additional items to the ADAS-cog subscale for better
assessment of executive function, a domain commonly
affected in VaD, were studied. This trial was conducted at 11
centers in nine countries, and 1320 patients were screened;
974 were randomly assigned to treatment with donepezil
5 mg (n = 648) or placebo (n = 326). The primary efficacy
outcome measures were scores on the Vascular ADAS-cog
sub-scale (V-ADAS-cog) and the CIBIC-plus. Assessment
of executive function included the V-ADAS-cog and the
ADAS-cog plus the Maze and Number Cancellation test
(NCT). Patients who received donepezil showed significant
improvement on V-ADAS-cog as compared with those
receiving placebo at all points in the study except at week 6
[least squares mean difference, -1.156; 95% confidence
interval (CI) -1.98 to -0.33; p \ 0.01]. However, there was
no difference on the CIBIC-plus at the final time endpoint
marker (p = 0.23). There was no significant difference in the
incidence of side effects between the donepezil (80.7%) and
placebo groups (77.6%). This was the largest clinical trial of
donepezil in patients with VaD that showed significant
improvement on the V-ADAS-cog in patients treated with
donepezil, but it did not show any significant difference on
the CIBIC-plus [57].
Donepezil has also been tried in patients with CADASIL
in an 18-week, placebo-controlled, double-blind, random-
ized trial. The main purpose of the study was to determine
whether donepezil improves cognition in these patients
with SIVaD. Patients with CADASIL (n = 168) were
assigned to donepezil 10 mg per day (n = 86) or placebo
(n = 82). The primary endpoint was change from baseline
of the V-ADAS-cog score at 18 weeks.
Unfortunately, this study did not show any significant
difference between patients treated with donepezil
(n = 84) and those who received placebo (n = 77) in
relation to the primary endpoint. The least squares mean
change from baseline score was -0.81 [standard error (SE)
0.59] in the placebo group and -0.85 (SE 0.57) in the
donepezil group (p = 0.956). Improvements were noted on
other measures of executive function in secondary analysis,
but the clinical relevance of these findings was not clear
[58]. Overall, the results of these trials indicate that
donepezil may have a greater impact on cognitive than
global function and activities of daily living in patients
with VaD. Thus, it may be useful for cognitive
M. U. Farooq et al.
enhancement in some patients with VaD (Class IIa; level of
evidence A) [3].
5.2 Galantamine
Galantamine is a reversible and competitive acetyl-
cholinesterase inhibitor and a modulator of nicotine
receptors. The drug is approved for the treatment of mild to
moderate AD [59, 60]. Limited data are available about the
impact of galantamine on VaD. We discuss two main
clinical trials assessing the efficacy of galantamine in
patients with VaD and AD combined with cerebrovascular
disease.
Erkinjuntti et al. [61] conducted a multicenter, double-
blind, 6-month trial to study the efficacy of galantamine in
VaD and AD combined with cerebrovascular disease. In this
randomized trial, 592 patients were enrolled. These patients
received galantamine 24 mg/day (n = 396) or placebo
(n = 196). Primary endpoints were cognition, assessed by
the ADAS-cog, and global functioning assessed by the
CIBIC-plus scale. AD with cerebrovascular disease was
diagnosed in 48% of patients who received galantamine and
50% of those who received placebo. Probable VaD was
diagnosed in 43% of patients in the galantamine group and
41% in the placebo group. Galantamine showed greater
efficacy than placebo on the ADAS-cog (-1.7, SE 0.4 vs. 1.0
SE 0.5, p \ 0.0001) and CIBIC-plus [213 (74%) vs. 95
(59%), p = 0.001] tests. There was also improvement of
activities of daily living as compared with placebo
(p = 0.002). However, the subgroup data that included a
pure population of patients with VaD showed no significant
differences in the ADAS-cog and CIBIC-plus when galan-
tamine was compared with placebo. This study was not
powered to detect a treatment difference in subgroups such
as the one with pure VaD patients. A possible limitation of
the study was that VaD was diagnosed without central
magnetic resonance imaging (MRI) over reading [61].
Auchus et al. [62] conducted a multicenter, randomized,
double-blind, placebo-controlled trial to study the efficacy
and safety of galantamine in patients with VaD. They
randomized 788 patients with probable VaD. They satisfied
criteria for centrally read MRI. The primary efficacy
measures were the ADAS-cog/11 and the Alzheimer’s
Disease Cooperative Study-Activities of Daily Living
Inventory (ADCS-ADL) total score. Patients who received
galantamine had greater improvement in the ADAS-cog/11
after 26 weeks compared with placebo (-1.8 vs. -0.3;
p \ 0.001). There was no significant difference between
galantamine and placebo at week 26 on the ADCS-ADL
score (0.7 vs. 1.3; p = 0.783). There was no statistically
significant improvement in global functioning measured by
the CIBIC-plus in galantamine-treated patients
(p = 0.069). More side effects were observed in patients
Pharmacotherapy for VCI
treated with galantamine and, thus, more patients withdrew
from the study: 13% in the galantamine group compared
with 6% in the placebo group. Most of the side effects were
nausea, diarrhea, vomiting, and falls. Overall, this study
showed benefits for improvement in the ADAS-cog
favoring galantamine treatment; however, there was no
significant benefit on the ADCS-ADL. Therefore, this
study’s primary objective to show a significant treatment
effect in both primary endpoints was not met [62].
The above data suggest that galantamine can be bene-
ficial for patients with mixed AD and VaD (Class IIa; level
of evidence A) [3, 60–62].
5.3 Rivastigmine
Rivastigmine is a dual inhibitor of acetylcholinesterase
and butyrylcholinesterase. Data about the efficacy and
safety of this drug for treatment of VaD are limited.
Various animal studies have shown evidence to support
the potential benefit of rivastigmine in VCI. This effect
may be related to vascular relaxation and improvement in
cerebral blood flow and metabolism in ischemic brain
tissue [63].
In a randomized, double-blind, placebo-controlled
24-week trial, Narasimhalu et al. [64] studied the safety
and efficacy of rivastigmine in patients with cognitive
impairment no dementia (CIND) due to cerebrovascular
disease. The patients were randomized to either rivastig-
mine up to 9 mg/day or placebo. The primary outcome
measure was mean change from baseline in the Ten Point
Clock Drawing and Color Trails 1 and 2 tests. These two
primary endpoints were used as surrogate markers for
executive function. A total of 50 patients were enrolled in
the study; 25 were randomized into the rivastigmine group
and the rest into the placebo arm. Patients in the rivastig-
mine group showed significant improvement (1.70 vs. 0.13;
p = 0.02) on the animal subtask of the verbal fluency
measure compared with placebo-treated patients. There
was also some benefit and improvement in the Color Trails
tests, but it was not statistically significant [64].
Overall, the rivastigmine was well tolerated. However,
some patients required a slower medication titration than
specified in the original protocol. This occurred in indi-
viduals with multiple comorbidities. This study had some
limitations, including the choice of paper and pencil tasks
as a primary outcome as applicable to stroke patients who
may have specific neurologic impairments. Other tests of
executive function, such as the Stroop Test and Complex
Figure Test, might have been better choices for testing
post-stroke patients [64].
Moretti et al. [65] conducted an open-label controlled
study to determine the effects of rivastigmine in patients
with sub-cortical VaD. Patients (n = 16) were divided into
two groups. The first group (n = 8) received rivastigmine
3–6 mg/day. Treatment was started at a dose of 3 mg/day
and increased to 6 mg/day after 4 weeks. The second group
(n = 8) received cardioaspirin 100 mg/day. Patients were
followed for 22 months. Global cognitive function was
assessed using the MMSE, and executive function was
assessed using the Ten-Point Clock Drawing test. Word
fluency was also assessed using semantic and phonological
tests. This was carried out to detect mild VCI. The index of
Activity of Daily Living was used to test performance on
activities of daily living.
At baseline, there were no statistical differences
between the two groups on any of the scales. The first
group showed significant improvements in the Ten-Point
Clock Drawing test scores of 2.1 points over baseline
(p \ 0.01) and 3.0 points over the cardioaspirin group
(p \ 0.001). This study also showed a reduction in care-
giver stress: an 8.5-point reduction on the relative stress
scale compared with baseline (p \ 0.05) and a mean
treatment effect of 11.8 points (p \ 0.01). Baseline scores
of global performance, cognition, word fluency, and daily
function were maintained in the first group. Patients in the
cardioaspirin group showed no improvements on any out-
come measure. There was significant deterioration on the
clinical dementia rating in the cardioaspirin group (0.6
points vs. baseline; p \ 0.05). There was also worsening
on the Ten-Point Clock Drawing test scores in the car-
dioaspirin group (0.9 points; p \ 0.05). The side effects
were well tolerated by the study patients and long-term use
of rivastigmine seemed to be safe. The most common side
effects were nausea, anorexia, postural hypotension, syn-
cope, and muscle contractions [65].
5.4 Memantine
Glutamate is an excitatory neurotransmitter in the brain that
is involved in cortical and hippocampal neurons. Cortical
neuronal loss in patients with dementia may be related to
glutamate toxicity. Glutamate activates the N-methyl-D-as-
partate (NMDA) receptors. Furthermore, excessive NMDA
stimulation induced by ischemia leads to excitotoxicity.
The drugs that block pathological stimulation of NMDA
receptors may be helpful to protect against further damage
in VaD. Memantine is a non-competitive and moderate
affinity NMDA receptor antagonist that has been shown to
prevent neurodegeneration and learning deficits in animal
models of dementia. In addition, memantine reduces neu-
ronal damage in global and focal animal models of brain
ischemia, and various clinical studies have shown
memantine to improve cognition and functional perfor-
mance in various stages of dementia [66–68].
Orgogozo et al. [69] conducted a phase III, multicenter,
randomized, double-blind, parallel-group trial to determine

the efficacy and tolerability of memantine in patients with
mild to moderate VaD. This trial was carried out at 50
centers in France, Belgium, and Switzerland. The patients
were randomized to receive memantine or placebo. After
an initial 3-week titration period with 5 mg/day at week 1,
10 mg/day at week 2, and 15 mg/day at week 3, or
matching placebo, patients received daily doses of
memantine 20 mg/day or placebo for the remainder of the
28 weeks of follow-up. Patients were assessed at baseline
and at subsequent weeks (i.e., weeks 2, 4, 12, 20, and 28).
There were two primary endpoints: the ADAS-cog and
CIBIC-plus. A total of 403 patients were screened for this
study; 321 were randomly allocated, with 165 receiving
memantine and 156 receiving placebo. The intent-to-treat
(ITT) population consisted of all randomized patients who
received at least one dose of study medication and had at
least one primary efficacy evaluation (CIBIC-plus or
ADAS-cog) on treatment. After 28 weeks, the mean
ADAS-cog scores were significantly improved in the
memantine group relative to placebo. In the ITT popula-
tion, in the memantine group, the mean score gained on
average was 0.4 points, whereas the placebo group mean
score declined by 1.6 points for a difference of 2.0 points
(95% CI 0.49–3.60). The response rate for CIBIC-plus,
defined as improved or stable, was 60% with memantine
compared with 52% with placebo (p = 0.227, by ITT
analysis). This study showed that, in patients with mild to
moderate VaD, memantine 20 mg/day improved cognition
consistently across different cognitive scales, but there was
no significant improvement in global functioning. There
were no significant side effects in this trial, and the med-
ication was well tolerated compared with placebo [69].
Wilcock at al. [70] studied the safety and efficacy of
memantine in mild to moderate VaD in a 28-week double-
blind, parallel, randomized controlled trial [70]. This trial
was conducted at 54 centers in the UK. A total of 579
patients were randomized to either memantine 20 mg or
placebo. Patients were titrated to a memantine dose of
20 mg/day but were started at a dose of 5 mg daily.
Memantine was increased at weekly increments of 5 mg to
a final dose of 10 mg twice a day. The primary endpoints
included the ADAS-cog and the Clinical Global Impression
of Change (CGI-C). The study aimed to evaluate these
primary endpoints after 6 months of treatment relative to
the placebo group. There was a significant improvement in
one of the primary endpoints, the ADAS-cog, in meman-
tine-treated patients; the change in the ADAS-cog from
baseline was -1.75 points (95% CI: -3.023 to -0.49)
(p = 0.000505). The CGI-C rating, the second primary
efficacy parameter, showed no significant difference
between the treatment groups (p = 0.1103). Thus, the trial
was not regarded as positive. However, memantine had a
positive effect on cognitive performance based on the
M. U. Farooq et al.
ADAS-cog endpoint. Overall, memantine was well toler-
ated, with the most frequent side effects including dizzi-
ness, confusion, and constipation [70].
5.5 Other Drugs
Other drugs have been administered to patients with VaD.
These include citicoline, calcium channel blockers,
cilostazol, propentofylline, naftidrofuryl, huperzine, ser-
traline, and vinpocetine.
5.5.1 Citicoline
Cytidine 5-diphosphocholine (CDP-choline) is also known
as citicoline when prepared as an exogenous sodium salt.
CDP-choline is a very important chemical used in the
synthesis of phospholipids in the cell membrane. Citicoline
is thought to have neuroprotective effects, and it enhances
neural repair. Therefore, it has been tried for the treatment
of chronic cerebrovascular disorders. Due to these effects
of citicoline, it has been considered for treatment of
patients with various neurological problems such as trau-
matic brain injury and cognitive impairment [71, 72].
Cohen at al. [73] conducted a randomized double-blind
clinical trial to determine whether daily citicoline treatment
improved neurocognitive and neuroimaging outcomes over
12 months in patients diagnosed with VaD. They enrolled
30 patients diagnosed with VaD and randomized them to
either citicoline 500 mg or placebo twice per day. Patients
were assessed at baseline and at 6 and 12 months on var-
ious neurocognitive tests. MRI brain studies were con-
ducted at baseline and at 12-month follow-up to measure
neuroimaging parameters of total brain volume and sub-
cortical/periventricular hyperintensity volume. Overall,
there was no benefit from citicoline on neuropsychological
performance and imaging study parameters comparing
baseline and the 12-month follow-up metrics [73].
Alvarez-Sabı́n et al. [75] conducted an open-label ran-
domized trial to study the safety of long-term administra-
tion of citicoline and its possible efficacy in preventing
post-stroke cognitive decline. It was a parallel study of
citicoline (n = 172) versus usual treatment (n = 175) [75].
The study subjects were selected 6 weeks after experi-
encing a stroke. They were randomized according to age,
sex, education, and stroke type strata into parallel arms of
citicoline 1 g/day for 12 months versus no citicoline
(control group). Amongst all of the study subjects, 199
patients underwent neuropsychological evaluation at
1 year. This study showed that cognitive functions
improved at 6 and 12 months after stroke in the entire
study cohort. However, in comparison with controls, citi-
coline-treated patients showed better outcomes in atten-
tion-executive functions [odds ratio (OR) 1.721, p = 0.027
Pharmacotherapy for VCI
at 6 months; OR 2.379, p = 0.007 at 12 months]. There
was also improvement in temporal orientation (OR 1.780,
p = 0.042 at 6 months; OR 2.155, p = 0.045 at
12 months) during the follow-up. Therefore, treatment with
citicoline for 12 months in patients with first-ever ischemic
stroke seems to be safe and might be effective for preser-
vation of some cognitive parameters [74].
A recent open-label, randomized, parallel study of citi-
coline versus usual treatment showed that citicoline treat-
ment improved cognitive status in patients post stroke. The
objective of this study was to study the effect of treatment
with oral citicoline 1 g/day on patients’ quality of life
(QoL) and cognitive performance in the long term in
patients with a first ischemic stroke. The mean age of
patients was 67.5 ± 10.7 years, and 50.9% were women.
The patients were enrolled 6 weeks after their first
ischemic stroke and randomized into parallel arms. These
patients (n = 163) underwent neuropsychological evalua-
tion, and QoL was measured using the EuroQoL-5
Dimension (EQ-5D) questionnaire over a period of 2 years.
Citicoline treatment improved cognitive status during fol-
low-up (p = 0.005). There was also improvement in QoL
in patients who were treated with citicoline (0.67 ± 0.26
vs. 0.58 ± 0.30; p = 0.041) [75].
5.5.2 Actovegin
Actovegin is manufactured from calf blood by ultrafiltra-
tion. It contains more than 200 bioactive constituents and is
a deproteinized pyrogen and antigen-free hemodialysate. It
has various neuroprotective properties and also improves
oxygen utilization and uptake in mitochondria. It reduces
amyloid-induced neuronal apoptosis.
Guekht et al. [76] conducted a 12-month, parallel-group,
randomized, multicenter, double-blind, placebo-controlled
study to test the beneficial effect of Actovegin in patients
with post-stroke cognitive impairment. The patients were
aged [60 years and had a MoCA score of B25 points.
Patients were randomized into two groups within 1 week of
acute supratentorial ischemic stroke (1:1 ratio). The first
group included patients (n = 248) treated with Actovegin
2000 mg/day for B20 intravenous infusions followed by
oral Actovegin 1200 mg/day; the second group included
patients treated with placebo (n = 255) for 6 months. The
primary endpoint was the change from baseline in ADAS-
cog, extended version, at 6 months. The least squares mean
change from baseline in ADAS-cog, extended version, was
-6.8 for Actovegin and -4.6 for placebo. The estimated
treatment difference was -2.3 (95% CI; p = 0.005). This
study showed Actovegin had a beneficial effect on cogni-
tive outcomes in patients with post-stroke cognitive
impairment [76].
5.5.3 Additional Medications
Other medications have been considered or tried for the
treatment of VCI or VaD. These include calcium channel
blockers [77–79], cilostazol [80–85], propentofylline
[86, 87], naftidrofuryl [88–91], huperzine A [92], vin-
pocetine [93], and piracetam [94]. There is no convincing
evidence about the efficacy of these medications in the
treatment of VCI. These drugs are reviewed according to
mechanism and key study results in Table 2.
6 Gaps in Knowledge
Dementia exerts a substantial financial burden on society.
The yearly monetary cost per person attributable to dementia
in the USA was recently estimated at about
$US41,000–56,000 [95]. Based on a dementia prevalence of
*15% for individuals aged [70 years, the estimated mon-
etary cost in the USA alone is $157 to $215 billion. Given
these considerations and the individual and family/societal
burden of dementia, a substantial treatment or preventive
that could delay or prevent cognitive impairment would be a
welcome addition [9]. Unfortunately, although stroke and
CVD risk targets and preventives are well-established, many
CVD trial opportunities to study the prevention of cognitive
impairment and dementia have been missed. Only more
recently has there been acknowledgment of the potential
value of such an approach by the Alzheimer research com-
munity and interest in how vascular mechanisms may con-
tribute to cognitive impairment [96]. A recent meeting of
scientific experts in the field convened by the Alzheimer
Association and key institutes of the US National Institutes
of Health addressed vascular contributions to cognitive
impairment to better understand how vascular factors con-
tribute to AD and related dementias and, thus, how these
disorders might be prevented [97]. The workgroup focused
on molecular and vascular mechanisms, animal models as a
research tool, and the discovery of biomarkers.
The failure to identify new drugs for VCI is related both
to the inadequacy of animal models and possibly to
incorrect concepts. Current animal models using rodents
are limited, for example, because of their lack of white
matter. Such a model might be more suitable for experi-
ments using larger species with abundant white matter, as
white matter may play an important role in human VCI.
Various translational models in animals may reflect a VCI-
related pathological process but do not satisfactorily rep-
resent the human disease spectrum and pathological pro-
cesses such as amyloid accumulation. More robust
neuropsychological methods and instruments for assessing
VCI in all models are also needed [98].

Table 2 Summary of the key mechanisms of action and pre-clinical and clinical studies of calcium channel blockers, cilostazol, propentofylline,
naftidrofuryl, huperzine A, vinpocetine, and piracetam in study subjects with vascular cognitive impairment
Drugs Mechanism of action
CCBs (nimodipine, 1. Effects the diameter of cerebral blood vessels and
amlodipine, nilvadipine, autoregulation. Nimodipine has specific effects on
and isradipine) [77–79] small vessels
2. Prevents cerebral hypoperfusion by relaxation of
cerebral vasculature and increasing blood flow
3. Neuroprotective effect: blockage of calcium channels
may attenuate amyloid-b-induced neuronal damage
[77]
Cilostazol [80–85] 1. Potent inhibitor of type III phosphodiesterase
increasing cAMP and inhibits platelet aggregation
2. Increases cerebral blood flow and improves cerebral
circulation
3. Inhibits lipid peroxidation and apoptosis and reduces
accumulation of amyloid-b in the brain
4. Scavenger of the hydroxyl and peroxyl radicals and
inhibits cell damage
5. May prevent progression of white matter lesions due
to its anticytotoxic and antiapoptotic effects [80–85]
Propentofylline [86, 87] 1. A xanthine derivative that blocks the reuptake of
adenosine by neurons and glial cells
2. Inhibitor of cAMP and cGMP phosphodiesterase
3. In animal studies of global and focal ischemia reduces
neuronal cell death
4. Stimulates long-term potentiation in the guinea pig
hippocampus enhancing memory and learning [86]
Naftidrofuryl [88–91] 1. A serotonin 5-HT2 receptor antagonist that inhibits
serotonin-induced vascular smooth muscle contraction
and platelet aggregation and under ischemic
conditions restricts aerobic metabolism [88]
Huperzine A [92] 1. The precise mechanism of action is not known. It is a
form of herbal medicine [92]
M. U. Farooq et al.
Key pre-clinical and clinical studies and their outcomes
1. In a post hoc subgroup analysis of the Scandinavian
Multi-Infarct Dementia Trial, patients with subcortical
VaD treated with nimodipine performed better on
attention and psychomotor performance vs. the
placebo group. There was no significant benefit in
patients with multi-infarct dementia [78]
2. In patients with cognitive impairment treated with
nilvadipine, cognition remained stable for 20 months.
Conversely, amlodipine, did not show any beneficial
effect. Both groups had lowering of their blood
pressure to the same extent, suggestive of a
neuroprotective effect independent of an
antihypertensive effect [79]
1. In an exploratory study of patients (n = 10) with AD
and cerebrovascular disease, cilostazol added to
donepezil for 6 months increased MMSE scores from
baseline [83]
2. In their rat experiments, neuroprotective effect
observed through the cAMP-responsive element
binding protein (CREB) phosphorylation pathway
leading to upregulation of Bcl-2 and cyclooxygenase-
2 expression [84]
3. In an animal experiment of L-methionine-induced
VaD, neuroprotective, anti-oxidant and anti-
inflammatory effect when used with simvastatin[85]
In four randomized studies of 901 patients with mild to
moderate AD and 359 patients with mild-to-moderate
VaD treated up to 12 months with propentofylline
300 mg tid, there was significant improvement over
placebo VaD patients on the Gottfries–Brane–Steen
Scale and an activities of daily living scale. The drug
was well tolerated [87]
1. In a small clinical study, there was improvement on a
psychometric test battery in patients with AD and VaD
[89]
2. In a randomized, double-blind study vs. placebo,
there was improvement in cognition with naftidrofuryl
(ADAS-cog, p \ 0.001 and MMSE, p = 0.008) [90]
3. In a prospective, randomized double-blind study of
naftidrofuryl 400 or 600 mg per day in VaD and
mixed-type dementia, significantly more patients in
the treatment groups showed no deterioration on both
ADAS-cog and SCAG vs. placebo (400 mg,
p = 0.005 and 600 mg p = 0.015) [91]
In one VaD trial, no significant beneficial effect of
Huperzine A on cognitive function as measured by
MMSE. In a recent analysis of placebo-controlled
randomized trials of Huperzine A for patients with AD
and VaD, only two VaD trials with 92 total
participants met the inclusion criteria. However,
Huperzine was associated with improvement on the
MMSE and ADL score of patients with VaD [92]
Pharmacotherapy for VCI

Table 2 continued
Drugs Mechanism of action Key pre-clinical and clinical studies and their outcomes

Vinpocetine [93] 1. A derivative of vincamine, an alkaloid of the common Improves cognition vs. placebo in poorly statistically
periwinkle plant powered studies, but few serious side effects [93].
2. Exerts neuro-protective effects by its action on Results are inconclusive in VaD
cerebral circulation and brain metabolism
3. An increase in cerebral metabolism that enhances
both oxygen and glucose utilization and improves
cerebral function. May also be protective in conditions
of hypoxia and ischemia [93]
Piracetam [94] 1. A nootropic, whose putative actions are not well There is no well-designed study about the use of
defined [94] piracetam in patients with VaD. Thus, the available
evidence does not support the routine use of piracetam
for treatment of VaD [94]
AD Alzheimer’s disease, ADAS-cog Alzheimer’s Disease Assessment Scale—cognitive subscale, ADL activities of daily living, cAMP cyclic
adenosine monophosphate, CCBs calcium channel blockers, CGI Clinical Global Impression, cGMP cyclic guanosine monophosphate, MMSE
Mini Mental State Examination, SCAG The Sandoz Clinical Assessment Geriatric Scale, tid three times daily, VaD vascular dementia

We acknowledge the need for the development of a
research network for the study of vascular mechanisms and
risks for cognitive phenotypes as we age, a focus on basic
pathophysiologic mechanisms and translational approa-
ches, multi-modal prevention and treatment studies, clini-
cal–neuroradiological–neuropathological correlative
studies, and a lifecycle approach that includes intervention
studies as early as midlife or before [3, 99]. Pharma-
cotherapeutic approaches for VCI can be better informed
once additional information from much needed patho-
physiological, biomarker, and genetic studies is available
[100]. Such studies will be important as we have learned
from studies of cholinesterase inhibitors and memantine in
VCI that translation of AD treatments to VaD based on
shared neurochemical mechanisms may or may not be
fruitful [99]. Many vascular targets and mechanistic path-
ways may respond positively to standard or novel phar-
macotherapeutics if applied during an appropriate window
of time opportunity, especially if biomarkers trigger such a
therapeutic approach [3].
Compliance with Ethical Standards
Funding No sources of funding were used to prepare this manuscript.
Conflict of interest MUF, JM, and CG have no conflicts of interest
in relation to this manuscript. PBG served as a member on the data
safety and monitoring board for a Novartis study of LCZ 696 in
cognitive vitality in heart failure.
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