Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer’s dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial
Efficacy and tolerability of rivastigmine patch therapy in patients with mild-to-moderate Alzheimer's dementia associated with minimal and moderate ischemic white matter hyperintensities: A multicenter prospective open-label clinical trial
Kyung Won Park 2 3
Eun-Joo Kim 1 3
Hyun Jeong Han 3
Yong S. Shim 3
Jae C. Kwon 3
Bon D. Ku 3
Kee Hyung Park 3
Hyon-Ah Yi 3
Kwang K. Kim 3 6
Dong Won Yang 3
Ho-Won Lee 3
Heeyoung Kang 3
Oh Dae Kwon 3
SangYun Kim 3
Jae-Hyeok Lee 3
Eun Joo Chung 3
Sang-Won Park 3
Mee Young Park 3 5
Bora Yoon 3 4
Byeong C. Kim 3
Sang Won Seo 0 3
Seong Hye Choi 3
0 Department of Neurology, Samsung Medical Center, Sungkyunkwan University School of Medicine , Seoul , South Korea , 22 Department of Neurology, Inha University School of Medicine , Incheon , South Korea
1 0 Department of Neurology, Chonnam National University School of Medicine , Gwangju , South Korea
2 Department of Neurology, Cognitive Disorders and Dementia Center, Dong-A University College of Medicine and Institute of Convergence Bio-Health , Busan , South Korea , 2 Department of Neurology, Pusan National University Hospital and Biomedical Research Institute, Pusan National University School of Medicine , Busan , South Korea , 3 Department of Neurology, Seonam University College of Medicine, Myongji Hospital , Goyang , South Korea , 4 Department of Neurology, Holy Family Hospital, The Catholic University of Korea, School of Medicine , Bucheon , South Korea , 5 Department of Neurology, Changwon Fatima Hospital , Changwon , South Korea , 6 Department of Neurology, Catholic Kwandong University College of Medicine , Gangneung , South Korea , 7 Department of Neurology, Gachon University Gil Hospital , Incheon , South Korea , 8 Department of Neurology, Keimyung University College of Medicine , Daegu , South Korea
3 Editor: Alfonso Fasano, University of Toronto , CANADA
4 Department of Neurology, Konyang University College of Medicine , Daejeon , South Korea
5 Department of Neurology, Yeungnam University College of Medicine , Daegu , South Korea
6 Department of Neurology, Dongguk University College of Medicine , Seoul , South Korea , 10 Department of Neurology, The Catholic University of Korea, School of Medicine , Seoul , South Korea , 11 Department of Neurology, Kyungpook National University School of Medicine , Daegu , South Korea , 12 Department of Neurology, Gyeongsang National University College of Medicine , Jinju , South Korea , 13 Department of Neurology, Catholic University of Daegu School of Medicine , Daegu , South Korea , 14 Department of Neurology, Seoul National University College of Medicine, Seoul National University Bundang Hospital , Seongnam , South Korea , 15 Department of Neurology, Pusan National University Yangsan Hospital , Yangsan , South Korea , 16 Department of Neurology, Busan Paik Hospital, Inje University College of Medicine , Busan , South Korea , 17 Department of Neurology, Daegu Fatima Hospital , Daegu , South Korea
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: This study was supported by Novartis
and the funding was received by KWP. This study
was also supported by the Original Technology
Research Program for Brain Science through the
National Research Foundation of Korea (NRF),
Background and objective
Studies investigating the impact of white matter hyperintensities (WMHs) on the response of acetylcholinesterase inhibitors in patients with Alzheimer's disease (AD) have presented inconsistent results. We aimed to compare the effects of the rivastigmine patch between patients with AD with minimal WMHs and those with moderate WMHs.
which is funded by the Korean government
(Ministry of Science, ICT and Future Planning; No.
2014M3C7A1064752); this funding was received
by SHC. The financial sponsors had no role in
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Competing interests: KWP received funding from
Novartis for this study. This does not alter the
authors' adherence to all the PLOS ONE policies on
sharing data and materials. There are no patents,
products in development or marketed products to
Three hundred patients with mild to moderate AD were enrolled in this multicenter prospec
tive open-label study and divided into two groups. Group 1 comprised patients with AD with
minimal WMHs and group 2 comprised those with moderate WMHs. The patients were
treated with a rivastigmine patch for 24 weeks. Efficacy measures were obtained at baseline
and after 24 weeks. The primary endpoint was the change in the AD Assessment
Cognitive subscale (ADAS-Cog) from the baseline to the end of the study.
Of the 300 patients, there were 206 patients in group 1 and 94 patients in group 2. The
intention-to-treat group comprised 198 patients (group 1, n = 136; group 2, n = 46) during the
24week study period. Demographic factors did not differ between group 1 and group 2. There
were no significant differences in change in ADAS-cog between group 1 (-0.62±5.70) and
group 2 (-0.23±5.98) after the 24-week rivastigmine patch therapy (p = 0.378). The patients
in group 1 had a 0.63-point improvement from baseline on the Frontal Assessment Battery,
while group 2 had a 0.16-point decline compared to baseline at the end of the study (p =
0.037). The rates of adverse events (AEs) (42.6 vs. 40.3%) and discontinuation due to AEs
(10.3% vs. 4.3%) did not differ between the groups.
Although the efficacy and tolerability of rivastigmine patch therapy were not associated with
WMH severity in patients with AD, some improvement in frontal function was observed in those with minimal WMHs.
Alzheimer's disease (AD) is the most common cause of neurodegenerative dementia .
Degenerative changes in cholinergic neurons of the nucleus basalis of Meynert, which
provides the major cholinergic input to the cerebral cortex, hippocampus, and temporal cortex,
lead to acetylcholine depletion. This depletion is associated with cognitive, behavioral, and
functional impairments in AD [
]. The safety and efficacy of three acetylcholinesterase
inhibitors (AChEIs)±donepezil, galantamine, and rivastigmine±in terms of cognitive improvement
in AD have been confirmed in multicenter placebo-controlled double-blind randomized trials,
and they have been widely used for the symptomatic relief of AD[3±5].
Vascular dementia (VaD), the second most common cause of dementia, accounts for about
20% of all dementia cases. Pure VaD is mainly caused by cerebrovascular disease (CVD) or
small-vessel disease (SVD), but over 40% of VaD is often mixed with AD pathology [
Indeed, there is growing evidence that parallel cerebrovascular and neurodegenerative pathologies are observed in AD and VaD (mixed AD with cerebrovascular disease). Furthermore, it has been reported that several vascular risk factors play important roles in the development of AD [7, 8].
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Since cholinergic structures, such as the basal forebrain and hippocampal CA1, are
vulnerable to ischemic injury and widespread white matter bundles of both the lateral and medial
cholinergic pathways reach almost all areas of the neocortex [
], cerebrovascular disease, such as
localized stroke or microangiopathy mainly involving white matter may interrupt these
]. Since AD and VaD share the common neurochemical characteristics of
cortical cholinergic depletion, AChEIs have been used as the major treatment for pure VaD or
mixed AD with CVD, as well as pure AD.
Rivastigmine, which inhibits both acetylcholinesterase and butyrylcholinesterase (BuChE),
was previously shown to be beneficial in preventing neuronal degeneration by increasing
regional cerebral blood flow in animal models [
]. The neuroprotective effects of rivastigmine
in the context of ischemic brain conditions have also been observed in animal studies[12±14].
Thus, rivastigmine may be an important treatment option for AD with concurrent vascular
In fact, one previous randomized trial has indicated that following rivastigmine treatment
for 26 weeks, patients with AD with vascular risk factors (VRFs) showed greater clinical benefit
in cognition, activities of daily living, and disease severity than those with AD without VRFs
]. Another recent retrospective analysis of a large international 24-week multicenter
randomized double-blind placebo-and active-controlled trial also indicated the significant impact
of VRF status on treatment response in AD [
]. In these studies, however, VRFs were
determined using only the Modified Hachinski Ischemic Score (HIS) [
] or by assessing the
presence or absence of reported VRFs at the time of screening. Therefore, it remains unknown
whether the patients with AD with VRFs had actual concurrent CVD pathology as confirmed
by brain magnetic resonance imaging (MRI). Furthermore, there have been no studies on the
effects of rivastigmine patch in patients with AD with varying degrees of WMH. According to
some studies [
], the presence of WMH predicted a favorable clinical response to
donepezil on tasks assessing frontal cognitive functions, while other studies reported the presence of
WMH was associated with a poorer response to AChEIs  or that it did not influence the
clinical response to AChEIs [
Thus, we sought to investigate the efficacy of the rivastigmine patch in patients with
mild to moderate AD with minimal versus moderate ischemic WMHs. The treatment effect
of rivastigmine is generally greater in patients with AD with VRF than in those with AD
without VRF [
], and VRFs are associated with greater WMHs or reduced white matter
]. We thus hypothesized that patients with AD with moderate WMHs would
have greater beneficial effects from baseline than those with AD with minimal WMHs. To
maximize the therapeutic effects of rivastigmine on cognitive function, we used a
transdermal 9.5 mg/24hour rivastigmine patch (10cm2), which offers continuous delivery of the
drug with minimal plasma fluctuations. This delivery method provides to potentially
comparable efficacy and fewer side effects compared to the highest dose of the rivastigmine
Materials and methods
Eligible patients were between 50 and 90 years of age and had a diagnosis of probable AD
according to National Institute of Neurological and Communicative Disorders and Stroke,
and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) [
subjects had mild to moderately severe cognitive impairment as defined by Mini-Mental State
Examination (MMSE) scores of 10±26 , minimal or moderate ischemia as indicated by an
MRI scan conducted at baseline or within 12 months prior to the baseline examination based
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on the Clinical Research Center for Dementia of South Korea (CREODS) WMH visual rating
], HIS 4, and a responsible care provider who had contact with the patient at least
once per week and could be a reliable informant. None of the patients had clinically significant
laboratory abnormalities, such as thyroid disease, vitamin B12 deficiency or folic acid
Patients were excluded from the study if they had received an investigational medication,
AChEIs, N-methyl-D-aspartate receptor antagonist, or anticholinergic drugs within 4 weeks
prior to the screening or if they had evidence of active skin lesions, allergy to the study drugs,
or any advanced or unstable disease that would prevent completion of the study. Diseases
precluding enrolment in the study included acute and severe asthmatic conditions, severe and
unstable cardiovascular disease (bradycardia with heart rate < 50 bpm, sick sinus syndrome,
sinoatrial block, or 2nd/3rd degree atrioventricular block), active peptic ulceration or
gastrointestinal bleeding, severe hepatic or renal disease, malignancy within the past 5 years, or
severely declined vision or hearing. Other exclusion criteria included a history or presence of
any contraindication for the application of AchEIs, a history of other concomitant
neurodegenerative or psychiatric disease, a history of drug or alcohol addiction within the previous 10
years, or severe ischemia based on the CREDOS WMH visual rating scale, and multiple large
territorial infarctions or single strategically placed infarctions on MRI scan conducted at
baseline or within 12 months of the baseline examination.
The study was performed in accordance with the International Harmonization Conference
guidelines on Good Clinical Practice and was approved by the Dong-A University Hospital
Institutional Review Board (IRB) and IRB ofeach center prior to the beginning the study. Prior to participation in the study, all participants or their legally authorized representatives provided written informed consent to participate in the study. This study was registered at clinicaltrials.gov as NCT01380288.
This was a 24-week prospective open-label multicenter trial conducted at 20 centers across
South Korea between July 6, 2011 and December 8, 2014 (date of the last patient's last visit).
After assessments for eligibility performed over a 4-week screening period, patients underwent
baseline efficacy and safety assessments and were divided into two groups based on their
DOS WMH visual rating scale scores. In brief, this classification system was developed using a
combination of deep WMH (DWMH) and periventricular WMH (PWMH) scores. On this
scale, PWMHs were classified as P1 (cap or band <5 mm), P2 ( 5 mm cap or band < 10
mm), and P3 (cap or band 10 mm), while DWMH were classified as D1 (maximum
diameter of deep white matter lesion < 10 mm), D2 (10 mm lesion <25 mm), and D3 ( 25 mm).
Combinations of D1 and P1 (D1P1) and D1 and P2 (D1P2) were classified as ªminimal.º The
D1P3, D2P1, D2P2, D2P3, D3P1, and D3P2 combinations were classified as ªmoderate,º and
D3P3 was classified as ªsevereº . Group 1 included patients with AD with minimal WMHs
(D1P1 and D1P2), and group 2 included patients with AD with moderate WMHs (D1P3,
D2P1, D2P2, D2P3, D3P1, and D3P2). All MRIs of participants were examined by 3 experienced neurologists blind to clinical information within the screening period and the WMH visual rating scales were assigned by consensus.
Participants in both groups were initially treated using on a 4.6mg/24hours rivastigmine
patch (5cm2) and were then up-titrated to a 9.5mg/24hours rivastigmine patch (10cm2) over
4weeks. This was followed by a 20-week maintenance phase. If patients were unable to reach the target dose during the titration period due to tolerability problems, the dose was increased over 8 weeks.
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Efficacy measures were assessed at baseline and at week 24. The primary outcome was the
change from baseline on the Alzheimer's Disease Assessment Scale-Cognitive subscale at week
24 (ADAS-Cog) [
]. Secondary outcomes were as follows: MMSE, Clinical Dementia
Rating Scale-Sum of Boxes (CDR-SB) , Frontal Assessment Battery (FAB) [
Administered Neuropsychiatric Inventory (CGA-NPI) , Alzheimer's Disease Cooperative
Study-Activities of Daily Living (ADCS-ADL) , and Caregiver Burden Scale-Korean Ver
sion of Mini-Zarit [
]. Safety evaluations, including vital signs, neurological examinations,
and adverse event (AE) and serious AE (SAE) monitoring were performed regularly (baseline,
4th week, 12th week and 24th week) for both groups throughout the study.
The sample size calculation was based on the change from baseline to week 24 of the primary
efficacy variable, the ADAS-Cog. A significant difference in the ADAS-Cog scores at 24 weeks
between the two groups of patients (AD associated with minimal WMH, group 1; and AD
with moderate WMH, group 2), was defined as a mean difference in scores of 2.3 points,
which would be assessed using an independent t test at a significance level of 0.05 with a
standard deviation (SD) of 6. Based on the above assumption, 162 participants for group 1 and 81
participants for group 2 were required. Taking into account an expected dropout rate of 20%,
a total of 300 patients, with 200 in group 1 and 100 in group 2, were sought for recruitment.
Data were summarized using descriptive statistics: frequency and percentage for categorical
variables and mean ± SD for continuous variables. Differences in study participants'
characteristics were compared across subgroups using chi-square tests or Fisher's exact tests for
categorical variables, and independent t tests or Mann-Whitney's U tests for continuous variables, as
appropriate. To check for normal distribution, we used the Shapiro-Wilk test. Changes from
baseline to end point were compared using an analysis of covariance (ANCOVA) model, using
the baseline score as a covariate. We used bar charts for data visualization. Intent to treat (ITT)
and per protocol (PP) analyses were performed and the last observed carried forward (LOCF)
method was used to impute missing values. P-values less than 0.05 were considered statistically
significant. All statistical analyses were carried out using Statistical Package for Social Sciences
22.0 (SPSS Statistics for Windows 22.0, Armonk, NY, IBM Corp.) software. All tests were
A total of 332 patients were screened for inclusion and 32 failed the screening. Of the 300
patients enrolled in the study, 206 had minimal WMH (group 1) and 94 had moderate WMH
(group 2). Seventy patients in group 1 and 32 patients in group 2 were excluded from the
efficacy assessment due to loss to follow-up (n = 22), transfer to another hospital (n = 9),
withdrawal (n = 45), or AEs (n = 26). Thus, the ITT population comprised 198 patients (group 1:
n = 136, group 2: n = 62). There were no significant differences in demographics and baseline
characteristics between group 1 and group 2 (Table 1). The PP populations consisted of 176
patients (122 in group 1 and 54 in group 2) from the ITT population for whom no major
protocol violations (such as drop±out or AEs) were reported (Fig 1).
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1P values were derived from the Mann-Whitney U test;
2P values were derived from the chi-square test;
3P values were derived from Fisher's exact test. The Shapiro-Wilk test was used to test for normality assumption.
Values are means ± standard deviations. ITT = intent to treat; LOCF = Last Observation Carried Forward; ADAS-Cog = Alzheimer's Disease Assessment
Scale-Cognitive subscale; MMSE = Mini-Mental State Examination; FAB = Frontal Assessment Battery; CGA-NPI = Caregiver-Administered
Neuropsychiatric Inventory; ADSC-ADL = Alzheimer's Disease Cooperative Study-Activities of Daily Living; CDR-SB = Clinical Dementia Rating Scale-Sum
No significant differences in the change from baseline to week 24 on the ADAS-Cog between
group 1 and group 2 were observed in the ITT-LOCF (p = 0.378) and PP populations
(p = 0.442). Table 2 shows the mean change in cognition, behavior, ADL, and caregiver's
burden in both groups at 24 weeks. Significant differences between group 1 and group 2 were
observed only in FAB scores (p = 0.037) (Fig 2). Group 1 had an improvement of 0.6 points in
the FAB score over baseline, while group 2 experienced a decline to 0.2 points below baseline.
The proportions of patients with MMSE scores under 20 with equal or better scores in effi
cacy variables at the end of the treatment period compared to baseline are shown in Table 3.
The responder rates for the FAB had a nearly significant tendency to be higher in group 1
compared to those in group 2 (69.4% vs. 48.1%, p = 0.057; Table 3). There were no significant
differences between the groups in the responder rates for the other efficacy variables. The
comparisons of responder rates at week 24 in patients with MMSE 20 were also performed,
however, no significant differences were observed between the groups in all efficacy variables (data
were not shown).
The number and percentage of patients who experienced AEs are summarized in Table 4. Itching (17.2%) and rash (11.6%) were the most commonly reported AEs. A total of 15 SAEs,
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Fig 1. Flow chart of the study design and patient participation.
including one death, were reported. However, there were no SAEs associated with the study
drug (Table 4). There were no significant differences in the incidence of AEs and SAEs
between the groups. Forty-four patients with AEs (including 1 patient with an SAE)
permanently discontinued the study. There was no significant difference in the incidence of
discontinuation between group 1 (n = 31, 10.3%) and group 2 (n = 13, 4.3%). Skin irritation was the
most common cause of discontinuation (n = 36, 12%).
Our results indicate that patients with AD with minimal WMHs had better responses to the rivastigmine patch compared to those of the patients with AD with moderate WMHs in terms of frontal lobe function, which was assessed using the FAB score. No significant differences in the changes in the primary outcome measure of ADAS-cog or other secondary efficacy
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Values are mean±standard deviation. ITT = intent-to-treat; LOCF = Last Observation Carried Forward; PP = per protocol; ADAS-Cog = Alzheimer's Disease
Assessment Scale-Cognitive subscale; MMSE = Mini-Mental State Examination; FAB = Frontal Assessment Battery; CGA-NPI = Caregiver-Administered
Neuropsychiatric Inventory; ADSC-ADL = Alzheimer's Disease Cooperative Study-Activities of Daily Living; CDR-SB = Clinical Dementia Rating Scale-Sum
Fig 2. Changes from the baseline at 24 weeks in the ADAS-cog, MMSE, FAB, CGA-NPI, CDR-SB, ADCS-ADL, and Mini-Zarit (ITT-LOCF
population) in the patients from groups 1 and 2.
Group 1 (n = 62)
Group 2 (n = 27)
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Overall (n = 198)
Group 1 (n = 136)
Group 2 (n = 62)
measures between patients with AD with minimal WMHs and those with moderate WMHs
were observed after 24 weeks of rivastigmine patch therapy.
One possible explanation for these findings might be that in AD with moderate WMHs, the
degree of cholinergic depletion due to ischemic damage to the cholinergic pathway maybe
greater than that in AD with minimal WMHs. This may reduce the efficacy of AChEI
treatment. This may also explain the results of previous studies showing that cerebral metabolic
changes in response to cognitive or psychophysical stimulation are normal during the early
stages and are delayed in the later stages of AD. In other words, the effects of AChEIs may be
attenuated when the hyperintensities involve more cholinergic pathways according to disease
]. Thus, higher reserves of acetylcholine in the frontal areas may lead to
more efficient responses to AChEI treatment.
Several studies have investigated the influence of WMHs on the response to AChEIs in AD,
VaD, and AD with CVD, although their results have been inconsistent [18±21, 37]. Erkinjuntti
et al. reported that patients with AD combined with CVD treated with galantamine 24 mg/day
for 6 months showed significant improvements in cognition and global functioning compared
to those treated with placebo [
]. Serial studies from Japan suggest that WMH might be an
MRI parameter predicting a favorable response to donepezil in terms of frontal function,
but not in terms of memory or language function [
]. Connelly et al. reported, however,
that patients with AD with combined HT and WMH had poorer responses to AChEIs than
patients with either HT or WMH as well as those with neither condition . Devine et al. also
reported that WMH severity visually rated on MRI or computed tomography did not influence
the clinical response to AChEIs in patients with AD [
]. Various methods used to measure
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the severity of WMH and different follow-up durations may explain the inconsistent results of
WMH in AD is known to be associated with executive dysfunction and psychomotor
slowing. It has been suggested that deficits in executive function caused by WMH are more
responsive to AChEIs than are other cognitive dysfunctions [
]. In our study, in line with this
proven rationale, patients with AD with minimal WMHs improved in terms of frontal
function. These findings are in agreement with the findings of other studies on rivastigmine,
wherein significant bilateral increases in frontal, temporal, and parietal brain perfusion,
enhanced frontal activation, or bilateral increases in regional frontal cerebral blood flow were
observed in patients with AD or VaD [39±41]. In addition, a study showing the selective
affinity of rivastigmine for frontal areas may explain the observed beneficial effects of this drug on
frontal function in our study [
Although several open-label clinical trials of rivastigmine conducted in patients with VaD
have demonstrated significantly improved behavior and executive function[43±45], a
largescale randomized double-blind placebo-controlled clinical trial of rivastigmine in patients
with probable VaD showed unsatisfactory results[
]. VaD is heterogeneous and the damage
to cholinergic pathways due to vascular injury is difficult to clearly define. Therefore, despite
the theoretical rationales for treatment of VaD with AChEIs discussed in the introduction
such studies may result in incoherent outcomes.
The most frequent AEs were skin irritations, such as itching and rash. Compared to a
previous western study, the incidence of skin reaction associated with the rivastigmine patch was
somewhat higher. However, gastrointestinal AEs in our study were comparable to those in a
western study . When compared to other Asian studies, the incidence of skin reaction
associated with the rivastigmine patch was lower and gastrointestinal AEs occurred less
frequently in our study [
]. No drug-drug interactions or SAEs related to the study drug were
reported. Thus, as suggested in other studies of transdermal rivastigmine patch, our results
support the viability of the rivastigmine patch as a treatment option for older patients with AD
who are taking many other concomitant medications.
This study has a few limitations. First, this is an open-label study without a placebo group,
and with a relatively high dropout rate. Second, WMH was measured in a semiquantitative
manner. Third, diagnoses of AD with minimal or moderate WMH were not confirmed by
neuropathological or biomarker measurements. Nevertheless, our data suggest that when
considering treatment options for patients with AD with WMH, AChEIs may confer more
benefits for patients with AD with minimal WMHs than those with moderate WMHs. Our
study results suggest that patients with milder WMHs have more AD pathology and
therefore a higher cholinergic deficit, and those patients with moderate WMHs have less AD
pathology with more VaD pathology and are less likely to have benefit from rivastigmine
therapy. Further studies with placebo controls, longer time periods, and quantitatively
measured WMH are needed to establish the efficacy of rivastigmine in AD with minimal or
There were no significant differences in general cognitive function between patients with AD
with minimal vs. moderate white matter hyperintensities after 24 weeks of rivastigmine patch
therapy. However, a significant improvement in frontal function was found in patients with
AD with minimal WMHs following rivastigmine patch therapy compared to patients with AD with moderate WMHs.
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S1 Dataset. Dataset for this manuscript.
S1 Protocol. Study protocol for this manuscript.
S1 Checklist. TREND statement checklist.
S2 Checklist. TREND statement checklist.
S3 Checklist. TREND statement checklist.
Conceptualization: Kyung Won Park, Eun-Joo Kim, Seong Hye Choi.
Data curation: Kyung Won Park, Eun-Joo Kim, Hyun Jeong Han, Yong S. Shim, Jae C.
Kwon, Bon D. Ku, Kee Hyung Park, Hyon-Ah Yi, Kwang K. Kim, Dong Won Yang, Ho
Won Lee, Heeyoung Kang, Oh Dae Kwon, SangYun Kim, Jae-Hyeok Lee, Eun Joo Chung,
Sang-Won Park, Mee Young Park, Bora Yoon, Byeong C. Kim, Sang Won Seo, Seong Hye
Formal analysis: Kyung Won Park.
Funding acquisition: Kyung Won Park, Seong Hye Choi.
Investigation: Kyung Won Park, Eun-Joo Kim, Hyun Jeong Han, Yong S. Shim, Jae C. Kwon,
Bon D. Ku, Kee Hyung Park, Hyon-Ah Yi, Kwang K. Kim, Dong Won Yang, Ho-Won Lee,
Heeyoung Kang, Oh Dae Kwon, SangYun Kim, Jae-Hyeok Lee, Eun Joo Chung, Sang-Won
Park, Mee Young Park, Bora Yoon, Byeong C. Kim, Sang Won Seo, Seong Hye Choi.
Methodology: Kyung Won Park, Byeong C. Kim, Seong Hye Choi.
Project administration: Kyung Won Park, Seong Hye Choi.
Supervision: Seong Hye Choi.
Writing ± original draft: Kyung Won Park.
Writing ± review & editing: Kyung Won Park, Seong Hye Choi.
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