Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis

Taguchi, Akihiko; Takata, Yasuyuki; Ihara, Masafumi; Kasahara, Yukiko; Tsuji, Masahiro; Nishino, Masami; Stern, David M.; Okada, Masahiro

doi:10.1111/psyg.12021

Cited by 58 publications

(57 citation statements)

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“…The PDE3 inhibitor cilostazol was tested in several studies and indications were found that it could improve cognition, in particular in MCI/mild AD patients (e.g. [34,38,39]). The PDE4 inhibitor MK-0952 was given to patients with mild to moderate AD [77].…”

Section: Resultsmentioning

confidence: 99%

“…for the prevention of stroke or peripheral artery disease) reported that average daily doses above 100 mg for at least 6 months improved MMSE scores in MCI patients [38] and mild AD patients as add-on to 10 mg donepezil per day [39]. The same research group at the National Cerebral and Cardiovascular Center Hospital (Osaka, Japan) has started a new study investigating the effects on MMSE scores of cilostazol 50 mg twice a day for 96 weeks in patients with MCI (ClinicalTrials.gov identifier: NCT02491268).…”

Section: Phosphodiesterasementioning

confidence: 99%

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Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

153

168

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Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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Section: Resultsmentioning

confidence: 99%

Section: Phosphodiesterasementioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

153

168

View full text Add to dashboard Cite

show abstract

“…A previous study has also indicated beneficial effects of cilostazol in a mouse model relevant to AD through increased amyloid β clearance due to improved cerebrovascular function 31 . Retrospective clinical studies indicated the potential for cilostazol treatment to suppress cognitive decline in elderly patients with mild dementia or cognitive impairment 32, 33 . However the current study suggests that whilst cilostazol improves hypoperfusion- induced memory deficits these are not completely restored, the improvement in memory plateaued after 12 days of testing.…”

Section: Discussionmentioning

confidence: 99%

Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion

Kitamura

Manso

Duncombe

et al. 2017

Sci Rep

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Chronic cerebral hypoperfusion is a major cause of age-related vascular cognitive impairment. A well-characterised mouse model has shown that hypoperfusion results in gliovascular and white matter damage and impaired spatial working memory. In this study, we assessed whether cilostazol, a phosphodiesterase III inhibitor, could protect against these changes. Adult, male C57Bl/6J mice were subjected to bilateral common carotid artery stenosis or a sham operation and fed normal or cilostazol diet for three months. Cilostazol treatment reduced the impairment in working memory and white matter function after hypoperfusion. Endothelial adhesion molecules and gliosis, increased after hypoperfusion, were ameliorated with cilostazol treatment. Interestingly, the improvement in working memory was closely correlated with reduced microglia and endothelial adhesion molecules. Further, the number of stroke lesions after hypoperfusion was reduced in the cilostazol-treated group. Altogether cilostazol showed potential to ameliorate the gliovascular damage and working memory impairments after hypoperfusion possibly via endothelial protection supporting its potential use in the treatment of vascular cognitive impairment.

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“…In a pilot study for 10 patients with moderate Alzheimer's disease (mean Mini-Mental Examination (MMSE) score, 11.9 points) who received donepezil, cilostazol add-on treatment for 5–6 months demonstrated significantly increased MMSE score in comparison to baseline [11]. Moreover, cilostazol was shown to be effective in halting cognitive decline in patients with AD with cerebrovascular diseases [12] and mild cognitive impairment [13].…”

Section: Introductionmentioning

confidence: 99%

Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study

et al. 2014

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GoalCombinatorial therapy directed at both vascular and neurodegenerative aspects of dementia may offer a promising strategy for treatment of dementia, which often has a multifactorial basis in the elderly. We investigated whether the phosphodiesterase III inhibitor cilostazol, which is often used in the prevention of stroke and peripheral artery disease, may delay cognitive decline in the elderly receiving donepezil.MethodsMedical records were retrospectively surveyed to identify patients who had received donepezil for more than one year and had undergone Mini-Mental State Examination (MMSE) at least at two time points. Those with an initial MMSE score of less than 27 points were subjected to analysis (n = 156), with a cut-point of 21/22 applied to assign them to mild (n = 70) and moderate/severe (n = 86) dementia. The change of total MMSE score per year was compared between patients who had received donepezil and those given both donepezil and cilostazol.FindingsIn patients with mild dementia who had received donepezil and cilostazol (n = 34; 77.2±6.8 years old), the annual change in MMSE score was −0.5±1.6 during an observational period of 28.6±11.7 months, with those receiving donepezil only (n = 36; 78.4±6.5 years old) scoring less (−2.2±4.1) during 30.4±12.8 months with a statistical intergroup difference (p = 0.022). Multivariate analysis showed that absence of cilostazol treatment was the only significant predictor of MMSE decline. A positive effect of cilostazol was found in three subscale scores of MMSE, orientation for time or place and delayed recall. By clear contrast, in patients with moderate/severe dementia, there were no intergroup differences in decrease of total or subscale MMSE scores between the two groups.ConclusionsThese results suggest potential for cilostazol treatment in the suppression of cognitive decline in patients receiving donepezil with mild dementia but not in those with moderate/severe dementia.

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Cilostazol improves cognitive function in patients with mild cognitive impairment: a retrospective analysis

Cited by 58 publications

References 10 publications

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Long-term cilostazol treatment reduces gliovascular damage and memory impairment in a mouse model of chronic cerebral hypoperfusion

Cilostazol Add-On Therapy in Patients with Mild Dementia Receiving Donepezil: A Retrospective Study

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