Statins and the risk of bleeding in patients taking dabigatran.

OBJECTIVES: Dabigatran etexilate is a direct thrombin inhibitor that clinicians increasingly prescribe to prevent stroke in patients with non-valvular atrial fibrillation (NVAF). Clinicians also commonly prescribe statins for primary and secondary prevention of cardiovascular diseases. Little is known about the bleeding risk in patients taking a statin and dabigatran together. The aim of this study was to evaluate the safety and persistence of dabigatran after co-medication with statins. MATERIALS AND METHODS: We performed a prospective, multicenter registry study of stroke patients with NVAF who initiated dabigatran therapy within 3 months after a clinically evident ischemic cerebrovascular event between 2013 and 2017. The main outcome measure was symptomatic bleeding after 90, 180, and 360 days. RESULTS: In total, 652 patients (336 statin users, 316 non-users) were followed for 1 year after dabigatran therapy. Cox multivariate analysis demonstrated that male sex, prior use of aspirin, and concurrent use of an antiarrhythmic drug were associated with a higher risk of bleeding at 360 days. After adjusting time-dependent covariates, statin users had a significantly lower bleeding risk (adjusted hazard ratio: 0.11, P < 0.001) than non-users. Kaplan-Meier analysis indicated that patients prescribed with statins had a higher rate of bleeding-free survival (P = 0.028). CONCLUSION: For secondary prevention of stroke in patients with NVAF who are taking dabigatran etexilate, co-prescription with a statin was associated with a lower risk of bleeding complications. Future research is needed to determine the pharmacological mechanism underlying this effect.

Delayed diagnosis of atrial fibrillation after first-ever stroke increases recurrent stroke risk: a 5-year nationwide follow-up study.

BACKGROUND: Delayed detection of atrial fibrillation (AF) is common in patients with stroke. However, it is not well known whether delayed identification of AF in patients with stroke affects the prognosis of patients. AIMS: To evaluate the association between the timing of AF diagnosis after stroke and clinical outcomes. METHODS: We identified a cohort of all patients admitted with a primary diagnosis of first-ever ischaemic stroke, which was categorised into three groups, namely, non-AF, AF presenting with stroke and delayed AF diagnosis groups. The study patients were individually followed for 5 years to evaluate the occurrence of recurrent stroke and death. RESULTS: In total, 17 399 patients were hospitalised with first-ever ischemic stroke, of whom 16 261 constituted the non-AF group, 907 the AF presenting with stroke group and 231 the delayed AF diagnosis group. During the 5-year follow up, 2773 (17.1%), 175 (19.3%) and 68 (29.4%) patients in the non-AF, AF presenting with stroke and delayed AF diagnosis groups, respectively, were hospitalised for recurrent stroke. The delayed AF diagnosis group exhibited a 1.57-times higher risk of recurrent stroke than the AF presenting with stroke group, after adjustment for the CHA2DS2-VASc scores (adjusted hazard ratio (HR): 1.57; 95% confidence interval (CI) = 1.19-2.08; P = 0.002). In addition, delayed diagnosis of AF significantly increased the risk of recurrent stroke in men, but not in women, after adjustment for the CHA2DS2-VASc scores. CONCLUSION: Delayed diagnosis of AF after stroke increased the risk of recurrent stroke, particularly in men.

Clinical implication of hemorrhagic transformation in ischemic stroke patients treated with recombinant tissue plasminogen activator.

To determine the clinical implications of hemorrhagic transformation (HT) after thrombolysis, 241 eligible patients receiving alteplase for acute ischemic stroke were studied. HT was classified, according to the European Cooperative Acute Stroke Study criteria, as hemorrhagic infarction (HI) or parenchymal hemorrhage (PH). Symptomatic intracranial hemorrhage (SICH) was defined according to the National Institute of Neurological Disorders and Stroke study. A novel classification, clinically significant intracranial hemorrhage (CSICH) was defined as HTs associated with an unfavorable clinical outcome (modified Rankin Scale 5-6) at 3 months. For all subtypes of HT, we found that patients receiving alteplase were more often in the standard-dose group (0.90 ± 0.02 mg/kg) than in the lower dose group (0.72 ± 0.07 mg/kg). PH and SICH were related to an unfavorable clinical outcome, while HI was not. There was a positive trend between age and CSICH in patients receiving the standard dose (P = 0.0101), and between alteplase dose and CSICH in patients ≥70 years old (P = 0.0228). All PHs (including asymptomatic PHs) and symptomatic HIs have been found to be associated with unfavorable outcome, and for this reason defined as CSICH. Independent predictors of CSICH were age ≥70 years and the standard dose of alteplase. Further studies of thrombolysis for ischemic stroke with different doses of alteplase are warranted.

Acute confusion in headache with neurologic deficits and cerebrospinal fluid lymphocytosis syndrome.

Abrupt headaches with focal neurologic deficits usually indicate medical emergencies that require advanced investigations and prompt treatment. The distinct syndrome of "headache with neurologic deficits and cerebrospinal fluid lymphocytosis" (HaNDL) is infrequent and considered a benign, self-limited disorder. We illustrated a 29-year-old man with HaNDL atypically presenting as episodic altered consciousness rather than sensorimotor prodromes. The diagnosis was made carefully by exclusion of other likely entities. It is important for clinical physicians to differentiate HaNDL from other potentially fatal.

Effects of Dabigatran on Dementia Pathogenesis and Neuropsychological Function: A Review.

BACKGROUND: Patients with atrial fibrillation (AF) carry higher risks of cognitive consequences and psychological burden. An optimal anticoagulant therapy would be expected to better preserve neuropsychological function in addition to effective prevention of stroke and systemic thromboembolism. OBJECTIVE: The aim of this review is to explore the effects of the non-vitamin K antagonist oral anticoagulant (NOAC) dabigatran, a direct thrombin inhibitor, on cognitive and psychological function as well as dementia pathogenesis. METHODS: We performed a comprehensive search of PubMed/Medline for all types of relevant articles using a combination of dabigatran and associated keywords updated to August 31, 2021. All titles and abstracts were screened for eligibility, and potentially relevant papers were collected for inclusion. RESULTS: The pooled results demonstrated neutral to positive impacts of dabigatran on cognitive and psychological outcomes, including laboratory results in animal models of Alzheimer's disease, and reduced incidences of anxiety/depression and dementia for AF patients. Dabigatran also exhibited better therapeutic profiles than warfarin in preclinical and observational research. CONCLUSION: Given limited strength of evidence from heterogeneous studies, our review proposed modest beneficial effects of dabigatran on neuropsychological function. Further clinical trials are warranted to affirm the pleiotropic protective effects of NOACs on dementia treatment.

Protocorm-like-body extract of Phalaenopsis aphrodite combats watermelon fruit blotch disease.

Bacterial fruit blotch, caused by the seedborne gram-negative bacterium Acidovorax citrulli, is one of the most destructive bacterial diseases of cucurbits (gourds) worldwide. Despite its prevalence, effective and reliable means to control bacterial fruit blotch remain limited. Transcriptomic analyses of tissue culture-based regeneration processes have revealed that organogenesis-associated cellular reprogramming is often associated with upregulation of stress- and defense-responsive genes. Yet, there is limited evidence supporting the notion that the reprogrammed cellular metabolism of the regenerated tissued confers bona fide antimicrobial activity. Here, we explored the anti-bacterial activity of protocorm-like-bodies (PLBs) of Phalaenopsis aphrodite. Encouragingly, we found that the PLB extract was potent in slowing growth of A. citrulli, reducing the number of bacteria attached to watermelon seeds, and alleviating disease symptoms of watermelon seedlings caused by A. citrulli. Because the anti-bacterial activity can be fractionated chemically, we predict that reprogrammed cellular activity during the PLB regeneration process produces metabolites with antibacterial activity. In conclusion, our data demonstrated the antibacterial activity in developing PLBs and revealed the potential of using orchid PLBs to discover chemicals to control bacterial fruit blotch disease.

Triglyceride-Glucose Index and Intravenous Thrombolysis Outcomes for Acute Ischemic Stroke: A Multicenter Prospective-Cohort Study.

BACKGROUND: The triglyceride-glucose (TyG) index has recently been proposed as a reliable marker of insulin resistance. There is insufficient evidence to verify that the TyG index is correlated with functional outcomes and hemorrhagic transformation and in patients with stroke treated with intravenous thrombolysis (IVT). METHODS: We designed a multicenter cohort study, which enrolled patients with acute ischemic stroke treated with IVT between December 2004 and December 2016. The TyG index was divided into tertiles and calculated on a continuous scale. Unfavorable functional outcomes were defined by the modified Rankin Scale of 3-6 at 90 days and the incident rates of symptomatic intracranial hemorrhage (SICH) within 36 h of IVT onset were surveyed. Stroke severity was defined as mild (4-8), moderate (9-15), or high (≥16) based on the National Institutes of Health Stroke Scale (NIHSS) scores. RESULTS: Among 914 enrolled patients, the tertiles of the TyG index were 8.48 for T1, 8.48-9.04 for T2, and 9.04 for T3. T3 showed an increased risk of unfavorable functional outcomes at 90 days [odds ratio (OR): 1.76; P = 0.0132]. The TyG index was significantly associated with unfavorable functional outcomes at 90 days (OR: 1.32; P = 0.0431 per unit increase). No association was found between the TyG index and SICH. These findings were applicable for T3 with stroke of moderate (OR, 2.35; P = 0.0465) and high severity (OR: 2.57, P = 0.0440) patients with stroke. CONCLUSION: This study supports the strong association between the increased TyG index and increased unfavorable functional outcomes at 90 days in patients with acute ischemic stroke treated with IVT. These findings were found to be robust in patients with moderate and high stroke severity.

Comparison of Different Dosages of Alteplase in Atrial Fibrillation-Related Acute Ischemic Stroke After Intravenous Thrombolysis: A Nationwide, Multicenter, Prospective Cohort Study in Taiwan.

Background Insufficient evidence is available for patients with acute ischemic stroke with atrial fibrillation (AF) to determine the efficacy and safety of different dosages of intravenous thrombolysis treatment. This study examined clinical outcomes in Chinese patients with stroke with and without AF after intravenous thrombolysis treatment with different intravenous thrombolysis doses. Methods and Results This multicenter, prospective cohort study recruited 2351 patients with acute ischemic stroke (1371 with AF and 980 without AF) treated with intravenous thrombolysis using alteplase. The Totaled Health Risks in Vascular Events score is a validated risk-scoring tool used for assessing patients with acute ischemic stroke with and without AF. We evaluated favorable functional outcome at day 90 and symptomatic intracranial hemorrhage within 24 to 36 hours and outcomes of the patients receiving different doses of alteplase. Compared with the non-AF group, the AF group exhibited a 2- to 3-fold increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (relative risk [RR], 2.10 [95% CI, 1.35-3.26]). Favorable functional outcome at 90 days and symptomatic intracranial hemorrhage rates according to the European Cooperative Acute Stroke Study II and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study standards did not significantly differ between the AF and non-AF groups. In addition, the low-dose alteplase subgroup exhibited an increased risk of symptomatic intracranial hemorrhage according to the National Institute of Neurological Disorders and Stroke standard (RR, 2.84 [95% CI, 1.63-4.96]). A validation study confirmed these findings after adjustment for scores determined using different stroke risk-scoring tools. Conclusions Different alteplase dosages did not affect functional status at 90 days in the AF and non-AF groups. Thus, the adoption of low-dose alteplase simply because of AF is not recommended.

Corrigendum: Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience.

[This corrects the article DOI: 10.3389/fneur.2021.628077.].

Pre-treatment of Single and Double Antiplatelet and Anticoagulant With Intravenous Thrombolysis for Older Adults With Acute Ischemic Stroke: The TTT-AIS Experience.

Background: This study aimed to investigate the safety and efficacy of single antiplatelet, anticoagulant and Dual Antiplatelet pre-treatment (DAPP) in older, moderate to high severity acute ischemic stroke patients treated with intravenous thrombolysis (IVT). Methods: A prospective cohort study was conducted to monitor the development of symptomatic intracranial hemorrhage (SICH) and functional outcomes at 90 days. Two different dosages of alteplase were used for IVT. Logistic regression models were used for analysis of the safety and efficacy outcomes. Results: A total of 1,156 patients were enrolled and categorized into six groups based on their pre-treatment medications: (1) aspirin (n = 213), (2) clopidogrel (n = 37), (3) DAPP of aspirin + clopidogrel (n= 27), (4) warfarin (n = 44), (5) any of the above pre-medications (n = 331), and (6) none of these medications as controls (n = 825). The DAPP group showed significantly increased SICH by the NINDS (adjusted OR: 4.90, 95% CI 1.28-18.69) and the ECASS II (adjusted OR: 5.09, 95% CI: 1.01-25.68) standards. The aspirin group was found to significantly improve the favorable functional outcome of the modified Rankin Scale (mRS) of 0-1 (adjusted OR: 1.91, 95% CI, 1.31.2.78), but no significance for mRS of 0-2 (adjusted OR: 1.39, 95% CI, 0.97-1.99). The DAPP group also significantly increased mortality (adjusted OR: 4.75, 95% CI: 1.77-12.72). A significant interaction between different dosages for IVT and the functional status was noted. Compared to standard dose, the DAPP group showed higher proportions of disability and mortality with low dose of IVT. Conclusion: For older adults with higher baseline severity of acute ischemic stroke, DAPP may increase the risk of SICH and mortality post IVT. However, DAPP is still not an indication to withdraw IVT and to prescribe low-dose IVT for older adults.

The long-term risk of epilepsy after transient global amnesia: A population-based cohort study.

OBJECTIVE: Transient global amnesia (TGA) is characterized by sudden onset of larger anterograde and milder retrograde amnesia lasting up to 24 h. We aimed to investigate the long-term risk of epilepsy up to 8 years in subjects after TGA in the population-based cohort study. PATIENTS AND METHODS: We conducted a control cohort study with an 8-year follow-up period. All data was collected retrospectively. From all potential participants more than 18 years of age without epilepsy and TGA history, we identified TGA subjects and non-TGA controls with age, gender and comorbidities matched in a 1:3 ratio. The yearly incidence of epilepsy was compared in TGA and non-TGA cohorts. The cumulative hazard ratio of epilepsy was estimated. The risk factors of epilepsy after TGA were investigated. RESULTS: A total of 185 TGA subjects and 555 non-TGA controls were included in the study. There were 7 epilepsy cases in the 185 TGA cohorts during the follow-up period with yearly incidence rates of 9.629 per 1000 person. The adjusted hazard ratio for epilepsy in TGA cohorts was 6.50 (95 % confidence interval 1.87-22.68, p = 0.003) compared with non-TGA cohorts after adjusting for age, gender and comorbidities. No notable factor was significantly associated with epilepsy after TGA. CONCLUSION: Our study highlighted TGA is associated with increased long-term risk of epilepsy.

Impaired conflict monitoring in cognitive decline.

Resolving conflicts is an important cognitive ability of executive function, and it may decrease with cognitive decline. The flanker task is a practical test used to assess the ability to suppress responses that are inappropriate in a particular context. The aims of the present study were to investigate conflict monitoring of cognitive control in subjects with different levels of cognitive impairment, and clarify the usefulness of the flanker task in screening cognitive decline. We recruited 50 subjects with mild cognitive impairment (MCI) and 34 patients with Alzheimer's disease (AD), and 44 mentally healthy elderly subjects as a control group. To evaluate cognitive performance, each participant underwent a neuropsychological assessment using the Cognitive Abilities Screening Instrument and a modified flanker task. Compared with the normal controls and those with MCI, the patients with AD had a significantly lower accuracy rate and longer reaction time in both congruent and incongruent trials. The diagnosis of AD predicted significantly poorer performances on the flanker tasks. Furthermore, behavioral data of the patients with AD were significantly correlated with the results of neuropsychological tests. Our results indicated that executive cognitive deficits in conflict monitoring as detected by the flanker task were significantly impaired in the patients with AD. The flanker task could be a quick and easier alternative tool for screening AD among elderly people with suspicious cognitive impairment.

Factors of post-stroke dementia: A nationwide cohort study in Taiwan.

AIM: We investigated the long-term risk of dementia for up to 10 years in patients with stroke and broadened the correlates. METHODS: We carried out a case-control study using the Taiwan National Health Insurance Research database in 2000 with a sampled population of 1 million. The study cohort comprised 8236 patients with stroke and no dementia history. We carried out a 1:1 case-control matched analysis on estimated propensity scores. Cox proportional hazards regressions were carried out to estimate the risk of dementia during the 5- and 10-year follow-up periods. The risk factors were also investigated. RESULTS: The stroke cohort was significantly at more risk of dementia during the 5- and 10-year follow-up periods, with adjusted hazard ratios 1.87 and 1.53, respectively. The patients with ischemic stroke, transient ischemic attack and intracerebral hemorrhage had a significantly higher risk of dementia after 5 and 10 years, with adjusted hazard ratios of 1.81 and 1.49, 1.92 and 1.61, and 2.14 and 1.61, respectively. The significant risk factors of dementia were age ≥60 years, resident in southern and eastern regions, having low insurance range, and antiplatelet use. CONCLUSIONS: Stroke and the subtypes, including ischemic stroke, transient ischemic attack and intracerebral hemorrhage, increase the long-term risk of dementia. The incidence of post-stroke dementia increases yearly, but the relative risk decreases gradually. Older adults, residents in southern and eastern regions, having low insurance range and antiplatelet use were prominent risk factors of post-stroke dementia in Taiwan. Careful management of stroke and risk factors of post-stroke dementia with long-term follow up of cognition should be reinforced. Geriatr Gerontol Int 2019; 19: 815-822.

Hemiparkinsonism secondary to an infiltrative astrocytoma.

BACKGROUND: Brain tumors are uncommon etiologies of parkinsonism. The clinical manifestations of tumoral parkinsonism may sometimes resemble those of idiopathic origin. Increased awareness of this rare entity is important for an earlier prompt diagnosis and treatment. REVIEW SUMMARY: A previously healthy, 60-year-old man developed slowly progressive right-sided resting tremor and bradykinesia over 8 months. Although idiopathic Parkinson disease was the initial diagnosis, the parkinsonian symptoms were not responsive to medical treatment with levodopa and a dopamine agonist. Brain computed tomography failed to reveal an intracranial lesion. Brain magnetic resonance imaging demonstrated an infiltrative, slightly enhancing mass in the left mesial temporal lobe extending to the left basal ganglion and insula. Histopathologic findings confirmed the diagnosis of high-grade astrocytoma. The parkinsonian symptoms subsided after tumor removal; however, ipsilateral hemiparesis developed postoperatively. CONCLUSIONS: Neuroimaging is recommended for investigation of atypical parkinsonism. We suggest that brain magnetic resonance imaging is preferred for patients with drug-resistant parkinsonism or concurrent signs apart from extrapyramidal symptoms, because some mass lesions are not observed by computed tomography scan.

Successful intrathecal baclofen therapy for seronegative stiff-person syndrome: a case report.

We reported a 27-year-old man presenting with progressive muscle rigidity and intermittent spasms for six years. The diagnosis of stiff-person syndrome was based on the clinical features and neuroelectrophysiologic findings of continuous motor unit activities. Autoantibody against glutamic acid decarboxylase in our patient was absent either in serum or in cerebrospinal fluid. The patient was successfully treated with intrathecal baclofen therapy after a series of unsatisfactory traditional medical treatments. From our experience, we propose that intrathecal baclofen could be a considerable alternative treatment for patients with refractory stiff-person syndrome.

Behcet's disease with involvement of major arteries: a case report.

Vascular involvement is not infrequent in Behcet's disease (BD). It is generally seen in the form of superficial thrombophlebitis or occlusion of major veins. In rare instances, arterial occlusion and aneurysm formation may be seen in BD. We reported a young male with BD, diagnosed at the age of twenty for relapsing and remitting oral ulceration, skin rash, arthralgia and ocular painful redness for three years. At the age of 21, he had recurrent abdominal aortic aneurysm and inconspicuous neurological manifestations including dizziness, tinnitus and transients of blurred vision. The carotid angiography disclosed the occlusion of bilateral common carotid arteries (CCA). A carotid endarterectomy was subsequently performed to reduce the risk of stroke. The pathological examination of the occluded segment of CCA revealed chronic inflammation, which was attributable to BD. There was no atherosclerotic change. To the best of our knowledge, this is the first case report of concurrent bilateral CCA occlusion and relapsing abdominal aortic aneurysm. Even in the absence of specific neurological symptoms, we suggest that cerebrovascular investigation need to take into consideration in BD patients with unexplained cranial symptoms.

Simultaneous thrombosis of cerebral artery and venous sinus.

Cerebral venous thrombosis (CVT) is infrequent among cerebrovascular diseases. The simultaneous thrombosis involving both cerebral artery and venous sinus is even extremely rare. We reported a 41-year-old woman who presented with acute headache and left hemiparesis due to concomitant arterial ischemic stroke and recurrent CVT. Extensive investigation disclosed acquired protein C and protein S deficiency, iron deficiency anemia (IDA) and cryoglobulinemia. She was treated with intravenous injection of heparin followed by oral anticoagulant therapy. The headache rapidly subsided; however, left hemiparesis persisted over five months. The rare condition of simultaneous thrombosis of cerebral artery and venous sinus may be caused by the synergistic effect of coagulation disorders, IDA and cryoglobulinemia.

Obstructive sleep apnea and cerebral white matter change: a systematic review and meta-analysis.

Obstructive sleep apnea (OSA) can cause sleep fragmentation and intermittent hypoxemia, which are linked to oxidative stress. White matter changes (WMCs) representing cerebrovascular burden and are at risk factor for oxidative ischemic injury. The current study explores the mutual relationships between OSA and WMCs. We performed a systematic review of electronic databases for clinical studies investigating OSA and WMCs. Random-effects models were used for pooled estimates calculation. A total of 22 studies were included in the meta-analysis. The results revealed a significantly higher prevalence rate of WMCs [odds ratio (OR) 2.06, 95% confidence interval (CI) 1.52-2.80, p < 0.001] and significantly higher severity of WMCs (Hedges' g = 0.23, 95% CI 0.06-0.40, p = 0.009) in the patients with OSA than in controls. Furthermore, the results revealed a significantly higher apnea-hypopnea index (Hedges' g = 0.54, 95% CI 0.31-0.78, p < 0.001) and significantly higher prevalence rate of moderate-to-severe OSA (OR 2.86, 95% CI 1.44-5.66, p = 0.003) in the patients with WMCs than in controls, however there was no significant difference in the prevalence rate of mild OSA between the patients with WMCs and controls (OR 0.71, 95% CI 0.20-2.54, p = 0.603). OSA was associated with a higher prevalence and more severe WMCs, and the patients with WMCs had an increased association with moderate-to-severe OSA. Future large-scale randomized controlled trials with a longitudinal design are essential to further evaluate treatment in patients with OSA.

Effects of pioglitazone on the incidence of dementia in patients with diabetes.

AIMS: Peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists exert neuroprotective effects in the brain. Therefore, in this population-based cohort study, we investigated the effects of pioglitazone, a PPAR-γ agonist, on the risk of dementia. METHODS: By using claims data from Taiwan's National Health Insurance Research Database, we included 6401 patients with diabetes who were treated with pioglitazone and 12,802 age- and sex-matched patients with diabetes who were never treated with pioglitazone from 2004 to 2009 and who were free of dementia at baseline. RESULTS: In total, 113 (1.8%) and 323 (2.5%) patients in the pioglitazone-treated and comparison cohorts, respectively, developed dementia during the 5-year follow-up. The risk of dementia decreased by 23% in the pioglitazone-treated cohort compared with that in the comparison cohort after adjustment for age, sex, hypertension, and stroke (adjusted hazard ratio [HR], 0.77; 95% confidence interval [CI]=0.62-0.96). In addition, the adjusted HRs (95% CIs) for dementia were 0.50 (0.34-0.75, P=.001) in high-cumulative dose users, 0.53 (0.36-0.77, P<.001) in long-term users, and 0.66 (0.49-0.90, P=.009) in high-mean daily dose users. CONCLUSIONS: Pioglitazone is a time- and dose-dependent protective factor against dementia in patients with diabetes. The risk of dementia is lower in long-term and high-dose pioglitazone users than in never users of pioglitazone.

Risk of dementia from proton pump inhibitor use in Asian population: A nationwide cohort study in Taiwan.

INTRODUCTION: Concerns have been raised regarding the potential association between proton pump inhibitor (PPI) use and dementia. OBJECTIVE: This study aimed to examine this association in an Asian population. METHODS: Patients initiating PPI therapy between January 1, 2000 and December 31, 2003 without a prior history of dementia were identified from Taiwan's National Health Insurance Research Database. The outcome of interest was all-cause dementia. Cox regression models were applied to estimate the hazard ratio (HR) of dementia. The cumulative PPI dosage stratified by quartiles of defined daily doses and adjusted for baseline disease risk score served as the primary variables compared against no PPI use. RESULTS: We analyzed the data of 15726 participants aged 40 years or older and free of dementia at baseline. PPI users (n = 7863; average follow-up 8.44 years) had a significantly increased risk of dementia over non-PPI users (n = 7863; average follow-up 9.55 years) (adjusted HR [aHR] 1.22; 95% confidence interval: 1.05-1.42). A significant association was observed between cumulative PPI use and risk of dementia (P for trend = .013). Subgroup analysis showed excess frequency of dementia in PPI users diagnosed with depression (aHR 2.73 [1.91-3.89]), hyperlipidemia (aHR 1.81 [1.38-2.38]), ischemic heart disease (aHR 1.55 [1.12-2.14]), and hypertension (aHR 1.54 [1.21-1.95]). CONCLUSIONS: An increased risk for dementia was identified among the Asian PPI users. Cumulative PPI use was significantly associated with dementia. Further investigation into the possible biological mechanisms underlying the relationship between dementia and PPI use is warranted.