Galantamine

Dementia incidence was determined through the use of prescribed an antidementia drug (donepezil, galantamine, rivastigmine, or memantine) [22 (link)], with ICD-10 codes (F00, F01, F02, F03, or G30) used for the first or second diagnosis for medical expense claims submitted to the NHIS until the end of follow-up (31 December 2013) [23 (link), 24 (link)]. This definition of dementia incidence was applied to outpatients as well as to hospitalized patients. In Korea, it is required to fulfill KNHI reimbursement criteria to claim expenses. To submit a valid claim for the prescription of an antidementia drug, physicians need to document the evidence for cognitive dysfunction according to relatively strict criteria: (1) Mini Mental State Examination score ≤ 26 and (2) either a Clinical Dementia Rating ≥ 1 or a Global Deterioration Scale score ≥ 3 [25 ].

The Swedish Alzheimer Treatment Study (SATS) was started to investigate the long-term efficacy of ChEI treatment in naturalistic AD patients in clinical practice. SATS is a three-year, open-label, observational, nonrandomized, multicenter study that was described in detail previously [26 (link)]. Its purpose is the evaluation of cognition, global performance, and ADL every six months. The subjects were prospectively recruited from 14 memory clinics located in different areas of Sweden. Most participants are in the mild-to-moderate stages of the disease and the SATS is still ongoing. All subjects exhibiting a baseline Mini-Mental State Examination (MMSE) [27 (link)] score ranging from 10 to 26 and for whom at least three measurements were available per individual (to model nonlinearity in the trajectories better) [28 (link),29 (link)] were included in this study. A total of 843 patients (donepezil, n = 456; rivastigmine, n = 183; and galantamine, n = 204) who were enrolled until the end of December 2005 fulfilled these criteria, thus having the opportunity to complete the full three-year SATS program.
Outpatients aged 40 years and older who met the criteria for the clinical diagnosis of dementia, as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4^th edition (DSM-IV) [30 ], and for possible or probable AD, according to the criteria of the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and related Disorders Association (NINCDS-ADRDA) [31 (link)], were considered for inclusion. All patients were diagnosed by physicians specialized in dementia disorders. Moreover, the selected patients had to live at home at the time of diagnosis, have a responsible caregiver, and be assessable with the MMSE at the start of the ChEI treatment (baseline). After the baseline assessments, patients were prescribed a ChEI treatment according to the approved product labeling and paid for their own medication, as in a routine clinical practice. The choice of drug and dosage for the individual patient was left entirely up to the physician's discretion and professional judgment. Medications other than anti-dementia drugs were allowed and documented during the study. Reasons for study withdrawal were recorded and presented for this cohort of patients. Nursing-home placement was not a reason for dropout if the patient was able to continue to visit the clinic.
All patients and/or caregivers provided informed consent to participate in the study, which was conducted according to the provisions of the Helsinki Declaration and was approved by the Ethics Committee of Lund University, Sweden.

The primary outcome of this study was the incidence of all-cause dementia, including Alzheimer’s disease (AD), vascular dementia (VaD), and other types of dementia (ICD-10 diagnostic codes: F00, F01, F02, F03, G30, or G31). Outcome events were defined when both ICD-10 codes and the prescription records of anti-dementia drugs, including donepezil, galantamine, rivastigmine, and memantine were used. This definition has been widely accepted with high accuracy, having 94.7% positive predictive value in K-NHID^{21 (link)}. The secondary outcomes included AD (F00 or G30) and VaD (F01). The date of the second health checkup was defined as the index date, and the participants were followed up until December 31, 2019 or until the development of the primary outcome, whichever came first.
We obtained information from the second general health checkup based on previous studies related to risk factors for dementia. Specifically, we obtained demographic data, including age, sex, height, body weight, and waist circumference, as well as information regarding health-related lifestyles, including smoking status, categorized as a current smoker or not, and alcohol consumption status, categorized as alcohol users (any alcohol consumption) or not. Baseline comorbidities including hypertension, dyslipidemia, diabetes mellitus, and chronic kidney disease were also obtained. The operational definition of covariates and outcomes in cardiovascular research is well documented in several studies based on K-NHID^{12 (link)}. CKD was defined as an estimated glomerular filtration rate (eGFR) of < 60 mL/min/1.73 m² calculated using the CKD Epidemiology Collaboration (CKD-EPI) equation. Low-income level was defined when the participants were medical benefit beneficiaries and were included in the lowest quartile of income levels. Further, laboratory data, including levels of random glucose, total cholesterol, glomerular filtration rate, and systolic/diastolic blood pressure, were also obtained at the ambulatory health exam visits after index stroke. Among these variables, age, sex, smoking status, alcohol consumption, income level, history of diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease were used as covariates.

Acetylcholinesterase from electric eel type VI-S, butyrylcholinesterase from equine serum, acetylthiocholine iodide (ATCI), butyrylthiocholine iodide (BTCI), 5,5′-dithiobis[2-nitrobenzoic acid] (DTNB), bovine serum albumin (BSA), tris buffer, and galantamine were purchased from Sigma–Aldrich. The organic solvents (methanol and ethanol) and reagents used in the analysis were of analytical grades.

Chi-square for categorical variables and Mann–Whitney U test for continuous variables due to non-normality were used to compare the baseline characteristics between patients with RLS and RLS-free controls. Cox proportional hazards regression models were applied to explore the association between RLS and the risk of dementia after adjusting for age, sex, income, residence, CCI, and history of other comorbidities. Among the Cox regression models, we used the Fine–Gray subdistribution hazard model with mortality as a competing risk given the old age of the study population. The proportional hazard assumption was satisfied in our Cox model (Schoenfeld individual test p-value > 0.05).
Sensitivity analyses were performed using four different models. In model 1, dementia was defined as the prescription of anti-dementia medications (donepezil, rivastigmine, galantamine, and memantine) at least twice and a diagnosis of the ICD-code of dementia. Although these medications were approved for only AD (rivastigmine additionally for Parkinson’s disease dementia), they can be used for cognitive symptoms in other types of dementia based on recommendations from multiple guidelines [31 (link)–33 (link)]. The previous study revealed that the definition of all-cause dementia by ICD-10 code plus anti-dementia medications had a positive predictive value of 94.7% when reviewing the medical records of 972 patients in two hospitals [34 (link)]. In model 2, medication history was added to the ICD code to define RLS. Patients with RLS ICD-code (G25.8) who had taken dopamine agonists (ropinirole or pramipexole) twice or more were regarded as patients with RLS (n = 1458). In this sensitivity model, we excluded patients with Parkinson’s disease because they could also take dopamine agonists. In model 3, patients taking antipsychotic agents were excluded because the antidopaminergic property of antipsychotic agents could lead to a misdiagnosis of RLS (n = 2482). The following antipsychotic agents approved in South Korea were used in this study: haloperidol, sulpiride, chlorpromazine, perphenazine, pimozide, risperidone, olanzapine, quetiapine, paliperidone, amisulpride, aripiprazole, ziprasidone, clozapine, blonanserin, and zotepine. In model 4, patients with RLS only diagnosed by psychiatrists or neurologists were included (n = 1154) to preclude the possible misdiagnosis by non-expert physicians.
To evaluate the effect of dopamine agonists (pramipexole and ropinirole) on the development of dementia, the risk of dementia was compared after dividing RLS patients by dopamine agonist use. Patients with RLS who were prescribed pramipexole or ropinirole at least once were considered dopamine agonist users. All missing data were addressed using listwise deletion. Data processing and statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). Statistical significance was set at a two-tailed p-value of < 0.05.