Participant flow
Patient flow in the study is described in Fig. 1.
Participants and procedure
The participants were recruited from December 2016 to June 2018 from the Memory Clinic at Juntendo University Urayasu Hospital. Newly diagnosed older adults with mild to moderate AD who were prescribed a rivastigmine patch were approached for recruitment. The participants were eligible to enter the trial if they met all of the following criteria at baseline: diagnosis of probable AD according to the criteria of the National Institute of Neurologic and Communicative Disorder and Stroke-AD and Related Disorders Association; Mini-Mental State Examination (MMSE) score greater than 14 to be considered mild or moderate AD; had a caregiver who could assist the participant with medication; and had the ability to walk independently, i.e., without a walking aid or without assistance from other people. Participants aged 65 years or older were recruited. Subjects were not included if they had a history of head trauma with loss of consciousness and concomitant medication including benzodiazepines or antipsychotics. We also excluded patients with any neurological disorder with motor residual deficits including parkinsonism, stroke, and polyneuropathy that influenced their ability to carry out a walking task. All participants received magnetic resonance imaging or computed tomography, and an N-isopropyl-p-(123 I)-iodoamphetamine single photon emission computed tomography cerebral blood flow test was performed in all participants. The absence of a large lesion, i.e., infarction, tumor, and inflammation, was confirmed in all participants. We also confirmed the presence of hypoperfusion in the parietal lobe, which is consistent with a diagnosis of AD.
Design
Baseline cognitive and gait assessments were performed on the day before rivastigmine was administered. The participants received 9 mg/day rivastigmine for 4 weeks and 18 mg/day by transdermal patch for the subsequent 8 weeks of follow-up. Gait, cognitive, and psychological functions and AChE activity in plasma were analyzed at baseline, 4 weeks, and 12 weeks.
Cognitive and psychological assessments
We administered the MMSE, Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL), Functional Assessment Staging (FAST), and Geriatric Depression Scale (GDS) to all participants.
Gait assessment
Quantitative gait variables were assessed using a portable gait rhythmograph (MG-M 1110; LSI Medience Corporation, Tokyo, Japan), which is a small device (8 × 6 × 2 cm; weight, 80 g) with an accelerometer. The portable gait rhythmograph measures the acceleration accompanied by limb and trunk movements and acceleration induced by step-in and kick-off during gait in three dimensions (ax, ay, az). Its accuracy has been verified previously [17].
Gait speed, average step length, acceleration, and cadence, which is the number of steps per minute, were measured in single- and dual-task gait trials. The single-task trials consisted of normal gait at a self-selected usual pace and fast gait. For the dual-task trials, the participants walked while counting backward from 100 in steps of 7 or while naming animals aloud. Ten-meter-walk tests were performed on the level floor of the hospital in the presence of two investigators (SA and HS). The order of gait analysis was normal gait for the first trial, fast gait for the second trial, counting backward by seven for the third trial, and animal naming for the fourth trial. The participants briefly practiced dual-task walking before the first assessment. The participants did not practice dual-task walking during the study period.
Gait analysis
Using the portable gait rhythmograph, gait-induced acceleration was extracted from limb and trunk movements with an automatic gait detection algorithm [17] [18]. The portable gait rhythmograph performs three-dimensional measurements of acceleration associated with voluntary limb and trunk movements, heel strike, and toe-off when walking. Data were collected at a sampling frequency of 100 Hz and stored on a microSD card in the device for subsequent analysis. When recording was complete, the absolute values of the acceleration vectors were calculated and displayed graphically on a PC.
Statistical analysis
A paired Student’s t-test was used to detect group differences before and at 12 weeks after rivastigmine treatment for gait speed, average step length, acceleration, and cadence in single- and dual-task gait trials. Statistical significance was considered for P-values less than 0.05.
Standard protocol approval registration and patient consent
This study was conducted in accordance with the ethical standards set forth in the Declaration of Helsinki (1983). This study was approved by the local ethics committee of Juntendo University Urayasu Hospital. Each participant provided written informed consent. If a participant had impaired decisional capacity, their family provided consent and the participants provided assent.