Abstract
Behavioral and psychological symptoms of dementia (BPSD) occur in up to 80% of AD patients and represent one of the largest factors contributing to caregiver burden. To analyze the effect of galantamine on BPSD and caregiver burden, we treated a total of 50 patients with mild AD for 12 weeks and evaluated them using the Neuropsychiatric Inventory (NPI) and Japanese version of the Zarit Caregiver Burden Interview (ZBI). We also performed regional cerebral blood flow single photon emission computed tomography (rCBF SPECT) at baseline using three-dimensional sterotatic surface projections. Total NPI and ZBI scores did not significantly change after 12-week galantamine treatment. To identify the characteristics of patients who showed improvement after galantamine treatment, we divided patients into two groups, those with and those without sub-items on the NPI. Patients with aggression showed improvement in ZBI scores (p < 0.05). A comparison of rCBF SPECT between these two groups indicated that patients with aggression exhibited increased rCBF in the right prefrontal cortex compared with those without aggression. In a patient with aggression, 20-month treatment with galantamine inhibited increases in the rCBF area in the right prefrontal lobe. These results suggest that galantamine response may be related to aggression and dysfunction of the prefrontal cortex.
INTRODUCTION
Alzheimer’s disease (AD) is a progressive dementia characterized by cognitive dysfunction, and behavioral and psychological symptoms of dementia (BPSD). As the disease progresses, diverse behavioral changes including depression, delusion, hallucination, agitation, and other symptoms, manifestthemselves with increasing severity of AD [1]. The cholinergic systems has been implicated in AD for over twenty years [2] and studies of autopsied brain samples demonstrated a relationship between BPSD and choline acetyltransferase activity [3] or muscarinic M2 receptors in AD [4]. Cholinergic pathways innervate all cortical areas, and cholinergic abnormalities in AD are most marked in the temporal and superior frontal gyri which would be associated with psychosis of AD [5].
Acetylcholinesterase inhibitors are the most established medication for the treatment of mild to moderate of AD. Three types of acetylcholinesterase inhibitors (donepezil, rivastigmine, and galantamine) have been shown to be effective in treating behavioral abnormality in patients with AD [5–7]. Galantamine has allosteric modulating activity at the nicotinic acetylcholine receptors in addition to acting as an acetylcholinesterase inhibitor [8]. The behavioral effects of galantamine have been assessed using the Neuropsychiatric Inventory (NPI) [7, 9–11]. Two double blind, placebo-controlled studies showed significant reduction in the total NPI score from baseline after administrating galantamine [7, 11]. One study showed reduction of emergence of behavioral disturbance among the AD patients who were not symptomatic at baseline [11].
BPSD of patients with dementia has been shown to be one of the largest factors contributed to caregiver burden [12, 13]. The stress of caregivers has negative effects on the quality of care for patients with dementia and early institutional placement. However, to the best of our knowledge, clinical trials of galantamine were not fully focused on caregiver burden. Only two studies evaluated caregiver burden using NPI caregiver burden [10] and the time spent supervising patients [14]. The Zarit Caregiver Burden Interview (ZBI) is based on caregiver-based interviews to evaluate caregiver burden [15]. Since the ZBI consists of 22 brief question and takes only 10 minutes, numerous studies have used this scale to assess the caregiver burden in various diseases [16–19] including AD [20, 21].
In the present study, we used the Japanese version of the ZBI [22] and NPI, and investigated changes using both scales before and after treatment with galantamine. To identify the characteristics of patients who show improvement with galantamine treatment, we divided patients into two groups, those with and those without sub-items of the NPI. We identified that patients with aggression showed more improvement than those without aggression. Patients with aggression exhibited increased cerebral blood flow in the prefrontal cortex compared with those without aggression.
METHODS
Patients
This is a prospective trial in patients with clinical diagnosis of probable AD according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition(DSM-IV), carried out from February 2012 to September 2013 at the Department of Neurology at Juntendo University. Further inclusion criteria were 60 to 90 years of age with mild to moderate AD patients (MMSE score was more than 11) and no cholinesterase inhibitor use prior to trial start. In this 12-week study, patients started galantamine at 4 mg twice daily, and doses were titrated up after intervals of 4 weeks, until individuals achieved a dose of 8 mg twice a day, and if there was no effect, 12 mg twice a day. At baseline and at 12 weeks, patients were evaluated using the MMSE, NPI, and ZBI. The NPI evaluates both frequency and severity of 10 neuropsychiatric symptoms by asking caregivers [23]. ZBI is also based on caregiver-based interviews, consisting of 22 questions to measure feelings of burden of the caregivers [22].
All patients provided informed consent, and the study protocol was approved by the committee for ethics in clinical research of the University of Juntendo, Japan.
SPECT analysis
One month before treatment, each patient underwent single photon emission computed tomography (SPECT) to evaluate regional cerebral blood flow (rCBF). The patients were imaged with a triple-head, rotating gamma camera (Toshiba GCA9300A, Toshiba, Tokyo, Japan) with a fan-beam collimator, which permits a spatial resolution of 6.4- mm full width at half maximum. Our hospital buildings were reconstructed in 2014, and the gamma camera changed to a dual-head variable-angle gamma camera (Symbia E, Siemens, The Hague, The Netherlands). The imaging was started 20 minutes after intravenous injection of 222-MBq 123l-IMP. Reconstruction of images was performed by filtered back projection using Butterworth and Ramp filters with attenuation correction (Chang μ= 0.07/cm). Matrix size and slice thickness of SPECT images were retrospectively.
To determine the regions demonstrating a significant alteration in rCBF, group analysis by three-dimensional stereotactic surface projection (3D-SSP) was used [24]. 3D-SSP images that represent the distribution of rCBF calculated in each pixel as a Z-score map were collected using the computer software iSSP4 (Nihon MediPhysics, Japan). Pixel-by-pixel two-sample t-test was made using iSSP35_2tZ (Nihon MediPhysics, Japan) to compare brain perfusion in iSSP4 set between the patients with and without agitation at baseline. To examine the effect of galantamine on rCBF, we searched patient records in our hospital. We found that a 67-year-old female patient had undergone SPECT images at baseline, 20 months, and 40 months after commencement of galantamine treatment. Since the SPECT camera was changed before and after starting galantamine, we were not able to directly compare the images. We performed 3D-SSP analysis using age-matched controls for each camera. For the triple-head, rotating gamma camera (Toshiba GCA9300A, Toshiba), a normal database (n = 57, female:male = 28:29, age 60.9±11.7 years old) was used. For the dual-head variable-angle gamma camera (Symbia E, Siemens), another normal database (n = 29, female:male = 10:19, age (64.2±8.2 years old) was used.
Statistics
Statistical analyses were performed using JMP11 software (SAS Institute Japan). We used the Wilcoxon Signed-Rank Test for comparison between two groups. Pearson’s correlation coefficient was calculated to examine the relationship between two groups.
RESULTS
Of the 86 patients recruited, 50 patients completed the study as planned (Fig. 1). 13 patients withdrew for adverse events: digestive symptoms (n = 8), irritability (n = 3), pallid face (n = 1), and tremor (n = 1), and 23 patients discontinued the treatment. Table 1 showed the sociodemographic features of included patients. Of the 50 patients, the mean age was 76.9±5.8 years and 20 were women (40%). The mean MMSE sore at baseline was 20.0±3.7. The relationship of caregiver to the patient was spouse in 54%, and child in 46%.
No significant differences were found in the MMSE, NPI, and ZBI scores between baseline and at 12 weeks (Supplementary Figures 1 and 3). There was no significant correlation between the change in MMSE and NPI, and MMSE and ZBI scores; however, the change in ZBI scores was weakly correlated with that of NPI total (r = 0.26) (Supplementary Figure 2). To reveal characteristics of patients who showed improvement in ZBI or NPI total scores after galantamine treatment, we divided the patients into two groups according to whether each subscale of NPI was present (≥1) or not (<1) (Fig. 2). Of note, in the patients with agitation at baseline, galantamine treatment decreased the scores of total ZBI (p = 0.0234), although there was no significant difference in total NPI scores (Supplementary Figure 4). To investigate the relationship between agitation and brain regional function, we compared SPECT images between groups with or without agitation at baseline. The group with agitation exhibited an increase in rCBF in the right lateral prefrontal cortex compared with that without agitation (Fig. 3). The change in rCBF SPECT in the patient with agitation is shown in Fig. 3b. This patient is a 67-year-old female. At baseline, she scored 19 points on MMSE, 13 points on ZBI, and 2 points on agitation of NPI. After 12 weeks of galantamine treatment, she improved by 6 points on the ZBI and 2 points on agitation of the NPI. Of note, the increased area in rCBF in the right lateral frontal lobe (single arrow) disappeared after 24 mg galantamine treatment for 20 months.However, after 36 months, the increased area in the right lateral frontal lobe reappeared (double arrow).
DISCUSSION
We analyzed the change in cognition, behavior symptoms, and caregiver burden in patients with mild to moderate AD after receiving 12 weeks galantamine treatment. The result showed that ZBI scores decreased in patients with agitation at baseline. The SPECT study comparing the groups with and without agitation suggests that the magnitude of rCBF increase in the right prefrontal cortex may affect a patient’s response to treatment with galantamine. The fact that 20-month treatment of galantamine inhibited increases in the area of rCBF in the right prefrontal cortex of a patient with aggression supports this view.
Several studies suggest that agitation and aggressive behavior may be associated with the prefrontal cortex in AD. It was shown that the onset of agitation in dementia patients was predicted by frontally mediated behaviors including irritability, delusions, and disinhibition [25]. Fluorodeoxyglucose positron emission tomography (PET) study showed a significant relationship between the agitation factor scores of NPI and hypometabolism in the frontal and temporal lobe in AD patients [26]. Hirano et al. demonstrated the relationship between the aggression factor of NPI and hypoperfusion of SPECT at bilateral dorsofrontal, left anterior, and right parietal cortex in AD patients [27].
Our study suggested that agitation could be correlated with increased but not decreased perfusion in the prefrontal cortex. A recent study of patients with mild cognitive impairment revealed that cortical hyperglucose metabolism area was consistent with [11C] Pittsburgh compound B negative area possibly indicating amyloid-β (Aβ) oligomer accumulation, and it was postulated that hypermetabolism might be indicative of greater adaptive plasticity as a compensatory mechanism before sufficient amyloid deposition [28]. Taken together, the accumulation of oligomeric Aβ species in the prefrontal lobe may play a role in the development of agitation in mild AD patients. Administration of galantamine to a transgenic mice model of AD reduced soluble Aβ via microglial Aβ phagocytosis and may contribute to the galantamine response [29].
In patients with mild and moderate AD, switching from donepezil to galantamine decreased the agitation score assessed by the Cohen-Mansfield Agitation Inventory [30]. Patients with amnestic mild cognitive impairment and mild AD were switched from donepezil to galantamine, however, only mild AD patients showed a significant beneficial effect on the NPI, especially the subscale of agitation, delusion, and aberrant motor activity [31]. Taken together, galantamine treatment may be more effective to alleviate agitation than donepezil. Since galantamine is a rather weak acetylcholinesterase inhibitor, but is a potent allosteric potentiating ligand of nicotinic acetylcholine receptors, it alters other neurotransmitters such as monoamine, dopamine, and glutamate [8, 32]. Galantamine treatment in a rodent model affected the level of acetylcholine, dopamine, and glutamate in the prefrontal cortex [32]. Therefore, galantamine may be effective for AD patients with aggression via the allosteric potentiating ligand mechanism.
The limitations of our study include the small and open-label, single-arm design. A blind comparative study is necessary to confirm our findings. Although the results indicated that AD patients with aggression reduced the ZBI scores, we were not able to show that galantamine treatment reduced aggression. Post hoc analysis of pooled data from three large trials of 3-, 5-,and 6-month galantamine treatment in AD patients showed a slight benefit of galantamine compared to placebo, and agitation was also included as one of the significantly improved domains [33]. Since this study is exploratory, we only analyzed rCBF SPECT data at baseline to look at the association with aggression. To understand the precise mechanism of aggression in AD patients, further study will be needed to examine the change of rCBF SPECT after galantamine treatment using more aggression-directed scales such as the Cohen-Mansfield Agitation Inventory.
In conclusion, we showed that 12-week galantamine treatment reduced caregiver burden in mild AD patients with agitation. It was shown that cognitive impairment cases with agitation were associated with greater number of additional hours of caregiver help [34], and the agitation subscale scores of NPI was associated with degree of caregiver burden and impact on caregivers on the Caregiver Appraisal scale [25]. These findings may indicate that physicians should consider galantamine treatment in mild AD patients with agitation. SPECT measurement of right prefrontal hyperperfusion at baseline may be helpful to predict response to galantamine treatment.
