Cognitive and functional progression and short-term prognosis of Alzheimer’s disease in Singapore

INTRODUCTION Dementia is a major public health issue in Singapore, which has one of the fastest ageing populations in the Asia-Pacific region. The number of persons with dementia (PWD) is expected to rise to 55,000 locally by 2020.[1] Dementia is among the largest drains on Singapore’s healthcare system, with an economic cost amounting to SGD1.4 billion every year.[2] The rising number of PWD on the back of a silver tsunami presents significant concerns, particularly the burden of care. A shrinking number of family members available to care for ageing PWD, coupled with a high caregiver burden, has led to an increased demand for long-term institutional care, evidenced by the anticipated expansion in nursing home capacity by 50% over the next decade.[3] Dementia is a leading cause of institutionalisation. Alzheimer’s disease (AD) is the most common form of dementia.[4] Most elderly PWD live in the community with their families, placing the primary burden of care on relatives. Caregivers often experience emotional stress and disruption of daily routines, leading to a high caregiver burden that strongly influences the timing and likelihood of institutionalisation.[5] Other predictors include greater severity of dementia at onset, disruptive behavioural and psychological symptoms of dementia (BPSD),[6] and incontinence.[7] Local data on the short-term prognosis of PWD, including institutionalisation and functional outcomes in the community, remain limited. The median time to institutionalisation reported in dementia studies is between 30 and 40 months from study entry.[8] This study aimed to evaluate the short-term outcomes of local patients over a 3-year period from the time of AD diagnosis, focusing on longitudinal changes in cognition, BPSD, functional status and caregiver burden, as well as caregivers’ decision regarding institutionalisation or continued community care. We hypothesised that the majority of patients with AD in Singapore remain relatively stable, with only a minority eventually requiring institutionalisation. METHODS This was a longitudinal study that retrospectively reviewed patients who presented to the Dementia Clinic, National Neuroscience Institute, Singapore General Hospital, between 2014 and 2016. Patients who fulfilled the diagnostic criteria for AD, based on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), were recruited. Patients diagnosed with dementia with Lewy body (DLB) were recruited for comparison, while those with other causes of dementia were excluded. Figure S1 (Supplemental Digital Appendix at https://links.lww.com/SGMJ/A251) shows the inclusion and exclusion criteria for our study cohort. The study was approved by the Institutional Review Board of Singapore General Hospital (2019/2382), and ethics approval was obtained. Baseline demographic information such as age, gender, race and the caregiver’s relationship to the patient were collected at the first clinic visit. For this study, we selected caregivers who had spent at least 9 h per week caring for the patient over the past 12 months and were familiar with the patient’s daily habits. Psychopharmacological medications — including cognitive enhancers, antipsychotic medications, and mood medications such as antidepressants and mood stabilisers — were documented throughout the study period. Patients were followed up regularly for a minimum of 2 years and up to 3 years. At each visit, a senior neurologist conducted a thorough clinical examination and the Mini-Mental State Examination (MMSE) according to the procedure described by Folstein et al.[9] The MMSE is a well-established cognitive test used to screen for and monitor the progression of dementing illnesses such as AD.[10] The total score ranges from 0 to 30, with lower scores indicating greater cognitive impairment. A score of less than 24 out of a possible 30 has been shown to be a fairly accurate indicator of dementia.[9,11] At each visit, caregivers were interviewed to assess their stress and fatigue level, use of daycare services, desire for institutionalisation, and observations of behavioural changes indicating BPSD. Most BPSD were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q),[12] a validated self-administered questionnaire used to assess neuropsychiatric symptoms in routine clinical practice. The domains included euphoria/elation, dysphoria/depression, apathy/indifference, anxiety, night-time behaviour, agitation/aggression, irritability/lability, delusions, motor disturbances, appetite changes, disinhibition and hallucinations. Additional behaviours, such as verbal outbursts and getting lost, were also evaluated. Functional status was assessed based on the patient’s ability to travel independently or ambulate in the neighbourhood and at home, wheelchair- or bed-bound status and presence of incontinence. Patients’ responses were corroborated by their caregivers. Data were collected using Microsoft Excel (Microsoft Inc, Redmond, WA, USA), and statistical analysis was performed using IBM SPSS Statistics version 25.0 (IBM Corp, Armonk, NY, USA). Univariate analysis was performed using two-tailed unpaired t-test for continuous variables and Pearson’s chi-square test (or Fisher’s exact test for cell count < 5) for categorical variables. A P value ≤ 0.05 was considered statistically significant. RESULTS A total of 40 patients (30 AD, 10 DLB) were included in the study. The demographic and clinical characteristics of the patients are shown in Table 1. The median age at presentation for patients with AD was 79 years, which is 6 years older than that of patients with DLB (P = 0.345). Of the patients, 77.3% (22/30) of those with AD and 70% (7/10) of those with DLB were female.Table 1: Patient demographics and clinical characteristics.All patients were prescribed at least one cognitive enhancer, while 26.7% (8/30) of patients with AD and 50% (5/10) of those with DLB were prescribed at least one mood medication. Antipsychotic medications were taken by 16.7% (5/30) of patients with AD and 50% (5/10) of patients with DLB. The difference in medication use between the two groups was not statistically significant. Changes in MMSE scores over the 3 years of follow-up are presented in Table 2. Most patients had moderate dementia at baseline (MMSE 13–20),[9] with a mean baseline MMSE score of 17.8 in the AD group and 18.2 in the DLB group. Patients with DLB patients had higher MMSE scores than those with AD during the first 2 years of follow-up, but the latter achieved a higher mean MMSE score after 3 years. However, these differences were not statistically significant.Table 2: Mini-Mental State Examination (MMSE) scores and neuropsychiatric symptoms over 3 years of follow-up.Table 2 shows the changes in neuropsychiatric symptoms over the 3 years of follow-up. At baseline, 40% (4/10) of patients with DLB experienced anxiety (P < 0.01) and 50% (5/10) had hallucinations (P < 0.01). None of the patients with AD experienced these symptoms. Night-time behaviour was observed in 70% (7/10) of patients with DLB as compared to 10% (3/10) of those with AD (P < 0.01). After 3 years of follow-up, the incidence of anxiety, hallucinations and night-time behaviour in DLB patients decreased to 0%, 12.5% (1/8) and 12.5% (1/8), respectively. At 2 years, 20% (2/10) of patients with DLB showed apathy (P = 0.012), while none of the patients with AD did. This difference was also seen at 3 years: 50% (4/8) of patients with DLB displayed apathy as compared to 4.55% (1/22) of patients with AD (P = 0.003). Over the 3 years, hallucination was the only symptom consistently present in patients with DLB, while delusion and irritability were consistently present in patients with AD. Changes in functional status, caregiver stress and nursing home placement over the 3 years of follow-up are shown in Table 3. At baseline, 80% (24/30) of patients with AD could travel independently as compared to 70% (7/10) of DLB patients. This trend persisted over the first and second years — 60% (18/30) vs. 30% (3/10) (P = 0.046) in the first year and 66.7% (20/30) vs. 20% (2/10) (P = 0.010) in the second year.Table 3: Functional status and caregiver stress over 3 years of follow-up.Over the 3-year period, more patients with AD were able to ambulate independently both at home and in the neighbourhood as compared to patients with DLB: (a) at home — Year 1: 90% (27/30) vs. 80% (8/10), P = 0.017; Year 2: 90% (27/30) vs. 60% (6/10), P = 0.031; Year 3: 90.9% (20/22) vs. 62.5% (5/8), P = 0.065; (b) in the neighbourhood — Year 1: 76.6% (23/30) vs. 40% (4/10), P = 0.006; Year 2: 76.6% (23/30) vs. 20% (2/10), P = 0.001; Year 3: 77.2% (17/22) vs. 12.5% (1/8), P = 0.001. More patients with DLB were incontinent compared to patients with AD. This trend was consistent over the 3-year period — Year 1: 20% (2/10) vs. 0% (0/30), P = 0.017; Year 2: 60% (6/10) vs. 16.6% (5/30), P = 0.008; Year 3: 75% (6/8) vs. 22.7% (5/22), P = 0.009. The functional status across both groups declined over the course of the study. However, patients with AD generally retained greater functional ability than their DLB counterparts. During the first clinic visits, the majority of caregivers reported that the patient had overall stable function — 86.7% (26/30) of patients with AD and 90% (9/10) of patients with DLB. After three years, only three (7.5%) patients were institutionalised (two with AD and one with DLB), and 27.2% (6/22) of patients with AD and 12.5% (1/8) of patients with DLB were enrolled in adult daycare. Additionally, caregivers reported that 72.7% (16/22) of patients with AD had overall stable function, with 4.6% (1/22) reporting caregiver stress or fatigue. DISCUSSION Our findings suggest that, despite BPSD in some patients, those with AD in Singapore generally remain stable in the short term, with relatively preserved function compared to those with DLB. The rate of institutionalisation was surprisingly low (7.5%), as compared with France (11.84%, over 2 years)[13] and Canada (50.9%, over 5 years).[14] This finding in our cohort could be due to several reasons. Firstly, the functional status of patients with AD was generally stable in the short term, with 90% (27/30) ambulant at home and 66.7% (20/30) able to travel independently at 2 years from diagnosis. It is well established that the severity of functional impairment is an independent predictor for caregivers’ decision to institutionalise a PWD.[7] Moreover, only 22.7% (5/22) of patients with AD were incontinent at 3 years. As incontinence increases the likelihood of institutionalisation,[7] this low rate likely contributed to the lower institutionalisation rate in our AD cohort. Furthermore, the majority of caregivers reported that the patients maintained overall stable function, with only 4.55% (1/22) experiencing stress or fatigue after 3 years. As caregiver stress is directly related to caregiver burden,[15] the combination of lower caregiver burden and preserved patient function may explain the low rates of institutionalisation among patients with AD in our study. Secondly, caregivers in Singapore may prefer caring for relatives with dementia in their own homes rather than placing them in nursing homes, possibly reflecting the intrinsic values of our Asian society, such as filial piety and duty, as suggested by Tew et al.[16] This could be another reason for the low rates of institutionalisation seen in our cohort. Caregiver gain is a protective factor that correlates with the decision to continue caring for the PWD at home.[16] Further studies should investigate the specific gains in dementia caregiving from a Singaporean perspective and whether they are predictive of delay in institutionalisation. Loss of independent function appears to occur earlier in patients with DLB compared to those with AD. This is in line with existing literature,[17] which indicates that functional decline in DLB is more rapid than in AD. Regarding BPSD, a smaller proportion of patients with AD exhibited anxiety, night-time behaviour and hallucinations at baseline compared to those with DBL, and apathy was less frequently reported during follow-up in the AD group. This is congruent with existing literature, which reported that psychiatric features are more likely to be present in the early stages of DLB as compared to AD,[18] particularly hallucinations, night-time behaviour and apathy.[19] Of note, BPSD symptoms were more prevalent among patients with DLB in the first year of diagnosis compared to subsequent years. We hypothesised that this could be due to the early commencement of medications at diagnosis and adoption of non-pharmacological interventions. Firstly, 80% (8/10) of patients with DLB were started on cognitive enhancers at the first visit. By the second visit, all patients were on rivastigmine, while 30% (3/10) and 40% (4/10) of patients were taking fluvoxamine and quetiapine, respectively. Rivastigmine has demonstrated behavioural benefits in patients with DLB,[20] and quetiapine has been found to be effective in managing BPSD.[21] In addition, caregivers’ use of positive coping strategies to manage behavioural symptoms of patients with DLB could have contributed to the improvement in BPSD. Hart et al.[22] found that motor disturbances, aggression, appetite changes and sleep disturbances played a bigger role than psychological symptoms in caregiver stress. In our cohort, only a small percentage of patients with AD displayed these behavioural changes throughout the 3 years, potentially contributing to lower levels of caregiver distress. Furthermore, physical aggression and depressive symptoms, two main predictors of institutionalisation,[23] were reported in very few patients with AD, which could explain the low incidence of institutionalisation seen in our study. Finally, the use of community daycare services was uncommon in both groups. The low uptake of daycare services in both groups could be due to the low incidence of neuropsychiatric symptoms, functional impairment and caregiver stress in our study, and thus daycare enrolment may not be warranted. Nonetheless, given that some studies[24] have demonstrated the effectiveness of dementia daycare services in delaying institutionalisation, it would be prudent to strengthen efforts to promote early enrolment. The study has several limitations. This was a retrospective study with a small sample, and thus, generalisation of our results to the larger community must be done cautiously. Furthermore, some of the observations at Year 3 of follow-up may have been affected by dropouts from the study. Most of the patients with AD had a modest mean MMSE score at diagnosis. Due to the retrospective nature of this study, patients with higher initial MMSE scores may have been preferentially sampled, potentially affecting our results, as the rate of institutionalisation is influenced by AD severity at baseline, with more severe patients at a higher risk of being institutionalised.[13] Moreover, the follow-up period may not have been adequate to observe deterioration in PWD, as our study cohort had a low incidence of behavioural issues and functional disability. Regarding the study methodology, we did not employ existing established questionnaires such as the Zarit Burden Interview to ascertain caregiver stress. Instead, the variable ‘expression of stress/fatigue’ was modelled after question 3 of the abbreviated Zarit Burden Interview.[25] In addition, ‘overall stable function’ was determined based on caregivers’ subjective perceptions of the patient’s function at each follow-up. A larger-scale study would be useful to validate these variables in evaluating the patient’s overall progress in a longitudinal manner from the caregiver’s point of view. Finally, our sample population consisted almost entirely of Chinese subjects. As Singapore is a multiracial society and sociocultural factors are important determinants of outcomes associated with dementia care, this study’s findings may not be generalisable to other local ethnic groups. In conclusion, the majority of patients with AD in Singapore remain stable in the short term (within 3 years of diagnosis), with minimal caregiver burden and low rates of institutionalisation. Providing support for caregivers through community care services deserves careful consideration, as such support could keep caregiver burden low and delay the decision for institutionalisation. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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