An Indoor Therapeutic Garden for Behavioral Symptoms in Alzheimer’s Disease: A Randomized Controlled Trial

Abstract

Background:

Behavioral and psychological symptoms of dementia (BPSD) affect 60–90% of patients with Alzheimer’s disease (AD).

Objective:

To determine if environmental therapy is an effective strategy to reduce BPSD, we tested 163 patients with AD with Neuropsychiatric Inventory (NPI) before and after 6 months of an indoor therapeutic garden (TG) or standard environment.

Methods:

A single-blind randomized controlled trial on AD patients with BPSD. Participants were randomized to an indoor TG (N = 82), or standard environment (control, N = 81) for 6 months. Primary outcome: change in the NPI score from baseline (T0) to end of treatment (T1). Secondary outcomes: change in use of quetiapine, cognition, activities of daily living, salivary cortisol, blood pressure from T0 to T1.

Results:

NPI score significantly ameliorated (TG versus control: –31.8 points), quetiapine dosage (–150 mg), blood pressure (–2.6 mm Hg), and salivary cortisol (–6.4 to –2.1 Nmol/l) were significantly reduced, the Mini-Mental State Examination significantly improved (1.8 points) in the TG versus control arm at T1 (p < 0.001). No adverse events were reported.

Conclusion:

The indoor TG seems safe and may reduce BPSD, medication intake, and cortisol levels in AD.

Keywords

Alzheimer’s disease behavioral symptoms cortisol gardens non-pharmacological treatment 0000-0002-1561-2187

INTRODUCTION

Behavioral and psychological symptoms of dementia (BPSD) affect 60–90% of patients with Alzheimer’s disease (AD), and include agitation, apathy, depression, psychosis, repetitive questioning, aggression, sleep problems, wandering, and inappropriate behaviors [1]. The etiology of BPSD is complex and not yet completely understood. Abnormal cortisol level, which has been reported in AD [2], may reflect dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and may be involved in clinical and cognitive worsening and BPSD pathogenesis [3].

Typical and atypical antipsychotic drugs are commonly prescribed for BPSD, but they carry a risk of cardiovascular and cerebrovascular side effects [4]. A variety of non-pharmacological treatments (NPTs) have been proposed for BPSD in AD, but their evidence is scarce and information on their dosing and timing is lacking [5, 6]. Environmental therapy (ET), a NPT based on the interaction between patients and the natural environment as a source of multisensory active and passive stimulation, has been shown to reduce aggression and improve satisfaction and quality of life in patients with dementia [7 –13]. However, to date, large randomized controlled trials (RCTs) on ET in AD patients are lacking.

The present RCT compared ET through an indoor therapeutic garden (TG) to exposure to standard environment in AD patients. We hypothesized that the indoor TG could improve BPSD through reduction of stress markers, such as cortisol level and blood pressure. Primary outcome was the effect of the TG on BPSD. Secondary outcomes included the use of medications for BPSD, overall cognition, activities of daily living, salivary cortisol, and blood pressure.

MATERIALS AND METHODS

Study design

This is a single-blind RCT to compare the effect of the interaction with natural environment in an indoor TG with that of a standard care unit in AD patients. Patients were allocated to the active arm, consisting of the TG (TG group) or the control arm, i.e., a standard AD care unit (control group).

Inclusion/exclusion criteria

Patients were recruited at Monsignor Mazzali Foundation (Mantua, Italy) by neurologists, geriatricians, and neuropsychologists through medical reports and assessment with the caregiver. Inclusion criteria were: 1) diagnosis of probable AD [14], 2) age 65 years or older, 3) Neuropsychiatric Inventory Scale (NPI) score≥55 (range 0–144) [15], 4) Mini-Mental State Examination (MMSE) score≤15 (range 0–30). Exclusion criteria were: 1) coexisting neurological or psychiatric diseases (e.g., stroke, Parkinson’s disease, other neurodegenerative diseases, schizophrenia or psychosis), 2) bedridden, 3) debilitating conditions (e.g., severe motor impairment, heart, liver or renal failure) that precluded full participation to the study; 4) treatment with corticosteroids or other conditions affecting the measurement of salivary cortisol. All patients continued their standard pharmacological therapy (e.g., cholinesterase inhibitors, memantine) during the study.

Randomization and masking

Once eligibility was confirmed and baseline assessments were completed, the patients were entered into the trial database, which randomly assigned them to one of the two groups (TG, control) in an allocation ratio of 1:1 without stratification. The randomization sequence was generated by the trial statistician at the time of protocol development using Stata (version 14.0) and programmed into the database. The sequence was unknown to the research staff and patients.

Blinding

The research staff was composed of two groups, i.e., ‘outcome evaluators’ and ‘session managers’; there was no overlap between the two groups of researchers. The outcome evaluators included experienced physicians, who were in charge of screening evaluation and performed serum and saliva sampling, experienced neuropsychologists, who administered NPI and MMSE, and other experienced medical staff members, who measured levels of energy expenditure. The outcome evaluators carried out the assessment procedures but were not involved in the TG or control sessions and were unaware of group assignment. The session managers included neuropsychologists and nurses, who assisted TG and control groups during the experimental sessions. None of the session managers took part in the assessment procedures. Maintenance of blinding was continuously monitored during the study.

Experimental design

All patients participated in experimental sessions lasting 2 hours each, 5 times a week for 6 months (120 sessions, 240 hours of exposure), either in the indoor TG or standard care environment. All sessions took place in the morning between 9.00 and 14.00 in groups of approximately 20 participants from June 2015 to June 2016. The session managers were instructed on the administration of the intervention prior to the beginning of the study. Since physical activity may be beneficial in AD, the daily energy expenditure was used as a proxy of the amount of physical activity and measured with an Actiheart device (CamNtech, Cambridge, UK), which simultaneously records heart rate and acceleration data for 24 h/day for 7 consecutive days [16]. The time spent for outdoor activities was the same in the two groups.

Interaction with natural environment in the TG (TG group)

ET sessions took place in the TG at Monsignor Mazzali Foundation. During free interaction with the environment, the patients were allowed to wander around the TG and touch the plants and flowers. The patients were walked to the TG by session managers, who were allowed to take part in the sessions. At the end of each session, the patients were accompanied back to their unit. The indoor TG measured 300 square meters in area and was built ad hoc for the purposes of this study in the courtyard of the institution that was in the center of the town (Fig. 1, 2). The TG may have a therapeutic meaning because, differently from a common garden, it provides a safe environment where patients can walk freely without the risk of wandering away or eloping thanks to its structured space that can reduce disorientation [8 , 18]. Moreover, the TG includes a variety of non-toxic plants to promote visual, olfactory, and tactile stimulation and has circular and continuous walking paths with no dead ends to promote movement, encourage contact with plants, and lead individuals to protected areas for sitting and socializing [8].

Fig.1

Plan of the indoor therapeutic garden (TG) where the TG sessions were conducted. The entrance is in the upper right corner with direct access to the path. The row of squares indicates two areas where participants can sit and socialize. The fountain with running water is in the lower right corner. The small purple circles (small shaded circles in the greyscale version of the figure) represent purple lights, which are turned on during the night hours.

Fig.2

Pictures showing the indoor therapeutic garden.

The TG has one entrance with direct access to the path that goes through the whole garden. The path is made of a smooth, anti-slippery material to guarantee safety to the participants. In the TG there are two spaces where participants could sit and socialize, and a fountain with running water. The walls of the TG are large windows made of glass covered with a safety film, with direct view to the courtyard from inside. The temperature and humidity inside the TG were controlled and kept constant throughout the whole year, to guarantee the same experimental conditions during all the experimental sessions.

Interaction with a standard AD unit (control group)

The control sessions took place in the AD care unit of the Monsignor Mazzali Foundation. Like the TG sessions described above, control ones included free interaction between the patients and the environment. Patients were allowed to walk in the corridor and the recreation rooms, with session managers. The AD care unit is located in a long-term facility; it measures 300 square meters in area and is composed of a long corridor and recreation rooms equipped with couches, chairs, and a television (Figs. 3, 4). Participants of the control group could not see the TG from the windows of the AD care unit.

Fig.3

Plan of the Alzheimer’s disease care unit. The areas in yellow shade (light grey shade in the greyscale version of the figure) represent the spaces where the patients in the control group could move freely.

Fig.4

Pictures showing the Alzheimer’s disease care unit.

Adherence to the sessions

The research staff recorded the amount of time each patient spent attending the TG or control sessions. Adherence rate was calculated as the percent difference between available time and effective time spent in the sessions.

Outcome measures

All outcome measures were assessed at baseline (T0) and after the end of the 6-month intervention (T1).

Primary outcome

The primary outcome measure was the change in the NPI score from T0 to T1. The NPI is a well-validated measure of the frequency and severity of BPSD, including twelve typical behavioral features of AD patients. BPSD included delusion, hallucinations, aggression, depression, anxiety, euphoria, apathy, disinhibition, irritability, and motor disturbance. The total score ranges from 0 to 144. For each patient, the NPI evaluator and caregiver were the same ones at T0 and T1.

Secondary outcomes

The dosage of quetiapine, which was the atypical antipsychotic drug routinely used for BPSD at Monsignor Mazzali Foundation, was obtained from the patients’ medical records. Cognition was measured with the MMSE, which is commonly used to measure the severity and progression of cognitive impairment in AD [16, 19]. Activities of daily living were evaluated with the Barthel Index (range 0–100), a reliable and valid tool for assessing self-care and mobility activities of daily living. Salivary cortisol was measured using plain Sarstedt Salivette collection devices (Nürmbrecht, Germany). Samples were collected at four time points of the day (7 am, 11 am, 3 pm, and 8 pm) at T0 and T1. Immediately after sample collection, the Salivette tubes were centrifuged for 2 minutes at 1000 rpm and stored at –20°C until analysis. Cortisol levels were determined by a time-resolved fluorescence immunoassay.

Sample size calculation

The sample size was calculated with G^*Power based on an estimated baseline NPI of 65±11 points (this value was derived from a sample of AD inpatients at Monsignor Mazzali Foundation), and a clinically relevant difference > 4 points (effect size = 0.45) [15]. Approximately 162 patients (81 patients for each study arm) were required for a power of 80% (two-sided testing at 0.05 alpha).

Statistical analysis

Statistical analysis was performed using StatPlus for iOS, version 6 (AnalystSoft Inc., Walnut, CA, USA). Analyses were done with an intention-to-treat basis, (i.e., all patients randomly assigned to treatment and assessed with the last-observation-carried-forward method). Between-group differences in baseline continuous variables were explored with Student’s t test. A two-way repeated measures ANOVA (group: TG, control; time: T0, T1) was used for continuous outcome variables, with the additional factors sex and baseline MMSE for NPI and hour (7 am, 11 am, 3 pm, 8 pm) for salivary cortisol level. The normality of distribution was analyzed with the skewness-kurtosis test and the homogeneity of variance was analyzed with the Levene’s test. The data were logarithmic transformed if the distribution was not normal or in case of inequality in the variances. Pearson’s χ² test was used for categorical variables. Correlations were explored with Spearman’s ρ coefficient. Between-group differences were expressed as mean and 95% confidence interval (CI). The significance level (two-tailed) was set at 0.05, and Bonferroni’s correction was applied in case of multiple comparisons.

Primary research question and classification of evidence

Can TG ameliorate BPSD in AD? This interventional study provides Class I evidence that TG is effective in reducing BPSD in patients with AD and mean age of 77 years, mean MMSE score of 13 and mean NPI score of 67 (NPI, T1 between-groups difference of –31.8 points; 95% CI: –35.1 to –28.5, p < 0.001).

Standard protocol approvals, registrations, and patients consents

The study was approved by the Ethical Committee of the Department of Neurological, Neuropsychological, Morphological and Movement Sciences of the University of Verona (approval #18201) and was carried out in accordance with the recommendations of the Declaration of Helsinki. Written informed consent was obtained from patients and/or their legal representatives who had an adequate time to decide whether to participate or not. Participants were free to withdraw the study at any time. The authors guarantee for the completeness and accuracy of the data and the fidelity of the trial to the registered protocol (ClinicalTrials.gov number, NCT02462291).

Data sharing

A full dataset of physician-level data and statistical code is available from author Massimo Venturelli (massimo.venturelli@univr.it), contingent on approval from the Institutional Review Board at the University of Verona.

RESULTS

Baseline characteristics of the participants

A total of 254 patients were screened for eligibility. After exclusion of 91 patients, the remaining 163 eligible participants underwent baseline evaluation and were randomly assigned to either TG or control groups (Fig. 5). Table 1 shows the baseline characteristics of the study population. Demographic and clinical baseline characteristics were not significantly different between groups. A total of 11 participants were lost to follow-up because of worsening of general conditions (N = 4), being bedridden (N = 3), severe pain (N = 1), more than one reason (N = 3). The average attendance to treatment across the 6-month RCT was 159 hours in the TG group (66%) and 146 hours in the control group (63%; p = 0.721). Patients did not attend the TG or control session if they felt sick or preferred to stay in their rooms. They left the session in advance if they got tired, agitated, or preferred to go back to their rooms. Daily energy expenditure did not differ across the two groups (TG: 1638±134; control: 1624±155; n.s.).

Fig.5

Flow chart of the study showing information on enrolment, group assignment, follow-up, and data analysis.

Table 1

Baseline demographic and clinical characteristics of the patients

	TG (N = 82)	Control (N = 81)
Demographic characteristics
Age	76.4±4.3	78.6±4.7
Men/women (N)	22/60	20/61
Weight (Kg)	61.7±7.5	61.4±6.2
Free fat (Kg)	43.5±5.9	42.8±7.6
Clinical characteristics
Time since admission (months)	12.3±5.4	13.4±7.8
AD duration (y)	7.6±2.1	7.3±2.0
CDR scale (range: 0–3)	1.8±0.3	1.8±0.4
MMSE (range:0–30)	13.2±1.7	13.1±1.5
NPI (range: 0–144)	67.7±19.0	66.4±16.5
Barthel index (range: 0–100)	51.9±9.5	52.3±9.4
Concurrent diseases (range: 0–4)^*	1.9±0.9	2.1±0.9
TAT balance (range: 0–16)	12.9±1.6	12.5±1.5
TAT gait (range: 0–16)	10.1±1.2	10.9±1.1
Systolic blood pressure (mm Hg)	132.1±10.4	131.1±10.4
Diastolic blood pressure (mm Hg)	81.1±3.8	80.9±3.9
Serum glucose (mg/dl)	87.0±3.2	88.4±4.0
Serum HDL cholesterol (mg/dl)	51.9±1.1	51.8±1.4
Serum LDL cholesterol (mg/dl)	98.3±3.0	98.4±2.6

Baseline characteristics were not significantly different between the two groups. AD, Alzheimer’s disease; CDR, Clinical Dementia Rating scale [25]; MMSE, Mini-Mental State Examination; N, number; NPI, Neuropsychiatric Inventory scale; TAT, Tinetti Assessment Tool scale [26]. ^*Concurrent diseases included heart disease, diabetes, depression, arthritis, osteoporosis.

Primary outcome

We found a significant improvement in the NPI score for the TG group in comparison to the control one at T1, with a mean between-groups difference of –31.8 points (95% CI: –35.1 to –28.5; ANOVA time×group interaction: F = 279.2, p < 0.001; Table 2). Sex and baseline MMSE did not influence the primary outcome.

Table 2

Clinical outcome measures

		TG (N = 82)	Control (N = 81)	Mean difference TG versus control (95% CI)	p ^*
Primary outcome measure
NPI (range: 0–144)					<0.001
	T0	67.7±19.0	66.4±16.5
	T1	38.7±14.3	70.0±15.6	–31.8 (–35.1 to –28.5)
Secondary outcome measures
Quetiapine (mg/day)					<0.001
	T0	250±50	240±50
	T1	100±25	250±50	–150 (–175 to –120)
MMSE (range: 0–30)					<0.001
	T0	13.2±1.7	13.1±1.5
	T1	14.0±1.6	12.2±1.7	1.8 (1.4 to 2.2)
Barthel index (range: 0–100)					n.s.
	T0	51.9±9.5	52.3±9.4
	T1	52.5±11.2	51.3±9.3	1.3 (–1.9 to 4.4)
Systolic blood pressure (mm Hg)					<0.001
	T0	132.1±10.4	131.1±10.4
	T1	129.5±8.5	132.5±9.6	–2.6 (–4.2 to –1.0)
Diastolic blood pressure (mm Hg)					<0.001
	T0	81.1±3.8	80.9±3.9
	T1	78.6±4.4	80.6±4.7	–2.6 (–3.5 to –1.7)

^*Two-way repeated measures ANOVA (group× x time interaction). MMSE, Mini-Mental State Examination; NPI, Neuropsychiatric Inventory scale; n.s., not significant; TG: therapeutic garden.

Secondary outcomes

The mean dosage of quetiapine was significantly reduced at T1 in the TG versus control group (between-groups difference: –150 mg; 95% CI: –175 to –120; F = 87.3, p < 0.001; Table 2). The number of patients under quetiapine did not differ between groups (TG, T0:41, T1:35; control, T0: 37, T1: 36; n.s.). Dosages of concomitant benzodiazepine, antidepressant, cholinesterase inhibitor, or other psychotropic drugs, which patients took before inclusion, were kept stable during the study.

The MMSE score was found to be significantly better in the TG than the control group at T1 (mean between-groups difference: 1.8 points; 95% CI: 1.4 to 2.2; F = 78.5, p < 0.001; Table 2). MMSE and NPI were significantly and negatively correlated, i.e., the higher the MMSE the lower the NPI, at T1 (ρ=–0.42; p < 0.001). No significant between-groups change was found for Barthel Index (F = 2.1; n.s.; Table 2). Systolic (between-groups difference: –2.6 mm Hg; 95% CI: –4.2 to –1.0; F = 27.3, p < 0.001) and diastolic blood pressure (–2.6; mm Hg 95% CI: –3.5 to –1.7; F = 32.3, p < 0.001; Table 2) were significantly reduced at T1 for TG versus control comparison.

Salivary cortisol levels were significantly reduced at T1 when comparing TG to control group, both overall (ANOVA time x group interaction: F = 25.1, p < 0.001) and for all four time points of the day (time×group×hour interaction: F = 26.9, p < 0.001; between-groups difference ranging from –6.4 to –2.1 Nmol/l; post-hoc comparison: p < 0.001; Table 3).

Table 3

Salivary cortisol levels

Salivary cortisol (Nmol/l)		TG (N = 82)	Control (N = 81)	Mean difference TG versus control (95% CI)	p ^*
7 am sample					<0.001
	T0	19.1±3.1	18.9±4.7
	T1	13.3±1.9	19.7±4.3	–6.4 (–7.0 to –5.9)
11 am sample					<0.001
	T0	11.6±1.8	11.6±2.2
	T1	8.9±0.9	12.4±2.5	–3.5 (–3.8 to –3.5)
3 pm sample					<0.001
	T0	7.5±1.4	7.5±1.6
	T1	4.8±1.5	8.5±1.5	–3.7 (–3.9 to –3.2)
8 pm sample					<0.001
	T0	8.7±1.2	9.2±1.1
	T1	7.7±1.2	9.8±1.1	–2.1 (–2.3 to –1.9)

^*Post-hoc with Bonferroni’s correction. TG: therapeutic garden.

Adverse events

No major adverse events (death, stroke, myocardial infarction, fracture) were reported in the TG and control groups. Other adverse events not related to treatment included pneumonia (TG: N = 2, control: N = 3), urinary infection (TG: N = 4, control: N = 4), and pulmonary edema (control: N = 1).

DISCUSSION

This RCT showed that 6-month ET with an indoor TG may improve BPSD in AD patients. The present study adds to available research on this type of treatment for AD, because the sample was larger, and the exposure to the TG was longer than in previous studies [20].

We met our primary outcome, in that we found a > 30-point reduction of NPI (i.e., nearly 50% amelioration) at T1 in the TG versus control group. The NPI improvement greatly exceeded the minimal clinically relevant change [15], and was surprising in comparison to previous studies [7, 9].

The single-blind design of the study might have represented a bias. It is unlikely that patients could remember the group assignment because of the severity of AD, as inclusion criteria included NPI score≥55 and MMSE score≤15. Since NPI needs to be evaluated with the caregiver, the blinding might have been suboptimal, despite our efforts and the attention paid to this point in the study design. The 150 mg reduction in quetiapine for the TG group in comparison to the control one, however, argues in favor of a true clinical effect of the ET.

We found a nearly 2-point difference in the MMSE score between the two groups at the end of the treatment. This is a new finding, as only one previous study on ET documented an improvement of cognition in patients with moderate dementia [21]. It is unlikely that the TG can prevent decline or improve cognitive resources in AD [22], but the amelioration of NPI might have resulted in better compliance to MMSE testing in our sample. This hypothesis is based on the significant and negative correlation between MMSE and NPI.

We found a reduction of cortisol levels at all the four time points we explored (i.e., 7 am, 11 am, 3 pm, 8 pm) at T1. These findings are in keeping with those documented in a previous study on forest therapy, an ET that was tested in middle-aged women [23]. Hippocampal damage in AD may increase the secretion of glucocorticoids [3]. We hypothesize that exposure to the TG might have reduced abnormally elevated cortisol levels, and in turn have contributed to amelioration of BPSD and cognition [2, 3].

Change in cortisol levels were paralleled by decrease of systolic and diastolic blood pressure, suggesting a reduction of stress in patients undergoing the indoor TG, and our results are supported by a recent publication [18]. When AD patients are forced to spend their time in a standard AD care, they may get sensory deprived, and become disoriented, jittery, and violent and these behaviors may raise distress and cortisol levels that, in turn, further increase BPSD. Exposure to ET may interrupt this vicious circle, and reduce the need for pharmacological treatment [24].

No serious adverse events were reported to the indoor TG, suggesting its safety in AD patients.

Our indoor TG differed from the original outdoor TG design reported in previous studies [8 , 20], and did not completely offer the sense of being outdoors and perhaps closer to nature in the broadest sense of that word. However, the strength of the indoor TG was to offer a truly four-season space that could be usefully applied in a wide range of institutions in any climatic zone. From this point of view, the present study represents an advance on the use of ET in AD patients.

The main limitation of the study is the single-blind design, which has been discussed above. This limitation is, to some extent, inherent in studies exploring ET. Other limitations include the single-center recruitment, the measurement at two time points only, which does not allow to document the onset and duration of the effect, the use of an overall NPI score that impede to explore whether BPSD clusters (e.g., depression, agitation/aggression, apathy) are differentially influenced by ET, the inclusion of AD patients, which hampers the generalization of the findings to mixed dementia, and the absence of a quality of life measure.

These limitations notwithstanding, ET seems to ameliorate BPSD and antipsychotic drugs intake through reduction of cortisol level.

The overall cost of the indoor TG, taking into consideration the construction costs, its life cycle, and the maintenance costs is around 6000 $/month. The TG can host groups of 20 patients/day for 5 days/week, (i.e., 400 patients/month), with a daily cost per patient around 15$. Future multicenter studies should confirm the present results and explore the cost-benefit profile of the indoor TG in comparison to standard drug treatment for BPSD.

Footnotes

ACKNOWLEDGMENTS

We wish thank the study participants and Drs. R. Bottura, R. Scarsini, R. Sanfelici, N. Zambellini, M. Trombini, and G.V. La Monica for their support and dedication to the research project, and Dr. G. Negri for designing the therapeutic garden.

This work was supported by grants from Cariverona (2010-0087) and Cariplo Foundations (2010-2258). The funding source had no role in study design, in the collection, analysis and interpretation of data, in the writing of the report, and in the decision to submit the article for publication.

Authors’ disclosures available online ().

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