Early recognition and treatment of neuropsychiatric symptoms to improve quality of life in early Alzheimer’s disease: protocol of the BEAT-IT study

Participants in the control group will receive CAU at their local hospital. We expect that the CAU will be quite heterogeneous over sites and may consist of psychoeducation about dementia by a nurse or consultant specialized in dementia, the prescription of psychotropic drugs, and/or the referral to a psychiatric outpatient clinic for specialized treatment in patients with severe NPS [46]. Because of these differences, we will carefully keep track of the procedures undertaken by clinicians for patients in the CAU group. Based on recommendations for assessing usual care in clinical trial [47], we will develop a study-specific CRF that will be filled out at the time of enrolment and will be updated at each follow-up visit.

All participants in the second wave will be enrolled in the intervention group. In this group, we will apply the DICE method to structure and standardize the assessment and management of NPS. Participants who withdraw from study participation after being informed by their physician and/or the researchers will receive CAU at their hospital as described above. The DICE method will take place at the Neurology Department of the Erasmus MC and will be carried out by a psychiatrist (MC) and neuropsychologists (EB, WSE, JMP) who are all involved in the memory clinic of this department.

The steps of the DICE method are depicted in Fig. 2. More detailed information on the development and background of the DICE method can be found elsewhere [10]. During the first visit, the patient and caregiver will undergo a consultation by an experienced psychiatrist to establish clinically relevant NPS (Describe). Factors related to the patient, caregiver, and environment will be examined following the DICE method [22, 48] and the DICE manual [49]. For factors related to the patient, we will record the chronic somatic conditions using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G) [50] semi-structured interview, followed by a clinical examination to explore the medication changes, pain, sleep hygiene, and sensory changes. If necessary, a lab evaluation will be conducted to screen for infections, thyroid problems, and metabolic disorders. Other patient-related factors including unmet needs, boredom, and emotional well-being will be assessed using the Checklist of Factors to Consider to Identify Potential Causes of Behavioral Symptoms developed by Gitlin et al. [48]. Caregiver-related factors will be screened by using the Relationship Closeness Scale [51], Center for Epidemiologic Studies Depression Scale [52], and the CareQol-7D [53]. This will be extended by history taking on family and cultural expectations, knowledge about dementia, and the availability of support. Environmental factors will be assessed to the patient and caregiver by the Informal Assessment: Brief Questions to Guide Describing Behavioral Symptoms [48]. A full and accurate description of specific behavior will provide more insight about the “who, when, where, and what” about the situations in which the behavior is occurring, while taking safety risks and the level of physical and social stimulation into account (Investigate). Thereafter, a multidisciplinary meeting will take place in which a personalized treatment advice is formulated based on the current guidelines on the diagnosis and assessment of NPS in dementia (Create) [24‐26]. During the second visit, this treatment advice is discussed and adjusted to the needs, values, and characteristics of the patient and caregiver following a PCC approach. Given the large heterogeneity in symptoms, interventions will vary for each individual and can include psychoeducation, psychosocial interventions, caregiver support, and/or pharmacological treatment based on the current (inter)national guidelines [24‐26, 54‐56]. Notably, the interventions and strategies that will be used to reduce NPS and enhance the QoL are all evidence-based treatment strategies that are or should be carried out in the current clinical practice. Finally, we will monitor treatment progression 1 month after the last visit by telephone (Evaluate). Patients and their caregivers are then invited for an extra visit if necessary. In such cases, alternative interventions will be discussed if planned interventions were not implemented or effective. Additional diagnostic procedures or interventions will be monitored in the CRF.

The QoL of the patient will be measured by the Quality of Life in Alzheimer’s Disease (QoL-AD) questionnaire [67]. This is one of the most widely used QoL questionnaires in AD and has good psychometric properties [80]. Patients are questioned via a 13-item interview format. The proxy version of the QoL-AD is also used and filled out by the caregiver since previous studies have shown that the caregivers’ perspective on the patients’ QoL might be a more valid indicator of treatment success [81].

The CarerQol-7D will be used to measure the care-related QoL in caregivers [53]. The instrument includes six burden dimensions and a subjective valuation scale for happiness.

Changes in NPS will be assessed with the NPI-Q [44], a general screening questionnaire including 12 distinct NPS. For each item, caregivers have to indicate the presence, the severity, and the extent of emotional distress that each symptom causes. Similar to Gitlin et al. [69], we will add a frequency score and will ask caregivers how confident they are in managing a certain symptom on a 5-point Likert scale (0 = not confident to 4 = extremely confident).

A two-step approach will be used to further assess NPS: if certain symptoms are present, as indicated by an NPI-Q frequency score ≥ 1, specific questionnaires will be used to assess these symptoms in more detail. All instruments will be administered to the caregiver. To measure the depressive symptoms, the Dutch version of the Cornell Scale for Depression in Dementia (CSDD) will be used [76]. The CSSD consists of 19 items covering mood, behavioral changes, and circadian changes related to depression and is validated in patients with dementia [76]. Anxiety symptoms will be measured by the Rating Anxiety in Dementia (RAID) scale, an 18-item inventory that includes specific fears and somatic symptoms related to anxiety [77]. Agitation, irritability, aggression, and motor disturbances will be measured by the Dutch version of the Cohen-Mansfield Agitation Inventory (CMAI-D) [82]. Hallucinations will be assessed by the subscale B of the Behavioral Pathology in Alzheimer’s Disease Rating Scale (BEHAVE-AD) [78], and delusions will be assessed by the subscale A of the BEHAVE-AD. Apathy is assessed with the informant-reported Apathy Evaluation Scale (AES-I) [75] and comprises of 18 items. Sleep disturbances will be measured by the 8-item Sleep Disorder Inventory (SDI) [79], an expanded version of the sleep disturbances item of the NPI. Similar to the NPI, caregivers have to score each symptom of the SDI on frequency, severity, and caregiver distress.

Caregiver burden will be measured with the perseverance time, a one-item questionnaire that assesses caregiver burden by asking the period of time (in months) that the informal caregiver thinks he or she is able to maintain the care if the current situation remains stable [68]. This questionnaire is a good predictor for institutionalization [83].

The Clinical Dementia Rating Scale (CDR), MMSE, and a neuropsychological assessment will be administered during the diagnostic procedure at the local memory clinic prior to inclusion. The CDR includes six domains covering cognitive function and IADL associated with dementia [57]. Disease severity will be determined based on clinical diagnosis and CDR global score with MCI due to AD (CDR score 0.5), mild AD dementia (CDR score 1), and moderate to severe AD dementia (CDR score 2–3). Global cognitive function will be measured with the MMSE [58]. The neuropsychological assessment will be carried out according to the Dutch Parelsnoer Institute for Neurodegenerative Diseases [40] and covers the major cognitive domains including memory, attention, processing speed, language, visuospatial abilities, and executive functioning.

The Amsterdam Instrumental Activities of Daily Living Questionnaire (A-IADL-Q) is a proxy measure to detect problems in IADL in patients with dementia [66]. This tool is a reliable and valid instrument to detect changes in IADL over time.

Physical health and comorbidities of the patient will be assessed using the CIRS-G [50]. The severity of 14 common medical problems in the geriatric population (e.g., heart, liver, vascular diseases) will be judged by one of the researchers during a short interview with the patient and caregiver.

Psychotropic medication use will be documented in the CRF. The total number of medications used will be registered and classified according to the ATC coding: antidepressants, antipsychotics, hypnotics and sedatives, anxiolytics, and anti-dementia medications [20].

For the cost-effectiveness evaluation, patients will complete the EQ-5D-5 L, the most commonly used health-related QoL instrument [70], and the ICEpop CAPability measure for Older people (ICECAP-O), a 5-item well-being scale [71], and caregivers will fill out the CarerQol-7D. In addition, the Institute for Medical Technology Assessment Valuation of Informal Care Questionnaire (iMTA iVICQ) [72] will be used to assesses the amount, costs, and appraisal of the care provided by the caregivers. The iMTA Medical Consumption Questionnaire (iMTA MCQ) consists of 31 questions regarding healthcare utilization [73] and incorporates direct healthcare use of the patient. Both the iMTA MCQ and the iMTA iVICQ will be sent to the caregivers and can be completed at home.

A random selection of one out of four of the dyads in the intervention group will be invited to participate in the qualitative part of this study, accounting for the site and disease stage. Semi-structured interviews will be conducted in order to achieve more insight into the experiences of participants who underwent the DICE method and what they considered as helpful elements. The interviews will be conducted face-to-face, will be audio-taped, and will last approximately 60 min. Interviews will be performed until saturation is reached, i.e., until no new concepts and themes are obtained [84], which we estimate to reach after we interviewed 15–20 patients with their caregivers [8, 85, 86]. Questions will be asked in an open non-directive manner, focusing on the subjects’ thoughts, feelings, and experiences. Topics include the subjects’ experience of the intervention, and which elements were considered to be effective and which not, with the aim to examine the efficacy of and experiences with the DICE method from the perspective of patients and caregivers.

The audiotapes of all interviews will be transcribed verbatim. This data will be analyzed by two independent researchers with ATLAS.ti 7 software according to the thick analysis approach [92]. This approach endorses multiple triangulations, i.e., the use of multiple interpreters and techniques to analyze the data, to enhance validity.

The coding and analyses will be an iterative process simultaneously with the interviews, allowing adjustment of questions and topics. We will make use of open coding, thematic coding, and causal coding [93]. Open coding is an explorative process in which all elements of the data are coded. Thematic coding is a more deductive technique that included the coding of themes and categories that are proposed by the researchers prior to the analysis or emerge from the material and are considered to be of importance by the researchers. Causal coding will help us to get more insight into the working elements of the DICE approach as proposed by the participants. Characteristics of patients and their caregivers (age, sex, relationship, disease severity) will be used for descriptive purposes.