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Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of thera‑ peutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB‑associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB‑specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease‑modifying therapy trials. Keywords: Dementia with Lewy bodies, Clinical trials, Outcomes, Measurement properties Introduction antibodies for AD and genetic therapies targeting glu- Dementia with Lewy bodies (DLB) is the second most cocerebrosidase mutations in Parkinson’s disease (PD) common type of neurodegenerative dementia after Alz- [3, 4]. Therefore, establishing robust outcome measures heimer’s disease (AD) [1]. Compared to AD, DLB is is crucial to permit the evaluation of symptomatic treat- associated with a poorer prognosis, higher healthcare ments and DMTs in DLB. To date, no specific DLB out - costs and caregiver burden, and greater impact on qual- come measures have been validated for use in clinical ity of life [2]. Currently, symptomatic therapies are lim- trials, which have typically relied on scales developed for ited in DLB and there are no disease-modifying therapies AD and PD [5] (Table  1). Previously, regulatory authori- (DMTs). However, disease-modifying approaches are ties have emphasized the need for outcome measures being strongly pursued in other neurodegenerative con- that address functional, cognitive, and global domains in ditions, for example, amyloid beta-directed monoclonal AD, but guidance is lacking in DLB [6–8]. Randomized clinical trials, the highest level of evi- dence to guide treatment, are scarce among DLB cohorts, *Correspondence: rodrigfe@musc.edu and most of the experience comes from case studies or Department of Neurology, Medical University of South Carolina, 208b open-label observations without control groups. There Rutledge Av., Charleston, SC 29403, USA Full list of author information is available at the end of the article are multiple challenges in conducting a clinical trial in © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. 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Translational Neurodegeneration (2022) 11:24 Page 2 of 18 Table 1 Outcomes used in DLB clinical trials cognitive fluctuations; and, the potential effects of con - comitant medications (e.g. increased parkinsonism from Domain Assessed in Primary Most common antipsychotics or anti-depressants). clinical trials: outcome: method used n (%) n (%) (n) This paper represents the first in a series by the Clini - cal Trials Workgroup of the Lewy Body Dementias Functional 22 (52) 5 (11) ZBI (7) Professional Interest Area—Alzheimer’s Association Cognitive 39 (92) 17 (40) MMSE (33) International Society to Advance Alzheimer’s Research Visual hallucinations 35 (83) 21 (50) NPI (22) and Treatment (ISTAART). In this paper, we will focus Fluctuations 9 (21) 1 (2) Mayo FSI (4) on the tools for measuring clinical outcomes (e.g., rat- Motor 28 (66) 10 (23) UPDRS‑III (23) ing scales, cognitive batteries), whilst biomarkers, such as RBD 1(2) 1 (2) RBDSS scale (1) imaging and cerebrospinal fluid biomarkers, will be dis - RBD REM sleep behavior disorder, ZBI Zarit Burden Interview, MMSE Mini‑Mental cussed elsewhere in our series. In this article, we discuss State Examination, NPI Neuropsychiatric Inventory, Mayo FS Mayo Fluctuation Scale, UPDRS-III Unified Parkinson’s Disease Rating Scale Part III, RBDSS RBD the outcome measures previously used in DLB clinical Severity Scale trials and specifically evaluate what might be considered necessary in future work to identify novel symptomatic and disease-modifying therapies in DLB that would meet DLB, including delayed and inaccurate diagnosis, signifi - the requirements of the regulatory agencies. In addition cant clinical heterogeneity, and the use of concomitant to cognitive and functional outcomes, we will also focus medications [9]. However, one of the greatest challenges on measuring the core features of DLB, which include in conducting robust DLB clinical trials is the selec- cognitive fluctuations, visual hallucinations, parkinson - tion of appropriate outcome measures. While choice of ism, and rapid eye movement sleep behavior disorder intervention, population, and trial design are all intui- (RBD) [13]. A discussion regarding the outcome meas- tively important, without the selection of an appropriate ures to address other aspects of the disease (e.g., auto- outcome and a rigorous method to measure it, any trial nomic function or mood, fatigue, specific cognitive could be unrevealing or misleading [10]. The appropriate domains) is beyond the scope of our review but will be outcome measures will not only affect the accuracy and addressed in the future by our working group. applicability of the trial, but also have implications for initial sample size estimations [10]. Assessment of clinical outcomes: measurement properties Outcome measures typically rely on clinical assess- Clinical outcomes are classified either as the occurrence ments rather than objective measures and whilst the of an event or milestone, or changes in clinical meas- severity of the measure may be implied by its score, this ures (Table  2). Such outcome measures may be obtained has typically not been validated in DLB. Additionally, any either by direct observation and quantification or by outcome measure needs to consider the type of inter- reports from patients and/or their caregivers [10]. Meas- vention being evaluated (symptomatic or DMT), as well urements can range in scope, from global functionality to as the disease severity of the population being studied. a specific aspect of the condition. For example, whilst symptomatic therapies will likely When selecting a clinical outcome measure, there focus on measurement of the specific domain being tar - are three major considerations: i) measurement prop- geted, DMTs may focus on the time to the development erties, ii) interpretability of the results, and iii) feasi- of clinical milestones. Moreover, the progression of the bility. The measurement properties reflect the tool’s disease may affect clinical domains differentially, wherein ability to measure a specific variable in the group of changes in one feature may not be a suitable marker of interest (validity), the random error associated with overall progression [11]. There is also an unresolved the outcome measure (reliability), and its sensitivity issue around what might constitute a meaningful clini- to detect change (responsiveness) [14]. Assessments cal change or minimal clinically important difference of these domains are crucial for the validation of out- (MCID) [12]. Many outcome measures in DLB are also come measures and can help to identify the appropriate likely to be impacted by poor patient recall, and reli- conditions under which each measure is used (Table 3). ance on caregivers may introduce recall bias and failure Interpretability refers to the degree to which one can to report clinical features that may be difficult to directly assign qualitative meaning to the outcome measure’s observe (e.g., hallucinations). Finally, disease-specific fac - quantitative scores or change, including the distribu- tors can also present their own set of unique challenges tion of scores within subgroups to assess for any floor in DLB trials, such as where one symptom might impact or ceiling effects [14]. One of the most important another (e.g. bradykinesia affecting cognitive response concepts within interpretability is that of the MCID, time tests); assessment sessions that coincide with R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 3 of 18 Table 2 Types of outcome measures Outcome measure Example Advantage Disadvantage Direct/objective Falls/death Easy to measure May not capture the symptom severity or impact on daily life Performance outcome Neuropsychological evaluation Objective measure Only evaluating one point in time—not a reflection of the current status Artificial environment Clinician reported outcome Clinical scales Clinical relevance Depends on expertise of administrator Patient‑reported outcome Quality of life questionnaires Centered on the patient Impaired cognition may affect reliability of responses Observer‑reported outcome Activities of daily living questionnaires Provides a better assess‑ Subject to bias or caregiver’s cognitive ability ment of daily function Table 3 Measurement properties of outcome measures Domain Measurement property Definition Methods of assessment Reliability The extent to which an OMI is free from random error Reproducibility The proportion of the total variance in the meas‑ Kappa coefficient urement due to true differences between patients. Interclass correlation coefficient Includes Inter‑rater rand test–retest reliability Internal consistency The degree of interrelatedness among the items Cronbach’s alpha Item‑total correlations Homogeneity coefficient Measurement error The systematic and random error of a patient’s Standard error of measurement score that is not attributed to true changes in the Bland–Altman method construct to be measured Validity The extent to which an OMI the construct that it is supposed to measure Content validity The degree to which the OMI covers the important Lynn’s Content Validity Assessment from an expert parts of the construct to be measured panel Construct validity The degree to which the scores of an OMI are Structural validity: Factor analysis consistent with the expected scores, based on Hypothesis‑testing: Convergent, divergent, and the existing knowledge of the construct. Includes internal validity compared to another validated structural, hypothesis‑testing, and cross‑ cultural measure validity Cross‑ cultural: measurement invariance in different populations Criterion validity The degree to which the scores of an OMI are an Criterion‑ outcome measure agreement or correla‑ adequate reflection of the gold standard (if avail‑ tion coefficient able) Responsiveness Responsiveness The ability to detect change over time in the con‑ Eec ff t size struct to be measured Standardized response mean Responsiveness statistic defined as the smallest amount that an outcome must burden to the patient, caregiver, and administrator. This change to be meaningful to patients [12]. It is recog- is particularly relevant for dementia research, where nized that there are different methods to determine the subjects may not be able to tolerate prolonged and MCID (e.g., anchor-based and distribution-based), but intense periods of evaluation. these are beyond the scope of this paper [12]. Estab- Initiatives such as the Core Outcome Measures in lishing what might constitute an MCID is fundamen- Effectiveness Trials (COMET) and the COnsensus- tal to designing studies with sufficient statistical power based Standards for the selection of health Meas- to detect an effect [15]. Finally, feasibility assesses the urement Instruments (COSMIN) provide practical practical aspects of the outcome measure, such as the Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 4 of 18 Functional, quality of life, caregiver burden, and global guidelines on how to select the appropriate outcome impression outcomes measurement instrument [16–18]. The term functional outcome is used as the measure of how a patient can successfully perform the meaning- Methods ful tasks and roles required as part of typical everyday In this paper, we focused on clinical outcome measures life [10]. Such real-world measures are important effi - used in DLB trials. We conducted a literature review of cacy endpoints for clinical trials in DLB and are usually clinical trials in patients with DLB. Using PubMed, we required by regulatory authorities. In addition, quality searched for pharmacological or neurostimulation tri- of life and caregiver burden are also relevant and war- als in DLB patients published between January 1975 rant measurement. Finally, the measurement of multi- and March 2021. We used a combination of the follow- ple aspects of function can answer the most important ing search terms: “Dementia with Lewy bodies”; “Lewy question of a clinical trial, i.e., whether the intervention body dementia”; “Lewy body”; “clinical trial”, “therapy”; produces a meaningful improvement in the patient’s “management”; and “treatment”. A total of 2079 non- condition. Therefore, the use of a clinical impression duplicate citations were identified. One reviewer (FRP) measurement is regarded as a useful and necessary out- then screened the abstracts and full-texts according to come, particularly in symptomatic trials. the following inclusion criteria: (1) Prospective studies The Alzheimer’s Disease Cooperative Study-Activities evaluating pharmacological modulation or neuromodu- of Daily Living Scale (ADCS-ADL) is one of the most lation and (2) studies of participants with DLB alone or widely used functional scales in clinical trials. It evaluates in combination with AD, PD, or PD dementia. Retro- the ability of the patient to perform basic and instrumen- spective studies, extension studies, and meta-analysis tal activities of daily living (iADLs) and is administered were excluded. A total of 42 trials were included. The only to the caregiver. The ADCS-ADL has previously outcome measures utilized in the clinical trials were been used in several trials for other conditions, such as then classified into 7 domains: (1) neuropsychologi - AD and PD dementia (PDD) [20]. While its measurement cal; (2) neuropsychiatric; (3) motor; (4) fluctuations; properties have not been established for DLB, the ADCS- (5) autonomic; (6) sleep; and (7) activities of daily liv- ADL is a valid and reliable measurement, sensitive to ing and quality of life. In addition, we included other clinical progression in AD [20, 21]. Although a change of instruments that the authors found promising or wor- 2 points has been suggested to be clinically meaningful thy of discussion, even not yet used in DLB clinical in AD, this has not been evaluated formally [20, 21]. In trials. PDD, the ADCS-ADL has demonstrated responsiveness A separate search was conducted to evaluate the in detecting treatment effects, which makes it a promis - measurement properties of the clinical outcome meas- ing scale for DLB trials [22]. The Disability Assessment ures. For all outcome measures, we used PubMed for Dementia (DAD) scale is a subscale of the Clinician’s to perform an additional search of empirical studies Interview-Based Impression of Change scale [23]. While assessing their validity and reliability, using the search the DAD shows validity and reliability in AD trials, its terms: “clinimetric”; “clinical significance”; “clinically sensitivity to AD clinical progression or responsiveness meaningful change”; “validity”; “validation”; “respon- to treatment has not been consistent [24–26]. Part II of siveness”; “reliability”; and “sensitivity to change”. The the Movement Disorders Society Unified Parkinson’s quality of the studies was evaluated using the COS- Disease Rating Scale (MDS-UPDRS) assesses activities MIN checklist for assessing the methodological quality of daily living but is not specific to dementia and is not of studies on measurement properties of health status responsive to detecting treatment effects in PD, limiting measurement instruments and the guideline to select its validity [22, 27]. The Schwab and England ADL scale outcome measurement instruments for outcomes [16, is widely used in PD, but the extent to which it is valid 19]. Based on these guidelines, if the outcome measures in dementia trials has also not been evaluated [28]. Tech- passed the acceptable cutoffs in one or more high-qual - nology-based objective measures (TOMs) offer an alter - ity studies, they were determined as “good/adequate”. If native to questionnaires [29]. Options range from motion there was conflicting evidence, or if there was evidence sensors to smart home technology, which consists of a showing the outcome measures did not pass acceptable combination of sensors and connected devices that mon- cutoffs, they were considered “questionable/medio - itor (and control if needed) the use of appliances at home cre”. If an MCID was published for neurodegenerative dementia, this information was included. Although no MCID values have been published for DLB, we included those published for other conditions, such as AD and PD, considering them to be a helpful guide. R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 5 of 18 [30]. These systems can monitor several iADLs at home, has been used in AD and PD trials as well as in observa- such as the ability to perform online banking or the time tional studies in DLB [37–39]. spent watching television or sleeping [31]. While these Global impression scales can be useful in captur- technologies are already available in the community, the ing treatment effects that may go unmeasured by other translation of the data collected to meaningful trial out- scales. The Clinician’s Interview-Based Impression of comes remains to be determined, particularly in DLB. Change scale plus combines clinician and caregiver input. Other important clinical aspects include quality of life Measures of clinically meaningful change are intrinsic measures and caregiver burden scales. Considering that to the scale, which have been shown to be responsive to the goal of disease treatment is the improvement in a treatment effects in AD and PDD [22, 23]. The Clinical patient’s quality of life, these measures should be incor- Global Impression Scale (CGI) consists of scales evalu- porated within clinical trials as secondary outcomes. ating three aspects: severity, improvement, and efficacy. Quality of life measures have only rarely been used in Similar to the Clinician’s Interview-Based Impression of DLB trials with the Quality of Life in Alzheimer’s Disease Change Scale (CIBIC+) , the scale measures meaningful Scale (QOL-AD) being used once to date [32]. In AD and clinical change per se and has demonstrated responsive- PDD, the QOL-AD shows good validity and responsive- ness to treatment effects in AD trials [22]. In addition, ness to treatment effects, but this has not been validated the CGI has been used in PDD and DLB trials, includ- in DLB [22]. Alternatives include the 39-item Parkinson’s ing one trial that showed benefit from memantine [40]. Disease Questionnaire (PDQ-39), which has good valid- Both the CIBIC and the CGI exhibit a good correlation ity and reliability for PD and for which the MCIDs for with the Clinical Dementia Rating-Sum of Boxes in AD the different domains included in the scale (e.g., mobility, [41]. The Alzheimer’s Disease Cooperative Study–Clini - ADLs) have been determined [33]. The PDQ-39 has been cian’s Global Impression of Change (ADCS-CGIC) is one used in one PDD trial, but it may be insensitive to clini- of the most commonly used scales in dementia trials [42]. cal progression [22, 34]. The impact on caregiver burden While responsiveness to treatment effects has been noted might also provide meaningful information regarding the in PDD and DLB trials, the lack of correlation with the impact of an intervention. The Zarit Burden Interview Functional Assessment Staging Scale warrants the use of (ZBI) was developed to measure caregiver burden related the ADCS-CGIC as a complement to other ADL scales to behavioral and functional impairment in dementia (Table 4) [22, 23, 43]. patients [35]. Although it has been shown to be respon- Currently, we suggest that a combination of an activi- sive to intervention, the ZBI has demonstrated mixed ties of daily living scale and a clinical impression of results in attempts to correlate its findings with other change would be necessary to determine the clinical clinical measures, such as cognition and sleep [22, 36]. effectiveness of an intervention in DLB. Furthermore, The Relative Stress Scale is an alternative to the ZBI and we propose adding an assessment of quality of life and Table 4 Selected functional, quality of life, caregiver burden and global impression outcomes Outcome Type of measure Rater Reliability Responsiveness MCID Used in DLB trials ADCS‑ADL ADLs Informant + + 2 points Yes [44–46] DAD ADLs Informant + + NE Yes [40, 47] UPDRS‑II ADLs Informant NE NE NE Yes [48, 49] Subject SEADL ADLS Informant NE NE NE No QOL‑AD QoL Subject + + NE Yes [32] PDQ‑39 QoL Subject +/− NE NE No ZBI CB Informant +/− + 13 points Yes [43, 45, 47, 50–53] RSS CB Informant + NE NE No CIBIC+ IoC Clinician/Informant +/− + NE Yes [43, 54–58] CGI IoC Clinician +/− + NE Yes [54, 59, 60] ADCS‑ CGIC IoC Clinician +/− + 1 point Yes [44, 45, 61, 62] +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre. ADLs activities of daily living, CB caregiver burden, IoC impression of change, MCID minimal clinically important difference, NE not evaluated, QoL quality of life, ADCS-ADL Alzheimer’s Disease Cooperative Study—Activities of Daily Living Scale, DAD Disability Assessment for Dementia, UPDRS-II Unified Parkinson’s Disease Rating Scale Part II, SEADL Schwab and England Activities of Daily Living, QOL-AD Quality of Life in Alzheimer’s Disaese Scale, PDQ-39 39‑Item Parkinson’s Disease Questionnaire, ZBI Zarit Burden Interview, RSS Relative Stress Scale, CIBIC+ Clinician’s Interview ‑ Based Impression of Change Scale, CGI Clinical Global Impression Scale, ADCS-CGI Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 6 of 18 caregiver burden as secondary aims to provide meaning- has modest sensitivity to cognitive deficits in patients ful additional information on the impact of any therapy with autopsy-confirmed DLB [70]. In addition, its floor being evaluated. Future consideration could be given effects in patients with severe dementia, its ceiling to collecting objective digital outcomes from wearable effects in patients with mild cognitive impairment, and devices [29]. We recommend that the development of its lack of responsiveness to small changes noted early specific DLB functional and global assessment instru - in PDD, limit its use as a cognitive endpoint for clini- ments also consider the importance of differentiating the cal trials in DLB [71–73]. However, it has been useful in degree to which cognitive, behavioral (including sleep), showing the benefit of donepezil in DLB and was identi - autonomic, and motor symptoms all contribute to the fied as a potential marker for change over just a 6-month functional impairment experienced by DLB patients. interval in a recent natural history study, suggesting possible utility in future DMTs [43, 74]. The Montreal Cognitive outcomes Cognitive Assessment (MoCA) is a reliable assess- Cognitive impairment is an essential criterion for the ment that includes items that assess attention (e.g., trail diagnosis of DLB and the primary target outcome for making test part B) and executive functions like work- most clinical trials conducted to date. The neuropsy - ing memory (e.g., digit span backward), making it a chological profile in DLB is typically characterized by more valid instrument for DLB trials and accepted as a impairments in attention, executive functioning, and measure of change in regulatory trials. Previous stud- visuospatial abilities in addition to memory [13]. How- ies have shown that MoCA is certainly more sensitive ever, heterogeneity in cognitive test performances is than the MMSE for the detection of cognitive impair- common, and impairment in language can also be pre- ment in DLB, particularly early-on in the disease [72, sent, particularly at later clinical stages of the disease [63, 75, 76]. However, its ability to detect subtle cognitive 64]. While the deficits in different cognitive domains are changes remains to be determined. The Alzheimer’s attributed to the pathological processes and distribu- Disease Assessment Scale-Cognitive (ADAS-Cog) has tion of neuropathology in DLB, other pathologies (e.g., also been utilized in several clinical trials of DLB [68, cerebrovascular disease) and pathophysiologic mecha- 77]. The addition of tests of executive functioning and nisms (e.g., cognitive fluctuations), may impact cogni - attention to the ADAS-Cog can increase the ability to tive performance differently. This may affect the potential detect cognitive decline in non-AD dementias, although response to treatment, in both symptomatic and disease- this measure may be insensitive in the earliest stages modifying therapy trials [65, 66]. [78, 79]. The ADAS-Cog has been shown to be respon - The inclusion of a global cognitive measure is rec - sive to change in PDD and AD and one group analysis ommended for all DLB clinical trials. The Mini-Mental has defined the MCID as 4 points in AD [80]. The Mat - State Examination (MMSE) has been utilized as a global tis Dementia Rating Scale (MDRS) has also been used in measure in numerous DLB studies [67, 68]. Although it multiple trials and has been validated for PDD but not has proven to be reliable, the validity of the MMSE in DLB. The MDRS seems to be superior in the assessment DLB has been questioned, mainly due to its limited test- of cognition when compared to the MMSE and has also ing of executive function [69]. Furthermore, the MMSE Table 5 Selected general cognition outcomes Outcome Detection Discrimination Reliability Responsiveness MCID Used in DLB trials MMSE +* +* + +/− NE Yes [40, 43, 44, 47, 52, 54–58, 60–62, 82–101] MoCA +* +* + +/− NE Yes [46] ADAS‑ CoG NE NE + + 4 points Yes [44–46, 48, 58, 62] MDRS + NE + + NE Yes [32, 59, 83] RBANS + NE + + NE No COGDRAS NE NE + + NE Yes [40, 44, 55, 57, 88] MCID minimal clinically important difference, NE Not evaluated, MMSE Mini Mental State Examination, MoCA Montreal Cognitive Assessment, ADAS-CoG Alzheimer’s Disease Assessment Scale‑ Cognitive, MDRS Mattis Dementia Rating Scale, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, COGDRAS Cognitive Drug Research Computerized Assessment System +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre *Evaluated in DLB population R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 7 of 18 shown good responsiveness in trials assessing PDD [22, but may fail to identify the degree of impairment within 81] (Table 5). a single cognitive domain [118, 119]. The selection of any In addition to measures of global cognitive perfor- specific cognitive outcome measure may also depend on mance, the use of more specific neuropsychological the therapeutic target. Symptomatic therapies addressing tests in clinical trials has several strengths, including specific domains, such as attention or executive function, established normative data for standardization of per- should consider specific testing, as an outcome, in addi - formances, and availability of published literature regard- tion to a general cognitive measure. Furthermore, cogni- ing psychometric properties such as reliability, construct tive outcomes in DMTs will depend on the stage of the validity, and practice effects in dementia (although not in condition being evaluated. Whilst measures of attention, DLB). Neuropsychological tests are also more sensitive executive and visuospatial function seem to be regarded to cognitive impairment than measures of global cogni- as being better predictors for the transition from MCI- tion and can more effectively assess individual domains LB to dementia in DLB, measurements of language and [102] (Additional file  1: Table  S1). However, neuropsy- memory function appear to be more sensitive to decline chological batteries may be too lengthy or cumbersome across dementia stages, although further validation is to routinely administer. Brief batteries utilizing the same needed [11, 120, 121]. normative data source, such as the Repeatable Battery for the Assessment of Neuropsychological Status, have not Cognitive fluctuations been utilized in previous DLB clinical studies but may be Fluctuating cognition is a characteristic feature of DLB a consideration for future trials. and forms part of the core diagnostic criteria [13]. Cogni- Computerized cognitive assessments could also have tive fluctuations present as cognitive changes secondary several strengths, including standardized administra- to impairments in attention or somnolence due to varia- tion and automated scoring. These can include a stand- tions in alertness [122]. The assessment of cognitive fluc - alone computerized test within a larger battery or a tuations in clinical trials may serve one of two purposes: fully automated battery. Many computerized assess- (i) as a primary symptom or disease treatment target ment measures can be administered remotely with or (ii) assessing a potential confounder in the perfor- generally similar results as in-clinic evaluations and mance of other domains, such as cognition. The choice can provide increased sensitivity to change compared of assessment will vary depending on the goal of the to pen-and-paper tests, reducing the required sample measurement. sizes, which would be helpful in reducing the difficulty The Clinician Assessment of Fluctuation (CAF) 4-item to recruit populations like DLB [103]. Computerized scale is a short tool that needs to be administered by an tests assessing reaction time and vigilance may be more experienced clinician. While the CAF has been corre- sensitive in detection of cognitive fluctuations than tra - lated with neuropsychological and electrophysiological ditional paper-and-pencil measures and may be bet- measures, it assumes that severity is dependent on fre- ter suited to capture cognitive fluctuations over short quency and duration, which can affect its validity and use timescales, although they may not capture longer more in clinical trials [123]. The CAF has shown nearly per - profound fluctuations that occur over hours or days. fect interrater reliability in severe cognitive fluctuations, In addition, computerized testing may allow dynamic while the reliability to establish the presence/absence adaptation of the degree of difficulty of the testing, of fluctuations is only fair [124]. The Mayo Fluctuations which would reduce floor and ceiling effects. Several Scale (19-item questionnaire) is a comprehensive ques- computerized batteries are sensitive enough to detect tionnaire that evaluates cognitive fluctuations during the a cognitive change in clinical trials for other neurode- previous month [125]. It allows a shorter version called generative diseases, and the Cognitive Drug Research Mayo Fluctuations Composite Score (4-item scale), Computerized Assessment System has been used in which is useful for the detection of cognitive fluctuations multiple DLB trials [44, 55, 57, 104–110]. Whilst such but does not determine their severity [125]. The One Day computerized cognitive assessments appear promising, Fluctuations Assessment Scale (7-item scale) correlates there is a clear need for their further development and with neuropsychological and electrophysiological meas- validation in DLB [104, 111, 112]. ures of cognitive fluctuations [123]. However, the evalu - We recommend that, at a minimum, DLB clinical trials ation is limited to the last 24-h and it includes features should include a measure of global cognition, acknowl- that are not specific to DLB, reducing its sensitivity [122, edging that whilst quick to administer, they are not always 126]. Finally, the Dementia Cognitive Fluctuation Scale sensitive in individuals with high levels of education or (17-item questionnaire) was derived from the previous those in the early stages of the disease [72, 113–117]. The scales and captures multiple aspects of cognitive fluc - use of a global composite cognitive score is promising tuations with good validity and reliability although it is Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 8 of 18 Visual hallucinations lengthy to administer, thus limiting its utility [127] (Addi- Neuropsychiatric symptoms are common in DLB and tional file 2: Table S2). recurrent visual hallucinations (VH) deserve particular In addition to the scales described above, the use of attention given  that they occur in up to 80% of patients neuropsychological tests that provide information on and form one of the core criteria for diagnosis. The pres - the variability of response times may also be considered ence and severity of VH can be assessed either through as a surrogate marker for cognitive fluctuations. Using composite scales that include at least one question focus- computerized batteries, such as the sustained attention ing on hallucinations (e.g., MDS-UPDRS, neuropsychi- response task, choice reaction time, simple reaction time, atric inventory-NPI), hallucination scales covering other or digit vigilance, the degree of variability in the response modalities (e.g., auditory), or scales specifically for VH. has been shown to correlate with performance in clini- Scoring for VH can typically be frequency-based, sever- cal cognitive fluctuation scales without being affected ity-based, or can capture both frequency and severity. by motor deficits [126, 128]. However, whilst these tools Frequency-based scoring is easier to administer but can show promise in the evaluation of response to medica- be subject to recall and perception bias. Both frequency- tions impacting cognitive fluctuations, they have yet to be and severity-based scores have been used in clinical tri- validated. Following the same principle, electroencepha- als, although severity may have greater clinical relevance. lography (EEG) has shown promise in the detection of However, deciding what severity aspect of the phenom- cognitive fluctuations, manifesting as changes in variabil - ena (e.g., intensity, emotional reaction) should be meas- ity in the dominant frequency band. Such changes have ured as an outcome has not been determined. a good correlation with the CAF and neuropsychological The Neuropsychiatric Inventory (NPI) is a structured measures of attentional variability [129, 130]. Further val- caregiver interview that was originally designed to detect, idation of EEG measures as surrogate markers for cogni- quantify and track neuropsychiatric symptom changes in tive fluctuations, including portable EEG, is warranted. people with dementia [134]. The NPI has shown good Excessive daytime sleepiness (EDS) is a separate clinical content validity, concurrent validity, inter-rater reliabil- feature, supportive of the diagnosis of DLB and its signifi - ity, and test–retest reliability in patients with dementia cant impact on daily functioning and caregiver burden, [135]. Some of the other validated and widely used ver- making it an important target for therapies [13, 131]. sions of NPI are the Nursing Home (NPI—NH)[136] and While EDS is considered to be closely related to cognitive the Brief Form (NPI-Q, validated in AD patients)[137]. fluctuations as well as cognition and sleep disturbances When it comes to DLB, it is important to emphasize that in DLB, further studies are needed to define these rela - the NPI covers hallucinations in all modalities (e.g., vis- tionships [126]. EDS is included as part of the Mayo Fluc- ual, auditory) under the same question, which may sig- tuation Scale [125]. However, specific scales, such as the nificantly affect the evaluation of visual hallucinations in Epworth Sleepiness Scale, which have been used in trials clinical trials. The hallucination questions have been used targeting EDS in DLB and PD, are available and may be in one DLB trial, while the combination of the hallucina- preferable if EDS is considered an outcome [62, 132, 133]. tion and delusion questions has been used as an outcome We propose that the choice of the assessment scale for one PD trial, showing that a combination is respon- used to evaluate cognitive fluctuations will depend on sive to treatment effects [60, 138]. However, it has not whether the goal of the study is to identify their pres- been validated for DLB, nor an MCID determined. The ence as a clinical milestone or measure their frequency/ Scale for the Assessment of Positive Symptoms for Par- severity and over what time period. Alternatively, if the kinson’s Disease Psychosis (SAPS-PD) evaluates multiple goal is to assess the presence of cognitive fluctuations as modalities of hallucinations and includes other elements a potential confounder of cognitive performance, then of psychosis, such as delusions. However, SAPS-PD was scales sensitive to the detection of fluctuations could be not developed as a tool for measuring change, which utilized along with computerized testing. Further evalua- affects its reliability, although it has been used this way tion of the measurement properties of all of the available in treatment trials for PD psychosis [139, 140]. Another scales measuring fluctuations is warranted. In addition, scale that includes multiple neuropsychiatric symptoms more consideration should be given to validating objec- is the Behavioral Pathology in Alzheimer’s Disease Rat- tive vigilance tasks (e.g., Choice Reaction Time, Sustained ing Scale (BEHAVE-AD), which covers multiple aspects Attention to Response Task, etc.) that could also be used of neuropsychiatric symptoms but is particularly focused at the beginning and end of cognitive assessments to cap- on AD [141]. This original version of this scale focused ture any significant variability in performance. Finally, on AD, including five questions covering the different the assessment of EDS could be used to complement the evaluation of cognitive fluctuations or be considered as an individual endpoint, depending on the goal of the trial. R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 9 of 18 modalities of hallucinations with only one question on tremor, and rigidity. The severity of these features varies the severity rather than frequency of VH. However, a among DLB patients and may be absent in up to 15% of newer version of the scale including the frequency of VH cases [13]. While dopamine depletion may be the under- has subsequently been developed [142]. The VH question lying cause for parkinsonism in DLB, each one of the from the BEHAVE-AD has been used in one DLB trial to cardinal symptoms can develop through different mecha - evaluate the benefit of rivastigmine in VH, which dem - nisms. This is important because a benefit in one symp - onstrated its sensitivity to treatment effects [94]. Both tom may lead to the worsening of another one, such as the UPDRS and MDS-UPDRS include a single question cholinergic effects potentially improving gait but worsen - on VH, which is combined with other features of psy- ing tremor [143, 155]. chosis such as delusions. This approach has been used Motor scales used for DLB are based on scales devel- in one DLB trial showing that increases in levodopa may oped for PD, which might be problematic since the help motor symptoms at the cost of worsening psychotic motor syndrome in DLB differs from that in PD [13]. The symptoms [143]. motor sections of the UPDRS and the MDS-UPDRS, also Regarding multimodal hallucination scales, the Uni- known as Part III, offer the possibility of evaluating the versity of Miami Parkinson’s disease Hallucinations main features of parkinsonism. The UPDRS is responsive Questionnaire is easy to administer and a useful tool for to therapeutic interventions and is the reference scale capturing both the severity and frequency of VH [144]. for regulatory agencies [156, 157]. Moreover, it has been Although its responsiveness to change has not yet been used as a primary outcome in DLB trials targeting motor fully validated, it is in use in a current treatment trial function [99, 158]. The MDS-UPDRS is a newer version for VH in PDD and DLB [145]. The Psychosis and Hal - that differs from the UPDRS especially in the evaluation lucinations Questionnaire offers a patient and informant of non-motor aspects of PD [27]. In addition, the MDS- self-report approach but to date has only been validated UPDRS adds further motor aspects, including freezing of in non-demented PD [146, 147]. The North-East Visual gait, separating postural and kinetic tremor, and separat- Hallucination Interview (NEVHI) was designed to spe- ing the amplitude and constancy of rest tremor. In addi- cifically assess visual-domain hallucinations and utilizes tion, the MDS-UPDRS score can be converted to the a semi-structured interview focusing on different aspects former UPDRS assessments [159]. The main drawback that affect the severity of VH. Further, this scale has both is that by measuring the composite score as a whole, an informant and patient versions which might allow for improvement in one domain can be masked by deficits in enhanced accuracy in terms of frequency. The NEVHI another. This is particularly important when it comes to has shown to be a valid and reliable scale with a strong using these scales, where tremor amplitude constitutes a correlation with the MDS-UPDRS hallucination item significant portion of the total score compared to other score, making it a promising scale for trials focusing on motor domains such as postural reflexes, which can be VH [148, 149] (Additional file 3: Table S3). more relevant for daily functioning [160]. Another draw- Potential alternatives to interviews and questionnaires back of both the UPDRS and the MDS-UPDRS is the are tasks eliciting visual misperceptions, such as the time needed to administer the scale and the experience Pareidolia Test and the Bistable Percept Paradigm, which of the rater, limiting its use in multi-site trials (Addi- have been suggested as surrogate markers for VH [150– tional file  4: Table S4). Among the motor changes in DLB, 153]. However, their sensitivity and specificity appear impairment in balance and falls are the most relevant. to be low within the early stages of the disease, and it is Falling in DLB is associated with substantial morbidity unclear whether these measures are suited for measuring and mortality [161]. While both versions of the UPDRS change in a meaningful way over time [154]. include an evaluation of gait and balance, they do not We recommend that the choice of the VH scale will include a measurement of the number of falls. depend on the goal of the trial. Hallucination-specific Many TOMs are also being developed and may rep- scales may be preferred in trials focusing on symptomatic resent an option to complement the motor assessment treatment of VH or DMTs where the progression of the [162]. TOMs may allow the capture of both motor disease is associated with the onset of VH. Instead, the and non-motor phenomena with greater accuracy and use of broader neuropsychiatric scales and question- reduced intra- and inter-rater variability than clinical naires that can capture other common features such as scales for a continuous period of time with good tem- depression, anxiety, and apathy should be considered. poral resolution [162]. However, little is known about whether this information represents a meaningful meas- Motor outcomes ure of the patients’ activities of daily living or func- Motor changes in DLB mostly fall under the umbrella tional activity [163]. Within the TOMs exist tools that of the parkinsonian syndrome, which includes slowness, allow kinematic analysis, such as gait mats and infrared Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 10 of 18 cameras, along with wearable sensors, such as gyroscopes with a simple yes/no response, has also shown appro- or accelerometers. These technologies hold the promise priate sensitivity and specificity [173]. Among the ques - of improving sensitivity, accuracy, reproducibility, and tionnaires described above, only the MSQ is based on feasibility of objectively capturing changes in motor func- responses from an informant, while the others are based tion, especially when assessed at home in unsupervised on responses from the patient; considering that cognitive conditions [164, 165]. However, their implementation in impairment is present in those with DLB, an informant- clinical trials of parkinsonism remains at an early stage. based questionnaire is potentially more valid. The REM The main limitations of TOMs are their lack of validation sleep behavior disorder symptom severity scale, which outside the clinic and the requirement for specific pieces measures the frequency and severity of RBD features of equipment, which may not be widely available. In DLB, over a defined period of time, as reported by the patient the presence of cognitive impairment and fluctuations and the informant, is currently undergoing reliability and may also limit the compliance of TOMS, and patient/car- validation analyses (unpublished data). egiver technology surveys are still lacking. Objectively, RBD can be quantified by vPSG using the For evaluation of motor features of DLB, we suggest RBD Severity Scale to quantify the occurrence and sever- using the validated UPDRS scales to measure parkinson- ity of RBD [174]. Multiple methods have already been ism and incorporating a survey for falls. Further consid- developed for the quantification of REM sleep without eration would need to be given to the medication state of atonia (RSWA) but current data are insufficient to sup - the patient and whether standardizing assessments in the port RSWA as a dynamic marker in DLB [174]. Due to ‘off’ dopaminergic medication state would be required. the variability in RBD symptom severity from night to The use of TOMs will require their further validation. night, two or more nights of vPSG have been recom- mended to improve any effect size. However, such an Rapid eye movement sleep behavior disorder approach would pose a major challenge to the feasibil- Rapid eye movement (REM) sleep behavior disorder ity of any future trials focused on this symptom [175]. (RBD) is highly prevalent and is the final core clinical It must also be appreciated that laboratory-based vPSG feature in the diagnosis of DLB [13]. In addition, given represents a potentially biased snapshot with patients that isolated RBD is the most reliable clinical marker sleeping in unfamiliar surroundings [174] (Additional of prodromal synucleinopathies, its detection and the file  5: Table  S5). Furthermore, there is no evidence to assessment of its severity are of particular importance for suggest that vPSG is superior to any clinical scales such DMTs [166]. Assessment of RBD can be done through as sleep diaries. Considering that there can be night-to- scales or objectively through video polysomnography night variability in RBD frequency and severity, the use (vPSG). of vPSG over a few nights before beginning a therapy and Scales provide an obvious advantage when it comes to again weeks or months later is debatable. the time needed from the research patient and the cost of Although home-based PSG devices are emerging as trials. However, the reliance on patients’ and bedpartners’ a promising alternative, some cannot currently ascer- recall regarding symptoms that occur during sleep makes tain whether the patient is in REM sleep. Furthermore, scales less desirable as outcome measures rather than for others do not assess EMG tone of skeletal muscles, and their use as screening tools [167]. The REM Sleep Behav - therefore their sensitivity to treatment has not yet been ior Disorder Screening Questionnaire is commonly used demonstrated [174, 176]. However, recent data suggest as a screening test but it does not provide much informa- that some devices warrant further study for detecting tion on the severity of symptoms nor has its sensitivity and monitoring RBD [177]. In addition, activity sensors, to change been studied [168]. The REM Sleep Behavior such as actigraphy, have been proposed as an objective Disorder Questionnaire Hong Kong is used to evaluate outcome for trials of RBD, along with automated video the presence of RBD and also quantifies the frequency analysis of the leg movements during REM sleep [176]. and severity of dream enactment [169]. This scale has Home-based actigraphy to characterize sleep distur- shown good validity and reliability. In addition, its sen- bances that cannot be captured by conventional clinical sitivity to change after treatment was previously dem- scales may be more ecologically valid than PSG [162]. onstrated across multiple studies [170, 171]. However, Complementing home-based measurement with sleep the English version of this tool is not yet validated. The diaries may be a more pragmatic approach for clinical tri- Mayo Sleep Questionnaire (MSQ) has been evaluated als of DLB in the near future [176, 178]. in patients with cognitive impairment where it has been We recommend that the choice of RBD assessment will shown to be adequate for the detection of RBD [172]. In likely need to focus on the presence and severity of RBD addition, the REM Sleep Behavior Disorder Single-Ques- behaviors and the impact of RBD on everyday life. While tion Screen, a screening question for dream enactment objective measures are preferable, their applicability may R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 11 of 18 hinder the feasibility of the study, and scales assessing the that all domains are evaluated in clinical trials with a spe- impact of RBD should complement these objective meas- cific emphasis depending on the intended target of the ures. The validation of portable technologies, such as intervention (i.e., symptomatic or DMT). actigraphy, will open the door to much needed accessible, The choice of the primary outcome depends on the robust, and objective outcome measures. goal of the therapeutic intervention being evaluated and the stage and severity of the population studied. Composite outcomes Symptomatic-treatment trials may choose to focus on a Increasingly, composite scales, particularly those that functional or global impression of change as a primary integrate both functional and cognitive dimensions, outcome with a secondary domain-specific outcome. have been used as primary endpoints in AD trials. This In the case of DMTs, the choice of the outcome var- approach has been favored in the preclinical, prodro- ies depending on the severity of the population studied. mal, and mild AD trials to replace the use of the previ- Trials focusing on prodromal or preclinical groups may ously required co-primary outcomes (i.e., one cognitive choose the emergence of a clinical feature of DLB (e.g., and one functional outcome) [179, 180]. Co-primary dementia or VH) or overall function or cognition as a pri- outcomes were considered to be too strict for use in pre- mary outcome. Further understanding of the progression dementia trials where few longitudinal changes occur of the different domains affected by DLB at each clini - over the course of the trials. However, concerns about cal stage of disease will be crucial to defining appropri - their ability to capture change and their validity have ate outcome measures [187, 188]. A different approach been raised [179]. The Clinical Dementia Rating Scale will likely be needed in trials focusing on diagnosed DLB Sum of Boxes (CDR-SOB) has been validated for use in patients, where the severity of core clinical features may both AD and PD and has been used as a primary out- be a more suitable outcome. In any case, those that are come in trials of potential DMTs [181]. In PDD, the CDR- not considered primary or secondary outcomes may be SOB showed a good correlation with activities of daily evaluated with measures used to detect their presence for living and cognitive performance [182]. Furthermore, it diagnostic classification. has been proposed that the Integrated AD Rating Scale, Currently, there is a lack of DLB-specific validated comprising the ADAS-Cog and a scale of activities of outcome measures. A bespoke clinical global outcome daily living (ADCS-iADL), may provide a better signal- scale that not only reflects a composite of cognitive and to-noise ratio than the CDR-SOB [183, 184]. The Cogni - functional impairment but also includes the contribu- tive-Functional Composite (CFC) has also emerged as a tion of other DLB symptoms, would represent the ideal useful scale due to its feasibility, validity, and reliability, primary endpoint for DLB trials, particularly those as well as clinical relevance in AD and has been used in evaluating DMTs. The development of a DLB-specific clinical trials [185, 186]. However, the CFC has only been outcome measure will need to be tailored to the type of used in a small number of patients with DLB, limiting trial in which it will be used (i.e., symptomatic vs dis- the conclusions on its applicability in DLB clinical trials ease-modifying therapies) and the stage of the disease [186]. We are not aware of composite scores including being investigated (e.g., prodromal, early, advanced). RBD, autonomic function, motor deficits, and cognition The process of scale development is a rigorous process yet developed in DLB (Table 6). that requires multiple steps, and the development of a novel outcome measure may be more time- and labor- Conclusions intensive than the validation of an existing one. Exist- The selection of robust and valid outcome measures is ing outcome measures developed for conditions such important when designing any clinical trial. However, the as AD or PD may be useful for DLB. However, they wide variety of symptoms and multiple clinical domains require validation in the DLB population and deter- poses challenges for clinical trials in DLB. We suggest mination of their measurement properties, including Table 6 Selected composite outcomes Outcome Domains Reliability Responsiveness MCID Used in DLB trials CDR‑SOB Cog, ADL +/− + NE Yes [60, 82] ADS‑iADL Cog, ADL + + NE No CFC Cog, ADL + NE NE No ADL Activities of daily living measure, Cog cognitive measure, MCID minimal clinically important difference, NE not evaluated, CDR-SOB Clinical Dementia Rating Scale Sum of Boxes, ADS-iADl Alzheimer’s Disease Assessment Scale Activities of Daily Living, CFC Cognitive Functional Composite +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 12 of 18 responsiveness. Moreover, increasing attention has and caregivers. In addition, feedback from regulatory been paid to the involvement of patients and caregiv- agencies early in the development process is advised. ers in clinical trial design, which also applies to clinical Finally, determining the MCID for these measures outcome measures [189]. A limitation of our review is and for TOMs will guide the design of the trials and the absence of patient and caregiver input. Future out- their interpretation (Table  7). This will lead to better- come measure initiatives need to include DLB patient powered clinical trials and, ultimately, to more rapid advocate groups in the development phase to gain per- progress towards therapeutic interventions providing spectives on important clinical outcomes for patients meaningful clinical improvement in patients with DLB. Table 7 Selected potentially useful technology‑based objective measures Technology Potential applications as outcome measures Tablets and smartphones Cognitive testing Cognitive fluctuations Sustained attention Response task Frequent completion of questionnaires in different domains Motor function (plotting speed and accuracy) Tracking devices Functional Activity Cognitive Wandering Motor Activity Falls Wearable sensors (e.g., gyroscope, accelerometers, heart rate monitors, etc.) Functional Activity Motor Parkinsonism Gait Falls RBD/sleep/EDS Autonomic Heart rate variability Blood pressure Kinematic analysis (e.g., gait mats, cameras, etc.) Functional Home sensor monitoring of activities Motor Gait Falls RBD Home sensor monitoring Functional Monitor use of appliances Portable EEG Cognitive fluctuation Sleep RBD Virtual reality Functional ADL simulator Use of appliances Driving simulator Financial simulator RBD REM Sleep Behavior Disorder, ADL Activities of Daily Living, EDS Excessive Daytime Sleepiness, EEG Electroencephalogram R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 13 of 18 Abbreviations Competing interests AD: Alzheimer’s disease; ADAS‑ Cog: Alzheimer’s Disease Assessment Scale‑ The authors declare that they have no competing interests. Cognitive; ADCS‑ADL: Alzheimer’s Disease Cooperative Study‑Activities of Daily Living Scale; ADCS‑ CGIC: Alzheimer’s Disease Cooperative Study–Clini‑ Author details cian’s Global Impression of Change; BEHAVE‑AD: Behavioral Pathology in Department of Neurology, Medical University of South Carolina, 208b Alzheimer’s Disease Rating Scale; CAF: Clinician Assessment of Fluctuation; Rutledge Av., Charleston, SC 29403, USA. Department of Neurology, Center CDR‑SOB: Clinical Dementia Rating‑Sum of Boxes; CFC: Cognitive ‑Functional for Memory and Aging, HealthPartners, Saint Paul, MN, USA. Autonomous Composite; CGI: Clinical Global Impression Scale; DAD: Disability Assessment University of Barcelona, Barcelona, Spain. Fixel Institute for Neurologi‑ for Dementia; DLB: Dementia with Lewy bodies; DMT: Disease‑modifying cal Diseases, University of Florida, Gainesville, FL, USA. Division of Clinical therapy; EDS: Excessive daytime sleepiness; EEG: Electroencephalography; Geriatrics, Department of Neurobiology, Care Sciences, and Society, Center MCI: Mild cognitive impairment; MCID: Minimal clinically important difference; for Alzheimer’s Research, Karolinska Institutet, Stockholm, Sweden. Depar t‑ MDRS: Mattis Dementia Rating Scale; MDS‑UPDRS: Movement Disorders Soci‑ ment of Radiology, Mayo Clinic, Rochester, MN, USA. AR TORG Center ety Unified Parkinson’s Disease Rating Scale; MMSE: Mini‑Mental State Exami‑ for Biomedical Engineering Research, University of Bern, Bern, Switzerland. 8 9 nation; MSQ: Mayo Sleep Questionnaire; NEVHI: North‑East Visual Hallucination Dementia Research Centre, University College London, London, UK. Centre Interview; NPI: Neuropsychiatric Inventory; NPI‑ Q: Neuropsychiatric Inventory‑ for Public Health, Queen’s University, Belfast, UK. Neurology Unit, Depart‑ Questionnaire; PD: Parkinson disease; PDD: Parkinson disease dementia; ment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. PDQ‑39: 39‑Item Parkinson’s Disease Questionnaire; QOL ‑AD: Quality of Life in Department of Research and Innovation, Helse Fonna, Haugesund Hospital, Alzheimer’s Disease Scale; RBD: Rapid eye movement sleep behavior disorder; Haugesund, Norway. Institute of Clinical Medicine (K1), The University of Ber‑ REM: Rapid eye movement; RSWA: REM sleep without atonia; SAPS‑PD: Scale gen, Bergen, Norway. Department of Neurology, Center for Sleep Medicine, for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis; Mayo Clinic, Rochester, MN, USA. Translational and Clinical Research Institute, TOMs: Technology‑based objective measures; UPDRS: Unified Parkinson’s Newcastle University, Newcastle upon Tyne, UK. Department of Old Age Disease Rating Scale; VH: Visual hallucinations; vPSG: Video polysomnography; Psychiatry Institute of Psychiatry Psychology and Neuroscience, King’s College ZBI: Zarit Burden Interview. London, London, UK. ForeFront Parkinson’s Disease Research Clinic, Brain and Mind Centre, School of Medical Sciences, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia. Supplementary Information The online version contains supplementary material available at https:// doi. Received: 10 November 2021 Accepted: 31 March 2022 org/ 10. 1186/ s40035‑ 022‑ 00299‑w. Additional file 1. Table S1: Cognitive and neuropsychological measures utilized in DLB clinical trials. References 1. Vann Jones SA, O’Brien JT. The prevalence and incidence of dementia Additional file 2. 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Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations

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Abstract

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of thera‑ peutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer’s or Parkinson’s disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB‑associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB‑specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease‑modifying therapy trials. Keywords: Dementia with Lewy bodies, Clinical trials, Outcomes, Measurement properties Introduction antibodies for AD and genetic therapies targeting glu- Dementia with Lewy bodies (DLB) is the second most cocerebrosidase mutations in Parkinson’s disease (PD) common type of neurodegenerative dementia after Alz- [3, 4]. Therefore, establishing robust outcome measures heimer’s disease (AD) [1]. Compared to AD, DLB is is crucial to permit the evaluation of symptomatic treat- associated with a poorer prognosis, higher healthcare ments and DMTs in DLB. To date, no specific DLB out - costs and caregiver burden, and greater impact on qual- come measures have been validated for use in clinical ity of life [2]. Currently, symptomatic therapies are lim- trials, which have typically relied on scales developed for ited in DLB and there are no disease-modifying therapies AD and PD [5] (Table  1). Previously, regulatory authori- (DMTs). However, disease-modifying approaches are ties have emphasized the need for outcome measures being strongly pursued in other neurodegenerative con- that address functional, cognitive, and global domains in ditions, for example, amyloid beta-directed monoclonal AD, but guidance is lacking in DLB [6–8]. Randomized clinical trials, the highest level of evi- dence to guide treatment, are scarce among DLB cohorts, *Correspondence: rodrigfe@musc.edu and most of the experience comes from case studies or Department of Neurology, Medical University of South Carolina, 208b open-label observations without control groups. There Rutledge Av., Charleston, SC 29403, USA Full list of author information is available at the end of the article are multiple challenges in conducting a clinical trial in © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 2 of 18 Table 1 Outcomes used in DLB clinical trials cognitive fluctuations; and, the potential effects of con - comitant medications (e.g. increased parkinsonism from Domain Assessed in Primary Most common antipsychotics or anti-depressants). clinical trials: outcome: method used n (%) n (%) (n) This paper represents the first in a series by the Clini - cal Trials Workgroup of the Lewy Body Dementias Functional 22 (52) 5 (11) ZBI (7) Professional Interest Area—Alzheimer’s Association Cognitive 39 (92) 17 (40) MMSE (33) International Society to Advance Alzheimer’s Research Visual hallucinations 35 (83) 21 (50) NPI (22) and Treatment (ISTAART). In this paper, we will focus Fluctuations 9 (21) 1 (2) Mayo FSI (4) on the tools for measuring clinical outcomes (e.g., rat- Motor 28 (66) 10 (23) UPDRS‑III (23) ing scales, cognitive batteries), whilst biomarkers, such as RBD 1(2) 1 (2) RBDSS scale (1) imaging and cerebrospinal fluid biomarkers, will be dis - RBD REM sleep behavior disorder, ZBI Zarit Burden Interview, MMSE Mini‑Mental cussed elsewhere in our series. In this article, we discuss State Examination, NPI Neuropsychiatric Inventory, Mayo FS Mayo Fluctuation Scale, UPDRS-III Unified Parkinson’s Disease Rating Scale Part III, RBDSS RBD the outcome measures previously used in DLB clinical Severity Scale trials and specifically evaluate what might be considered necessary in future work to identify novel symptomatic and disease-modifying therapies in DLB that would meet DLB, including delayed and inaccurate diagnosis, signifi - the requirements of the regulatory agencies. In addition cant clinical heterogeneity, and the use of concomitant to cognitive and functional outcomes, we will also focus medications [9]. However, one of the greatest challenges on measuring the core features of DLB, which include in conducting robust DLB clinical trials is the selec- cognitive fluctuations, visual hallucinations, parkinson - tion of appropriate outcome measures. While choice of ism, and rapid eye movement sleep behavior disorder intervention, population, and trial design are all intui- (RBD) [13]. A discussion regarding the outcome meas- tively important, without the selection of an appropriate ures to address other aspects of the disease (e.g., auto- outcome and a rigorous method to measure it, any trial nomic function or mood, fatigue, specific cognitive could be unrevealing or misleading [10]. The appropriate domains) is beyond the scope of our review but will be outcome measures will not only affect the accuracy and addressed in the future by our working group. applicability of the trial, but also have implications for initial sample size estimations [10]. Assessment of clinical outcomes: measurement properties Outcome measures typically rely on clinical assess- Clinical outcomes are classified either as the occurrence ments rather than objective measures and whilst the of an event or milestone, or changes in clinical meas- severity of the measure may be implied by its score, this ures (Table  2). Such outcome measures may be obtained has typically not been validated in DLB. Additionally, any either by direct observation and quantification or by outcome measure needs to consider the type of inter- reports from patients and/or their caregivers [10]. Meas- vention being evaluated (symptomatic or DMT), as well urements can range in scope, from global functionality to as the disease severity of the population being studied. a specific aspect of the condition. For example, whilst symptomatic therapies will likely When selecting a clinical outcome measure, there focus on measurement of the specific domain being tar - are three major considerations: i) measurement prop- geted, DMTs may focus on the time to the development erties, ii) interpretability of the results, and iii) feasi- of clinical milestones. Moreover, the progression of the bility. The measurement properties reflect the tool’s disease may affect clinical domains differentially, wherein ability to measure a specific variable in the group of changes in one feature may not be a suitable marker of interest (validity), the random error associated with overall progression [11]. There is also an unresolved the outcome measure (reliability), and its sensitivity issue around what might constitute a meaningful clini- to detect change (responsiveness) [14]. Assessments cal change or minimal clinically important difference of these domains are crucial for the validation of out- (MCID) [12]. Many outcome measures in DLB are also come measures and can help to identify the appropriate likely to be impacted by poor patient recall, and reli- conditions under which each measure is used (Table 3). ance on caregivers may introduce recall bias and failure Interpretability refers to the degree to which one can to report clinical features that may be difficult to directly assign qualitative meaning to the outcome measure’s observe (e.g., hallucinations). Finally, disease-specific fac - quantitative scores or change, including the distribu- tors can also present their own set of unique challenges tion of scores within subgroups to assess for any floor in DLB trials, such as where one symptom might impact or ceiling effects [14]. One of the most important another (e.g. bradykinesia affecting cognitive response concepts within interpretability is that of the MCID, time tests); assessment sessions that coincide with R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 3 of 18 Table 2 Types of outcome measures Outcome measure Example Advantage Disadvantage Direct/objective Falls/death Easy to measure May not capture the symptom severity or impact on daily life Performance outcome Neuropsychological evaluation Objective measure Only evaluating one point in time—not a reflection of the current status Artificial environment Clinician reported outcome Clinical scales Clinical relevance Depends on expertise of administrator Patient‑reported outcome Quality of life questionnaires Centered on the patient Impaired cognition may affect reliability of responses Observer‑reported outcome Activities of daily living questionnaires Provides a better assess‑ Subject to bias or caregiver’s cognitive ability ment of daily function Table 3 Measurement properties of outcome measures Domain Measurement property Definition Methods of assessment Reliability The extent to which an OMI is free from random error Reproducibility The proportion of the total variance in the meas‑ Kappa coefficient urement due to true differences between patients. Interclass correlation coefficient Includes Inter‑rater rand test–retest reliability Internal consistency The degree of interrelatedness among the items Cronbach’s alpha Item‑total correlations Homogeneity coefficient Measurement error The systematic and random error of a patient’s Standard error of measurement score that is not attributed to true changes in the Bland–Altman method construct to be measured Validity The extent to which an OMI the construct that it is supposed to measure Content validity The degree to which the OMI covers the important Lynn’s Content Validity Assessment from an expert parts of the construct to be measured panel Construct validity The degree to which the scores of an OMI are Structural validity: Factor analysis consistent with the expected scores, based on Hypothesis‑testing: Convergent, divergent, and the existing knowledge of the construct. Includes internal validity compared to another validated structural, hypothesis‑testing, and cross‑ cultural measure validity Cross‑ cultural: measurement invariance in different populations Criterion validity The degree to which the scores of an OMI are an Criterion‑ outcome measure agreement or correla‑ adequate reflection of the gold standard (if avail‑ tion coefficient able) Responsiveness Responsiveness The ability to detect change over time in the con‑ Eec ff t size struct to be measured Standardized response mean Responsiveness statistic defined as the smallest amount that an outcome must burden to the patient, caregiver, and administrator. This change to be meaningful to patients [12]. It is recog- is particularly relevant for dementia research, where nized that there are different methods to determine the subjects may not be able to tolerate prolonged and MCID (e.g., anchor-based and distribution-based), but intense periods of evaluation. these are beyond the scope of this paper [12]. Estab- Initiatives such as the Core Outcome Measures in lishing what might constitute an MCID is fundamen- Effectiveness Trials (COMET) and the COnsensus- tal to designing studies with sufficient statistical power based Standards for the selection of health Meas- to detect an effect [15]. Finally, feasibility assesses the urement Instruments (COSMIN) provide practical practical aspects of the outcome measure, such as the Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 4 of 18 Functional, quality of life, caregiver burden, and global guidelines on how to select the appropriate outcome impression outcomes measurement instrument [16–18]. The term functional outcome is used as the measure of how a patient can successfully perform the meaning- Methods ful tasks and roles required as part of typical everyday In this paper, we focused on clinical outcome measures life [10]. Such real-world measures are important effi - used in DLB trials. We conducted a literature review of cacy endpoints for clinical trials in DLB and are usually clinical trials in patients with DLB. Using PubMed, we required by regulatory authorities. In addition, quality searched for pharmacological or neurostimulation tri- of life and caregiver burden are also relevant and war- als in DLB patients published between January 1975 rant measurement. Finally, the measurement of multi- and March 2021. We used a combination of the follow- ple aspects of function can answer the most important ing search terms: “Dementia with Lewy bodies”; “Lewy question of a clinical trial, i.e., whether the intervention body dementia”; “Lewy body”; “clinical trial”, “therapy”; produces a meaningful improvement in the patient’s “management”; and “treatment”. A total of 2079 non- condition. Therefore, the use of a clinical impression duplicate citations were identified. One reviewer (FRP) measurement is regarded as a useful and necessary out- then screened the abstracts and full-texts according to come, particularly in symptomatic trials. the following inclusion criteria: (1) Prospective studies The Alzheimer’s Disease Cooperative Study-Activities evaluating pharmacological modulation or neuromodu- of Daily Living Scale (ADCS-ADL) is one of the most lation and (2) studies of participants with DLB alone or widely used functional scales in clinical trials. It evaluates in combination with AD, PD, or PD dementia. Retro- the ability of the patient to perform basic and instrumen- spective studies, extension studies, and meta-analysis tal activities of daily living (iADLs) and is administered were excluded. A total of 42 trials were included. The only to the caregiver. The ADCS-ADL has previously outcome measures utilized in the clinical trials were been used in several trials for other conditions, such as then classified into 7 domains: (1) neuropsychologi - AD and PD dementia (PDD) [20]. While its measurement cal; (2) neuropsychiatric; (3) motor; (4) fluctuations; properties have not been established for DLB, the ADCS- (5) autonomic; (6) sleep; and (7) activities of daily liv- ADL is a valid and reliable measurement, sensitive to ing and quality of life. In addition, we included other clinical progression in AD [20, 21]. Although a change of instruments that the authors found promising or wor- 2 points has been suggested to be clinically meaningful thy of discussion, even not yet used in DLB clinical in AD, this has not been evaluated formally [20, 21]. In trials. PDD, the ADCS-ADL has demonstrated responsiveness A separate search was conducted to evaluate the in detecting treatment effects, which makes it a promis - measurement properties of the clinical outcome meas- ing scale for DLB trials [22]. The Disability Assessment ures. For all outcome measures, we used PubMed for Dementia (DAD) scale is a subscale of the Clinician’s to perform an additional search of empirical studies Interview-Based Impression of Change scale [23]. While assessing their validity and reliability, using the search the DAD shows validity and reliability in AD trials, its terms: “clinimetric”; “clinical significance”; “clinically sensitivity to AD clinical progression or responsiveness meaningful change”; “validity”; “validation”; “respon- to treatment has not been consistent [24–26]. Part II of siveness”; “reliability”; and “sensitivity to change”. The the Movement Disorders Society Unified Parkinson’s quality of the studies was evaluated using the COS- Disease Rating Scale (MDS-UPDRS) assesses activities MIN checklist for assessing the methodological quality of daily living but is not specific to dementia and is not of studies on measurement properties of health status responsive to detecting treatment effects in PD, limiting measurement instruments and the guideline to select its validity [22, 27]. The Schwab and England ADL scale outcome measurement instruments for outcomes [16, is widely used in PD, but the extent to which it is valid 19]. Based on these guidelines, if the outcome measures in dementia trials has also not been evaluated [28]. Tech- passed the acceptable cutoffs in one or more high-qual - nology-based objective measures (TOMs) offer an alter - ity studies, they were determined as “good/adequate”. If native to questionnaires [29]. Options range from motion there was conflicting evidence, or if there was evidence sensors to smart home technology, which consists of a showing the outcome measures did not pass acceptable combination of sensors and connected devices that mon- cutoffs, they were considered “questionable/medio - itor (and control if needed) the use of appliances at home cre”. If an MCID was published for neurodegenerative dementia, this information was included. Although no MCID values have been published for DLB, we included those published for other conditions, such as AD and PD, considering them to be a helpful guide. R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 5 of 18 [30]. These systems can monitor several iADLs at home, has been used in AD and PD trials as well as in observa- such as the ability to perform online banking or the time tional studies in DLB [37–39]. spent watching television or sleeping [31]. While these Global impression scales can be useful in captur- technologies are already available in the community, the ing treatment effects that may go unmeasured by other translation of the data collected to meaningful trial out- scales. The Clinician’s Interview-Based Impression of comes remains to be determined, particularly in DLB. Change scale plus combines clinician and caregiver input. Other important clinical aspects include quality of life Measures of clinically meaningful change are intrinsic measures and caregiver burden scales. Considering that to the scale, which have been shown to be responsive to the goal of disease treatment is the improvement in a treatment effects in AD and PDD [22, 23]. The Clinical patient’s quality of life, these measures should be incor- Global Impression Scale (CGI) consists of scales evalu- porated within clinical trials as secondary outcomes. ating three aspects: severity, improvement, and efficacy. Quality of life measures have only rarely been used in Similar to the Clinician’s Interview-Based Impression of DLB trials with the Quality of Life in Alzheimer’s Disease Change Scale (CIBIC+) , the scale measures meaningful Scale (QOL-AD) being used once to date [32]. In AD and clinical change per se and has demonstrated responsive- PDD, the QOL-AD shows good validity and responsive- ness to treatment effects in AD trials [22]. In addition, ness to treatment effects, but this has not been validated the CGI has been used in PDD and DLB trials, includ- in DLB [22]. Alternatives include the 39-item Parkinson’s ing one trial that showed benefit from memantine [40]. Disease Questionnaire (PDQ-39), which has good valid- Both the CIBIC and the CGI exhibit a good correlation ity and reliability for PD and for which the MCIDs for with the Clinical Dementia Rating-Sum of Boxes in AD the different domains included in the scale (e.g., mobility, [41]. The Alzheimer’s Disease Cooperative Study–Clini - ADLs) have been determined [33]. The PDQ-39 has been cian’s Global Impression of Change (ADCS-CGIC) is one used in one PDD trial, but it may be insensitive to clini- of the most commonly used scales in dementia trials [42]. cal progression [22, 34]. The impact on caregiver burden While responsiveness to treatment effects has been noted might also provide meaningful information regarding the in PDD and DLB trials, the lack of correlation with the impact of an intervention. The Zarit Burden Interview Functional Assessment Staging Scale warrants the use of (ZBI) was developed to measure caregiver burden related the ADCS-CGIC as a complement to other ADL scales to behavioral and functional impairment in dementia (Table 4) [22, 23, 43]. patients [35]. Although it has been shown to be respon- Currently, we suggest that a combination of an activi- sive to intervention, the ZBI has demonstrated mixed ties of daily living scale and a clinical impression of results in attempts to correlate its findings with other change would be necessary to determine the clinical clinical measures, such as cognition and sleep [22, 36]. effectiveness of an intervention in DLB. Furthermore, The Relative Stress Scale is an alternative to the ZBI and we propose adding an assessment of quality of life and Table 4 Selected functional, quality of life, caregiver burden and global impression outcomes Outcome Type of measure Rater Reliability Responsiveness MCID Used in DLB trials ADCS‑ADL ADLs Informant + + 2 points Yes [44–46] DAD ADLs Informant + + NE Yes [40, 47] UPDRS‑II ADLs Informant NE NE NE Yes [48, 49] Subject SEADL ADLS Informant NE NE NE No QOL‑AD QoL Subject + + NE Yes [32] PDQ‑39 QoL Subject +/− NE NE No ZBI CB Informant +/− + 13 points Yes [43, 45, 47, 50–53] RSS CB Informant + NE NE No CIBIC+ IoC Clinician/Informant +/− + NE Yes [43, 54–58] CGI IoC Clinician +/− + NE Yes [54, 59, 60] ADCS‑ CGIC IoC Clinician +/− + 1 point Yes [44, 45, 61, 62] +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre. ADLs activities of daily living, CB caregiver burden, IoC impression of change, MCID minimal clinically important difference, NE not evaluated, QoL quality of life, ADCS-ADL Alzheimer’s Disease Cooperative Study—Activities of Daily Living Scale, DAD Disability Assessment for Dementia, UPDRS-II Unified Parkinson’s Disease Rating Scale Part II, SEADL Schwab and England Activities of Daily Living, QOL-AD Quality of Life in Alzheimer’s Disaese Scale, PDQ-39 39‑Item Parkinson’s Disease Questionnaire, ZBI Zarit Burden Interview, RSS Relative Stress Scale, CIBIC+ Clinician’s Interview ‑ Based Impression of Change Scale, CGI Clinical Global Impression Scale, ADCS-CGI Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 6 of 18 caregiver burden as secondary aims to provide meaning- has modest sensitivity to cognitive deficits in patients ful additional information on the impact of any therapy with autopsy-confirmed DLB [70]. In addition, its floor being evaluated. Future consideration could be given effects in patients with severe dementia, its ceiling to collecting objective digital outcomes from wearable effects in patients with mild cognitive impairment, and devices [29]. We recommend that the development of its lack of responsiveness to small changes noted early specific DLB functional and global assessment instru - in PDD, limit its use as a cognitive endpoint for clini- ments also consider the importance of differentiating the cal trials in DLB [71–73]. However, it has been useful in degree to which cognitive, behavioral (including sleep), showing the benefit of donepezil in DLB and was identi - autonomic, and motor symptoms all contribute to the fied as a potential marker for change over just a 6-month functional impairment experienced by DLB patients. interval in a recent natural history study, suggesting possible utility in future DMTs [43, 74]. The Montreal Cognitive outcomes Cognitive Assessment (MoCA) is a reliable assess- Cognitive impairment is an essential criterion for the ment that includes items that assess attention (e.g., trail diagnosis of DLB and the primary target outcome for making test part B) and executive functions like work- most clinical trials conducted to date. The neuropsy - ing memory (e.g., digit span backward), making it a chological profile in DLB is typically characterized by more valid instrument for DLB trials and accepted as a impairments in attention, executive functioning, and measure of change in regulatory trials. Previous stud- visuospatial abilities in addition to memory [13]. How- ies have shown that MoCA is certainly more sensitive ever, heterogeneity in cognitive test performances is than the MMSE for the detection of cognitive impair- common, and impairment in language can also be pre- ment in DLB, particularly early-on in the disease [72, sent, particularly at later clinical stages of the disease [63, 75, 76]. However, its ability to detect subtle cognitive 64]. While the deficits in different cognitive domains are changes remains to be determined. The Alzheimer’s attributed to the pathological processes and distribu- Disease Assessment Scale-Cognitive (ADAS-Cog) has tion of neuropathology in DLB, other pathologies (e.g., also been utilized in several clinical trials of DLB [68, cerebrovascular disease) and pathophysiologic mecha- 77]. The addition of tests of executive functioning and nisms (e.g., cognitive fluctuations), may impact cogni - attention to the ADAS-Cog can increase the ability to tive performance differently. This may affect the potential detect cognitive decline in non-AD dementias, although response to treatment, in both symptomatic and disease- this measure may be insensitive in the earliest stages modifying therapy trials [65, 66]. [78, 79]. The ADAS-Cog has been shown to be respon - The inclusion of a global cognitive measure is rec - sive to change in PDD and AD and one group analysis ommended for all DLB clinical trials. The Mini-Mental has defined the MCID as 4 points in AD [80]. The Mat - State Examination (MMSE) has been utilized as a global tis Dementia Rating Scale (MDRS) has also been used in measure in numerous DLB studies [67, 68]. Although it multiple trials and has been validated for PDD but not has proven to be reliable, the validity of the MMSE in DLB. The MDRS seems to be superior in the assessment DLB has been questioned, mainly due to its limited test- of cognition when compared to the MMSE and has also ing of executive function [69]. Furthermore, the MMSE Table 5 Selected general cognition outcomes Outcome Detection Discrimination Reliability Responsiveness MCID Used in DLB trials MMSE +* +* + +/− NE Yes [40, 43, 44, 47, 52, 54–58, 60–62, 82–101] MoCA +* +* + +/− NE Yes [46] ADAS‑ CoG NE NE + + 4 points Yes [44–46, 48, 58, 62] MDRS + NE + + NE Yes [32, 59, 83] RBANS + NE + + NE No COGDRAS NE NE + + NE Yes [40, 44, 55, 57, 88] MCID minimal clinically important difference, NE Not evaluated, MMSE Mini Mental State Examination, MoCA Montreal Cognitive Assessment, ADAS-CoG Alzheimer’s Disease Assessment Scale‑ Cognitive, MDRS Mattis Dementia Rating Scale, RBANS Repeatable Battery for the Assessment of Neuropsychological Status, COGDRAS Cognitive Drug Research Computerized Assessment System +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre *Evaluated in DLB population R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 7 of 18 shown good responsiveness in trials assessing PDD [22, but may fail to identify the degree of impairment within 81] (Table 5). a single cognitive domain [118, 119]. The selection of any In addition to measures of global cognitive perfor- specific cognitive outcome measure may also depend on mance, the use of more specific neuropsychological the therapeutic target. Symptomatic therapies addressing tests in clinical trials has several strengths, including specific domains, such as attention or executive function, established normative data for standardization of per- should consider specific testing, as an outcome, in addi - formances, and availability of published literature regard- tion to a general cognitive measure. Furthermore, cogni- ing psychometric properties such as reliability, construct tive outcomes in DMTs will depend on the stage of the validity, and practice effects in dementia (although not in condition being evaluated. Whilst measures of attention, DLB). Neuropsychological tests are also more sensitive executive and visuospatial function seem to be regarded to cognitive impairment than measures of global cogni- as being better predictors for the transition from MCI- tion and can more effectively assess individual domains LB to dementia in DLB, measurements of language and [102] (Additional file  1: Table  S1). However, neuropsy- memory function appear to be more sensitive to decline chological batteries may be too lengthy or cumbersome across dementia stages, although further validation is to routinely administer. Brief batteries utilizing the same needed [11, 120, 121]. normative data source, such as the Repeatable Battery for the Assessment of Neuropsychological Status, have not Cognitive fluctuations been utilized in previous DLB clinical studies but may be Fluctuating cognition is a characteristic feature of DLB a consideration for future trials. and forms part of the core diagnostic criteria [13]. Cogni- Computerized cognitive assessments could also have tive fluctuations present as cognitive changes secondary several strengths, including standardized administra- to impairments in attention or somnolence due to varia- tion and automated scoring. These can include a stand- tions in alertness [122]. The assessment of cognitive fluc - alone computerized test within a larger battery or a tuations in clinical trials may serve one of two purposes: fully automated battery. Many computerized assess- (i) as a primary symptom or disease treatment target ment measures can be administered remotely with or (ii) assessing a potential confounder in the perfor- generally similar results as in-clinic evaluations and mance of other domains, such as cognition. The choice can provide increased sensitivity to change compared of assessment will vary depending on the goal of the to pen-and-paper tests, reducing the required sample measurement. sizes, which would be helpful in reducing the difficulty The Clinician Assessment of Fluctuation (CAF) 4-item to recruit populations like DLB [103]. Computerized scale is a short tool that needs to be administered by an tests assessing reaction time and vigilance may be more experienced clinician. While the CAF has been corre- sensitive in detection of cognitive fluctuations than tra - lated with neuropsychological and electrophysiological ditional paper-and-pencil measures and may be bet- measures, it assumes that severity is dependent on fre- ter suited to capture cognitive fluctuations over short quency and duration, which can affect its validity and use timescales, although they may not capture longer more in clinical trials [123]. The CAF has shown nearly per - profound fluctuations that occur over hours or days. fect interrater reliability in severe cognitive fluctuations, In addition, computerized testing may allow dynamic while the reliability to establish the presence/absence adaptation of the degree of difficulty of the testing, of fluctuations is only fair [124]. The Mayo Fluctuations which would reduce floor and ceiling effects. Several Scale (19-item questionnaire) is a comprehensive ques- computerized batteries are sensitive enough to detect tionnaire that evaluates cognitive fluctuations during the a cognitive change in clinical trials for other neurode- previous month [125]. It allows a shorter version called generative diseases, and the Cognitive Drug Research Mayo Fluctuations Composite Score (4-item scale), Computerized Assessment System has been used in which is useful for the detection of cognitive fluctuations multiple DLB trials [44, 55, 57, 104–110]. Whilst such but does not determine their severity [125]. The One Day computerized cognitive assessments appear promising, Fluctuations Assessment Scale (7-item scale) correlates there is a clear need for their further development and with neuropsychological and electrophysiological meas- validation in DLB [104, 111, 112]. ures of cognitive fluctuations [123]. However, the evalu - We recommend that, at a minimum, DLB clinical trials ation is limited to the last 24-h and it includes features should include a measure of global cognition, acknowl- that are not specific to DLB, reducing its sensitivity [122, edging that whilst quick to administer, they are not always 126]. Finally, the Dementia Cognitive Fluctuation Scale sensitive in individuals with high levels of education or (17-item questionnaire) was derived from the previous those in the early stages of the disease [72, 113–117]. The scales and captures multiple aspects of cognitive fluc - use of a global composite cognitive score is promising tuations with good validity and reliability although it is Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 8 of 18 Visual hallucinations lengthy to administer, thus limiting its utility [127] (Addi- Neuropsychiatric symptoms are common in DLB and tional file 2: Table S2). recurrent visual hallucinations (VH) deserve particular In addition to the scales described above, the use of attention given  that they occur in up to 80% of patients neuropsychological tests that provide information on and form one of the core criteria for diagnosis. The pres - the variability of response times may also be considered ence and severity of VH can be assessed either through as a surrogate marker for cognitive fluctuations. Using composite scales that include at least one question focus- computerized batteries, such as the sustained attention ing on hallucinations (e.g., MDS-UPDRS, neuropsychi- response task, choice reaction time, simple reaction time, atric inventory-NPI), hallucination scales covering other or digit vigilance, the degree of variability in the response modalities (e.g., auditory), or scales specifically for VH. has been shown to correlate with performance in clini- Scoring for VH can typically be frequency-based, sever- cal cognitive fluctuation scales without being affected ity-based, or can capture both frequency and severity. by motor deficits [126, 128]. However, whilst these tools Frequency-based scoring is easier to administer but can show promise in the evaluation of response to medica- be subject to recall and perception bias. Both frequency- tions impacting cognitive fluctuations, they have yet to be and severity-based scores have been used in clinical tri- validated. Following the same principle, electroencepha- als, although severity may have greater clinical relevance. lography (EEG) has shown promise in the detection of However, deciding what severity aspect of the phenom- cognitive fluctuations, manifesting as changes in variabil - ena (e.g., intensity, emotional reaction) should be meas- ity in the dominant frequency band. Such changes have ured as an outcome has not been determined. a good correlation with the CAF and neuropsychological The Neuropsychiatric Inventory (NPI) is a structured measures of attentional variability [129, 130]. Further val- caregiver interview that was originally designed to detect, idation of EEG measures as surrogate markers for cogni- quantify and track neuropsychiatric symptom changes in tive fluctuations, including portable EEG, is warranted. people with dementia [134]. The NPI has shown good Excessive daytime sleepiness (EDS) is a separate clinical content validity, concurrent validity, inter-rater reliabil- feature, supportive of the diagnosis of DLB and its signifi - ity, and test–retest reliability in patients with dementia cant impact on daily functioning and caregiver burden, [135]. Some of the other validated and widely used ver- making it an important target for therapies [13, 131]. sions of NPI are the Nursing Home (NPI—NH)[136] and While EDS is considered to be closely related to cognitive the Brief Form (NPI-Q, validated in AD patients)[137]. fluctuations as well as cognition and sleep disturbances When it comes to DLB, it is important to emphasize that in DLB, further studies are needed to define these rela - the NPI covers hallucinations in all modalities (e.g., vis- tionships [126]. EDS is included as part of the Mayo Fluc- ual, auditory) under the same question, which may sig- tuation Scale [125]. However, specific scales, such as the nificantly affect the evaluation of visual hallucinations in Epworth Sleepiness Scale, which have been used in trials clinical trials. The hallucination questions have been used targeting EDS in DLB and PD, are available and may be in one DLB trial, while the combination of the hallucina- preferable if EDS is considered an outcome [62, 132, 133]. tion and delusion questions has been used as an outcome We propose that the choice of the assessment scale for one PD trial, showing that a combination is respon- used to evaluate cognitive fluctuations will depend on sive to treatment effects [60, 138]. However, it has not whether the goal of the study is to identify their pres- been validated for DLB, nor an MCID determined. The ence as a clinical milestone or measure their frequency/ Scale for the Assessment of Positive Symptoms for Par- severity and over what time period. Alternatively, if the kinson’s Disease Psychosis (SAPS-PD) evaluates multiple goal is to assess the presence of cognitive fluctuations as modalities of hallucinations and includes other elements a potential confounder of cognitive performance, then of psychosis, such as delusions. However, SAPS-PD was scales sensitive to the detection of fluctuations could be not developed as a tool for measuring change, which utilized along with computerized testing. Further evalua- affects its reliability, although it has been used this way tion of the measurement properties of all of the available in treatment trials for PD psychosis [139, 140]. Another scales measuring fluctuations is warranted. In addition, scale that includes multiple neuropsychiatric symptoms more consideration should be given to validating objec- is the Behavioral Pathology in Alzheimer’s Disease Rat- tive vigilance tasks (e.g., Choice Reaction Time, Sustained ing Scale (BEHAVE-AD), which covers multiple aspects Attention to Response Task, etc.) that could also be used of neuropsychiatric symptoms but is particularly focused at the beginning and end of cognitive assessments to cap- on AD [141]. This original version of this scale focused ture any significant variability in performance. Finally, on AD, including five questions covering the different the assessment of EDS could be used to complement the evaluation of cognitive fluctuations or be considered as an individual endpoint, depending on the goal of the trial. R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 9 of 18 modalities of hallucinations with only one question on tremor, and rigidity. The severity of these features varies the severity rather than frequency of VH. However, a among DLB patients and may be absent in up to 15% of newer version of the scale including the frequency of VH cases [13]. While dopamine depletion may be the under- has subsequently been developed [142]. The VH question lying cause for parkinsonism in DLB, each one of the from the BEHAVE-AD has been used in one DLB trial to cardinal symptoms can develop through different mecha - evaluate the benefit of rivastigmine in VH, which dem - nisms. This is important because a benefit in one symp - onstrated its sensitivity to treatment effects [94]. Both tom may lead to the worsening of another one, such as the UPDRS and MDS-UPDRS include a single question cholinergic effects potentially improving gait but worsen - on VH, which is combined with other features of psy- ing tremor [143, 155]. chosis such as delusions. This approach has been used Motor scales used for DLB are based on scales devel- in one DLB trial showing that increases in levodopa may oped for PD, which might be problematic since the help motor symptoms at the cost of worsening psychotic motor syndrome in DLB differs from that in PD [13]. The symptoms [143]. motor sections of the UPDRS and the MDS-UPDRS, also Regarding multimodal hallucination scales, the Uni- known as Part III, offer the possibility of evaluating the versity of Miami Parkinson’s disease Hallucinations main features of parkinsonism. The UPDRS is responsive Questionnaire is easy to administer and a useful tool for to therapeutic interventions and is the reference scale capturing both the severity and frequency of VH [144]. for regulatory agencies [156, 157]. Moreover, it has been Although its responsiveness to change has not yet been used as a primary outcome in DLB trials targeting motor fully validated, it is in use in a current treatment trial function [99, 158]. The MDS-UPDRS is a newer version for VH in PDD and DLB [145]. The Psychosis and Hal - that differs from the UPDRS especially in the evaluation lucinations Questionnaire offers a patient and informant of non-motor aspects of PD [27]. In addition, the MDS- self-report approach but to date has only been validated UPDRS adds further motor aspects, including freezing of in non-demented PD [146, 147]. The North-East Visual gait, separating postural and kinetic tremor, and separat- Hallucination Interview (NEVHI) was designed to spe- ing the amplitude and constancy of rest tremor. In addi- cifically assess visual-domain hallucinations and utilizes tion, the MDS-UPDRS score can be converted to the a semi-structured interview focusing on different aspects former UPDRS assessments [159]. The main drawback that affect the severity of VH. Further, this scale has both is that by measuring the composite score as a whole, an informant and patient versions which might allow for improvement in one domain can be masked by deficits in enhanced accuracy in terms of frequency. The NEVHI another. This is particularly important when it comes to has shown to be a valid and reliable scale with a strong using these scales, where tremor amplitude constitutes a correlation with the MDS-UPDRS hallucination item significant portion of the total score compared to other score, making it a promising scale for trials focusing on motor domains such as postural reflexes, which can be VH [148, 149] (Additional file 3: Table S3). more relevant for daily functioning [160]. Another draw- Potential alternatives to interviews and questionnaires back of both the UPDRS and the MDS-UPDRS is the are tasks eliciting visual misperceptions, such as the time needed to administer the scale and the experience Pareidolia Test and the Bistable Percept Paradigm, which of the rater, limiting its use in multi-site trials (Addi- have been suggested as surrogate markers for VH [150– tional file  4: Table S4). Among the motor changes in DLB, 153]. However, their sensitivity and specificity appear impairment in balance and falls are the most relevant. to be low within the early stages of the disease, and it is Falling in DLB is associated with substantial morbidity unclear whether these measures are suited for measuring and mortality [161]. While both versions of the UPDRS change in a meaningful way over time [154]. include an evaluation of gait and balance, they do not We recommend that the choice of the VH scale will include a measurement of the number of falls. depend on the goal of the trial. Hallucination-specific Many TOMs are also being developed and may rep- scales may be preferred in trials focusing on symptomatic resent an option to complement the motor assessment treatment of VH or DMTs where the progression of the [162]. TOMs may allow the capture of both motor disease is associated with the onset of VH. Instead, the and non-motor phenomena with greater accuracy and use of broader neuropsychiatric scales and question- reduced intra- and inter-rater variability than clinical naires that can capture other common features such as scales for a continuous period of time with good tem- depression, anxiety, and apathy should be considered. poral resolution [162]. However, little is known about whether this information represents a meaningful meas- Motor outcomes ure of the patients’ activities of daily living or func- Motor changes in DLB mostly fall under the umbrella tional activity [163]. Within the TOMs exist tools that of the parkinsonian syndrome, which includes slowness, allow kinematic analysis, such as gait mats and infrared Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 10 of 18 cameras, along with wearable sensors, such as gyroscopes with a simple yes/no response, has also shown appro- or accelerometers. These technologies hold the promise priate sensitivity and specificity [173]. Among the ques - of improving sensitivity, accuracy, reproducibility, and tionnaires described above, only the MSQ is based on feasibility of objectively capturing changes in motor func- responses from an informant, while the others are based tion, especially when assessed at home in unsupervised on responses from the patient; considering that cognitive conditions [164, 165]. However, their implementation in impairment is present in those with DLB, an informant- clinical trials of parkinsonism remains at an early stage. based questionnaire is potentially more valid. The REM The main limitations of TOMs are their lack of validation sleep behavior disorder symptom severity scale, which outside the clinic and the requirement for specific pieces measures the frequency and severity of RBD features of equipment, which may not be widely available. In DLB, over a defined period of time, as reported by the patient the presence of cognitive impairment and fluctuations and the informant, is currently undergoing reliability and may also limit the compliance of TOMS, and patient/car- validation analyses (unpublished data). egiver technology surveys are still lacking. Objectively, RBD can be quantified by vPSG using the For evaluation of motor features of DLB, we suggest RBD Severity Scale to quantify the occurrence and sever- using the validated UPDRS scales to measure parkinson- ity of RBD [174]. Multiple methods have already been ism and incorporating a survey for falls. Further consid- developed for the quantification of REM sleep without eration would need to be given to the medication state of atonia (RSWA) but current data are insufficient to sup - the patient and whether standardizing assessments in the port RSWA as a dynamic marker in DLB [174]. Due to ‘off’ dopaminergic medication state would be required. the variability in RBD symptom severity from night to The use of TOMs will require their further validation. night, two or more nights of vPSG have been recom- mended to improve any effect size. However, such an Rapid eye movement sleep behavior disorder approach would pose a major challenge to the feasibil- Rapid eye movement (REM) sleep behavior disorder ity of any future trials focused on this symptom [175]. (RBD) is highly prevalent and is the final core clinical It must also be appreciated that laboratory-based vPSG feature in the diagnosis of DLB [13]. In addition, given represents a potentially biased snapshot with patients that isolated RBD is the most reliable clinical marker sleeping in unfamiliar surroundings [174] (Additional of prodromal synucleinopathies, its detection and the file  5: Table  S5). Furthermore, there is no evidence to assessment of its severity are of particular importance for suggest that vPSG is superior to any clinical scales such DMTs [166]. Assessment of RBD can be done through as sleep diaries. Considering that there can be night-to- scales or objectively through video polysomnography night variability in RBD frequency and severity, the use (vPSG). of vPSG over a few nights before beginning a therapy and Scales provide an obvious advantage when it comes to again weeks or months later is debatable. the time needed from the research patient and the cost of Although home-based PSG devices are emerging as trials. However, the reliance on patients’ and bedpartners’ a promising alternative, some cannot currently ascer- recall regarding symptoms that occur during sleep makes tain whether the patient is in REM sleep. Furthermore, scales less desirable as outcome measures rather than for others do not assess EMG tone of skeletal muscles, and their use as screening tools [167]. The REM Sleep Behav - therefore their sensitivity to treatment has not yet been ior Disorder Screening Questionnaire is commonly used demonstrated [174, 176]. However, recent data suggest as a screening test but it does not provide much informa- that some devices warrant further study for detecting tion on the severity of symptoms nor has its sensitivity and monitoring RBD [177]. In addition, activity sensors, to change been studied [168]. The REM Sleep Behavior such as actigraphy, have been proposed as an objective Disorder Questionnaire Hong Kong is used to evaluate outcome for trials of RBD, along with automated video the presence of RBD and also quantifies the frequency analysis of the leg movements during REM sleep [176]. and severity of dream enactment [169]. This scale has Home-based actigraphy to characterize sleep distur- shown good validity and reliability. In addition, its sen- bances that cannot be captured by conventional clinical sitivity to change after treatment was previously dem- scales may be more ecologically valid than PSG [162]. onstrated across multiple studies [170, 171]. However, Complementing home-based measurement with sleep the English version of this tool is not yet validated. The diaries may be a more pragmatic approach for clinical tri- Mayo Sleep Questionnaire (MSQ) has been evaluated als of DLB in the near future [176, 178]. in patients with cognitive impairment where it has been We recommend that the choice of RBD assessment will shown to be adequate for the detection of RBD [172]. In likely need to focus on the presence and severity of RBD addition, the REM Sleep Behavior Disorder Single-Ques- behaviors and the impact of RBD on everyday life. While tion Screen, a screening question for dream enactment objective measures are preferable, their applicability may R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 11 of 18 hinder the feasibility of the study, and scales assessing the that all domains are evaluated in clinical trials with a spe- impact of RBD should complement these objective meas- cific emphasis depending on the intended target of the ures. The validation of portable technologies, such as intervention (i.e., symptomatic or DMT). actigraphy, will open the door to much needed accessible, The choice of the primary outcome depends on the robust, and objective outcome measures. goal of the therapeutic intervention being evaluated and the stage and severity of the population studied. Composite outcomes Symptomatic-treatment trials may choose to focus on a Increasingly, composite scales, particularly those that functional or global impression of change as a primary integrate both functional and cognitive dimensions, outcome with a secondary domain-specific outcome. have been used as primary endpoints in AD trials. This In the case of DMTs, the choice of the outcome var- approach has been favored in the preclinical, prodro- ies depending on the severity of the population studied. mal, and mild AD trials to replace the use of the previ- Trials focusing on prodromal or preclinical groups may ously required co-primary outcomes (i.e., one cognitive choose the emergence of a clinical feature of DLB (e.g., and one functional outcome) [179, 180]. Co-primary dementia or VH) or overall function or cognition as a pri- outcomes were considered to be too strict for use in pre- mary outcome. Further understanding of the progression dementia trials where few longitudinal changes occur of the different domains affected by DLB at each clini - over the course of the trials. However, concerns about cal stage of disease will be crucial to defining appropri - their ability to capture change and their validity have ate outcome measures [187, 188]. A different approach been raised [179]. The Clinical Dementia Rating Scale will likely be needed in trials focusing on diagnosed DLB Sum of Boxes (CDR-SOB) has been validated for use in patients, where the severity of core clinical features may both AD and PD and has been used as a primary out- be a more suitable outcome. In any case, those that are come in trials of potential DMTs [181]. In PDD, the CDR- not considered primary or secondary outcomes may be SOB showed a good correlation with activities of daily evaluated with measures used to detect their presence for living and cognitive performance [182]. Furthermore, it diagnostic classification. has been proposed that the Integrated AD Rating Scale, Currently, there is a lack of DLB-specific validated comprising the ADAS-Cog and a scale of activities of outcome measures. A bespoke clinical global outcome daily living (ADCS-iADL), may provide a better signal- scale that not only reflects a composite of cognitive and to-noise ratio than the CDR-SOB [183, 184]. The Cogni - functional impairment but also includes the contribu- tive-Functional Composite (CFC) has also emerged as a tion of other DLB symptoms, would represent the ideal useful scale due to its feasibility, validity, and reliability, primary endpoint for DLB trials, particularly those as well as clinical relevance in AD and has been used in evaluating DMTs. The development of a DLB-specific clinical trials [185, 186]. However, the CFC has only been outcome measure will need to be tailored to the type of used in a small number of patients with DLB, limiting trial in which it will be used (i.e., symptomatic vs dis- the conclusions on its applicability in DLB clinical trials ease-modifying therapies) and the stage of the disease [186]. We are not aware of composite scores including being investigated (e.g., prodromal, early, advanced). RBD, autonomic function, motor deficits, and cognition The process of scale development is a rigorous process yet developed in DLB (Table 6). that requires multiple steps, and the development of a novel outcome measure may be more time- and labor- Conclusions intensive than the validation of an existing one. Exist- The selection of robust and valid outcome measures is ing outcome measures developed for conditions such important when designing any clinical trial. However, the as AD or PD may be useful for DLB. However, they wide variety of symptoms and multiple clinical domains require validation in the DLB population and deter- poses challenges for clinical trials in DLB. We suggest mination of their measurement properties, including Table 6 Selected composite outcomes Outcome Domains Reliability Responsiveness MCID Used in DLB trials CDR‑SOB Cog, ADL +/− + NE Yes [60, 82] ADS‑iADL Cog, ADL + + NE No CFC Cog, ADL + NE NE No ADL Activities of daily living measure, Cog cognitive measure, MCID minimal clinically important difference, NE not evaluated, CDR-SOB Clinical Dementia Rating Scale Sum of Boxes, ADS-iADl Alzheimer’s Disease Assessment Scale Activities of Daily Living, CFC Cognitive Functional Composite +, good/adequate; +/−, acceptable; −, performance is questionable/mediocre Rodriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 12 of 18 responsiveness. Moreover, increasing attention has and caregivers. In addition, feedback from regulatory been paid to the involvement of patients and caregiv- agencies early in the development process is advised. ers in clinical trial design, which also applies to clinical Finally, determining the MCID for these measures outcome measures [189]. A limitation of our review is and for TOMs will guide the design of the trials and the absence of patient and caregiver input. Future out- their interpretation (Table  7). This will lead to better- come measure initiatives need to include DLB patient powered clinical trials and, ultimately, to more rapid advocate groups in the development phase to gain per- progress towards therapeutic interventions providing spectives on important clinical outcomes for patients meaningful clinical improvement in patients with DLB. Table 7 Selected potentially useful technology‑based objective measures Technology Potential applications as outcome measures Tablets and smartphones Cognitive testing Cognitive fluctuations Sustained attention Response task Frequent completion of questionnaires in different domains Motor function (plotting speed and accuracy) Tracking devices Functional Activity Cognitive Wandering Motor Activity Falls Wearable sensors (e.g., gyroscope, accelerometers, heart rate monitors, etc.) Functional Activity Motor Parkinsonism Gait Falls RBD/sleep/EDS Autonomic Heart rate variability Blood pressure Kinematic analysis (e.g., gait mats, cameras, etc.) Functional Home sensor monitoring of activities Motor Gait Falls RBD Home sensor monitoring Functional Monitor use of appliances Portable EEG Cognitive fluctuation Sleep RBD Virtual reality Functional ADL simulator Use of appliances Driving simulator Financial simulator RBD REM Sleep Behavior Disorder, ADL Activities of Daily Living, EDS Excessive Daytime Sleepiness, EEG Electroencephalogram R odriguez‑Porcel et al. Translational Neurodegeneration (2022) 11:24 Page 13 of 18 Abbreviations Competing interests AD: Alzheimer’s disease; ADAS‑ Cog: Alzheimer’s Disease Assessment Scale‑ The authors declare that they have no competing interests. Cognitive; ADCS‑ADL: Alzheimer’s Disease Cooperative Study‑Activities of Daily Living Scale; ADCS‑ CGIC: Alzheimer’s Disease Cooperative Study–Clini‑ Author details cian’s Global Impression of Change; BEHAVE‑AD: Behavioral Pathology in Department of Neurology, Medical University of South Carolina, 208b Alzheimer’s Disease Rating Scale; CAF: Clinician Assessment of Fluctuation; Rutledge Av., Charleston, SC 29403, USA. Department of Neurology, Center CDR‑SOB: Clinical Dementia Rating‑Sum of Boxes; CFC: Cognitive ‑Functional for Memory and Aging, HealthPartners, Saint Paul, MN, USA. Autonomous Composite; CGI: Clinical Global Impression Scale; DAD: Disability Assessment University of Barcelona, Barcelona, Spain. Fixel Institute for Neurologi‑ for Dementia; DLB: Dementia with Lewy bodies; DMT: Disease‑modifying cal Diseases, University of Florida, Gainesville, FL, USA. Division of Clinical therapy; EDS: Excessive daytime sleepiness; EEG: Electroencephalography; Geriatrics, Department of Neurobiology, Care Sciences, and Society, Center MCI: Mild cognitive impairment; MCID: Minimal clinically important difference; for Alzheimer’s Research, Karolinska Institutet, Stockholm, Sweden. Depar t‑ MDRS: Mattis Dementia Rating Scale; MDS‑UPDRS: Movement Disorders Soci‑ ment of Radiology, Mayo Clinic, Rochester, MN, USA. AR TORG Center ety Unified Parkinson’s Disease Rating Scale; MMSE: Mini‑Mental State Exami‑ for Biomedical Engineering Research, University of Bern, Bern, Switzerland. 8 9 nation; MSQ: Mayo Sleep Questionnaire; NEVHI: North‑East Visual Hallucination Dementia Research Centre, University College London, London, UK. Centre Interview; NPI: Neuropsychiatric Inventory; NPI‑ Q: Neuropsychiatric Inventory‑ for Public Health, Queen’s University, Belfast, UK. Neurology Unit, Depart‑ Questionnaire; PD: Parkinson disease; PDD: Parkinson disease dementia; ment of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy. PDQ‑39: 39‑Item Parkinson’s Disease Questionnaire; QOL ‑AD: Quality of Life in Department of Research and Innovation, Helse Fonna, Haugesund Hospital, Alzheimer’s Disease Scale; RBD: Rapid eye movement sleep behavior disorder; Haugesund, Norway. Institute of Clinical Medicine (K1), The University of Ber‑ REM: Rapid eye movement; RSWA: REM sleep without atonia; SAPS‑PD: Scale gen, Bergen, Norway. Department of Neurology, Center for Sleep Medicine, for the Assessment of Positive Symptoms for Parkinson’s Disease Psychosis; Mayo Clinic, Rochester, MN, USA. Translational and Clinical Research Institute, TOMs: Technology‑based objective measures; UPDRS: Unified Parkinson’s Newcastle University, Newcastle upon Tyne, UK. Department of Old Age Disease Rating Scale; VH: Visual hallucinations; vPSG: Video polysomnography; Psychiatry Institute of Psychiatry Psychology and Neuroscience, King’s College ZBI: Zarit Burden Interview. London, London, UK. ForeFront Parkinson’s Disease Research Clinic, Brain and Mind Centre, School of Medical Sciences, University of Sydney, 100 Mallett Street, Camperdown, NSW 2050, Australia. Supplementary Information The online version contains supplementary material available at https:// doi. Received: 10 November 2021 Accepted: 31 March 2022 org/ 10. 1186/ s40035‑ 022‑ 00299‑w. Additional file 1. Table S1: Cognitive and neuropsychological measures utilized in DLB clinical trials. References 1. Vann Jones SA, O’Brien JT. The prevalence and incidence of dementia Additional file 2. Table S2: Selected cognitive fluctuations outcomes. with Lewy bodies: a systematic review of population and clinical stud‑ Additional file 3. Table S3: Selected visual hallucinations outcomes. ies. Psychol Med. 2014;44(4):673–83. Additional file 4. Table S4: Selected motor outcomes. 2. Mueller C, Ballard C, Corbett A, Aarsland D. The prognosis of dementia with Lewy bodies. Lancet Neurol. 2017;16(5):390–8. Additional file 5. Table S5: Selected REM ‑sleep behavior disorder 3. Senkevich K, Rudakou U, Gan‑ Or Z. New therapeutic approaches to outcomes. Parkinson’s disease targeting GBA, LRRK2 and Parkin. Neuropharmacol‑ ogy. 2022;202:108822. 4. Usman MB, Bhardwaj S, Roychoudhury S, Kumar D, Alexiou A, Kumar Acknowledgements P, et al. Immunotherapy for Alzheimer’s disease: current scenario and The authors want to thank the Alzheimer’s Association International Society to future perspectives. J Prev Alzheimers Dis. 2021;8(4):534–51. Advance Alzheimer’s Research and Treatment (ISTAART ) for providing a venue 5. Patel B, Irwin DJ, Kaufer D, Boeve BF, Taylor A, Armstrong MJ. Outcome to conceive, develop and discuss this manuscript. measures for dementia with Lewy body clinical trials: a review. Alzhei‑ mer Dis Assoc Disord. 2021;6:66. Author contributions 6. CfMPfH Use. Draft guideline on the clinical investigation of medicines FRP conceived and designed the review, did the literature search, writing for the treatment of Alzheimer’s disease and other dementias. Eur Med and editing of the article. KWC, CAR, JBT, DF, and PU designed the review, did Agencies. 2016;6:66. the literature search and initial draft of a section and revised the manuscript. 7. Barcikowska M. Guideline on the clinical investigation of medicines for RSW and JK did the literature search and initial draft of a section and revised the treatment of Alzheimer’s disease. Lekarz POZ. 2018;4(5):370–4. the manuscript. AP, AR, BB and J‑PT revised the manuscript. IM, DA and SGJL 8. Morant AV, Vestergaard HT, Lassen AB, Navikas V. US, EU, and Japanese designed and revised the manuscript. All authors read and approved the final regulatory guidelines for development of drugs for treatment of Alzhei‑ manuscript. mer’s disease: implications for global drug development. Clin Transl Sci. 2020;13(4):652–64. Funding 9. Goldman JG, Forsberg LK, Boeve BF, Armstrong MJ, Irwin DJ, Ferman IM and J‑PT are supported by the NIHR Newcastle Biomedical Research Centre TJ, et al. Challenges and opportunities for improving the landscape for based at Newcastle Upon Tyne Hospitals NHS Foundation Trust and Newcastle Lewy body dementia clinical trials. Alzheimers Res Ther. 2020;12(1):137. University. SJGL is supported by a National Health and Medical Research 10. Narayanaswami P. The spectrum of functional rating scales in neurology Council Leadership Fellowship (1195830). clinical trials. 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Price A, Albarqouni L, Kirkpatrick J, Clarke M, Liew SM, Roberts N, et al. Patient and public involvement in the design of clinical trials: an over‑ fast, convenient online submission view of systematic reviews. J Eval Clin Pract. 2018;24(1):240–53. thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions

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Translational Neurodegeneration – Springer Journals

Published: May 2, 2022

Keywords: Dementia with Lewy bodies; Clinical trials; Outcomes; Measurement properties

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