Assessment of outcome in clinical trials of mild Alzheimer’s disease: Why we need a new approach

Yvonne Morrison Prof Emma Reynish, Dr Fiona Kelly, Dr Crispin Bennett, Fiona Duffy, Susan McGoldrick

Prof Lindsay Wilson

October 2013

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List of abbreviations ................................................................................................................................ 2

Glossary of terms .................................................................................................................................... 3

Introduction ............................................................................................................................................ 4

A Brief Guide to the Cognitive Domains Relevant to Alzheimer’s disease ............................................. 5

Perception ........................................................................................................................................... 5

Memory ............................................................................................................................................... 6

Attention ............................................................................................................................................. 6

Executive Function .............................................................................................................................. 7

Language ............................................................................................................................................. 7

Visuospatial Function .......................................................................................................................... 7

Praxis ................................................................................................................................................... 7

Measurable Concepts in Early Alzheimer’s Disease ............................................................................... 8

Cognition ............................................................................................................................................. 8

Function and Global impact ................................................................................................................ 9

Assessment Methods ............................................................................................................................ 10

The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) ................................... 11

The Neuropsychological Test Battery (NTB) ..................................................................................... 12

Test Methods .................................................................................................................................... 12

Functional measures ......................................................................................................................... 13

Global Assessments .......................................................................................................................... 14

Bibliography .......................................................................................................................................... 17

Appendix A ............................................................................................................................................ 21

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List of abbreviations Abbreviation Definition AD Alzheimer’s disease ADAS-Cog Alzheimer’s Disease Assessment Scale-Cognitive Subscale ADCS-ADL Alzheimer’s Disease Cooperative Society-Activities of Daily Living Inventory ADCS-CGIC Alzheimer’s Disease Cooperative Society-Clinician’s Global Impression of Change ADNI Alzheimer’s Disease Neuroimaging Initiative BADL Basic activities of daily living CDR Clinical Dementia Rating CDR-SB Clinical Dementia Rating-Sum of Boxes CIBIC-Plus Clinicians Interview Based Impression of Change-Plus (caregiver) DAD Disability Assessment for Dementia EMA European Medicines Agency FDA Food and Drugs Administration IADL Instrumental Activities of Daily Living MMSE Mini Mental State Exam NTB Neuropsychological Test Battery

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Glossary of terms Clinical Relevance: the interpretation of measurements in terms of their effect on the individual’s life. Cognitive domain: area of mental function such as memory, attention, language, and problem solving. Conceptual Framework: a theory that attempts to connect to all aspects of inquiry (e.g. problem, definition, purpose, literature review, methodology, data collection and analysis). Dependent variable: a variable measured in a study (e.g. test scores) Global measure: tool to assess the overall health status of an individual. Heterogeneous: not uniform across all individuals. Neurodegeneration: progressive loss of function of nerve cells (cells that transmit information through electrical and chemical signals). Neuropsychological measures (tests): specific tasks designed to measure mental functions. Outcome measure: tool or test designed to assess the efficacy of medications or therapies at a defined time-point. Perceptual speed: Speed with which individuals can accurately compare letters, numbers or objects. Placebo group: Group of patients receiving simulated treatment as a control in a trial to assess the effectiveness of therapy. Primary endpoint: test that measures the most important outcome in a clinical trial. Psychometric properties: the measurement characteristics of a test that assess reliability, validity and responsiveness. Psychomotor: relationship between mental function and movement. Response Latency: interval between presentation of a stimulus and responding to it. Validated: confirmation a tool is suitable for its intended purpose or population.

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Introduction Alzheimer’s disease (AD) is a syndrome of acquired brain impairment sufficient to interfere with social or occupational functioning and is primarily defined by its impact on cognition (Salmon and Bondi 2009). Major efforts are underway to develop and test new treatments, with particular focus on those that modify the neurodegenerative disease process itself (disease modifying treatment). Lack of success in recent clinical trials has been attributed to both the need to intervene earlier in the disease process before significant neurodegeneration and obvious clinical symptoms occur, and to absence of sensitive outcome measures in the early stages of AD. Outcomes within the context of clinical trials are the effects of treatment or intervention on health status, and the tools or scales used to assess these effects are called outcome measures. The regulatory bodies responsible for granting approval of new medicines, European Medicines Agency (EMA) and Food and Drug Administration (FDA) (European Medicines Agency 2009, Food and Drug Administration Center for Drug Evaluation and Research 2013) have acknowledged the need for development of more sensitive outcome measures in early AD; however, AD is complex with a heterogeneous profile which makes selection of outcome measures particularly challenging. Successful outcome measures need to accurately assess the domains known to be affected by the disease and the change in these measures over time must be clinically relevant. Clinical relevance is described by Sampaio (2007) as the interpretation of measurements in terms of their meaning to an individual’s life. The concept of clinical relevance is complex and should take into account the perspective of the patient, caregiver and clinician. It is necessary to define the degree of treatment effect that would result in a benefit of any new treatment, weighted against the known side effects and cost (Sampaio 2007). The assessment of patient outcomes in clinical trials are generally measured using multiple item numeric scales. The numbers generated by these scales must be measures of the variable of interest (e.g. cognitive function). Fundamental criteria for scales are that the items contained within the scale represent the variable they intend to measure and that the values obtained are actually measures and not just numbers (Hobart, Cano et al. 2007). Numbers do not translate to measures unless they are connected by theory. This means the development of measures needs to be theory-based with variables defined and a conceptual framework that explains how each item contributes to the scale and its relationship to other items in the scale (Black, Greenberg et al. 2009). To achieve this for an AD measure, it is necessary to have an understanding of the cognitive domains relevant to AD and the impact the disease has on them. The historical approach to the selection of outcome measures in AD clinical trials is of limited utility for trials involving those in the earliest stages. The FDA continue to advocate evidence of efficacy on both cognitive and functional or global measures and FDA draft guidelines indicate that the use of a composite, cognitive/functional measure as a single primary endpoint and validated in individuals with early AD, would now be considered appropriate. Traditionally the perspective of the patient and caregiver has not featured in the development of outcome measures. Rather, researchers and clinicians select tests or items to be included based on their particular knowledge of AD. Whilst these measures are developed with sound scientific underpinnings, their clinical meaningfulness is lacking (Rockwood, Fay et al. 2006). Given that clinical meaningfulness is fundamental for regulatory approval, it is essential any newly developed measure meets this criterion. Frank, Lenderking et al. (2011) point out there are some aspects of the disease for which the clinician’s judgement is likely to be most accurate; however, at the earliest stages, subtle yet significant impairments may be accessible only to the patient or caregiver. Interviews with patients and caregivers have highlighted dissociation between cognitive test scores and functional impairment, with those scoring highly on cognitive tests experiencing a number of

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difficulties with activities of daily living (Morrison, Kelly et al. 2012). A study by Hutchings, Vanoli et al. (2010) investigating the impact of cholinesterase inhibitors on symptoms of AD found the improvements reported by treatment users were not those measured in clinical trials. This highlights the need to include the perspective of the patient in the development of new outcome measures. As a background to developing recommendations for the development of a new measure for early AD, the following sections will outline the domains relevant to AD, the cognitive profile that has emerged from research evidence, how cognitive impairment impacts on daily functions, the properties an outcome measure should contain, and a brief review of currently used outcome measures in clinical drug trials for AD. A Brief Guide to the Cognitive Domains Relevant to Alzheimer’s disease Cognitive functions are the mechanisms by which the brain processes information; they are the brain-based skills necessary for carrying out any task. Cognition is a broad umbrella term for a number of component processes (outlined below). Cognitive abilities cannot be directly observed, but are instead inferred from how they manifest as behaviour. On an ‘information processing’ model there are four main stages of brain function: – input, storage, processing and output.

Input refers to our perception of the environment; how we encode incoming information through the senses.

Storage concerns our ability to learn and remember information we perceive so that it is available for retrieval at a later date.

The processing or ‘thinking’ stage relates to the mental organisation and manipulation of information.

Output refers to action and behaviour, such as how we communicate information (e.g. speech, writing, gestures and expressions).

Despite being able to be conceptually distinguished, the main stages of cognitive function are inextricably bound. Cognition is sometimes regarded as a continuous flow of information between input and output, with all four stages interacting and overlapping. The ability to create and retrieve memories is fundamental to all aspects of cognition and our ability to function. Attention is also a vital component of cognitive function in that it underlies and maintains the activity of all other cognitive functions. The components and sub-components of cognition (also referred to as domains and sub-domains) defy simple definition and have been conceptualised and divided in diverse ways by different researchers (Glisky 2007). In one such scheme the individual components or domains that have been subsumed under the umbrella of cognition are: perception, memory, attention, executive function, language/semantic knowledge, visuospatial ability and praxis. These will be described below whilst examples of the everyday tasks impacted by each domain and typical assessment methods are provided in the accompanying table (see appendix A). Perception Our perceptual abilities relate to the identification, organisation and interpretation of sensory information (e.g. sight, sound, taste, touch, smell) necessary to understand our environment. Perception is sometimes thought of as a precognitive function; however perceptual processing has a clear impact on cognition and perceptual deficits such as impaired hearing or vision are likely to impact upon cognitive functions.

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Memory Several theories and models of memory have been proposed and debated over the decades highlighting the complexity of the memory processes in individuals. Broadly speaking memory can be conceptualised as comprising long-term, short-term and working memory stores. Long-term memory concerns retrieval of information that is no longer present and can be information learned a few minutes previously or a number of years ago. There are two long-term storage systems:

o A declarative or explicit system concerned with the storage of facts and personal events available for conscious recollection. Declarative memory can be further divided into episodic memory which is our memory for personal events and associated contextual information (e.g. attending a family party), semantic memory which is our general knowledge of the world and learned facts (e.g. Paris is the capital of France), and prospective memory which is remembering to do something at a particular time (e.g. take medication before going to bed).

o An implicit or non-conscious memory system. Implicit memory can be thought of as memories which do not require conscious recollection to facilitate an action (e.g. performing overlearned tasks such as how to tie shoelaces), and they are also sometimes called ‘procedural’.

Short-term or primary memory process allows us to hold in mind a limited amount of information for a short period of time; for example, maintaining a telephone number we have just looked up for long enough to dial it.

Working memory has several components including short-term memory and a system for manipulating information to solve immediate problems or guide behaviour (e.g. mental arithmetic).

Learning new material can be divided into three processing stages – encoding (input), storage or consolidation, and retrieval (output).

The encoding stage involves storage in the brain of a perceived item in a way that it can be retrieved at a later date. Encoding can be visual (image-based), acoustic (sound-based) or semantic (meaning-based). Many of the everyday failures of episodic memory are thought to be due to deficient encoding.

Storage or consolidation is where the various aspects of a perceptual experience are bound together to form a memory trace. This allows the learned information to be stored and available for retrieval at a later date.

Retrieval is the recall of previously learned information. Each of the processing stages needs to be successfully completed to allow retrieval of a memory. Furthermore, memory is highly attention dependant and performance on memory tasks can also be affected by impairments in the modality of testing (i.e. impaired verbal, visual or motor skills). Attention Broadly speaking, attention is the term given to the means by which individuals allocate processing resources to stimuli in our environment. Aspects of attention are involved in all cognitive tasks, unless the action is automatic or habitual. There are a number of attention processes which are somewhat hierarchical in nature.

Selective attention refers to the ability to attend to one or more salient stimuli whilst ignoring irrelevant information or distractions.

Sustained attention, also known as vigilance, is the ability to maintain focus on an activity or stimulus for an extended period of time.

Divided attention, sometimes referred to as ‘multi-tasking’ is the most complex level of attention and involves attending to more than one task or stimulus or to complex tasks with multiple components at the same time. The ability to multi-task successfully is impacted by

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the difficulty level of the tasks, their similarity to each other (e.g. whether both tasks tap auditory resources) and how practised the individual is at completing the tasks.

Executive Function At present there is no consensually agreed definition of “executive function”; however, executive function can be broadly defined as the capacities that allow an individual to engage in ‘independent, purposive, self-serving behaviour’(Lezak 2012). The term is applied to a wide range of higher order cognitive processes that control, integrate, organise and maintain other cognitive abilities. Executive functions incorporate a number of processes; central to these is the ability to plan and execute actions that are behaviourally advantageous and to withhold inappropriate actions through the process of monitoring and self-regulating behaviour. Included in the domain of executive functions are:

Volition and goal-directed action

Divided attention

Concept and strategy formation

Planning

Judgement and decision making

Inhibiting automatic or inappropriate actions

Self-monitoring Executive control is particularly important for novel tasks or when routine tasks have to be performed in a novel way. Language Our knowledge of language can be regarded as a specialised aspect of memory. Our ability to understand and generate language is central to our everyday functioning. Intact language functions allow us to communicate using speech, writing, gesture and expression. Language also allows us to understand the meaning of communications from others and to name objects, people and places. Areas of oral linguistic ability include:-

Speech perception (naming)

Processing for meaning (comprehension)

Speech production (repetition, fluency) Similar distinctions can be made for written language. Visuospatial Function Visuospatial functions reflect our ability to understand and conceptualise visual representations and spatial relationships when learning and performing a task. These functions allow us to link visually perceived information to spatial location and to our store of semantic knowledge. Visuospatial functions allow us to estimate distance and depth, to mentally visualise images and scenarios and to construct objects or produce drawings. Linking visually perceived information to our store of semantic knowledge allows us to recognise familiar objects, people and places. A distinction is often made between:

Ability to perceive where objects are in space; called the ‘dorsal stream’ after the areas of the brain thought to be involved.

Ability to recognize what objects are; called the ‘ventral stream’. Praxis Praxis is the ability to plan and execute learned, skilled movements or gestures. Impairment in these functions is referred to as apraxia. Apraxia is described as an inability to perform familiar, purposeful motor acts despite intact sensory and motor systems, and comprehension. There are a number of categories of apraxia:

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Ideomotor apraxia involves difficulty performing an action or gesture with a limb in response to a command, imitating another’s gesture or use of an object for its intended purpose.

Ideational apraxia is the inability to carry out a multi-step task (e.g. make a cup of tea) in the correct sequence.

Conceptual apraxia has been defined as impaired object or action knowledge, observed through an impaired ability to use objects correctly.

Constructional apraxia describes those who are unable to draw or construct simple configurations.

Measurable Concepts in Early Alzheimer’s Disease The impact of AD on the domains described above has been widely studied, resulting in a profile of cognitive, functional and global symptoms. These will be outlined in the following section. Cognition Impaired episodic memory (memory for personal events and associated contextual information) is well established as the prominent feature of Alzheimer’s disease; however, the presence and staging of other cognitive deficits is less clear. Research has demonstrated that AD pathology occurs years before clinical criteria for the diagnosis of AD are met (Carter, Caine et al. 2012) and also the existence of a long preclinical period in the AD process (Collie and Maruff 2000). Understanding the rates of cognitive decline apparent in this preclinical stage is essential to advance our understanding of the cognitive profile of AD and allow the effective design of clinical drug trials for putative AD treatments (Collie and Maruff 2000). That said, AD is a heterogeneous syndrome with well-known variability between patients that makes staging difficult (Caccappolo-Van Vliet, Manly et al. 2003). Whilst progressive cognitive decline is unarguably the hallmark feature of AD, detecting AD in the earliest stages is complicated due to insidious onset and slow progression (Salmon and Bondi 2009). In addition, cognitive abilities are known to diminish gradually with increasing age in the general population (Caccappolo-Van Vliet, Manly et al. 2003). A further complication is that several factors unique to individuals (e.g. education, occupation, socio-demographic status, comorbid conditions) impact upon cognitive test performance. This makes the earliest symptoms of AD difficult to identify unambiguously using neuropsychological measures. Nevertheless, in the absence of a reliable biological marker, the importance of neuropsychological testing to evaluate the pattern of cognitive impairment is clear, as is the need for effective neuropsychological measures (Collie and Maruff 2000). Preclinical AD refers to individuals who do not have sufficient cognitive impairment to meet criteria for probable AD, but greater than would be expected in ‘normal’ ageing. A range of terms have been proposed to describe the preclinical period, such as age-associated memory impairment, age-related cognitive decline, questionable dementia, benign senescent forgetfulness, mild neurocognitive disorder and mild cognitive impairment (Collie and Maruff 2000). However, (Bäckman, Jones et al. 2005) suggest the range of stages between normal ageing and overt AD are best viewed as a continuum rather than discrete categories. Attempts to identify the cognitive changes occurring on the AD continuum are on-going and currently one of the most active areas of research (Salmon and Bondi 2009). Several authors have attempted to clarify the cognitive profile of the AD syndrome by comparing performances of older individuals without impairment, those thought to be in the preclinical period, and those who meet criteria for early stage AD. There is evidence that impairment in multiple cognitive domains several years prior to a clinical diagnosis is characteristic of AD (Bäckman, Jones et al. 2005). The most prominent of these deficits is said to occur in episodic memory, working memory, perceptual (processing) speed and executive function. Smaller, but still significant, deficits

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occur in the domains of language/semantic knowledge, attention and visuospatial skill. However, the strength of the evidence from Bӓckman et al.’s (2005) meta-analysis, which incorporated 47 studies, is hampered by the fact that fewer than 10 studies provided information on the domains of visuospatial skill, attention, perceptual speed and executive function. Others have supported the above-mentioned impairments in episodic memory, working memory, executive function, language/semantic knowledge, perceptual speed and attention (Collie and Maruff 2000, Storandt 2008, Salmon and Bondi 2009). Evidence for impaired visuospatial skill is less conclusive in the very early stages (Carter, Caine et al. 2012). In addition, Carter, Caine et al. (2012) also found only minimal attention impairment. Salmon and Bondi (2009) claim attention deficits are less salient than other domains unless they are tested in a dual-task paradigm or are working memory tasks that rely on control of attention; therefore, also tapping executive functions. Studies that have found visuospatial impairment have typically used block design tests which include problem solving and psychomotor elements (Caccappolo-Van Vliet, Manly et al. 2003). This is an acknowledged issue with cognitive testing in general as individual tests often make demands on multiple domains. A further issue concerns the approach used to objectively identify level of cognitive impairment. At present, there is still a reliance on Mini Mental Status Exam (MMSE) (Folstein, Folstein et al. 1975) or Clinical Dementia Rating (CDR) (Morris 1993) scores to define the degree of cognitive impairment and categorise individuals into groups for research or clinical trials. Bondi, Jak et al. (2008) point out that the traditional MMSE cut-off score of >24 as indicative of no cognitive impairment is flawed, as many individuals scoring above this threshold are accurately diagnosed with probable AD. Cut-offs derived from the general population are misleading when applied to people with either higher or lower pre-existing ability. These authors contend that the lack of a universally accepted approach to objective identification of cognitive impairment in the earliest stages has resulted in inconsistencies in the literature. Furthermore, Bondi, Jak et al. (2008) claim much of what is framed as mild cognitive impairment in the literature, would be classified as early AD, but for the use of outdated psychometric tests. This claim is supported by Lezak (2012) who states, ‘examiners are missing a yardstick that reliably describes the stages of the disease’ (p 213). Although research evidence is hampered by heterogeneity of individual presentations, divergent assessment methods, samples, and antiquated staging tools, it appears the earliest stages of AD can be characterised by subtle deficits in a broad range of cognitive domains. This suggests scales focussing primarily on memory and language function are unlikely to be successful in capturing the subtleties of early manifestations of AD. Evidence suggests episodic memory, working memory, aspects of executive function and attention, processing speed, and semantic ability are the domains most likely to show the earliest signs of impairment. Evidence in the visuospatial domain is less conclusive and may depend to an extent on the complexity of the task. Function and Global impact In addition to understanding the cognitive domains affected by AD, it is also important to understand and measure how impaired cognition impacts upon individuals’ ability to function in daily life. As previously stated, AD is a heterogeneous syndrome; therefore, no two people will experience AD in the same way. Several factors contribute to the impact and severity of symptoms even in people with the same apparent degree of impairment and pathology. An individual’s social and health status influence the extent to which impairments impede the ability to function in their everyday environment. Nevertheless, there are a number of common symptoms and difficulties experienced in the early stage of AD. Organisations such as the Alzheimer’s Association and Alzheimer’s Disease International list a number of activities that may become problematic for those

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with early AD. These are analogous to those cited in publications that report the patient experience of early AD (Harris 2002, Whitman 2009, Stokes 2010). Some of the most common difficulties experienced by those in the early stages of AD are listed below:

Difficulty remembering recently learned information which results in repetitive questioning and problems participating in conversation.

A tendency to forget appointments and important dates.

Losing or misplacing items around the home or forgetting where the car is parked.

Getting lost.

Getting dates and times muddled.

Difficulty finding the right words to use in conversation.

An impaired ability to plan that can result in difficulties in scheduling activities at home or work, trouble managing finances and paperwork, difficulty with food shopping and preparation.

Impaired ability to solve problems.

Difficulty with tasks that require allocation of attention to more than one thing at a time (e.g. driving).

Difficulty using technology or household appliances, particularly newly acquired ones.

Susceptibility to distraction and lapses in concentration. The above list represents the most commonly reported symptoms and is not exhaustive. Individuals may experience some or all of these symptoms to varying degrees in the early stages. The extent of the impact will be moderated by characteristics of the individual, their support network and environment. The global impact of these impairments can lead to an inability to continue working, withdrawal from participation in social activity and difficulty maintaining independence. All of these can lead to changes in mood and behaviour and significant stress for caregivers. Assessment Methods Putative effects of new medicines can be assessed for their impact on cognition, function, global health status and behaviour. Assessment of behaviour, is however, thought to be more relevant to the moderate-late stages of AD and will not be discussed in this section. The properties considered necessary in a good measure for early AD will be outlined below, followed by current approaches to measuring cognition, function, and global status, a discussion of their strengths and weaknesses, and the utility of the scales most frequently used in clinical drug trials for AD. The assessment of patient outcomes in clinical trials is carried out using numeric scales to monitor the effect of particular medicines on AD symptoms and pathology. The psychometric properties of a scale affect its ability to detect changes that are clinically relevant. Outcomes measures are the main dependent variables upon which treatment decisions are made. It is, therefore, imperative these measures are fit for purpose (Black, Greenberg et al. 2009). The psychometric properties a test or scale must demonstrate to be considered appropriate are:

Responsiveness – a scale must be able to adequately detect subtle changes in functioning resulting from disease progression or drug treatment. Related to responsiveness, scales should not be subject to floor effects in late stages or ceiling effects in early stages. These effects are present when scores for a sample group cluster around the lower (floor) or upper

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(ceiling) limits of a test and demonstrate a mismatch between item difficulty and participant ability.

Reliability - Scales should demonstrate reliable results across multiple assessors (inter-rater) and repeated testing (test-re-test) and should not be subject to practice effects; that is, changes in scores should reflect cognitive loss or gain, rather than increased ability from repeated testing.

Validity – contents of a scale should reliably measure the construct under investigation (e.g. cognitive function) and be able to distinguish between individuals on the basis of measured behaviour (e.g. mildly impaired versus severely impaired). Items within the scale should also correlate to show they are measuring the same concept (internal consistency). In addition, scores on a particular scale should correlate with scores on other measurement instruments designed to measure the same construct (construct validity). Measurement scales should also demonstrate good ecological validity, meaning deficits in areas of test performance should correspond to deficits in performance of every day functions.

As well as the above mentioned properties, the EMA state scales should be short, easy to administer, and not overtax participants (European Medicines Agency 2009). Furthermore, they should be suitable for use in different subpopulations with various educational, social and cultural backgrounds, and any possible age or gender effects should be controlled for. Objective cognitive tests require participants to perform specific tasks and are considered essential in AD clinical trials (EMA and FDA). This is because AD is essentially characterised by cognitive decline and cognitive functions underlie our ability to engage successfully in daily activities (Wesnes and Harrison 2003). Assessment of cognition can range from individual tests tapping specific cognitive functions to comprehensive clinical neuropsychological test batteries; however, clinical neuropsychological test batteries are not normally employed in clinical trials due to the length of time taken to administer and score them (Wood and Cummings 1999). A good test or scale should sample all major cognitive functions affected by AD and possess favourable psychometric properties (Black, Greenberg et al. 2009). Individual tests can be grouped into categories according to the construct or domain they measure (e.g. episodic memory, executive function or attention). Typically these are scored according to the number of correct responses or errors made. Scores can be calculated for individual domains and are usually summed to give a total or scale score that assesses where an individual is placed on the spectrum of cognitive ability. Assessment of cognitive function for AD can be divided into two categories. The first, measurement of cognitive impairment, compares individuals’ test performance to that of a similar group of individuals in order, for example, to make a diagnosis. The second, measurement of change, involves repeated assessment, whereby the first test score serves as a baseline to which subsequent test scores can be compared. The latter is relevant to clinical trials where the goal is to determine cognitive preservation or change due to treatment efficacy (Harrison and Maruff 2008). Two of the commonly and currently used scales for clinical trials are outlined below. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog)(Rosen, Mohs et al. 1984) is the most widely used assessment of cognition for clinical trials. The ADAS-Cog is simple to administer and is relatively brief (approximately 30-45 minutes), and this makes it attractive as an instrument for clinical trials. It has thus become established as a ‘gold standard’ for assessment of cognition in AD, and has been used as a primary endpoint in over 170 clinical trials. Performance on the ADAS-Cog is measured by 11 components representing six areas of cognition (memory, language, orientation, construction, planning, and performing tasks to a predefined goal). In the years since its development, the ADAS-Cog has been translated into multiple languages and has undergone modifications (e.g. measures of attention and executive function have been incorporated into expanded versions); however, it is most frequently used in its standard format (Doraiswamy,

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Kaiser et al. 2001). Currently a minimum 4-point improvement in ADAS-Cog score between treatment and placebo groups is considered sufficient to indicate a clinically significant response to medication; however, this is the result of post-hoc agreement rather than prospective findings (Vellas, Andrieu et al. 2008). Despite the ADAS-Cog’s position as the primary measurement instrument used in clinical trials, its psychometric properties are not ideal and fall below the standards desired by regulatory bodies. Most notable are its exclusion of tests of executive function, working memory and attention, and susceptibility to ceiling effects in those with mild AD. In addition, an apparent lack of standardised administration and scoring procedures (Connor and Sabbagh 2008, Schafer, De Santi et al. 2011), as well as a considerable amount of measurement error (Doraiswamy, Kaiser et al. 2001), have the potential to undermine the results of clinical trials. The Neuropsychological Test Battery (NTB) The Neuropsychological Test Battery (NTB) has recently been added as a candidate primary efficacy measure by the EMA. The NTB combines six established cognitive tests, focussing on memory and executive function and administration time is approximately 40 minutes. Research evidence suggests the sensitivity of the NTB is superior to the ADAS-Cog, in particular, its ability to detect reduced impairment as a result of treatment in a sample of people with mild AD (Harrison, Minassian et al. 2007). The increased sensitivity of the NTB to detect change would allow smaller sample sizes to be used in future clinical trials. However, the NTB’s focus on memory and executive function, mean additional tests are required for a targeted assessment of relevant cognitive functions. Although considered essential, there are acknowledged issues with traditional approaches to cognitive assessment in clinical trials. A significant issue results from the need for repeated assessment. The tests employed in clinical trials are typically those borrowed from experimental or neuropsychology which are generally not designed for repeated assessment of the same individual (Harrison and Maruff 2008); therefore, performance in these measures can change with repeated testing due to practice and learning of testing strategies, rather than as a result of treatment given. To overcome this issue, tests need to have multiple parallel versions available, which most current measures lack. Furthermore, versions would need to demonstrate equivalency to avoid variability of scores due to differences between versions (Knopman and Caselli 2012). This issue of practice effects can be mitigated by training participants prior to baseline assessment (Harrison and Maruff 2008). Test Methods Historically, cognitive performance has been tested using pencil and paper tasks, administered and scored by trained personnel. However, advances in technology have resulted in the development of computerised tests. Automation of cognitive testing is said to have a number of benefits over the more traditional pencil and paper tests. The ability to record response latency with millisecond precision is an important advantage as psychomotor speed impacts cognitive performance. Computerised testing can also lead to greater standardisation of administration and scoring of tests, resulting in less measurement error (Snyder, Jackson et al. 2011). It is also claimed computerised testing allows multiple parallel versions to be created which would allow for repeated assessment of individuals (Silverberg, Ryan et al. 2011). Despite these advantages, there are potential barriers to the use of automated testing. A substantial proportion of older individuals have visual and motor impairments which could make computerised assessment challenging. Another potential weakness is they do not record qualitative information about individuals’ approach to the tasks. In addition, validation of computerised batteries is costly and the proprietary nature of these tests may be prohibitive (Knopman and Caselli 2012). Furthermore, a lack of experience with technology still

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exists in some of the target population which may increase the test burden. According to Knopman and Caselli (2012) it has yet to be proven that the conceptual advantages of computerised testing translate into actual advantages over traditional methods, whilst Silverberg, Ryan et al. (2011) highlight the need for more information regarding the psychometric properties of computerised tests before they can replace pencil and paper methods in clinical decision-making. That said, new testing paradigms that take advantage of advancing technology are continually being developed meaning there is great potential in the use of technology to improve cognitive assessment. A further criticism of traditional cognitive measures is that the tasks individuals are required to carry out seldom resemble the activities they engage in on a daily basis. This has led regulatory authorities to require a co-primary functional measure in order to demonstrate clinical relevance. Evidence suggests a strong relationship between executive function measures and the ability to perform instrumental activities of daily living (e.g. managing finances, planning activities); therefore, the incorporation of executive function tests into any new measure of cognitive function, should improve the utility of cognitive function as a marker for ability to carry out daily activities (Harrison 2007, Black, Greenberg et al. 2009). Functional measures A key component of treatment efficacy in AD is the ability to improve or preserve an individual’s functioning and independence. Assessment of function can be via performance-based assessment, self-report (patient) or informant report (family member or carer). In clinical trials, informant-based measures are most frequently used. Performance-based measures are lengthy to conduct, making them prohibitive, whilst self-report measures are thought to be less reliable due to a perception that those with AD lack insight into their condition. Assessment of function is usually divided into basic activities (e.g. bathing, dressing, going to the toilet) and instrumental activities (e.g. medication management, planning activities and managing finances). Informant-based measures generally take the form of an interview with a person who knows the patient well, during which a trained interviewer asks the informant about the individual’s ability to carry out basic activities of daily living (BADL) and instrumental activities of daily living (IADL). Functional scales vary in the number of items assessed and whether their focus is on BADL or IADL. Scoring mechanisms vary according to the scale being used, but generally require the informant to rate whether the person can perform an activity (either independently or with assistance) or not. For example, an informant may be asked to rate whether the person can make a telephone call independently, with assistance or not at all. In contrast to cognition where the ADAS-Cog has dominated clinical trials, there is greater variability in the choice of functional measures; however, two of the more frequently used are the Alzheimer’s Disease Co-operative Study – Activities of Daily Living Inventory (ADCS-ADL) (Galasko, Bennett et al. 1997) and the Disability Assessment for Dementia (DAD) (Gélinas, Gauthier et al. 1999). The ADCS-ADL takes approximately 20 minutes to administer with 23 questions covering a range of basic and instrumental activities. Questions relate to performance of activities over the previous four weeks. Scoring ranges from 0-78 points, with higher scores indicative of higher levels of functioning. The DAD involves a 15 minute interview with a caregiver to assess the ability to initiate, organise, plan and perform BADL, IADL and leisure activities independently. One point is awarded only if the activity was carried out without help or reminder during the two weeks prior to the interview. Scores range from 0-41 points, with higher scores equal to greater independence. Sikkes, De Lange-de Klerk et al. (2009) systematic review of informant-based functional scales evaluated the psychometric properties of these measures and found an overwhelming lack of adequate data and analysis. Most notable was a universal lack of information on responsiveness to change, that is, no definition of the change in score necessary to signal a clinically significant response to treatment. This raises questions regarding their suitability for use in clinical trials.

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Sikkes, De Lange-de Klerk et al. (2009) claim further validation work is necessary in order to justify the use of currently available functional measures in clinical trials. One of the major criticisms of functional measures is their reliance on information from an informant, making them highly subjective. A further criticism is that they over-emphasise BADL and IADL, but lack items relating to social function. Also lacking are items such as use of technology which may be more relevant today. The EMA believe separate measures for the early stages of AD are needed to allow greater sensitivity to change. In the earliest stages of AD basic functions are generally well preserved; therefore, scales that measure instrumental activities are thought to be most useful. However, as the earliest stages of AD are associated with little functional change,Black, Greenberg et al. (2009) have questioned whether subtle functional measures will be useful from the drug development perspective. If functional measures are to continue to be used in clinical trials, current measures will need to be revised or new measures created to improve relevance and sensitivity. Furthermore, rigorous testing of their psychometric properties will need to be carried out to justify their continued use. New measures continue to be developed that may address some of the weaknesses in currently available scales. Further validation of these measures is needed to assess their suitability for clinical trials. Global Assessments Global scales are used in clinical trials to measure the overall benefits of potential treatments and can be viewed as a clinically relevant method of validating the scores of objective cognitive measures. Global functioning scales can either track severity or change in an individuals’ condition. Typically these measures involve (semi) structured interviews between a clinician and the person with AD and/or an informant to evaluate cognition, function and behaviour. The Clinical Dementia Rating Scale (CDR) (Morris 1993) is a frequently used global staging measure often employed as part of the inclusion/exclusion criteria for clinical trials. The CDR assesses memory, orientation, judgement and problem-solving, community affairs, home and hobbies, and personal care via a clinician administered, semi-structured interview with patient and caregiver. A scoring algorithm rates the individual in 0.5 intervals from 0 – no dementia to 3 – severe dementia. A more quantitative approach, the sum of boxes, can be used by adding each of the six category scores to give a range of scores between 0 and 18. The CDR and CDR-SB have been shown to be reliable and sensitive to change, but have been criticised for their lack of behavioural component (Vellas, Andrieu et al. 2008). Global change scales assess the clinical status of an individual relative to a baseline assessment. The most commonly used global change scales are the Clinicians Interview Based Impression of Change – Plus Caregiver Input (CIBIC-Plus) (Knopman, Knapp et al. 1994) and the Alzheimer’s Disease Co-operative Study Clinical Global Impression of Change (ADCS-CGIC)(Schneider, Olin et al. 1997). Both measures involve a semi-structured interview with a patient and caregiver covering areas of cognition, behaviour, and social and daily function. Clinicians and informants rate whether and to what degree change has occurred in the person with AD relative to the baseline assessment. Ratings are at intervals between very much improved and very much worse. The CIBIC-Plus is not well standardised and has been found to have poor reliability between clinicians. The ADCS-CGIC is a more structured scale reported to have greater reliability (Black, Greenberg et al. 2009). Global scales have been regarded by some as the ‘ultimate test of a drug’s anti-dementia effects’ (Black, Greenberg et al. 2009). An often cited advantage of global measures is their ability to assess multiple domains simultaneously, independent of other scale scores. Also, individuals serve as their own controls; therefore, scores are not affected by confounds that affect cognitive measures (e.g. other illnesses, education, culture). Administration by a skilled clinician and input from caregivers

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has led to claims that these scales detect clinically meaningful change; predicated on the belief that if a clinician and informant judge that improvement has occurred, it must be clinically relevant (Black, Greenberg et al. 2009). Critics of global assessment have highlighted a number of weaknesses in these measures. Interviews can be lengthy and require judgement by clinicians and informants. Subjective rating by informants can be unreliable. In addition, a review by Oremus, Perrault et al. (2000) highlighted an apparent dissociation in rating criteria between clinicians and caregivers, with clinicians tending to focus on cognitive abilities, whilst caregivers were more focussed on behavioural and functional abilities. A further issue concerns the use of total scale scores, for example, improvement in functional ability could be cancelled out by a decline in cognitive ability, resulting in no change to the total score. Oremus, Perrault et al. (2000) review of the psychometric properties of global measures found estimates of reliability and validity of the most commonly used measures in clinical trials varied from fair to very good. Small sample sizes, inappropriate use of statistics and a lack of information on responsiveness to change, limit the extent to which these scales can be classed as appropriate for use in clinical trials. Draft guidelines recently released by Food and Drug Administration Center for Drug Evaluation and Research (2013) acknowledge the historical approach to the selection of outcome measures in AD clinical trials is of limited utility for trials involving those in the earliest stages. Whilst continuing to advocate evidence of efficacy on both cognitive and functional or global measures, use of a composite, cognitive/functional measure as a single primary endpoint and validated in individuals with early AD, would now be considered appropriate. The CDR-SB (Hughes, Berg et al. 1982) has been suggested as an example of an appropriate measure. Its suitability as a single primary endpoint in AD clinical trials has recently been investigated using data from a French cohort study (Coley, Andrieu et al. 2011) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database (Cedarbaum, Jaros et al. 2012). Preliminary psychometric analysis showed the CDR-SB measures cognition and function simultaneously, with each domain contributing approximately equally to the change in total score. The CDR-SB appears to capture clinically relevant change in function as demonstrated by moderate-strong correlations between the functional element and other functional measures; however, correlations between the cognitive element and the ADAS-Cog were weaker questioning the CDR-SB’s ability to capture cognitive decline. Despite some apparent strengths of the CDR-SB, there are limitations which may affect its suitability as a single primary outcome measure. Most notably, it does not include objective measures of patient performance, rather it relies solely on information from an informant and the clinician’s rating of the patient, making it a subjective measure. In addition, it is time consuming to administer and those administering the measure need to be highly trained (Coley, Andrieu et al. 2011, Cedarbaum, Jaros et al. 2012). Conclusion Cognitive function is a complex entity with many interacting and overlapping domains. Nevertheless, research evidence has expanded our knowledge of cognitive processes, and despite the issue of heterogeneity of individual presentation, a cognitive profile of early AD has emerged together with an understanding of the impact impaired cognition has on daily functions. In the years following the development of the currently used measures, researchers have applied rigorous statistical analysis to examine their psychometric properties. From the evidence presented it is clear currently used outcome measures fall below the standards outlined by regulators. Regulators and the research community have acknowledged the weaknesses of current measures and the need for more sensitive measures to be developed for clinical trials in early AD. The assessment of outcomes is currently an active area of AD research and much has been done to capitalise on advances in

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technology to improve the accuracy and sensitivity of measures. Recent discussions have highlighted these emerging assessment methods, but as yet, no conclusions have been reached as to which test or combination of tests would be capable of capturing the subtle changes in cognition and function associated with early AD in a reliable and valid way. To develop a reliable, valid and clinically meaningful outcome measure is complex and challenging and requires consideration of all of the identified issues underlying cognitive, functional and global endpoints for clinical trials in early AD. Questions that need to be addressed include:

Which domains should be assessed by the outcome measure.

The relative importance of the domains.

How these domains should be assessed. Consultation between researchers, clinicians, regulators, industry and patient advocates is essential in order to develop a new outcome measure for use in clinical trials that is modelled on and reflects the clinical experience of the patient in the early stages of AD.

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Bibliography Bäckman, L., S. Jones, A.-K. Berger, E. J. Laukka and B. J. Small (2005). "Cognitive impairment in preclinical Alzheimer's disease: a meta-analysis." Neuropsychology 19(4): 520-531. Black, R., B. Greenberg, J. M. Ryan, H. Posner, J. Seeburger, J. Amatniek, M. Resnick, R. Mohs, D. S. Miller, D. Saumier, M. C. Carrillo and Y. Stern (2009). "Scales as outcome measures for Alzheimer's disease." Alzheimer's & Dementia 5(4): 324-339. Bondi, M. W., A. J. Jak, L. Delano-Wood, M. W. Jacobson, D. C. Delis and D. P. Salmon (2008). "Neuropsychological contributions to the early identification of Alzheimer’s disease." Neuropsychology Review 18(1): 73-90. Caccappolo-Van Vliet, E., J. Manly, M. Tang, K. Marder, K. Bell and Y. Stern (2003). "The neuropsychological profiles of mild Alzheimer’s disease and questionable dementia as compared to age-related cognitive decline." Journal of the International Neuropsychological Society 9(5): 720-732. Carter, S. F., D. Caine, A. Burns, K. Herholz, L. Ralph and A. Matthew (2012). "Staging of the cognitive decline in Alzheimer's disease: insights from a detailed neuropsychological investigation of mild cognitive impairment and mild Alzheimer's disease." International journal of geriatric psychiatry 27(4): 423-432. Cedarbaum, J. M., M. Jaros, C. Hernandez, N. Coley, S. Andrieu, M. Grundman and B. Vellas (2012). "Rationale for use of the Clinical Dementia Rating Sum of Boxes as a primary outcome measure for Alzheimer’s disease clinical trials." Alzheimer's & Dementia: S45-S55. Coley, N., S. Andrieu, M. Jaros, M. Weiner, J. Cedarbaum and B. Vellas (2011). "Suitability of the Clinical Dementia Rating-Sum of Boxes as a single primary endpoint for Alzheimer’s disease trials." Alzheimer's & Dementia 7(6): 602-610. Collie, A. and P. Maruff (2000). "The neuropsychology of preclinical Alzheimer's disease and mild cognitive impairment." Neuroscience & Biobehavioral Reviews 24(3): 365-374. Connor, D. J. and M. N. Sabbagh (2008). "Administration and scoring variance on the ADAS-Cog." Journal of Alzheimer's Disease 15(3): 461-464. Doraiswamy, P. M., L. Kaiser, F. Bieber and R. L. Garman (2001). "The Alzheimer's Disease Assessment Scale: evaluation of psychometric properties and patterns of cognitive decline in multicenter clinical trials of mild to moderate Alzheimer's disease." Alzheimer Disease And Associated Disorders 15(4): 174-183. European Medicines Agency. (2009). "Guideline on medicinal products for the treatment of Alzheimer's disease and other dementias." from http://www.emea.europa.eu/doc/en_GB/document_library/Scientific/guideline/2009/09/WC500003562.pdf. Folstein, M. F., S. E. Folstein and P. R. McHugh (1975). "“Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician." Journal of psychiatric research 12(3): 189-198.

Page 18 of 28

Food and Drug Administration Center for Drug Evaluation and Research. (2013). "Guidance for Industry Alzheimer's Disease: Developing Drugs for the Treatment of Early Stage Disease - Draft Guidance." from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM338287.pdf. Frank, L., W. R. Lenderking, K. Howard and M. Cantillon (2011). "Patient self-report for evaluating mild cognitive impairment and prodromal Alzheimer’s disease." Alzheimer's research & therapy 3(6): 35. Galasko, D., D. Bennett, M. Sano, C. Ernesto, R. Thomas, M. Grundman and S. Ferris (1997). "An inventory to assess activities of daily living for clinical trials in Alzheimer's disease." Alzheimer Disease & Associated Disorders 11: 33-39. Gélinas, I., L. Gauthier, M. McIntyre and S. Gauthier (1999). "Development of a functional measure for persons with Alzheimer’s disease: the disability assessment for dementia." The American Journal of Occupational Therapy 53(5): 471-481. Glisky, E. L. (2007). Changes in cognitive function in human aging. Brain aging: models, methods, and mechanisms. D. R. Riddle. USA, CRC Press. Harris, P. B. (2002). The person with Alzheimer's disease: Pathways to understanding the experience. Baltimore, John Hopkins University Press. Harrison, J. (2007). "Measuring cognitive change in Alzheimer's disease clinical drug trials." Jounal Of Nutrition Health And Aging 11(4): 327-332. Harrison, J. and P. Maruff (2008). "Measuring the mind: assessing cognitive change in clinical drug trials." Expert Review of Clinical Pharmacology 1(4): 471-473. Harrison, J., S. L. Minassian, L. Jenkins, R. S. Black, M. Koller and M. Grundman (2007). "A neuropsychological test battery for use in Alzheimer disease clinical trials." Archives of neurology 64(9): 1323-1329. Hobart, J. C., S. J. Cano, J. P. Zajicek and A. J. Thompson (2007). "Rating scales as outcome measures for clinical trials in neurology: problems, solutions, and recommendations." The Lancet Neurology 6(12): 1094-1105. Hughes, C. P., L. Berg, W. L. Danziger, L. A. Coben and R. L. Martin (1982). "A new clinical scale for the staging of dementia." The British Journal of Psychiatry 140(6): 566-572. Hutchings, D., A. Vanoli, I. Mckeith, S. Brotherton, P. Mcnamee and J. Bond (2010). "Good days and bad days: the lived experience and perceived impact of treatment with cholinesterase inhibitors for Alzheimer’s disease in the United Kingdom." Dementia 9(3): 409-425. Knopman, D. S. and R. J. Caselli (2012). "Appraisal of cognition in preclinical Alzheimer’s disease: a conceptual review." Neurodegenerative disease management 2(2): 183-195. Knopman, D. S., M. J. Knapp, S. I. Gracon and C. S. Davis (1994). "The Clinician Interview‐Based Impression (CIBI) A clinician's global change rating scale in Alzheimer's disease." Neurology 44(12): 2315-2321.

Page 19 of 28

Lezak, M. D., Howieson, D.B., Bigler, E.D., Tranel, D. (2012). Neuropsychological Assessment. USA, Oxford Press. Morris, J. C. (1993). "The Clinical Dementia Rating (CDR): current version and scoring rules." Neurology 43(11): 2412-2414. Morrison, Y., F. Kelly, C. Bennett, F. Duffy, S. McGoldrick and A. Bowes (2012). Knowledge Transfer Partnership Report: A consultation with key stakeholders to inform the development of a new rating scale for Alzheimer's disease, University of Stirling/QCTR. Oremus, M., A. Perrault, L. Demers and C. Wolfson (2000). "Review of outcome measurement instruments in Alzheimer's disease drug trials: psychometric properties of global scales." Journal of geriatric psychiatry and neurology 13(4): 197-205. Rockwood, K., S. Fay, X. Song, C. MacKnight and M. Gorman (2006). "Attainment of treatment goals by people with Alzheimer's disease receiving galantamine: a randomized controlled trial." Canadian Medical Association Journal 174(8): 1099-1105. Rosen, W. G., R. C. Mohs and K. L. Davis (1984). "A new rating scale for Alzheimer's disease." The American Journal of Psychiatry 141(11): 1356-1364. Salmon, D. P. and M. W. Bondi (2009). "Neuropsychological assessment of dementia." Annual review of psychology 60: 257-282. Sampaio, C. (2007). "Clinical relevance on Alzheimer's disease endpoints." The journal of nutrition, health & aging 11(4): 316-317. Schafer, K., S. De Santi and L. S. Schneider (2011). "Errors in ADAS-cog administration and scoring may undermine clinical trials results." Current Alzheimer Research 8(4): 373-376. Schneider, L., J. Olin, R. Doody, C. Clark, J. Morris, B. Reisberg, F. Schmitt, M. Grundman, R. Thomas and S. Ferris (1997). "The Alzheimer's Disease Cooperative Study. Validity and reliability of the Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change." Alzheimer Dis Assoc Disord 11(suppl 2): S22-S32. Sikkes, S., E. De Lange-de Klerk, Y. Pijnenburg and P. Scheltens (2009). "A systematic review of Instrumental Activities of Daily Living scales in dementia: room for improvement." Journal of Neurology, Neurosurgery & Psychiatry 80(1): 7-12. Silverberg, N. B., L. M. Ryan, M. C. Carrillo, R. Sperling, R. C. Petersen, H. B. Posner, P. J. Snyder, R. Hilsabeck, M. Gallagher and J. Raber (2011). "Assessment of cognition in early dementia." Alzheimer's and Dementia 7(3): e60-e76. Snyder, P. J., C. E. Jackson, R. C. Petersen, A. S. Khachaturian, J. Kaye, M. S. Albert and S. Weintraub (2011). "Assessment of cognition in mild cognitive impairment: A comparative study." Alzheimer's & Dementia 7(3): 338-355. Stokes, G. (2010). And Still the Music Plays. London, Hawker Publications. Storandt, M. (2008). "Cognitive deficits in the early stages of Alzheimer's disease." Current Directions in Psychological Science 17(3): 198-202.

Page 20 of 28

Vellas, B., S. Andrieu, C. Sampaio, N. Coley and G. Wilcock (2008). "Endpoints for trials in Alzheimer's disease: A European task force consensus." The Lancet Neurology 7(5): 436-450. Wesnes, K. A. and J. E. Harrison (2003). "The evaluation of cognitive function in the dementias: methodological and regulatory considerations." Dialogues in clinical neuroscience 5(1): 77-88. Whitman, L. (2009). Telling tales about dementia: Experiences of caring. London, Jessica Kingsley Publishers. Wood, S. and J. L. Cummings (1999). "Measuring Outcomes in Alzheimer’s Disease Research." Disease Management and Health Outcomes 5(1): 1-12.

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Appendix A

Memory

3 stages in information and retrieval Encoding – registration of info Storage – creating record Retrieval - recall

Declarative Memory(explicit)

memory for facts and events available for conscious recollection

Sub domain Description Needed to/for Measured by

Episodic memory Personal events and associated contextual information

Remember recent and remote events e.g. what you had for dinner yesterday, where you went last year on holiday, an earlier telephone conversation

Logical Memory/paragraph recall

Word list learning

Interview

Semantic memory What is learned as knowledge

‘Paris is the capital of France’

Finding right words to use

Participate in social and leisure activities

Confrontation naming

Verbal fluency

Prospective memory Remembering to do something at a particular time

Remember an appointment Rivermead Behavioural Memory Test

Topographic memory Orient oneself in space Way-finding/navigation Route finding tasks

Implicit Memory

not based on conscious recollection

Procedural memory Motor and cognitive skill learning Tie shoelaces or ride a bike Performance of overlearned tasks

Memory is attention dependant and can be affected by impairments in modality of testing (visual/verbal/motor). Retrieval by recognition is easier than free recall.

Appendix A (continued)

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Attention

Sub domain Description Needed to/for Measured by

Selective attention Focusing on one relevant stimulus whilst ignoring irrelevant or distracting stimuli

Being able to concentrate on a task without being distracted by other things around you (e.g. attend to one conversation in a noisy room)

Visual/auditory discrimination

Visual search

Spatial cueing tasks

Sustained attention Focus attention over extended period of time

Any task that requires maintaining focus/vigilance such as driving, watching TV or reading

Continuous performance tasks

Speed and accuracy of target detection

Appendix A (continued)

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Executive Functions A set of higher order cognitive processes that control, integrate, organise and maintain other cognitive abilities – including memory and attention.

Sub-domain Description Needed to/for Measured by

Volition To formulate a goal or intention

Requires motivation, awareness and the ability to initiate activity

Initiate activity (without explicit instructions may not think of things to do)

No formal test –assessed only by observation and interview

Planning Identification and organisation of steps needed to achieve a goal.

Requires ability to look ahead, conceptualise, weigh alternatives and make choices

Food shopping and preparation

Organise daily activities

Manage finances

Pack for a holiday

Medication management

Picture Arrangement

Block Design

Copying tasks (organization of drawings)

Tower Tests

Purposive Action Initiate, maintain, switch and stop sequences of behaviour in an orderly manner

Successful performance of non-routine tasks

Impairment may lead to dissociation between plans and actual behaviour

Set shifting tasks e.g. Trails B

Fluency tests

Stroop

Effective Performance Monitor, regulate and self-correct behaviour

Adapt behaviour as situation or task demands

Identify and correct errors

Solve problems that arise

Random generation tasks

Observation of behaviour on other tests

Working memory To hold information in mind, internalise and use to guide behaviour in the absence of reliable external cues

Follow/remember instructions or directions

Remember a telephone number

Mental arithmetic

Arithmetic tasks

Letter/number span tasks

Divided attention Sharing of attention by focusing on more than one stimulus at one time

Multi-tasking – any activity that requires attending to two or more things at once

Dual-task paradigm

Appendix A (continued)

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Language

Sub domain Description Needed to/for Measured by

Naming The ability to identify objects by name

Impaired language skills can result in withdrawal from social situations and abandoning hobbies, difficulty with written communication, conversation and an inability to use the telephone.

Boston naming test

Confrontation naming

Comprehension The ability to understand meaning of words and phrases

Token test

Obeying Commands

Repetition The ability to articulate and sequence sound

Repetition of words and phrases

Fluency The ability to generate speech fluently

Phonemic and category fluency

Reading Adult Reading Test

Writing Generate or copy words and sentences

Appendix A (continued)

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Visuospatial

Understanding and conceptualising visual representations and spatial relationships (2D & 3D) in learning and performing a task.

Sub domain Description Needed to/for Measured by

Dorsal stream - where Links visually perceived information with spatial position and orientation

Includes mental imagery, navigation, distance and depth perception and visuospatial construction

Navigate space without bumping into things, give directions, judge distances and construct or draw objects.

Wayfinding, crossing the road, driving, parking a car, drawing and constructing objects, solving puzzles

Judgement of line orientation

Drawing and copying tasks

Object assembly

Visual tracking

Ventral stream - what Links perceived information to the store of semantic knowledge

Recognise and name objects Object recognition

Appendix A (continued)

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Orientation The awareness of self in relation to one’s surroundings.

Requires consistent integration of memory, attention and perception.

Sub domain Description Needed to/for Measured by

Time Awareness of day, date, month, year and time of day

Keep track of appointments

Distinguish night and day

Assessed by oral or written questions

Place

Awareness of current surroundings Navigate familiar and unfamiliar environments

Locate objects

Person Awareness of name, address, age, marital status

Knowledge of basic personal information

Appendix A (continued)

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Praxis – the ability to plan and execute movement

Apraxia – impairment of expressive functions

Sub domain Description Needed to/for Measured by

Ideational apraxia The loss of ability to carry out familiar purposeful movements in the absence of any motor or sensory impairment, especially the inability to use objects correctly, despite intact knowledge of their function.

Correct use of everyday objects (e.g. use toothbrush for teeth not hair)

Carry out sequence of actions in the correct order (e.g. toast bread before buttering)

Imitation of gestures

Commands

Letter task (ADAS-Cog)

Ideomotor apraxia An impaired ability to plan or complete motor actions that rely on semantic memory. Being unable to ‘imagine’ or act out movement (e.g. pretend to brush teeth). Can carry out some actions automatically when cued (e.g. pick up phone if it rings).

Unable to carry out meaningful gestures e.g. wave, salute

Imitation of gestures

Commands

Constructional apraxia The inability to draw or construct simple configurations

Maintain spatial relationships Copying tasks, clock drawing, intersecting pentagons