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We begin with a brief overview of the neuropathological changes seen in the AD brain and an outline of some of the clinical neuropsychological assessments used to measure cognitive deficits associated with the disease. This is followed by a critical assessment of behavioral tasks that are used in AD mice to model the cognitive changes seen in the human disease. We discuss the strengths and weaknesses of each of these behavioral tasks, and how they may correlate with clinical assessments in humans.
Mouse models of AD and the behavioral tasks used in conjunction with those models are immensely important in contributing to our knowledge of disease progression and are a useful tool to study AD pathophysiology and the resulting cognitive deficits. However, investigators need to be aware of the potential weaknesses of the available preclinical models in terms of their ability to model cognitive changes observed in human AD. It is our hope that this review will assist investigators in selecting an appropriate mouse model, and accompanying behavioral paradigms to investigate different aspects of AD pathology and disease progression.
Alzheimer's disease AD is characterized by a progressive decline in cognitive function, usually starting with memory complaints and eventually progressing to involve multiple cognitive, neuropsychological and behavioral domains. The definitive diagnosis of AD comes from postmortem analysis of the neuropathological changes in the brain.
Analyses of both clinical and pathological features, i. Complementing these studies in humans has been the development of preclinical model systems of AD pathology.
These preclinical animal models, especially mouse models, have been extremely useful to test mechanistic hypotheses about AD pathophysiology and to predict outcomes from pharmacological interventions. However, no animal model recapitulates the entirety of AD in humans, and therefore it is important to understand both the utility and limitations of particular animal models.
With this in mind, we will present an overview of the neuropathological changes seen in the AD patient population as individuals transition from normal cognitive aging to dementia, review the clinical neuropsychological assessments used in the AD field, review the mouse behavioral tasks commonly used in preclinical testing and discuss how they relate to these clinical neuropsychological assessments, and outline the temporal progression of cognitive and non-cognitive deficits seen in the commonly used mouse models of AD.
In , new consensus guidelines for neuropathologic evaluation of AD were adopted Hyman et al. Standard approaches for the workup of cases, preferred staining methods, reporting of results and clinicopathological correlations are also recommended. Unlike the prior AD neuropathologic criteria Hyman and Trojanowski, that required a history of dementia, the current guidelines recognize that AD neuropathologic changes can be present in the brain in the apparent absence of cognitive impairment.
The updated guidelines thus emphasize the continuum of neuropathologic changes that underlie AD. For a disease process that is known to occur over a decade or more Blennow and Zetterberg, ; Rosen and Zetterberg, ; Rosen et al. This consideration points to the complexity that clinicopathological studies face when examining AD pathological contributions to cognitive deficits Nelson et al.
There have been numerous clinicopathological studies attempting to correlate amyloid plaques with the cognitive deficits seen in AD Blessed et al. Apparent inconsistencies in the conclusions of these studies are due to differences in study cohorts, methodology used to classify plaque subcategories, plaque-counting techniques, and metrics used to assess cognitive deficits.
Nevertheless, several important concepts have emerged pertaining to plaque pathology and cognition. First, the strongest correlation between amyloid plaques and cognition is in the early stages of the disease and this association weakens as NFTs and gross neocortical neurodegeneration become more widespread Thal et al. As the disease progresses into the later stages, there is little evidence to support a continued contribution by amyloid plaques to the late-stage AD cognitive decline Nelson et al.
In contrast to the literature concerning amyloid plaques, a large number of studies have arrived at a common finding, namely, there is a strong link between neocortical NFTs and cognitive decline Tomlinson et al.
It should be noted that outside of frontotemporal lobar degeneration FTLD , one does not see widespread cortical NFTs without abundant plaque pathology. During the late stages Braak stage V—VI , NFTs increase in number and manifest in neocortical areas responsible for higher cognitive domains such as executive function, visuospatial capacities, and speech in synchrony with observed AD-related cognitive deficits in these respective cognitive domains.
In sum, the correlations noted in human material support the hypothesis that plaques and tangles correlate with cognitive status. Neuropsychological assessment is the most reliable means to clinically evaluate the cognitive deficits seen in humans. Many neuropsychological tests have been developed which are highly sensitive to the cognitive behavioral symptoms seen in AD, and these tests are extensively used as clinical diagnostic tools Schmitt, as well as to track the progression of the disease Flicker et al.
Current neuropsychological assessments from the National Institute on Aging workgroups on diagnostic guidelines for AD aim to detect disruptions in cognitive domains such as episodic memory, semantic memory, working memory, and attention, as well as dysfunction in language, praxis, and executive functioning Flicker et al.
In the following section, we will cover several of the most common neuropsychological tests used clinically to assess the mental status and memory disruptions in AD for more in depth reviews see Perry and Hodges, ; Budson and Price, ; Bondi et al.
Both categories of tests are clinically useful in assessing the cognitive progression of AD. Most mental status examinations assess mental functions and cognitive ability across a wide range of areas such as: language skills, arithmetic ability, visuospatial ability, attention, memory, and orientation to time and place. The MMSE is a brief questionnaire that can both diagnose cognitive impairment and track the severity of this cognitive impairment throughout the pathogenesis of the disease.
The MMSE covers multiple areas such as: attention, memory semantic and episodic , orientation to time and place, and working memory. The scoring system ranges from 0 to 30 points. In general, a score of 27 or greater reflects normal cognition, a score of 19—24 represents mild impairment, a score of 10—18 represents moderate impairment, and a score below 9 indicates severe cognitive impairment.
The MMSE has excellent reproducibility that lends itself well to longitudinal use in tracking the progression of the cognitive impairments associated with AD Jacqmin-Gadda et al.
This test battery takes approximately 10 min to administer and covers many similar cognitive domains to that of the MMSE. The total possible score is 30 points, with a score of 26 or above considered within the normal range. An example of a task included in the MoCA is the forward and backward digit span test.
In the forward digit span test, a sequence of five numbers is read at a rate of one number per second and the test taker is required to repeat a set of numbers in exactly the same sequence as they were presented. In the backward digit span task, the test taker is required to repeat a three number sequence in the reverse order in which it was presented.
One point is awarded for each of the digit span tests in which the test taker made no errors. The MoCA also includes a delayed recall memory test. Relatively near the beginning of the test, the examiner presents a short word list for the patient to remember. At the end of the test, the patient is again prompted to recall the word list and for each of the words correctly remembered one point is awarded. Another commonly used test battery is that of the Short Blessed Test SBT which consists of a six-item test designed to identify the cognitive dysfunction seen in AD Katzman et al.
An appealing advantage of the SBT is the ease and speed with which it can be administered often taking only a few minutes. In the SBT, errors are scored for incorrect answers and the scoring range falls between 0 and 28, with a score of 0—4 representing normal cognition, a score of 5—9 representing early impairment, and a score of 10 or more representing impaired cognition. Despite the simplicity and brevity of the SBT, the results that it produces have demonstrated excellent reliability Fuld, Similarly, the SBT was the first mental status examination to be correlated with amyloid plaque burden at autopsy Carpenter et al.
Initially, it was developed in two parts sub-scales : one for cognitive symptoms and one for non-cognitive symptoms.
The scoring for the ADAS-cog ranges from 0 to 70, with a low score representing a cognitively intact person and a high score representing someone with cognitive impairment. Because the ADAS-cog has an excellent test-retest reliability and is considered to be one of the most sensitive scales for assessing cognitive changes related to AD Emilien et al. Individual memory tests are generally shorter than mental status examinations and focus solely on assessing memory deficits.
Both verbal and visual memory tests are commonly used clinically as stand alone tests or incorporated into a more comprehensive mental status examination. Both are verbal based memory tests that involve a short story read to the patient.
In the LM-I, the patient answers immediate questions related to the narrative, whereas in the LM-II there is a delay between the presentation of the story and the questions.
In the BVRT, the patient is shown 10 different visual designs, one at a time, and is then asked to reproduce each one from memory exactly as it appeared.
While scoring the BVRT, errors of omissions, distortions, perseverations, rotations, misplacements, and size are all looked for and can give some insight into the progression of the disease. For example, if the patient has a high number of perseveration errors it is likely that the AD pathology has manifest itself in neocortical areas responsible for higher cognitive domains such as executive function, and visuospatial capacities Braak Stage V—VI.
Each of the tests described above is aimed at assessing deficits in different cognitive domains. Each of these domains has been shown to be impaired at some point in the spectrum of human AD. However, they are not uniformly affected throughout the course of the disease. Deficits in some domains occur relatively early, while deficits in others occur much later in the progression of the disease. It has become increasingly clear that identifying and targeting the cognitive deficits that occur early in the course of the disease is critical to producing the maximum impact of treatment on cognitive function and quality of life Salmon et al.
Thus, great efforts have been made to better understand the profile of cognitive deficits associated with early AD, and have resulted in earlier and more reliable clinical diagnosis Bondi et al.
Overview of the progression of cognitive deficits in human AD and in mouse models of AD. A In the human disease, the earliest AD-related cognitive deficits present themselves as episodic memory impairment during the late preclinical phase of the disease Backman et al. Semantic memory deficits are the next to develop Tuokko et al. As MCI progresses, deficits in verbal recall Kryscio et al. As the patient transitions into AD, all cognitive domains become affected. Consistently, the earliest observable impairments are in spatial working memory Webster et al.
These impairments are generally followed temporally by impairments in associative learning and reference memory, as assessed by maze alternation Lalonde et al.
Deficits in recognition memory usually present later in the spectrum of cognitive impairment than deficits in other domains Eriksen and Janus, ; Hall and Roberson, ; Webster et al. Some of the earliest neuropathological changes in AD are in the hippocampus and entorhinal cortex, followed by changes in the medial temporal lobe. Consistent with this progression of pathology, the earliest detectable deficits in cognition are seen in medial temporal lobe-dependent episodic memory Bondi et al.
These early deficits in episodic memory are followed closely by deficits in semantic memory, and both are developed before other deficits in cognitive domains such as attention, visuospatial memory, or executive function Bondi et al. This suggests that cognitive functions such as episodic and semantic memory that depend heavily on the neural circuitry of the medial and lateral temporal lobes may be impaired earlier than cognitive abilities that depend on the circuitry of other brain regions.
Further support for this idea comes from the time course of the frontal lobe dependent executive function deficits observed in patients. Slight deficits in executive functioning are first detectable near the end of the preclinical phase of AD but after the observed deficits in episodic and semantic memory Storandt et al.
As the patient moves from the preclinical phase of AD into MCI, more cognitive domains begin to be affected. Most studies of MCI patients show consistent impairments in verbal recall Larrieu et al. Once the AD patient progresses past MCI and into dementia, general cognition continues to decline with deficits appearing in all respective cognitive domains Huff et al. The importance of neuropsychological testing cannot be overstated, as it is the only measure that provides information about a patient's current cognitive status and remains the most reliable means to clinically diagnose probable AD.
Neuropsychological testing provides information on both general cognitive status and specific information on different cognitive domains affected in AD. Composite scores encompassing multiple neuropsychological tests are often used and can provide some of the most reliable assessments of global cognitive status relating to AD as well as serving as efficacy outcome measures in clinical trials Bernick et al.
Ideally, preclinical rodent cognitive testing would assess identical cognitive domains to those examined through neuropsychological testing in human AD. Indeed, many rodent behavioral tasks have been specifically designed with this in mind, and while each task varies with respect to face, construct, and predictive validity, they all attempt to model different aspects of the cognition disrupted in AD and targeted by the human neuropsychological assessments listed in the previous section. Some cognitive domains disrupted in AD have been extensively modeled reference memory, working memory and executive function , some less so attention , and some nearly not at all episodic memory.
Reference memory, while not used clinically to describe human cognition, refers to learned knowledge for an aspect of a task that remains constant throughout the behavioral task and most closely correlates to human semantic memory. Working memory refers to a mental processing system used to hold transitory information for a limited time where it can be manipulated and operated on and used to guide behavior. Recognition memory refers to the ability to recognize previously encountered events, objects, or individuals and is classified as part of long-term declarative memory.
Other cognitive domains impaired in human AD such as those involving language i.
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