Chapter 5 Contributions of Neuropsychology and Neuroimaging to Understanding Clinical Subtypes of Mild Cognitive Impairment

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Mild cognitive impairment (MCI) is a clinical construct that describes individuals with mildly impaired performance on objective neuropsychological tests but relatively intact global cognition and daily functioning. The chapter discusses that MCI has been validated as qualitatively different from both normal aging and dementia and is a risk factor for the development of dementia. Because of its potential importance for early identification and intervention in those at risk for the development of dementia, the concept of MCI has received considerable research attention. Conceptualizations of MCI have emerged that encompass cognitive domains other than memory. These characterizations delineate clinical subtypes that commonly include amnestic and non-amnestic forms, and that involve single and multiple cognitive domains against the backdrop of intact daily functioning. The chapter provides an overview of neuropsychological, neuroimaging, functional, and treatment findings specific to clinical subtypes of MCI. It also discusses the methodological issues involved in studying this heterogeneous population and future directions to continue to improve one's understanding of MCI and its clinical subtypes.

Introduction

Mild cognitive impairment (MCI) is a clinical construct that describes individuals with mildly impaired performance on objective neuropsychological tests but relatively intact global cognition and daily functioning (Petersen et al., 1999, Petersen and Morris, 2005). MCI has been validated as qualitatively different from both normal aging and dementia (Petersen, 2004, Smith and Ivnik, 2003) and is a risk factor for the development of dementia. Because of its potential importance for early identification and intervention in those at risk for the development of dementia, the concept of MCI has received considerable research attention. However, the definition has evolved considerably over time. As originally proposed by Petersen and colleagues, MCI was characterized primarily as an amnestic disorder that represented an intermediate stage between normal aging and Alzheimer's dementia (AD) (Petersen et al., 1999). More recently, broader conceptualizations of MCI have emerged that also encompass cognitive domains other than memory (Petersen et al., 2005, Petersen et al., 2001). These characterizations delineate clinical subtypes that commonly include amnestic and non‐amnestic forms, and that involve single and multiple cognitive domains (Manly et al., 2005, Petersen and Morris, 2005, Petersen et al., 2001, Tabert et al., 2006) against the backdrop of intact daily functioning. With the advent of these broader classifications schemes, more specific information is emerging regarding the neuropsychological presentation of individuals with MCI, risk for dementia associated with different subtypes of MCI, daily functioning, and neuropathologic substrates connected to the clinical subtypes. The aim of this review is to provide an overview of neuropsychological, neuroimaging, functional, and treatment findings specific to clinical subtypes of MCI. In addition, methodological issues involved in studying this heterogeneous population and future directions to continue to improve our understanding of MCI and its clinical subtypes will also be highlighted and discussed.

Section snippets

Neuropsychological Presentation

It is certainly of great interest to determine factors placing individuals at highest risk for development of dementia so as to target them for early intervention. To this end, a better understanding of who is at risk for developing MCI may be an important first step. Presently, there are limited data about risk factors that correspond to conversion from cognitively normal to specific clinical subtypes of MCI; although, the existing evidence suggests that advancing age and lower education

Stability of Diagnosis

Multiple studies indicate that not all individuals diagnosed with MCI will decline and progress to a dementia diagnosis. In fact, a proportion of individuals appear to “improve” over time such that, at follow up, those initially identified as MCI are later categorized as cognitively normal. Anywhere from 20 (Fischer et al., 2007) to 40% (Bickel et al., 2006) of those with MCI appear to revert to the normal range upon retesting. Single domain classifications appear particularly susceptible to

Conversion to Dementia

Perhaps the largest amount of information exists on likelihood of conversion to dementia from various MCI clinical subtypes. Some evidence suggests that those with multi‐domain amnestic MCI appear to be at greatest risk for future dementia (Di Carlo et al., 2007, Palmer et al., 2008, Tabert et al., 2006), whereas others indicate that amnestic MCI places one at highest risk for conversion to dementia (Ravaglia et al., 2006, Yaffe et al., 2006). Amnestic MCI subtypes do seem to impart significant

MCI and Health Variables

Understanding any additional health factors that may be more prevalent in distinct MCI subtypes is also noteworthy as a way to further delineate risk profiles. For example, cardiovascular risk factors, presence of the apolipoprotein ε4 allele, mood symptoms, and parkinsonian symptoms have all been investigated in MCI subtypes. Recent research has shown that multi‐domain or non‐amnestic MCI subtypes may be more likely to have cardiovascular risk factors than either those with single domain

Daily Functioning and MCI

Embedded in the controversy surrounding the establishment of specific diagnostic criteria for MCI, there is much debate regarding whether impairment in everyday activities should be included as a criterion. In its initial conceptualization, MCI guidelines required that functional abilities remain intact (Petersen et al., 1999) as this specific criterion helped distinguish MCI from dementia. However, as Farias et al. (2006) note, cognitive and functional deterioration clearly occurs over the

Structural MRI

In determining the clinical viability of the various clinical subtypes, many would assert that different subtypes should have distinct neuropathology or different courses of change in brain integrity. Certainly, structural neuroimaging provides a non‐invasive way to begin to examine brain changes associated with MCI, and there is emerging evidence to support distinct neuropathological profiles in clinical subtypes of MCI. Whitwell et al. (2007) found that those with amnestic presentations

Treatment

One motivation to better understand the heterogeneous concept of MCI and the risk it imparts for future development of dementia is to provide early interventions that could halt or at least slow progression of symptoms. To date, unfortunately, there are no FDA‐approved therapies for MCI. Further, aMCI has received all the attention with regard to treatment trials with no trials investigating other distinct clinical subtypes of MCI. Of the existing treatment trials in MCI, most have used a

Conclusions

MCI remains a heterogeneous concept, though division of MCI into distinct clinical subtypes serves as a promising approach to better understanding MCI as a diagnostic entity and a risk factor for future cognitive decline. Evidence to date suggests that multi‐domain amnestic presentations are more prevalent than either single domain amnestic or multi‐domain non‐amnestic presentations, though relatively little attention has been paid to the latter subtype. Converging neuropsychological, daily

Acknowledgments

This work was supported by grants from the National Institutes of Health (K24 AG026431, R01 AG012674, and P50 AG05131), by Career Development Awards from the Department of Veterans Affairs, and by Investigator‐Initiated and New Investigator Research Grants from the Alzheimer's Association. The authors gratefully acknowledge the assistance of staff, patients, and volunteers of the UCSD Alzheimer's Disease Research Center, and the UCSD Laboratory of Cognitive Imaging.

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