Although not all patients with amnestic mild cognitive impairment (MCI) progress to Alzheimer's disease (AD), MCI is generally considered a preclinical phase of AD and is characterized by memory complaint by patient or reliable informant, objective memory impairment, preserved general cognitive function, essentially normal everyday functional activities, and absence of a dementia diagnosis (Gauthier et al., 2006). MCI is currently considered a strategic intervention point in the clinical management of AD and, as a result, individuals with MCI are increasingly receiving pharmacologic interventions aimed at delaying or preventing progression to AD (Petersen & Morris, 2005; Sherwin, 2000).
The marked functional and behavioral deficits that characterize AD have stimulated research into the functional characteristics of patients with MCI (Griffith et al., 2003; Ritchie et al., 2001; Tuokko et al., 2005). Studies show that individuals with MCI experience mild decrements in the performance of everyday activities compared with healthy older adults (Griffith et al., 2003; Tuokko et al., 2005) and that such emergent functional restrictions may predict subsequent progression to AD (Tabert et al., 2002).
Medical decision-making capacity (MDC), hereafter also referred to as treatment consent capacity or consent capacity, represents an important functional domain to investigate in MCI (Okonkwo et al., 2007). Loss or diminution of MDC raises a range of ethical and medical–legal issues for patients with dementia, and for surrogate decision makers, healthcare professionals, and society as a whole (Marson et al., 1995b). There is unequivocal evidence in the literature that consent capacity is compromised in some AD patients even in the very early stages of the disease (Karlawish et al., 2005; Kim & Karlawish, 2003; Marson et al., 1995b; Moye et al., 2004). Recently, our group investigated consent capacity in patients with MCI (Okonkwo et al., 2007). We found that, as a group, patients with MCI also demonstrate impairments in MDC. Specifically, patients with MCI exhibited significant impairments on complex and clinically relevant consent standards of appreciating consequences of treatment choice, providing rational reasons for treatment choice, and understanding the treatment situation and choices (Okonkwo et al., 2007).
An important research question concerns the cognitive mechanisms that underlie MDC impairments in MCI. Neurocognitive studies have the potential to improve our understanding of the relationship between cognitive impairment and functional loss in MCI by illuminating specific cognitive processes essential to discrete consent abilities. With regard to MDC, such studies can alert clinicians to specific cognitive impairments threatening consent capacity in MCI. In turn, these findings can facilitate the development of enhanced consent procedures for persons with MCI (Gurrera et al., 2006; Marson et al., 1996; Mittal et al., 2007).
In this study, we investigated cognitive predictors of MDC in a well-characterized sample of patients with MCI using an objective capacity measure and a standard neuropsychological battery. We also sought to identify cognitive predictors of MDC in groups of healthy older adults and patients with mild AD to provide reference points on the dementia continuum for understanding the findings in the MCI group. We expected to find that measures of memory would be primary predictors of MDC in MCI, whereas a combination of executive and memory measures would predict performance in the mild AD group.
Providing informed consent to treatment is a complex decision-making task that is subserved by multiple neurocognitive abilities related to type/stage of disease and to the consent standard under examination. Some cognitive abilities that have been implicated by prior research include verbal reasoning, verbal memory, executive function, and semantic knowledge (Dymek et al., 1999; Marson et al., 1996; Moye et al., 2007). In the present study, we sought to identify cognitive models of MDC in patients with MCI, and in control and mild AD groups. In the context of neurodegenerative dementias like AD, understanding is the most stringent consent standard, requiring comprehensive factual knowledge and understanding of the treatment situation and choices (Marson et al., 1996). Within the MCI group, we found that a measure of delayed verbal recall (Logical Memory II) was the primary predictor of this consent ability. Secondary predictors were a measure of high-load verbal learning (CVLT-2 Total Recall score) and an executive measure of visuomotor tracking, processing speed, planning, and mental flexibility (Trails 3). In contrast, among mild AD patients the primary predictor of understanding was a measure of processing speed and visuomotor tracking (Trails A). Secondary predictors were a measure of simple memory (DRS-2 Memory) and a measure of immediate verbal recall (Logical Memory I). For control participants, the only predictor of understanding was the complex executive measure Trails 3.
The neurocognitive models for understanding were similar for MCI and mild AD groups, with measures assessing memory, executive function, and processing speed emerging as predictors in both groups. This finding suggests that the ability of preclinical and mild AD patients to comprehend a treatment situation and its associated risks and benefits is primarily undergirded by memory, executive function, and processing speed. Executive function also predicted performance on understanding among controls. Taken together, these findings are consistent with our knowledge of the understanding consent ability. Because it is highly factually intensive, successful performance on understanding demands that the individual be able to mentally process, comprehend, encode, organize, and initially consolidate fairly complex medical information presented to them, and to recall this information on demand shortly thereafter. Disruption of any of these cognitive abilities, either as a function of normal cognitive aging (Dodge et al., 2006; Salthouse, 1996) or of a dementing disorder (Okonkwo et al., 2006; Tuokko et al., 2005) threatens the integrity of this consent ability. For the MCI group, the prominence of short-term verbal memory predictors suggests that their primary amnestic deficit is the key factor affecting performance on this standard.
Reasoning is also a demanding standard that evaluates an individual's ability to reason about the relative risks and benefits of various treatment options and to arrive at a decision on the basis of this comparative process (Appelbaum & Grisso, 1988). On this standard, a measure of high-load verbal acquisition/recall (CVLT-2 Total Recall score) was the primary predictor within the MCI group, whereas an executive measure (Trails 3) was the secondary predictor. Among patients with mild AD, the primary predictor of reasoning was a measure of semantic word fluency (Semantic Fluency), and the secondary predictor was immediate visual memory recall (10/36 Immediate). Semantic word fluency tasks involve the generation of words belonging to specified categories within a limited time period (Lezak et al., 2004). They are characterized as executive in nature; rely on higher order cognitive processes such as initiation, conceptual reasoning, self-monitoring, and cognitive flexibility; have been linked to frontal lobe functioning; and are known to be impaired in AD (Henry & Crawford, 2004; Lezak et al., 2004; March & Pattison, 2006). We also note that impairment on measures of semantic fluency, relative to phonemic fluency, is a hallmark of AD (Murphy et al., 2006; Taylor et al., 2005). Therefore, it is likely that the emergence of Semantic Fluency as the key predictor of reasoning in mild AD also reflects the impact of degradation in semantic networks on reasoning abilities regarding medical information.
Taken together, the MCI and mild AD models for reasoning suggest that cognitive difficulties related to memory, executive function, and semantic knowledge underlie diminishing ability to reason about a treatment choice. Cognitive measures of memory and executive function are relevant to reasoning, because this standard requires the individual to both recall the various risks and benefits of each treatment option, and to logically and comparatively weigh this information in explaining his/her treatment decision. The present findings are generally consistent with evidence from earlier MDC studies by our group. In one study (Marson et al., 1995a), we found that measures of word fluency were key univariate and multivariable correlates of the reasoning consent ability among normal controls and AD patients. In another study (Earnst et al., 2000), we found that measures of semantic knowledge and memory predicted physicians' judgments of treatment consent capacity in AD patients under this consent standard.
Appreciation is a moderately stringent and clinically relevant consent standard. It calls for a person to go beyond the factual treatment information presented in the CCTI vignettes and to identify the short- and long-term personal consequences of a treatment choice (Marson et al., 1996). Performance on this standard thus requires capacities for empathy, emotional processing, social functioning, foresight, and planning (Marson et al., 1996). Such abilities have been found to be subserved by a frontotemporal network of brain regions that is compromised in AD and other degenerative dementias (Rankin et al., 2006). In MCI patients, we found that a measure of delayed verbal recall (Logical Memory II), a temporal lobe mediated cognitive ability, was the only multivariable predictor of this consent ability. Among mild AD patients, a measure tapping processing speed and visuomotor tracking (Trails A), cognitive abilities that largely have their neural substrate in frontosubcortical pathways (Denney et al., 2004; Sachdev et al., 2004) was the predictor of this consent standard. In an earlier study, we also found that measures of executive function (word fluency) and processing speed (Trails A) were very strong predictors of AD patients' performance on appreciation, jointly attaining a remarkable classification accuracy of 100% (Marson et al., 1996).
We note that of the five consent standards, appreciation had the least variance accounted for by cognitive models within the MCI (16%) and mild AD (33%) groups. This relative weakness in the cognitive models of appreciation is consistent with findings from prior studies (Dymek et al., 2001; Gurrera et al., 2006), and underscores that appreciation is the consent standard that probably relies most heavily on abilities not fully represented in the neuropsychological armamentarium (Marson et al., 1996). Consequently, performance on appreciation is less well modeled by standard cognitive measures.
In addition to the three clinically relevant standards of understanding, reasoning, and appreciation, we also examined neuropsychological models of clinically less stringent consent standards: expressing choice and reasonable choice. Expressing choice simply requires the individual to express a treatment choice, whereas reasonable choice evaluates the reasonableness of a treatment choice by inquiring whether the person made a decision that is congruent with the decision a reasonable person in similar circumstances would make. Within the MCI group, a measure of simple visuospatial construction and visual attention (DRS-2 Construction) was the predictor of reasonable choice performance, whereas among mild AD patients, immediate visual recall (10/36 Immediate) was the predictor. These findings suggest that MCI patients arrive at a “poor” treatment choice by means of disruption of attentional processes, whereas mild AD patients make a poor choice as a result of disruption of short-term memory. Mild AD patients arguably do not remember sufficient detail from the vignette to realize that a particular treatment choice is not a good option. It is notable but not entirely clear why the predictors of reasonable choice in both the MCI and mild AD models have a visual component.
Among MCI patients, no neuropsychological model emerged for S1. The multivariable predictors of S1 within the mild AD group were measures of response perseveration (CPT Perseveration) and visuospatial construction/simple attention (CLOX 2). By design and scoring algorithm, the latter measure is also sensitive to deficits in planning, organization, self-monitoring, and intrusion (Royall et al., 1998). Both measures, therefore, appear to have varying components of complex attention and simple executive function. On S1, verbal prompts are provided (and a point deduction is made) when a participant fails to make a choice, or when the initial response is vague or circuitous. A participant receives no points if they fail to provide an explicit treatment choice even after cueing. In the present study, the impaired performance of mild AD patients on S1 appears related to problems with simple attention and perseveration, resulting in both initial decisional hesitancy and a failure to use proffered cues to appropriately modify a vague response.
The convergent evidence from our neurocognitive models, across consent standards and study groups, suggests that treatment consent capacity in dementia is primarily subserved by two broad domains of cognitive abilities—memory and executive function (Marson, 2001). Other cognitive domains that also contributed to performance, especially within the mild AD group, include semantic knowledge and processing speed. Within the MCI group, memory measures were more prominent, relative to executive function measures, on all consent standards. As discussed, this finding suggests that the impaired MDC of MCI patients is primarily a consequence of their cardinal amnestic deficits. On the other hand, measures of executive function, semantic knowledge, and processing speed were more prominent in the mild AD models. However, the mild AD findings, specifically the absence of memory predictors, should be interpreted with caution. It is likely that the role of memory measures in the mild AD models was muted by floor effects—an increasingly restricted range of memory test scores. As reflected in other studies, memory impairment is a crucial, and arguably the pre-eminent, cognitive basis for declining MDC in AD (Dymek et al., 1999; Gurrera et al., 2006; Marson et al., 1997).
Our findings have several scientific and clinical implications. First, as discussed, they demonstrate the importance of memory deficits to MDC, and presumably to other higher functional capacities, in MCI. Second, it is plausible that memory and executive function processes represent a final common pathway between neuropathological changes in AD and loss of higher order functional abilities such as MDC. Specifically, neuropathological alterations in AD result in memory problems and executive dysfunction that, in turn, impact functional abilities because of information loss and diminished ability to adequately organize or manipulate residual information (Marson et al., 1997). The contributions of processing speed and semantic knowledge to consent capacity in AD are also worth noting because a valid consent entails an ability to internally process relatively large chunks of information and to ultimately communicate a treatment decision to a clinical professional (Alexander, 1988; Marson, 2001). Third, given these findings, it will be important for healthcare professionals working with MCI patients to be increasingly sensitive to the potential impact of memory and executive function impairments on informed consent capacities—both for treatment and research. Fourth, the different patterns of cognitive correlates of MDC across study groups provide insight into the dynamic way MDC is differentially impacted by diverse cognitive deficits at various stages of a dementing process such as AD. Finally, clinical strategies and interventions that address memory and executive function abilities may be helpful in enhancing the consent capacities of both MCI and mild AD patients (Moye et al., 2007; Okonkwo et al., 2007). There is preliminary evidence for the efficacy of such clinical procedures (Mittal et al., 2007).
Some limitations of this study should be noted. First, medical decisions based on hypothetical vignettes may not be fully representative of the decisions individuals might make when faced with actual, personal medical problems. We also note that, although our assignment of relative stringency to the consent standards is consistent with findings from other studies of decisional capacity in dementia (Lai & Karlawish, 2007; Moye et al., 2004, 2007), such a hierarchy has not been found in some studies conducted with psychiatric and medically ill patients (e.g., Grisso & Appelbaum, 1995). Third, because statistical regression procedures may overfit data to specific samples, it will be important for our findings to be validated in replication studies.
Finally, although we found that measures of memory and executive function were significant predictors of consent capacity, it is unlikely that all cognitive tests of memory or executive function will be equally sensitive to decrements in MDC in patients with preclinical and mild AD. Future research should use the current findings as a platform for identifying the most sensitive and specific memory and executive function measures. These can be organized into a specialized neuropsychological battery to be used, in conjunction with direct assessment capacity instruments such as the CCTI, in supporting clinician judgments of treatment consent capacity in patients with MCI and AD (Marson et al., 1997).