Different mechanisms of episodic memory failure in mild cognitive impairment
Introduction
Even in the absence of dementia, many elderly persons develop a degree of cognitive loss beyond what is expected in normal aging. There are many characterizations of this intermediate stage of cognition, one of which is mild cognitive impairment (MCI) (Petersen et al., 1999). Individuals diagnosed with MCI typically have severe episodic memory deficits with otherwise relatively preserved cognitive and functional abilities. MCI was originally defined to identify individuals who are in the preclinical stage of Alzheimer's disease (AD). Given that the hippocampus plays a central role in episodic memory and is the initial target of AD pathology, many studies have focused on hippocampal dysfunction as an etiology of MCI. Indeed, there is evidence that individuals with MCI show distinct hippocampal activation patterns (Machulda et al., 2003; Small, Perera, DeLaPaz, Mayeux, & Stern, 1999) and that individuals with MCI and hippocampal atrophy (HA) have greatly increased risk of developing AD (Jack et al., 1999). Such results suggest a strong link between hippocampal dysfunction and MCI.
However, it is has also become clear that some individuals diagnosed with MCI do not have hippocampal atrophy and are not in the preclinical stages of AD, suggesting that other pathological processes are at work. Epidemiological studies suggest that MCI is heterogeneous and likely arises from multiple etiologies (DeCarli, 2003a). One possible etiology is small vessel cerebrovascular disease (CVD). Small vessel CVD is commonly seen in elderly individuals and has been associated with increased risk for MCI (DeCarli et al., 2001, Lopez et al., 2003). Rather than causing large cortical strokes, small vessel CVD is associated with small subcortical infarcts and white matter abnormalities.
These white matter changes appear on MRI as white matter hyperintensities (WMH) and are used as a marker for small vessel CVD severity in this study. WMH appear as areas of high signal intensity in deep or periventricular white matter on proton density and T2-weighted MRIs. The underlying pathology is non-specific and includes multiple types of injury to white matter such as reduction in myelination of axons, narrowing of small vessels, and gliosis (see Bronge, 2002, for review). WMH have been associated with hypertension, diabetes mellitus, and history of stroke, three risk factors for CVD (Breteler et al., 1994b, DeCarli et al., 1995).
We propose that WMH related to small vessel CVD may play a role in the episodic memory impairment characteristic of MCI. Given the evidence that WMH may be associated with frontal lobe dysfunction (Breteler et al., 1994a, DeCarli et al., 1995; Gunning-Dixon & Raz, 2003), we predicted that WMH may compromise executive control processes that are critical for working memory, which in turn may lead to episodic memory deficits and a diagnosis of MCI. This theory presupposes that if information cannot be actively maintained and manipulated at an immediate or short-term level, episodic encoding and retrieval impairments may arise. Thus, whereas hippocampal dysfunction may be associated with isolated episodic memory impairments, small vessel CVD may lead to a distinct pattern of deficits that includes both episodic memory impairment and deficits in executive control processes.
To test our hypothesis, we examined a group of individuals who were clinically diagnosed with MCI and used MRI to identify two subgroups of subjects: (1) those with severe WMH without hippocampal atrophy (MCI-WMH), and (2) those with severe hippocampal atrophy without extensive WMH (MCI-HA). Cognitive performance for each of these groups was compared to a group of age-matched control subjects. Importantly, these specific subgroups of MCI subjects were selected for the purpose of trying to understand the different mechanisms by which WMH and HA may lead to episodic memory impairment in MCI. Although there is increasing evidence suggesting that cerebrovascular disease and degenerative processes associated with AD often co-occur, the nature of the interaction is unclear and complex to study due to the difficulty of disentangling the two in standard clinical samples. Thus, we examined a highly selected sample in order to begin to understand the separate roles that each type of brain lesion may play in producing memory impairment.
The study is divided into two parts. First, we compared performance of MCI patients and controls on the neuropsychological tests that were used to diagnose MCI. This allowed us to determine whether standard neuropsychological tests used widely in clinical practice could distinguish between two MCI groups with different underlying brain pathologies. Second, we compared the performance of these subjects on a battery of behavioral tasks used widely in the cognitive neuroscience literature. The purpose of using these tasks was to attempt to understand the different cognitive mechanisms that underlie memory loss in MCI. The battery included an episodic memory task, two working memory tasks, and a version of the continuous performance test (CPT). We predicted that both groups of MCI participants would show deficits on the episodic memory task, but that the MCI-WMH group would show additional impairments on the working memory tasks and on the CPT.
Section snippets
Participant selection
This study was approved by the UC Davis IRB. All participants were recruited from the UC Davis Alzheimer's Disease Center (ADC) and were over the age of 65 years, in stable health. Exclusion criteria were limited to clinical depression, history of cortical strokes, and red–green color blindness. Five of the 11 MCI-HA participants and 6 of the 11 MCI-WMH were on stable doses of cholinesterase inhibitors. All participants received a clinical diagnosis through the ADC of either normal cognition or
Results
Demographic information, MRI measures of hippocampal volumes and WMH load, and incidence of vascular risk factors for each group are shown in Table 1. Fig. 1 depicts examples of the MRI measures used to subcategorize MCI subjects. Because the gender distribution was not balanced, especially for the control group, we looked for potential gender effects on performance of all of the tasks and did not observe any. Therefore, gender was not controlled for statistically. Although age (F = 2.353, p = .11)
Discussion
In the present study, we tested the hypothesis that among individuals diagnosed with MCI, small vessel CVD and hippocampal dysfunction give rise to different profiles of cognitive deficits. We found that although these two groups were similar on standard neuropsychological tests administered at the time of diagnosis of MCI, more detailed testing revealed reliable differences between the two subgroups of MCI subjects. Whereas MCI-HA patients exhibited relatively specific episodic memory
Acknowledgements
The authors wish to thank Jean Coleman and Esther Lara for their assistance in recruiting participants for this study. This project was supported by NIH grants P30 AG10129 and R01 AG021028 and in part by funding from the NIMH predoctoral National Research Service Award (MH-065082).
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