Aims and Hypotheses
4.1 Rationale for study
As shown in this review of the literature, the clinical utility of SMC to identify subjects who develop dementia is unclear. SMC have been related to many different cognitive outcomes. These include retaining normal cognitive function, a fluctuating cognitive performance and the development of a full dementia syndrome of the Alzheimer’s type (Gallassi et al., 2008;
Glodzik-Sobanska et al., 2008; Jungwirth et al., 2008; van Oijen et al., 2007).
Much of what is currently known about SMC has been obtained from studies that have predominantly used older subjects, brief screening instruments or a limited range of tests (Geerlings et al., 1999; Palmer et al., 2003). Also, a majority of these studies have recruited subjects from ongoing studies on healthy ageing, such as the Maastricht Ageing Study by Mol et al. (2006) or the Iowa 65 + Rural Health Study by Purser et al.
(2006). These studies have not employed fully comprehensive cognitive assessments. It remains unclear whether the use of SMC can predict the subsequent development of cognitive impairment in subjects under the age of 70 years.
The studies reviewed have differed in their methodology, which may also account for the observed discrepancies regarding the role of SMC in cognitive impairment.
Firstly, many studies have examined memory complaints in older subjects over the age of 70 (e.g., Palmer et al., 2003; Jungwirth et al., 2008). Since the prevalence of SMC increases with age, some of these findings may reflect normal ageing rather than the effects of memory complaints on cognition. Much less is known about the role of SMC in younger subjects under the age of 70 years. Current available evidence examining younger subjects is scarce (Cargin et al., 2008; Dufoil et al., 2005; Jorm et al., 2004; Rouch et al., 2008) It is not known whether memory complaints are useful in predicting dementia in younger subjects.
In addition, many of the studies reviewed have used simple measures of global cognitive functioning (e.g., MMSE). The MMSE is considered to be insensitive for identifying both MCI and dementia (Tariq et al., 2006). This is relevant because the initial deficits are often subtle (Clement et al., 2008) and can be missed by the use of these tests. Based on earlier evidence provided by Solomon et al. (2002) the MMSE may be more appropriate for identifying individuals in the later phases of the disease. Many studies do not consider a wider array of cognitive tasks. This limits the available evidence regarding the role of SMC in cognitive function. The few studies that have used several neuropsychological tests to examine other cognitive domains frequently report domain specific associations, even when no
impairment on the MMSE is apparent (Jessen et al., 2007; Minett et al., 2008; Mol et al., 2006; Rouch et al., 2008).
Finally, a methodological issue relates to the techniques used to quantify SMC. These have varied widely across studies. Some use a single question; others employ questions about everyday abilities, or memory questionnaires. This has rendered comparisons between studies difficult. Of the studies reviewed, the use of questionnaires has to lead to the exclusion of subjects who did not meet the threshold for having SMC, despite reporting a memory complaint (e.g., Mol et al., 2006; Wang et al., 2004a).
The current study was specifically designed to address these issues.
The main aim of the present study was to identify subjects who are at greater risk of developing Alzheimer’s disease at an earlier age, based on their risk profile and neuropsychological assessment. Therefore, this study examines the role of SMC as well as established risk factors (i.e. age, family history) on cognitive function using a comprehensive neuropsychological test battery. These tests assessed cognitive processes thought most likely to be impaired in the early phases of a dementia of the Alzheimer’s type.
To identify subjects at greater risk of developing Alzheimer’s disease at an earlier age, community-dwelling subjects (aged from 50-79) were recruited. GP referrals, or those under the care of a specialist in a memory clinic, are likely to have a more advanced stage of cognitive impairment or dementia and were deemed to be unsuitable candidates for this study.
As SMC has been linked with an increased risk of cognitive decline and dementia (Jungwirth et al., 2008; Gallassi et al., 2008; Geerlings et al.,
1999), this study recruited subjects from the community with SMC.
However, as SMC has also been linked to different psychoaffective states, a well-validated episodic memory task was used to further classify the subjects into three groups (discussed below). This occurred after the initial analysis of both subjects with SMC and without SMC.
As reviewed in Chapter 2, there are many risk factors which contribute to an increased risk of Alzheimer’s disease. Therefore, this study applied exclusion criteria to minimise the possibility that SMC were due to other psychiatric (e.g., depression) medical conditions (e.g., stroke), drug or alcohol problems and head trauma. However, subjects with mild (non-major) depression were not excluded because we were also interested in examining the relationship between SMC and mild depression.
To maximise the possibility of identifying subjects with an increased risk of Alzheimer’s disease, subjects were screened to identify their ApoE genotype. The present study was also interested in examining whether the ApoE ε4 affects cognitive function over time in subjects with SMC. Previous research indicated that over a 33 month interval, ApoE ε4 carriers aged between 50 and 59, showed a modest decline in memory skills from the age of 50 onwards (Caselli et al., 2004). There have been few studies that have examined the effect of the ApoE ε4 and its association with cognitive decline using younger subjects (Caselli et al., 2004; Christensen et al., 2008; Jorm et al., 2007), especially in subjects with SMC (Cargin et al., 2008).
As discussed in Chapter 3, deficits in episodic memory, especially in delayed recall, appear to be sensitive early clinical indicators of the
Alzheimer’s dementia prodrome (Andersson et al., 2006; Howieson et al., 2008; Guarch et al., 2008). Therefore, performance on the delayed recall task was used to classify subjects as having normal memory, SMC or aMCI.
It is important to emphasize that in the present study subjects with aMCI were not defined using the strict criteria of Winblad et al. (2004). To maximise subject numbers, those with impairment in other cognitive domains were not excluded. All subjects were classified according to their performance on delayed recall and response to a single question on memory difficulties. A more detailed discussion of group classification is provided in Chapter 5 (Methods).
4.2 Aims and Hypotheses The aims are as follows:
1. To determine whether age and/or other factors such as mild depression influence the relationship between SMC and objective measures of cognitive function;
2. To ascertain whether the DRS or 7MS are sensitive screening tools to identify MCI;
3. To examine whether the presence of SMC affects the 3-year cognitive outcome of subjects
4. To examine whether the ApoE ε4 affects cognitive function over time in subjects with SMC.
Hypotheses
The hypotheses related to these aims are as follows:
1. Subjects with SMC will demonstrate significant cognitive impairment on formal neuropsychological assessment compared to those without SMC;
2. There is in existence screening tests that are both sensitive and relatively easy to administer and can be used to potentially identify subjects with MCI;
3. Subjects with SMC will demonstrate evidence of worsening cognitive function over a 3-year interval;
4. Subjects with SMC and the ApoE e4 allele will show evidence of worsening cognitive function over time;
The next chapter describes in detail the neurocognitive test battery used for the formal clinical assessment of cognitive function and discusses the different aspects of memory and cognition measured by each test. It also lays the foundation of the pattern analysis for assessing deficits to single and multiple cognitive domains.