Case
A 55-year-old teacher who lives alone seeks help for memory complaints. She reports forgetting the names of students and losing items around the house but has minimal evidence of functional impairment, no difficulty driving and no history of mental or physical illness. She has a history of hypertension but is otherwise well. She has previously been tested on the MMSE which revealed a score of 29/30. Testing on the CAMCOG and ACE suggest she is on the 90th percentile for her age with no appreciable objective cognitive decline. She is worried about the risk of future dementia.
Should this patient be concerned about the risk factors is the MMSE sufficient as a screening test? At this stage are further investi-gations indicated and in the absence of a formal diagnosis can anything be done to help? Subjective memory complaints (SMCs) are everyday memory and related cognitive concerns expressed by people who may or may not have deficits on objective testing. SMC are of course common in people with mild cognitive impairment (MCI) and dementia and depending of how they are defined may occur in up to 50% of the healthy elderly population although after exclusion of depression a rate of around 20-30% is more typical [1,2]. The rate of complaints in those under 55 years is very poorly studied but Commissaris and colleagues (1998) found that 39% of people with a mean age of 33.9 answered positively to the question “Do you consider yourself forgetful [3]?”, suggesting perceived deficits are probably more common than thought.
One important issue when trying to elicit SMC is that awareness of deficits generally decreases as severity of cognitive impairment increases (particularly in the most severe stages). Moreover many people who suspect cognitive problems may be reticent about disclosing them and in many cases are reluctant to undergo formal testing. For this reason informant report is strongly recommended where available, and is independently predictive of diagnosis and decline [4]. Although definitions of SMC have not been operationalised numerous several self-report questionnaires have been developed and can be used simply in clinical practice. Examples of validated tools are the Everyday Memory Questionnaire – Revised (EMQ-R) and the Short Memory Questionnaire (SMQ). It is now recognised that the presence of SMC is associated with distress and reduced quality of life [5]. Causes of SMC without objective complaints are diverse but conceptually it may be helpful to try and separate those with no evidence of cognitive impairment from those with subclinical cognitive change and those with mild cognitive impairment. A simple classification based on these three domains is illustrated (Figure 1).
Indeed psychological factors such as depression influence expression of memory complaints. Therefore perceived forgetfulness is not always a sinister irreversible finding and even when examined cross-sectionally most purely subjective memory complaints do not interfere with daily function [6,8]. Practically anyone with memory complaints should also be asked about symptoms of depression, and ideally screened with a severity questionnaire such as the Patient Health Questionnaire (PHQ9).
The prognostic significance of SMC is important but until recently poorly studied. A review identified only seven studies published up to 2000 that considered dementia longitudinally and of these five studies found an association between baseline SMC and dementia after two years or more [9]. However these studies were all in the elderly population and also did not account for baseline MCI and/or objective neuropsychological impairment. Two recent studies have been informative. Wang et al (2004) examined 1,883 subjects without dementia or objective cognitive impairment (they scored 91 or higher on the 100- point Cognitive Ability Screening Instrument) [10].126 developed dementia during five years of follow up. For subjects who reported SMCs at baseline ages of 70, 75 and 80 years, the hazard ratios of developing dementia were 6.0, 3.2 and 1.6 respectively. That is, risk was most elevated in younger groups. Additionally, a subset of people with baseline normal cognition who reported a high level of subjective deterioration had a higher risk for developing dementia (OR = 2.7; CI 95%, 1.45–4.98). In a small study Gallassi et al (2010) followed 92 SMC patients for four years stratified into those with SMC alone and those with MCI. During the follow-up, 45.5% of SMC remained unchanged, 13.9% were diagnosed as MCI and only one progressed to dementia. Of the MCI patients, 32.3% remained stable, 18.4% developed dementia and 4% reverted to SMC alone. Visual attention, behavioural memory, long-term verbal memory, apathy and caregiver distress were independent predictors of progression to dementia [11]. This preliminary data suggests a modest but significant risk of decline in older people with purely subjective complaints but no data has been forthcoming in younger adults. Our group recently conducted a meta-analysis of conversion studies. Compared to those without SMC the relative risk of progression (SMC vs healthy elderly) from these studies was 2.18 (1.48 – 3.20). More informative perhaps the annual conversion rate for those with SMC was 2.7% (95% CI 2.0% to 3.6%). A major modifying variable in determining risk in those with subjective but no objective decline is function (activities of daily living). Unfortunately this is one area that is often inadequately tested in routine clinical care, leading to the assumption that function was always normal in MCI and SMC. Whilst gross function impairment is uncommon, new research suggests an important subset are subtly impaired. Data from the Spanish Neurological Diseases in Central Spain study (NEDICES) cohort involving 1,073 participants reported SMC questions this assumption. Of 730 with pure SMC, 18.1% had significantly impaired function and 9.5% had severely impaired function measured by the Pfeffer scale [12]. It is likely, that those with SMC and impaired function are at increased risk of dementia even when symptoms present under 65 years. Clinically this means that everyone reporting SMC should also be tested for impaired function and whilst this can be done clinically it can also be useful to use an objective scale.
The clinical approach to people with possible early dementia or MCI has been extensively described elsewhere [13,14]. I would recommend putting clinically worrying SMC in that category. Clinically worrying SMC would include SMC with evidence of objective cognitive or functional decline, informant concern,evidence for early progression as well individuals with concomitant risk factors for dementia (such as concurrent vascular disease). A reasonable work up would include physical and neurological examination, neuropsychological testing and neuroimaging focussing on a standardized tests for dementia and MCI. Focalatrophy on magnetic resonance imaging (MRI) of the medial temporal region and decreased metabolism in this area as well as parietal lobes on 18F-fluorodeoxyglucose-positron-emissiontomography (FDG-PET) has been shown to predict the conversion from mild cognitive impairment to Alzheimer’s disease [15]. However imaging, in particular PET, is not widely available and CSF biomarkers may offer an alternative [16]. However no method has excellent accuracy in the earliest stages. In this case the preliminary MMSE of 29/30 is probably insufficient if there is any clinical reason for concern. The MMSE, although popular, has been found to have insufficient accuracy in the diagnosis of MCI (sensitivity 62.7%; specificity 63.3%) [17]. The accuracy of other cognitive tools is under active investigation but the reported 90th percentile score on the ACE certainly seems to rule out appreciable objective decline. Nevertheless a remaining question in this case is whether any formal intervention can be recommended. Although there is extensive data on the treatment of early dementia and modest data on treatment of MCI, there is a paucity of RCT evidence for those with memory complaints alone [18]. Work involving the asymptomatic elderly and observation of cohorts is currently inconclusive and doesn’t appear to strongly support the use of donepezil, ginkgo biloba, NSAIDs, COX-2 inhibitors, vitamin E, vitamin B6, vitamin B12, statins, hormone replacement therapy, or omega-3 fatty acids to delay progression to dementia [19,21]. Therefore whilst it is important to remember that pure SMC is not an entirely benign condition, the risk of dementia in working age adults remains to be clarified [22] and no good preventative strategies other than correcting obvious risk factors and sensible lifestyle advice currently exist.
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Clearly there are many areas of uncertainty when it comes to subjective without objective complaints and it is difficult indeed potentially misleading to give too rigid a forecast at baseline. Nevertheless in the absence of functional decline although the risk is elevated in absolute terms it is still modest (about 3% per year). This risk can not be assumed to be constant but should be re-evaluated with annual examinations. For younger people under 55 years without functional decline or cognitive impairment on neuropsychological tests (not simply the MMSE alone which is insufficient) then neuroimaging and CSF testing can be considering useful but not yet essential. A careful psychiatric history is certainly essential. Whilst we await strong evidence for preventive strategies monitoring in the form of serial bi-annual testing with a convenient battery such as the CAMCOG is recommended along with robust treatment of vascular risk factors such as hypertension.
References
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