In this study, we assessed the impact of clinical, neuropsychological, and MRI measures on incident dementia within a heterogeneous group of MCI patients that included 23 individuals with CVD-related brain injury. Many of these individuals also had multiple vascular risk factors consistent with previous epidemiologic studies that report increased risk for MCI in association with CVD.12
Given that vascular risk factors are known to increase the likelihood of both MCI and expressed dementia, we hypothesized that clinical and MRI estimates of CVD would significantly contribute to incident dementia within this more broadly defined group of MCI individuals. Despite recruiting a more diverse cohort of MCI patients, including those with substantial CVD, however, average memory performance for the group was 77.4 ± 16.5 or approximately 1.5 SD below normal. In addition, the relation between memory performance and yearly rate of progression to dementia was nearly identical to previously reported studies.6,34
Finally, multivariate analyses found that neuropsychological testing of memory and executive function best predicted those MCI patients who would convert to dementia over the 3.1-year period of observation. From these results, we conclude that even moderate amounts of CVD (as evidenced by vascular risk factors, subcortical stroke, MRI lacunes, or extensive WMH) do not substantially alter the clinical course of MCI when memory impairment is significantly less than normal. Moreover, neuropsychological measures better predicted conversion to dementia than did a variety of MRI measures. Role of CVD.
Whereas considerable epidemiologic evidence suggests that cerebrovascular risk factors are associated with various types of dementia, including AD,35-40
only limited prospective information exists regarding the impact of CVD on incident dementia.20,41
In one of these studies,41
qualitative estimates of white matter lucencies (leukoariosis)42
seen on x-ray CT were associated with increased risk of progression to dementia within a group of 27 MCI patients. The extent of leukoariosis was estimated according to a previously published assessment scale.43
With use of this scale, approximately one-half of the subjects had leukoariosis on CT. Individuals converting to dementia had leukoariosis scores nearly five times those who did not, and 7 of 8 subjects converting to dementia had leukoariosis on CT as compared with 5 of 19 who did not convert.41
Linear measures of medial temporal lobe were also significantly associated with progression. The authors conclude that both cerebrovascular and AD processes likely contribute to dementia progression among cognitively impaired individuals. Although it is difficult to compare qualitative estimates of leukoariosis defined by CT to WMH volumes determined from MRI, it is generally believed that white matter abnormalities are more severe when detected by CT. It is possible, therefore, that the group examined in this study41
included individuals with more severe CVD than did our group, suggesting that a threshold of cerebrovascular brain injury may be necessary to impact on cognition.14,44
Although our own data lend some support to this hypothesis, as individuals categorized as having “high” WMH volumes showed an intermediate rate of progression to dementia, the prevalence of clinical stroke, number of MRI lacunes, and number of vascular risk factors were actually lower in those who converted to dementia. Moreover, large WMH volumes were relatively uncommon in our group (only 16 MCI patients, of which there were only 4 converters), reducing the power to detect an effect. Finally, these authors41
made no mention of prevalent cerebrovascular risk factors, clinical stroke, or lacunar infarctions, further limiting comparison to the group reported here.
A second study20
had both a larger cohort (1,015 participants) and a more consistent 3-year duration of follow-up as compared with our follow-up duration that ranged from 10 months to 6 years. The prevalence of MCI, however, was not determined within their dementia-free cohort. A total of 30 individuals converted to dementia (approximately 1%/year). Prevalent silent lacunar infarction and incident silent lacunar infarctions were both associated with an increased risk to develop dementia or rapid cognitive decline, although this was particularly true for individuals with incident lacunar infarction.20
Interestingly, memory performance did not decline significantly for individuals with incident lacunar infarctions. Finally, the prevalence of APOE4
genotype was much lower in this group of nondemented elderly20
as compared with the individuals reported here.
Contrasting the results of these studies examining the impact of MRI measures of CVD on incident dementia20,41
with our own data raises interesting questions about the role of CVD on progression from MCI to dementia. Although it is evident that CVD can cause cognitive decline13,14,16,20
and is more prevalent among individuals with MCI,11,12
for this small group of individuals, CVD did not appear to influence progression to dementia when memory impairment was severe. One explanation for our inability to detect such a relationship may have been our use of the CDR23,24
as the outcome measure. This scale emphasizes memory-related cognitive impairments common to AD. CVD does not appear to impact significantly on memory performance as shown by our data and data previously reported.20
Future studies of individuals with more severe CVD using outcome measures less dependent on memory performance may help to reconcile the differences between our own study and those previously published. Selection bias may be another explanation. All subjects were recruited to this study through memory impairment clinics, and average memory performance was significantly reduced compared with normal. Moreover, the prevalence of APOE4
genotype was substantially enriched in this group of subjects, likely reflecting the selection bias of referrals to memory disorder clinics and suggesting a high probability of coincident AD. Therefore, despite our attempts to broaden the sample through inclusion of individuals with substantial vascular disease, use of memory impairment clinics for recruitment may still have resulted in our sample being enriched with individuals having considerable coincident AD. Future studies with either a community-based sample with more typical distributions of APOE4
or a sample enriched for nonmemory impairment (e.g., impaired in executive performance alone) may better serve to examine the impact and time course of CVD on cognitive decline and progression to dementia. A final explanation may be that CVD exerts a more pernicious effect on cognition. For example, CVD may take years to move an individual from normal cognition through MCI and on to dementia. The brief observation period used in this study, therefore, may favor identification of prognostic factors for neurodegenerative diseases such as AD where progression is likely to occur quickly. Future analysis of this cohort after a longer observation period may better elucidate the impact of CVD on dementia incidence.
Neuropsychological vs MRI measures to predict progression of MCI to dementia
A number of studies have examined clinical and imaging predictors associated with increased risk to convert from MCI to dementia,6,34,45-49
but we are unaware of any previous study to directly compare neuropsychological performance to MRI measures within the same group of individuals.
Substantial evidence from quantitative MRI studies suggests that HC atrophy is present before dementia onset46,47,50
and progresses with progression to clinically apparent disease.51
A large prospective study of MCI patients47
found a fourfold increase in the percentage of individuals converting to dementia within 5 years when HC size was 2.5 SD below ageand gender-defined norms. Similar findings were noted in a second study, although memory scores were also significant predictors.46
Another study using qualitative estimates of HC size found similar results.52
Similarly, reports of neuropsychological testing among individuals with MCI suggest that the severity of memory impairment strongly predicts progression to dementia,6,53
although associated deficits in language or impairments in other cognitive domains may contribute to more rapid progression.34
It appears, therefore, that the more closely cognitive impairments are to AD, the greater the likelihood an individual will progress to dementia, particularly if the cognitive complaints are accompanied by care-giver reports of impaired daily function.54,55
As HC volume is associated with AD pathology and surviving neurons52,56
as well as memory impairment,57
it would be expected that neuropsychological testing and MRI measures should show comparable and highly correlated associations with dementia progression. Although our data do show significant associations between HC measures and memory performance, it is not at all surprising to find that impairments in both memory and executive performance—indicative of individuals closer to the clinical definition of dementia—were better predictors of dementia progression. There are a number of plausible explanations for this finding. For example, our measures of HC may have been less accurate than those of other reported studies.46,47,50,58
This seems unlikely given that approximately 50% of our “low” HC group converted to dementia in 3 years, a figure remarkably similar to other published results.47,58
Alternatively, the neuropsychological measures may capture processes not accurately measured by the more discrete MRI measures. For example, memory impairments are known to occur from vascular disease through disruption of frontal cortical systems59
that would not be accounted for by HC measurement. Moreover, subtle cognitive impairments related to WMH may be captured by executive function measures21,60
that could impact additively on likelihood to convert to dementia. Whatever the explanation, it appears the neuropsychological assessment of memory and executive function is a better predictor than MRI measures of progression to dementia within a group of MCI patients with prominent memory impairment.
We therefore conclude that among a small group of broadly defined MCI patients, including individuals with substantial amounts of CVD, the presence of impairments in memory and executive performance best predicted future likelihood of progression to dementia. These results likely reflect the strong effect of the AD process when MCI individuals have substantial memory impairment but may also reflect the clinical utility of neuropsychological measures to more fully describe individuals at risk for progression when AD is the suspected cause for MCI. Moreover, these findings support the notion that the concept of MCI is applicable to the general population where comorbid diseases such as CVD are common. Future studies of a larger cohort of MCI patients with nonmemory impairment and a normal prevalence of the APOE4 genotype may help to clarify the impact of CVD on incident dementia among MCI patients. Until further information is available, however, the presence of moderate WMH, subcortical stroke, or MRI evidence of lacunar infarction does not appear to impact substantially on the course of MCI patients presenting with substantial memory impairment. In addition, this small study does not offer conclusive evidence for quantitative MRI assessment of HC or cGM to identify individuals at high risk for progression to dementia among a group of MCI subjects identified as having substantial memory impairment and a high prevalence of APOE4 genotype.