Both MRI and CT have been used to assess rates of global hemispheric atrophy or ventricular enlargement in AD (19
). The goals of the study were to measure the annualized rates of hippocampal volume change in different clinical groups who lie along the cognitive continuum, normal to MCI to AD, and to test the hypothesis that these rates differed as a function of initial and followup group membership. Dividing the cognitive continuum into control, MCI, and AD groups can be construed as artificial, but is commonly done for descriptive clinical purposes, for example, dividing the continuous measure of blood pressure into a normal and abnormal range. As no single test is accepted for defining discrete ranges within the cognitive continuum, we chose to use the designations of control, MCI, and AD which are ultimately clinical judgments that are derived from a number of different factors. We also acknowledge that dichotomization of the control and MCI groups into those who remained stable vs decliners is a crude way to define change in cognition because the change in cognition over time occurs as a continuous rather than a step-wise function. A patient may well have experienced a mild cognitive decline over time yet still be classified as stable if the magnitude of the decline was not sufficient to "move" him/her to a lower functioning cognitive group. However, the design of this study lent itself to reporting results in a dichotomous fashion because some patients did and some did not change group designation over the period of observation. This also corresponds to useful clinical distinctions.
While the rates of hippocampal atrophy we report were by default a linear fit to two time points, we do not mean to imply that the rates of change in vivo are necessarily linear. MRI studies were performed at two points in time in each subject, multiple MRI exams over time in each subject would be necessary to determine whether rates of atrophy are linear or non-linear. It is also possible that different non-linear functions will best fit the data in different clinical groups.
To be included in the analysis, subjects had to have two relatively artifact free MRI studies separated by 2–4 years. This requirement would exclude patients who were unable to co-operate for a followup MRI due to rapidly progressive dementia. The reported rates of atrophy in the decliner groups may therefore be underestimated, because the largest volume loss over time should occur in patients who were the most rapid clinical decliners.
To our knowledge this is the first study which describes the rates of hippocampal atrophy in MCI patients. Our data indicate that the rates of hippocampal atrophy in MCI patients are heterogeneous. Those who declined clinically had greater rates of atrophy than those who did not. With the recent recognition of MCI as a clinically important group, controversy has arisen whether every individual who meets criteria for MCI will eventually progress to AD. Is MCI simply early AD or will some MCIs remain stable indefinitely albeit functioning at a lower level than control age mates? Our data address this question. The rate of hippocampal atrophy of cognitively stable MCIs was on average significantly greater than that of stable controls and comparable to control decliners. This observation supports the idea that some proportion of MCIs who on clinical grounds appear cognitively stable over a 3± 1 year period are actually undergoing anatomic changes that differ significantly from stable controls, and therefore are progressing toward AD. However, our data also demonstrate that the rate of atrophy in MCI decliners was significantly greater than that in stable MCIs and in this respect support the notion that some patients who meet the criteria for MCI may remain relatively stable.
On the surface the term control-decliner is a misnomer. Certainly individuals who began the study as controls but declined to MCI or AD were actually in a presymptomatic phase of AD at baseline. However, they were functioning at a level which placed them into our operationally defined control category. AD pathology then progressed between baseline and followup to such an extent that cognitive impairment became clinically apparent. Prior studies on rates of hippocampal atrophy have not distinguished stable controls from control decliners. The rate which we calculated in this study for stable controls (−1.73%/year) is very close to the −1.55%/year which we calculated in a previous study (6
), and is comparable to that described for older controls (−2.09%) by another group (25
). While subjects were excluded from our study if they had experienced a stroke either before or during the observation period, none of the subjects, patients or controls, were excluded by the presence of vascular risk factors such as hypertension, cardiovascular disease, or diabetes (26
). The prevalence of these conditions therefore should be present in our subjects roughly in the same proportion as in the general elderly population. The rate of hippocampal atrophy calculated for our group of stable controls should be representative of cognitively stable elderly individuals in the general population.
The annualized rate of hippocampal volume loss in probable AD patients in a prior longitudinal study of ours was 3.98% (6
). This is close to the rate of 3.5%/yr observed in the current study. This rate was also within the range described in another study (27
) using MRI volumetrics, but less than described by a different group (28
) who measured the change in thickness of the medial temporal lobe on CT. Over the course of longitudinal clinical observation 17 members of the AD group declined to a lower functioning level as defined by an increase in CDR score, and the remaining 11 retained their baseline CDR score. This indicates the clinical heterogeneity of disease progression within this group. We elected to not analyze rates of atrophy separately for AD-decliners vs "AD-stable". AD is by definition a progressive disorder and so designating a group as "stable" ADs seemed counterintuitive.
We have previously shown however, that baseline hippocampal volume can provide predictive information about which MCIs will decline to AD vs which will remain stable (29
). In the current study as well, baseline hippocampal volumes of MCI decliners were significantly more atrophic than those of stable MCIs. A trend was present indicating that baseline hippocampal volumes were more atrophic in control-decliners than in stable controls (p = 0.09). The number of controls who converted was fairly small (n=10). We believe that with a larger sample size, the difference in baseline hippocampal volume between stable vs declining controls and may reach statistical significance. Other groups have also shown that assessments of hippocampal atrophy can provide predictive information in patients who are at elevated risk for AD(27
). Whether the rate
of hippocampal atrophy can add to this prediction is unclear and is not formally addressed in this study. However, the fact that the rates of hippocampal atrophy were significantly different between stable controls vs control decliners and between stable MCI vs MCI decliners, shows promise that the rate
of hippocampal atrophy may add additional predictive power to baseline hippocampal volume in assessing the risk of converting to AD for individual patients. This remains to be determined however, and diagnostic utility in predicting future development of AD in individuals will likely be limited by inter-group overlap.
In any individual patient the pathologic progression leading to AD may extend over decades. Sampling clinically defined groups of patients who span the cognitive continuum with serial MRI studies permits ascertainment of rates of anatomic change which are characteristic of the disease at various points in its decades–long time course. This is a potentially useful tool with which to characterize one feature of the natural history of the disease–brain atrophy.
An important consideration in assessing the utility of any biomarker is its reproducibility. In the current context the parameter of interest is the reproducibility of serial hippocampal volume measurements. In a prior study of serial hippocampal volume measurements in normal young adults we demonstrated a median coefficient of variation of 0.28% (0.02% – 0.70%) (6
). Theoretically the measured change in hippocampal volume in every elderly individual should be ≤ 0, indicating either no change or volume loss over time. In the current study, measurements in 128 out of 129 patients met this criteria. A positive change over time, an increase in volume of 0.1%, was measured in one of the patients. We attribute this to measurement error.
The data presented demonstrate a correlation between the rate of change in hippocampal volume and change in cognitive status. Serial measurements of hippocampal volume may therefore be a useful adjunctive tool to monitor the efficacy of therapeutic trials in groups of patients. If a therapeutic agent slows or arrests the anatomic progression of AD pathology, this should be detectable as a decrease in the rate of atrophy in a treated vs a placebo group. Our data also indicate that the distinction between stable vs a declining members of a group should be detectable both in early symptomatic patient groups (i.e., MCI) and in presymptomatic subjects (i.e., controls).