Volume measurements of the MTL are associated with the rate of clinical decline in a large cohort of MCI patients. This study, using fully-automated segmentation, demonstrates the novel finding that in addition to smaller baseline hippocampus, patients with smaller amygdala, or larger temporal horn declined more rapidly on two widely available clinical assessments of general cognitive and functional ability. Measures of MTL atrophy contributed to prediction beyond that provided by age, education, APOE-ε4 and baseline clinical scores. In addition to associations between hippocampal volume and baseline learning and delayed recall scores25, 26
, measures of amygdala volume and temporal horn volume were also related to memory performance.
In this study, we used fully-automated brain MR image segmentation to examine MTL volume in MCI patients, and identified an association between MTL volume and clinical decline within a 6-month interval. Previous studies using manual or semi-automated measures of segmental MTL volumes with longer follow-up times (1 year or more) have shown a significant association between rate of clinical decline and extent of MTL atrophy in elderly patients.27, 28
AD is associated with early MTL atrophy29
, and prodromal AD may underlie the memory complaints of most, but not all, amnestic MCI patients.30, 31
MCI patients with MTL atrophy may be more likely to have prodromal AD and a more rapid clinical decline. Furthermore, the extent of MTL atrophy may reflect disease severity, which also contributes to a rapid decline. Further studies with attention to long-term clinical course and pathological findings will be essential to understanding the observed relationship between MTL atrophy in MCI patients and subsequent development of AD.
Both subtypes of amnestic MCI, single-domain and multiple-domain, are known to have a high rate of conversion to AD, and were studied in the ADNI cohort. As expected, a number of MCI patients (20 out of 269, 7 %) converted to AD within the 6-month period examined at the time of this study. Interestingly, conversion rates from MCI to AD have been reported to be approximately 16 % per year31, 32
and our analysis of the 6-month ADNI data supports this finding. Prior studies have compared baseline MR image volumetry in patients who progress to AD versus those who do not.33-35
Such studies have suggested that MTL atrophy is associated with subsequent conversion to AD. The current study assessed whether MTL atrophy predicts rate of clinical decline, which may be associated with earlier conversion from MCI to AD. The results from this large multi-center sample of MCI patients are consistent with the findings reported in previous studies that typically used smaller samples and manual tracing or visual assessment techniques in evaluating hippocampal or entorhinal atrophy in prediction of conversion from MCI to AD.33-42
Few studies have evaluated amygdala atrophy and temporal horn enlargement in prediction of disease progression in MCI subjects.43-46
Neuropathological studies have implicated involvement of amygdala in AD progression.47
However, findings from previous manual volumetric studies of amygdala have been inconsistent.48
In the current study, amygdala atrophy was a significant predictor of decline as measured by MMSE and CDR SB, and remained a significant predictor after adjustment for baseline clinical scores.
Fully-automated temporal horn measurements were also significant predictors of decline as measured by MMSE and CDR SB even after accounting for age, education, and baseline clinical scores. Enlargement of the temporal horn of the lateral ventricle reflects atrophy of the hippocampus as well as atrophy of the surrounding tissue, and thus may gauge regional atrophy beyond the MTL. It remains to be seen whether such fully-automated measures are able to predict clinical decline in patients with more severe disease, such as when the pathology of AD extends beyond MTL structures. Temporal horn measures may complement hippocampal measures in predicting cognitive decline in such a group of patients. The current results suggest that temporal horn measures may provide information that is supportive to hippocampal measures in predicting subsequent decline when a memory deficit is noted, but overall level of functional impairment is mild.
In this study, treatment with AChE-I was allowed, and 45% of subjects received treatment for the duration of the follow-up or longer. Given that modest treatment effects on behavioral performance have been reported in AChE-I trials, to control for treatment effects on prediction of clinical decline, treatment status was included in the analysis. Controlling for treatment status in prediction of decline did not change qualitatively the association between MTL volumes and decline on MMSE and CDR SB. Beneficial effects of treatment could have been obscured in this study because selection of patients for treatment could have been biased towards more severe cases. In fact, the treated group had more MTL atrophy and lower baseline clinical and memory scores. However, the goal was not to study treatment effects per se, but to control for them if they exist. It is important that future studies control for AChE-I medication effects as many MCI patients receive such treatment off label.
Some limitations of this study warrant mentioning. Due to the brief follow-up period, the cohort included very few converters to clinical AD and, therefore, relating baseline volumetry to clinical conversion was not possible. In addition, the outcome measures, MMSE and CDR SB, widely used to define clinical decline, are relatively insensitive to clinical decline over a 6-month period. On the other hand, the more specialized neuropsychological batteries used to assess memory in these patients are time-consuming (approximately 3 hours) and not as widely available in all clinical settings. Though these measures have been shown to have a higher predictive value in relation to cognitive decline in some studies49
, the use of additional brain regions in the analysis44, 50
may prove to be superior when compared to these specialized tests.
This study demonstrates that fully-automated MTL volume measurement can be performed rapidly and without manual input, yielding measures that are consistent with manual tracing and that are associated with the rate of clinical decline in a large cohort of MCI patients. Association of baseline atrophy with rapid decline was noted even with the short follow-up time of 6 months. Quantitative and objective measures, such as these, may improve selection of patients appropriate for early intervention against AD, and will be especially valuable as new medications that target AD pathophysiology are developed. Given that MR imaging is widely available and is already performed on patients with cognitive impairment, fully-automated methods for subregional volume assessment may provide additional clinically relevant information at little added cost. The findings of the current study suggest that this capability may help clinicians identify which MCI patients are at greatest risk for rapid clinical decline.