This study examined both total ventricular volume at baseline and ventricular enlargement over six months using a large ADNI subset of NEC, subjects with MCI and subjects with AD. Both AD and MCI subjects had significantly greater mean baseline ventricle volumes compared to controls. However, considerable overlap between individuals existed between all groups. Statistically significant ventricular enlargement was observed in all groups after six months. Subjects with AD had a 60% greater ventricular enlargement compared to subjects with MCI and a 4-fold greater enlargement compared to NEC measured over a six-month interval. In the MCI group, ventricular volume and ventricular enlargement were associated with baseline cognitive scores and cognitive decline, while in the AD group ventricular enlargement was associated with baseline cognitive score. After dichotomizing the MCI group based on clinical status at six months, those individuals who progressed to AD had greater ventricular enlargement and lower MMSE scores on average after six months.
Raw T1-weighted images (without gradient warp correction, B1 correction, N3 correction, or phantom scaling correction) were used for the analyses. Ventricle volume measurements from these images were highly reproducible within and between raters. Additionally, comparison to scaled and corrected images using a subset of data produced very high inter-class correlation coefficients suggesting that the raw images provided comparable measurements to the phantom-scaled and corrected images–with respect to the measurement of ventricular volume. These data suggest that our ventricular volume marker is robust to scanner inhomogeneities and supports the use of either raw images or the corrected images for this metric. The robust nature of the measurement is in part due to the geographical position of the ventricles near the centre of the brain which places this structure near the magnetic isocentre where gradient non-linearities are minimized.
The primary outcome in this study is absolute ventricular change. A previous study has concluded that absolute rates of change are more statistically efficient measures than normalized change (Vickers, 2001
) and demonstrated that fractional change or percent change from baseline does not correct for imbalance between groups at baseline. Percent change measures may also create a non-normally distributed statistic from normally distributed data (Vickers, 2001
). In the current study, normalized ventricular change was found to be a less efficient metric, as there was more variation relative to the mean for the normalized ventricular change data in comparison to the absolute ventricular change measures.
The finding that subjects with MCI have similar total ventricular volumes to subjects with AD, suggests significant levels of atrophy may occur in the brain prior to a clinical diagnosis of dementia. Nevertheless, there was large overlap in volumes between both pathological groups and controls, which corroborates other cross-sectional volumetric studies (). However, only one other cross-sectional study in reported baseline ventricular volume in MCI subjects (Giesel et al.
). A gender difference did exist within both the MCI and AD study groups, however, there were no gender differences between groups; thus, it is unlikely that skewed gender ratios affected the volumetric results.
Absolute baseline ventricular volumes and annual or annualized rate of lateral ventricular enlargement reported in the literature
The mean rates of ventricular enlargement for the NEC and AD group in this multi-centre study are consistent with previously published single-centre measures (). The MCI group had a rate of enlargement intermediate to the difference between the NEC and AD groups. The large intra-group variance in both cross-sectional and six-month longitudinal data may reflect biological differences within and between subgroups, which has been characterized in other studies (Wang et al.
; Giesel et al.
). Specifically, cross-sectional measures in the current study reveal relatively large variations across all groups, which suggest large morphological differences among individuals. The AD group had particularly large ventricular variation compared to NEC subjects at baseline. This result suggests that the pathology of dementia and rate of atrophy varies widely within AD subjects. In addition, there is a large variation in ventricular enlargement within pathological groups in comparison to control subjects, which is likely attributable to differential rates of disease progression (slow and fast progressors) and disease severity.
The subset of subjects with MCI at baseline who progressed to AD after six months demonstrated nearly twice the rate of ventricular enlargement compared to stable MCI subjects. Progressors presented a similar rate of enlargement to that of subjects with AD. Mild cognitively impaired subjects that progressed to AD also demonstrated cognitive decline measured by the MMSE. Thus, absolute ventricular enlargement is demonstrably sensitive to clinically measured disease progression over short intervals in a multi-centre study. This result supports the notion that longitudinal absolute measures of structural change measured over a set interval may provide more predictive value of progression from MCI to AD than cross-sectional volumes. However, a previous single centre study by Jack et al.
with relatively small sample sizes did not show a significant difference between the percent ventricular enlargement of subjects that converted from MCI to AD and subjects with stable MCI (Jack et al.
). They did, however, see a significant percent change difference between these groups for whole brain atrophy (Jack et al.
). In the current study, the MCI progressor group did not have a significantly different change on the ADAS-cog when compared to the MCI stable group. However, decline as measured by an increase in ADAS-cog score, was moderately associated with ventricular enlargement. This suggests that as cognition worsens on global cognitive measures, there is associated macroscopic loss of brain tissue.
The current study demonstrates that AD carriers with at least one ε4 allele have a pronounced increase in ventricular enlargement, in the absence of detectable cognitive differences, in comparison to ε4- subjects. There were no differences in ventricular change between MCI genotypes; however, the rate of cognitive decline was greater for ε4+ MCI subjects. These results suggest a pronounced effect of the APOE ε4 gene on cerebral atrophy for mild AD. A recent comprehensive qualitative review lists only four previous cross-sectional studies and one longitudinal study examining the association between ventricular volume and APOE genotype (Cherbuin et al.
). The only reported longitudinal study found no difference between APOE genotypes within an AD group, although it found a greater rate of enlargement in ε4 carriers with other dementias in comparison to non-carriers (Wahlund et al.
); however, this study used manual methods, was based on a small sample of AD subjects and examined a younger AD group with greater cognitive deficit measured on the MMSE than the current study. The majority of studies that incorporate an AD group are cross sectional and thus fail to capture the association of APOE and dynamic structural changes in subjects with AD. Measures of change are important when considering the heterogeneity of ventricular volumes among all AD subjects at baseline. A longer follow-up interval may also demonstrate more appreciable difference in structural brain changes between MCI and NEC APOE groups.
The temporal horns of the lateral ventricles are adjacent to paralimbic tissue and demonstrably capture changes in these regions, which are pathologically susceptible during the prodromal stages of dementia (Chetelat and Baron, 2003
). A previous study of surface map changes in the temporal horns of controls and subjects with AD found regional enlargement correlates to disease progression (Thompson et al.
). A recent ventricular subfield analysis of subjects with AD, however, postulates there are several other hemispherical brain structures contributing to ventricular dilatation in conjunction with MTL structures (Ferrarini et al.
). This result is congruous with the topographical staging of cerebral neurodegeneration delineated by Braak and Braak in subjects with AD (Braak and Braak, 1994
). Hence, the total lateral ventricular measures may capture hemispherical atrophy in conjunction with MTL atrophy, which analysis of strictly the temporal horns would exclude. These more global lateral ventricular enlargement measures, may explain the significantly greater rates of enlargement in subjects with AD compared to patients with MCI. Furthermore, one study found that a robust measure of temporal horn volume incorporated total lateral ventricular volume (Giesel et al.
). Thus, total lateral ventricular volume may be the most sensitive single measure to discriminate enlargement between NEC, subjects with MCI and subjects with AD over short durations.
An important application of volumetric MRI measurements of disease progression is towards evaluating drug therapy in AD multi-centre clinical trials, and during prodromal stages of dementia, notably in subjects with MCI. In addition, measures at short intervals, for example six months, expedite the process of drug innovation. Currently, cognitive scores are used as endpoints in clinical trials. Neuroimaging is increasingly used to evaluate structural changes in response to therapeutic intervention. In the current study, the AD group had a stable mean MMSE score after six months, which may be ascribed to the efficacy of therapeutic interventions to ameliorate cognitive symptoms over short durations, as the majority of AD subjects were administered cholinesterase inhibitor therapy. However, the same group did have an increase in mean ADAS-cog score, which is a more sensitive cognitive measure. The MCI group demonstrated both a modest average increase on the ADAS-cog and decrease on the MMSE over the same time interval. Ventricular volume changes were also detected in these groups during this period. Sample sizes needed to detect ventricular enlargement for MCI subjects and AD subjects were lower than the sample sizes required when using psychometric measures to detect changes from the natural history of cognitive or functional decline (). The smaller sample size derived from structural measures is due to the lower variability in measures of ventricular volume compared to the change in neurocognitive scores. Moreover, high education levels and the prevalent use of cholinesterase inhibitor therapy in conjunction with the use of Memantine, may partially explain the relatively large samples required to detect a 20% reduction in the rate of decline as measured by the MMSE and ADAS-cog (). Thus, ventricular volume can provide complementary insight into insidious disease progression in the absence of cognitive decline. Moreover, there is recent evidence to suggest ventricular volume may provide additive diagnostic utility to other neuroimaging measures (Jack et al.
There are several threats to the internal validity of neurocognitive tests that short testing intervals may exacerbate (van Belle et al.
). Furthermore, certain individuals may develop greater cognitive reserves in response to longer durations of education and/or cognitively demanding occupations (Sanchez et al.
), which may generate high cognitive scores despite underlying disease progression. In summary, neurocognitive measures require greater samples to detect significant cognitive decline in patients, particularly in subjects with mild AD over short intervals, whereas measurements of ventricular dilatation may provide insight into AD progression, particularly for multi-centre studies.
Furthermore, pharmacogenetic interactions may mediate the efficacy of certain therapeutic agents (Farlow et al.
; Bizzarro et al.
; Frankfort et al.
). There are several retrospective studies (Farlow et al.
) and a few prospective studies (Bizzarro et al.
; Frankfort et al.
) that have examined the differential cognitive response to cholinesterase inhibitors between APOE genotypes; however, the results are equivocal with varying methodologies. In addition, there is some evidence to suggest ε4+ subjects with MCI have greater cognitive response to Donepezil (Petersen et al.
). Nevertheless, there are few studies examining structural brain changes between APOE genotypes in response to treatment (Bigler et al.
; Wilcock et al.
; Bizzarro et al.
; Visser et al.
; Blesa et al.
; Frankfort et al.
). The current study demonstrates greater ventricular enlargement in AD subjects with an ε4+ genotype and supports the notion that dichotomizing subjects based on genotype may provide the greatest sensitivity to detect changes in the natural history of disease progression (). Although it is possible that temporal effects (time since diagnosis), age of sample and disease severity may alter APOE and therapeutic interactions, fewer subjects are required when examining ventricular differences, particularly for ε4+ genotypic groups. In addition, there was a significant association between ventricular enlargement and cognitive decline observed in ε4+ subjects with MCI. This association was not demonstrated in ε4− subjects, and suggests that the ε4+ subjects are driving the significant association between ventricular enlargement and cognitive decline demonstrated when pooling all subjects with MCI.
In summary, absolute ventricular volumes and ventricular enlargement measured over a six-month interval were greater in subjects with AD and MCI compared to age-matched controls. Ventricular enlargement also demonstrated sensitivity to disease progression by way of discriminating between subjects with stable MCI and those that progressed to AD. Further, ventricular enlargement demonstrated effects of genotype on pathological phenotype in AD. As a potential measure of disease progression for multi-centre studies of both AD and MCI subjects, ventricular enlargement measures would significantly reduce the number of subjects required to demonstrate a change from the natural history of Alzheimer's disease progression.