Alzheimer’s disease is the most common cause of dementia in elderly people, and it is a progressive disease and its prevalence is predictable to increase as populations continue to age around the world. It is associated with neurofibrillary tangles and neuritic plaques, along with other changes as well as amyloid angiopathy and age-related brain atrophy which may contribute to cognitive impairment [19].
The hippocampus was found to have a special affinity for AD pathology and considered an early site for involvement, so hippocampal atrophy is used to be an imaging marker of AD and included in the diagnostic criteria [20].
Visual rating methods used in the assessment of the volume of the medial temporal lobe and the size of the surrounding CSF spaces showed obviously that they are lacking the accuracy in anatomical segmentation, as a result has low sensitivity and specificity for distinguishing AD from normal subjects with senile changes. In other words, there were dementia subjects with minimal MTA score who have only increased width of the choroid fissure without the temporal horn dilatation and were found to have already established regionally pronounced hippocampal atrophy by volumetric means. It was noted also that cases showing some degree of temporal horn dilatation in conventional imaging could have normal volumetric studies without any significant atrophy [21].
This study aimed to identify a specific regional atrophy pattern characteristic for Alzheimer’s disease in comparison to normal age-matched control, and this could enable us to better understand the course of the disease and help in its early effective treatment. FreeSurfer software was used for automated hippocampal segmentation using the preprocessed images, after initiation of the segmentation algorithm and calculation of hyperparameters and then using the output to calculate their volumes. Volumes were normalized by the intracranial volume and the gray matter volume [22].
One of the advantages of FreeSurfer software is that it is applicable for images produced by any MRI machine. Patients were classified according to MMSE and CDR clinical examinations into mild, moderate, and severe groups. The mean age of each group was 62.4, 65.7, and 66 years for mild, moderate, and severe groups, respectively. The number of years of education was included in the criteria, and their means for the three groups were 12.2, 11.2, and 12.5 years, respectively. The patients also had mean number of years since first diagnosed as AD: 3.5, 4.7, and 6.25 years for the three groups, respectively. They had presented variable medial temporal lobe atrophy-MTA scores and white matter lesion FAZKEAS scale.
After the segmentation process of the hippocampal subfields, it was found that both subiculum and CA1 on both sides had significantly reduced volumes in AD patients relative to the control group. This finding is matching with other previous studies as Kerchner et al. [23] , Zhao et al. [24], and Trujillo-Estrada et al. [25] which suggested the involvement of CA1 and subiculum subfields in particular.
These findings were correlated with the MMSE and CDR scores. All results showed significant P value and correlation. Correlation to age was determined by Pearson’s correlation coefficient. The other subfields showed no significant volume differences between AD and controls.
This work is also matching with recent studies; Hett et al. [26] have presented in their study that CA1 and subiculum are the subfields which show the most significant atrophy in AD. Also, Zhao et al. [24] has found that significant atrophy is seen in CA1, subiculum, presubiculum, molecular layer, and fimbria subfields among subjective mild cognitive decline, amnestic mild cognitive impairment, and Alzheimer’s groups; they in turn had suggested that this could be used as a biomarker in early stages of AD. Using the same image analysis approach, Hanseeuw et al. [27] showed some difference as their study reported significant volume losses in the subiculum and CA2-3 subfields in a small group of 15 amnestic MCI subjects and 15 healthy controls.
Mueller et al. [28] evaluated correlations between subfield volumes and two different memory scores based on the California Verbal Learning Test in a mixed group including cognitively normal healthy controls with a subjective memory complaint and patients with cognitive impairment, and it was found that atrophy of CA subfields appear to be related to associative memory dysfunction observed in patients with cognitive impairment. In a similar way, analysis was run on 490 individuals (including controls, MCI, and AD patients), and the authors did not find any specific correlates in healthy controls, while regions corresponding to CA1 and subiculum were associated with delayed recall performances in patients [29].
An automated hippocampal shape-analysis method by using a pattern-recognition algorithm revealed a positive correlation between CERAD delayed recall scores and hippocampal deformation in the CA1 and subiculum [30].
The earlier postmortem pathologic studies showed that degeneration of the CA1 and subiculum found to be more severe as compared with other hippocampal components in early stages of AD, and these findings are correlated with this study. Human autopsy studies suggest that volume loss of subiculum and CA1 is related to the number of neurofibrillary tangles in these areas, neuronal loss, loss of dendritic arbor, or afferent innervation. Previous studies suggested that marked degeneration of the perforant path, that is providing input from layer III of entorhinal cortex to CA1 and subiculum, was a characteristic feature of AD [29].
However, CA3 and the DG, in contrast to subiculum and CA1, are not affected by the formation of plaques, tangles, and neuronal loss until a later stage in AD [31]. Mueller et al. [28] found that atrophy of CA subfields, as grouped together in a single region, appear to be related to associative memory dysfunction observed in patients with cognitive impairment and correlate with incapability of the patients to benefit from semantic processing during encoding new information. In a similar way, analysis was run on 490 individuals (including controls, MCI, and AD patients from the Alzheimer’s disease neuroimaging initiative), and the authors did not find any specific correlates in healthy controls, while regions corresponding to CA1 and subiculum were associated with delayed recall performances in patients. A reliable result appears to determine the role of CA1 atrophy in memory dysfunction in MCI and AD [29]. The results of this study reveal that sensitivity, specificity, PPV and NPV of CA1, and subiculum volume reduction in AD in relation to healthy elderly control were high, and the sensitivity of the study is increased by combination between volumes and the clinical exam scores. Limitations of this study are firstly that it is not possible to separate the temporal relation between subfield volume changes and the clinical symptoms because of its design as a cross-sectional study, and secondly, the relatively small number of studied subjects. Future longitudinal study and larger sample size combined with other biomarkers will be needed to determine which hippocampal subfields show the earliest atrophy in the disease process and to confirm the findings.