Structural Neuroimaging of the Medial Temporal Lobe in Alzheimer’s Disease Clinical Trials

Atrophy in the medial temporal lobe (MTA) is being used as a criterion to support a diagnosis of Alzheimer’s disease (AD). There are several structural neuroimaging approaches for quantifying MTA, including semiquantitative visual rating scales, volumetry (3D), planimetry (2D), and linear measures (1D). Current applications of structural neuroimaging in Alzheimer’s disease clinical trials (ADCTs) incorporate it as a tool for improving the selection of subjects for enrollment or for stratification, for tracking disease progression, or providing evidence of target engagement for new therapeutic agents. It may also be used as a surrogate marker, providing evidence of disease-modifying effects. However, despite the widespread use of volumetric magnetic resonance imaging (MRI) in ADCTs, there are some important challenges and limitations, such as difficulties in the interpretation of results, limitations in translating results into clinical practice, and reproducibility issues, among others. Solutions to these issues may arise from other methodologies that are able to link the results of volumetric MRI from trials with conventional MRIs performed in routine clinical practice (linear or planimetric methods). Also of potential benefit are automated volumetry, using indices for comparing the relative rate of atrophy of different regions instead of absolute rates of atrophy, and combining structural neuroimaging with other biomarkers. In this review, authors present the existing structural neuroimaging approaches for MTA quantification. They then discuss solutions to the limitations of the different techniques as well as the current challenges of the field. Finally, and due to their relevance, they discuss how the current advances in AD neuroimaging can help AD diagnosis.
Reference: Journal of Alzheimer's Disease, DOI: 10.3233/JAD-150226 Full text

Different structural methods to quantify hippocampal atrophy. Starting from the anatomical image obtained with MR, or another imaging technique, there are four possible analyses. First, visual rating scales, by which specialists compare images over time. Second, linear methods, in which lines are drawn on top of images to assess the size of the hippocampi. Third, planimetric methods, in which a ROI is drawn on top of several images, and an area is then calculated by summing their surfaces. Finally, volumetric methods, in which segmentation of the image is done through the use of advanced software tools, and volumes of the hippocampi are estimated.

The role of structural neuroimaging across the different phases of ADCTs. In the light blue boxes, we have the different stages of an ADCT. Boxes in light green represent the applications of an ADCT in clinical practice. Under each stage of the ADCT, a list is given of the improvements that structural imaging can offer to scientists and medical doctors.

Comparison of volumetry, planimetry, linear measures, and visual scales in the assessment of medial temporal lobe atrophy on MRI.Reproducibility is considered very good when ICC >0.90), good when ICC is between 0.80–0.90, moderate 0.60–0.80 and poor 

	Visual rating Scales	Linear methods (1D)	Planimetric methods (2D)	Volumetric methods (3D)
Objective and reliable	No	Yes	Yes	Yes
Requirements of	Any MRI scan	Any MRI scan	Any MRI scan	May need specific
MRI studies	is suitable	is suitable	is suitable	MRI studies
Time consuming	Little	Little	Little	Extensive
Training	Little	Little	Little	Extensive
Software	Not required	Any software for MRI	Any software for MRI visualization is suitable	Special software for volumetric studies
Reproducibility	Poor	Still needs to be tested	Good	-Automated: good to very good
				- Manual: depends on experience
Feasible in clinical practice	Yes	Yes	Yes	Not widely available
Feasible in clinical trials	Still needs to be tested	Still needs to be tested	Still needs to be tested	Yes