The new diagnostic criteria emphasize the use of biomarkers. One important marker of neuronal injury is hippocampal volume as measured by MRI. However, for this marker to become widely used in clinical routine, two things are necessary: 1) the measure must be standardized so one number in one place means the same as the same number measured in another place; and 2) fully automated methods for quantification are necessary.

A necessary step for development of an automated method that uses a standardized protocol is, of course, that the scientific community agrees on such a protocol. This is also where I see the importance of the Frisoni/Jack project—it is a great approach for getting such a consensus around a segmentation protocol. In addition, the project will generate hippocampal masks that will be used for development of automated methods. The project will also generate gold standard data against which automated methods can be validated.

View all comments by Lennart Thurfjell

Having measured thousands of hippocampi, allow me to disagree.

Pro primum, I see no need to harmonize hippocampal volumes. Since 1988, when hippocampal atrophy in AD was first presented, there has been no need for such harmony. Hundreds of studies have been published, without harmonization, and a great deal of those studies are perfectly good. Pro secundum, creating a universal hippocampal size is doomed to fail from the very beginning.

Picture this—if I needed to draw hippocampal volumes, I would not compare the volumes from a control pool of mine, or such, or use prior volumes as a reference volume. I would measure patients and controls at the same time. This is because estimates of hippocampal volumes change even among raters over time. The first hippocampal volumes I measured—way back when—were quite a bit larger than later ones. Volumes need to be measured by one person and one person only. Even for a given rater, controls may need to be retraced after a certain period of time, because the volumes may be dynamic. That is, comparing hippocampal volumes to...  Read more

Having measured thousands of hippocampi, allow me to disagree.

Pro primum, I see no need to harmonize hippocampal volumes. Since 1988, when hippocampal atrophy in AD was first presented, there has been no need for such harmony. Hundreds of studies have been published, without harmonization, and a great deal of those studies are perfectly good. Pro secundum, creating a universal hippocampal size is doomed to fail from the very beginning.

Picture this—if I needed to draw hippocampal volumes, I would not compare the volumes from a control pool of mine, or such, or use prior volumes as a reference volume. I would measure patients and controls at the same time. This is because estimates of hippocampal volumes change even among raters over time. The first hippocampal volumes I measured—way back when—were quite a bit larger than later ones. Volumes need to be measured by one person and one person only. Even for a given rater, controls may need to be retraced after a certain period of time, because the volumes may be dynamic. That is, comparing hippocampal volumes to those one drew, say, a year ago, introduces error. In fact, in my opinion, there is no harmony even with one rater. If hippocampal voumes I drew at time 1 and time 2 are out of tune, i.e., not in harmony, how can there be harmony among two or more raters? The hippocampal volume measured by two or more raters results in a fatal error.

Also, there can be no universal hippocampal volume, because the hippocampal size is subject to the size of a person. By this token, the Dutch, who are the tallest population in the world, should have the largest volumes. Eastern races, being shorter, should have smaller volumes. Women—being shorter than most men—have smaller volumes. Then there are a number of other factors to consider: the usual drift, the scanner, the imaging parametres, the alignment, the software used for imaging—i.e., the measuree, the hardware, the software—and in the end, the rater. And you even need to standardize the measurees, given that we know that at least apolipoprotein E alleles and other known and unknown genetic factors influence the volumes. In a manner of speaking, there is too much noise in the concept of harmonized volumes to provide a signal.

In addition, I believe fully automated methods to measure the hippocampus are not science; they are science fiction. Such is the nature of hippocampal structure that it needs a human rater. A machine won't probably ever detect the hippocampal boundaries. That'll be the day when it does.

Some volumes from the literature (right hippocampus) show that measures are highly variable:

Bhatia et al., 1993: 3,770 +/- 610; Bremner et al., 1995: 1,286 +/- 175; Hasboun et al., 1996: 3,420 +/- 490 to 4,180 +/- 530 (depending on alignment); Reiman et al., 1998: 2,462 +/- 347 to 2,519 +/- 454 (depending on ApoE genotype); Watson et al., 1992: 5,263 +/- 652.

The numbers above display almost a fivefold difference in the volumes, and I'd rate all of them acceptable studies. The study by Watson et al., wich has been cited the most, provides volumes which, in my opinion, are twice their actual size. In the end, what really matters is the outcome of the study. In terms of memory impairment, most often it is either conversion to, or the diagnosis of, dementia. The actual numbers have not the slightest interest value. It is the hit rate which counts.

Finally, it takes less than 10 minutes to measure the hippocampus bilaterally. Maybe a tad more if you have to realign or fine-tune some parameters. Some software may be easier to operate than others. Some computers are faster than others. But there really is no trick to manually grade the hippocampus. So why make a very simple issue so hard? Harmonized volumes don't matter. Several studies have provided a ”harmonized” outcome; that, and only the outcomes of the studies, are what matter.

References:
Bhatia S, Bookheimer SY, Gaillard WD, Theodore WH. Measurement of whole temporal lobe and hippocampus for MR volumetry: normative data. Neurology. 1993 Oct;43(10):2006-10. Abstract

Bremner JD, Randall P, Scott TM, Bronen RA, Seibyl JP, Southwick SM, Delaney RC, McCarthy G, Charney DS, Innis RB. MRI-based measurement of hippocampal volume in patients with combat-related posttraumatic stress disorder. Am J Psychiatry. 1995 Jul;152(7):973-81. Abstract

Hasboun D, Chantôme M, Zouaoui A, Sahel M, Deladoeuille M, Sourour N, Duyme M, Baulac M, Marsault C, Dormont D. MR determination of hippocampal volume: comparison of three methods. AJNR Am J Neuroradiol. 1996 Jun-Jul;17(6):1091-8. Abstract

Reiman EM, Uecker A, Caselli RJ, Lewis S, Bandy D, de Leon MJ, De Santi S, Convit A, Osborne D, Weaver A, Thibodeau SN. Hippocampal volumes in cognitively normal persons at genetic risk for Alzheimer's disease. Ann Neurol. 1998 Aug;44(2):288-91. Abstract

Watson C, Andermann F, Gloor P, Jones-Gotman M, Peters T, Evans A, Olivier A, Melanson D, Leroux G. Anatomic basis of amygdaloid and hippocampal volume measurement by magnetic resonance imaging. Neurology. 1992 Sep;42(9):1743-50. Abstract

View all comments by Mikko Laakso