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What does the corpus callosum tell us about brain changes in the elderly? Expert Rev. Neurother. 11(11), 1557–1560 (2011)
Margherita Di Paola†1,2, Carlo Caltagirone1,3 and Gianfranco Spalletta1 Clinical and Behavioral Neurology, IRCCS Santa Lucia Foundation, Via Ardeatina 306, 00179, Rome, Italy 2 Department of Internal Medicine and Public Health, University of L’Aquila, Piazzale Salvatore Tommasi 1, 67010, L’Aquila – Coppito, Italy 3 Department of Neuroscience and Memory Clinic, Tor Vergata, University of Rome, Via Montpellier, 1 00133, Rome, Italy † Author for correspondence: Tel.: +39 065 150 1215 Fax: +39 065 150 1213
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Evaluation of: Ryberg C, Rostrup E, Paulson OB et al. On behalf of the LADIS study group. Corpus callosum atrophy as a predictor of age-related cognitive and motor impairment: a 3 year follow-up of the LADIS study cohort. J. Neurol. Sci. 307(1–2), 100–105 (2011). The corpus callosum is the largest hemispheric interconnection bundle in the human brain. Its anterior–posterior fiber caliber gradient can help in understanding the pathophysiological mechanisms underlying white matter changes both in old age and dementia. Here, the Leukoaraiosis and Disability (LADIS) study, a longitudinal cohort study, which shows an association between corpus callosum atrophy and cognitive and motor decline in the elderly, provides the possibility to consider the use of multimodal macro-microstructural imaging of corpus callosum as a marker of structural brain changes of physiological and pathological aging. Keywords : age-related white matter changes • corpus callosum • demyelination process • diffusion tensor imaging • elderly • region of interest • Wallerian degeneration
Corpus callosum
The corpus callosum (CC) is the largest white matter (WM) fiber bundle in the human brain interconnecting the two cerebral hemispheres. The fiber composition in the human CC has a well-defined structure with a consistent pattern of regional differentiation. Callosal fibers mainly connect homotopic cerebral areas between the hemispheres [1] . In addition, it contains fibers with different caliber and time of myelination. The posterior callosal subregions have large and early myelinated fibers, while the anterior subregions have small and latemyelinated fibers [2] . Thus the callosal fibers are sensitive to brain insults and aging in a different way. In particular, according to the demyelination (retrogenesis) hypothesis advanced by Reisberg, late-myelinated small fibers are more susceptible to primary myelin breakdown, while early myelinated large fibers are more resistant to retrogenesis but may suffer from Wallerian degeneration [3] . In this latter case, gray matter cortical neuronal death determines a secondary axonal damage. Thus, WM fibers of those callosal subregions connected to the affected cortical areas are secondarily damaged. This hypothesis accounts for the early changes in the posterior CC in the elderly as a consequence 10.1586/ERN.11.130
of aging, while retrogenesis (i.e., primary WM degeneration) explains the anterior CC early structural changes. The recent article from Ryberg et al. presents a set of data on CC changes in an elderly healthy population from the Leukoaraiosis and Disability (LADIS) study [4] . Methods & results
The aim of this 3-year follow-up LADIS cohort study was to investigate whether CC atrophy may predict motor and cognitive impairment in the healthy elderly population, with ages ranging between 64 and 85 years at baseline. Age-related white matter changes (ARWMC) were investigated using MRI (MR measurements include T1, T2, proton-density-weighted and fluid-attenuated inversion recovery pulse sequences) or computed tomography (CT). Participants included in the study had no or only mild functional disability, as determined by the Instrumental Activities of Daily Living Scale. The study was conducted on 563 subjects. A total of 116 out of an initial 639 subjects were excluded for various reasons (73 dropouts and 43 deaths). Patients received clinical assessment at baseline and at 1-, 2- and 3-year follow-up using
© 2011 Expert Reviews Ltd
ISSN 1473-7175
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Witelson segmentation
Weis segmentation
Hampel segmentation
Mesh-based method
follow-up. While the CC isthmus structure at baseline was related to a history of falls at 3-year follow-up. Investigating the association between the CC structure at baseline and continuous variables of functional performances, such as the Mini Mental State Examination (MMSE), Short Physical Performance Battery test and walking speed, the authors found smaller CC size in the rostrum, genu and splenium at baseline associated with a decrease in MMSE score during the 3-year follow-up period. Furthermore, a smaller CC size of the rostral body, midbody and splenium was associated with reduced motor test performance over time. Discussion & significance
The results of the present study show that the CC structure changes with aging. These data emphasize the potential pathophysiological role of the CC, as the key brain structure both in aging and in the early phase of neurodegenerative disease. The macrostructural callosal changes associated with cognitive deficits (changes Figure 1 Different corpus callosum manual tracing. In Witelson segmentation, the were found in rostrum, genu and splemidsagittal slice of the corpus callosum (CC) is split into five distinct sectors of different percentages: 33, 17, 17, 13 and 20%. The subregions are: CC1 = rostrum, genu and nium) and motor dysfunction (changes anterior body; CC2 = midbody; CC3 = caudal body; CC4 = isthmus; and CC5 = splenium. in rostral body, midbody and splenium) In Weis segmentation, the midsagittal slice of the CC is split into five distinct sectors of are in line with what we expected on the equal size (20%) along a line joining the most anterior and posterior points of the genu basis of callosal anatomy [1] . Briefly, rosand splenium. Subregions are the following: CC1 = rostrum and genu; CC2 = rostral trum and genu connect orbital–frontal body; CC3 = midbody; CC4 = isthmus; and CC5 = splenium. In Hampel segmentation, the midsagittal slice of CC is split into five distinct sectors of equal degrees (36°) along a regions and prefrontal association cortices line joining the most anterior and posterior points of genu and splenium. The subregions [1] . Thus, in elderly people, a reduction in are: CC1 = rostrum; CC2 = anterior truncus; CC3 = middle truncus; CC4 =posterior anterior CC sections (rostrum and genu) truncus; and CC5 = splenium. In the mesh-based method, there is no splitting. Upper could account for general deficits in execuand lower callosal boundaries are manually outlined in the midsagittal section. Then, the tive function and attention performance, spatial average from 100 equidistant surface points representing the upper and lower boundaries is calculated. The result is a new midline segment (the spatial average), also probably due to a dysfunction in prefronconsisting of 100 equidistant points. Finally, the midline segment is quantified, so that it tal association cortices. CC anterior seccorresponds to CC thickness. tion abnormalities may also be linked with Reprinted from [15] © (2011), with permission from IOS Press. emotional lability and behavioral disinhibition, probably due to a dysfunction in a battery of clinical and functional tests measuring global orbital–frontal regions. functioning, cognitive, motor, psychiatric and quality-of-life The splenium of the CC subserves two-thirds of the higherperformances. order processing areas of the lateral temporal lobes and of the Callosal changes were quantified using one of the region of parietal lobes, which, together with the mesial temporal structures interest (ROI) analysis techniques – that is, the Witelson segmen- [1] , are the brain areas primarily involved in neurodegeneration of tation [5] . In Figure 1, we summarize this and other frequently used Alzheimer’s disease [9,10] . Thus, the callosal reduction in posterior ROI methods, such as Weis segmentation [6] , Hampel segmenta- sections could impair the functioning of the posterior cortical tion [7] and surface-based mesh modeling [8] . Finally, to reduce memory network that subserves the episodic memory operations, inter-individual variability in gross brain size, the authors nor- precociously impaired in Alzheimer’s disease patients [11] . malized each MRI brain volume into the Talairach proportional On the other hand, premotor, supplementary motor and motor stereotaxic space (using 12 parameters). fibers cross the rostral body and the midbody [1] of the CC. Thus Ryberg et al. found that the rostrum and genu callosal struc- a change in those callosal subregions may account for the motor tures, at baseline, predicted the presence of dementia at 3-year dysfunctions present in aging. 1558
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What does the corpus callosum tell us about brain changes in the elderly?
The data of Ryberg et al. are also in agreement with those reported in previous studies. One of those studies described an early involvement of anterior and posterior portions of callosal subregions in patients at risk of developing dementia [12] . A second study underlined the importance of preserved CC structure for well-functioning motor coordination [13] . Despite these interesting features, the authors failed to report the recent literature on callosal changes in aging [12,14,15] . Furthermore, the authors did not mention that the use of Witelson splitting, as CC segmentation, has generated controversy with respect to the assumed topography of the callosal fibers [16] . Compared with other in vivo MRI techniques, Witelson’s splitting locates the callosal motor fibers more anteriorly. In addition, it has been demonstrated [17] that the predefinition of callosal regions with Witelson splitting [5] can give rise to erroneous results. When applying the Witelson splitting method, the resulting callosal changes could be caused by both an increased size of the extreme regions (i.e., the anterior part and the splenium) and a decreased extension of the central regions (i.e., midsection and caudal part of the body and isthmus). Thus, in our opinion, the results of this study need to be confirmed by applying a different callosal segmentation that is not biased by the shape and, additionally, by using a multimodal MRI approach. Another limitation is the lack of the fine assessment of memory impairment, which is strongly related with aging and eventually dementia. The evaluation of the association between CC structural changes and memory performances in such a large sample is strongly required. Finally, some unexpected results need to be better understood, such as the atrophy at baseline in the rostral body, midbody and isthmus of the CC, which predicted subjective memory complaints, and the negative correlation between callosal midbody structure and MMSE scores. The LADIS study also has a number of strengths, including the large sample size and the duration of follow-up. These may facilitate positive findings and reduce the possibilities of falsenegative results. Expert commentary & five-year view
Obtaining more definitive results requires the simultaneous application of different MRI techniques. A multimodal MRI
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approach, collecting different measurements, could offer a clearer picture of the callosal changes in elderly. In this regard, diffusion tensor imaging (DTI) would be of help. With respect to macrostructural ROI MRI, the DTI technique has the advantage of being very sensitive in detecting microstructural abnormalities not revealed by other volumetric measures [18] . In fact, structural MRI techniques, which reflect macrostructural changes, may not be sensitive to the degeneration of myelin and axons in the WM microstructure [18] . Indeed, DTI parameters have been applied in CC studies and have demonstrated much greater sensitivity in revealing WM degeneration than conventional MRI imaging techniques [19] . In general, mean diffusivity and fractional anisotropy have been used as the main diffusivity parameters in DTI studies. However, in anatomically well-oriented structures, such as the CC, these two parameters can remain in the normal range. According to Choi et al. we suggest, for a deeper understanding of CC changes, calculating two different measures of diffusion: the radial diffusivity (DR) and axial diffusivity (DA) [20] . There is a general agreement in considering DR as a measure of diffusion perpendicular to the WM fibers, and DA as a measure of diffusion parallel to the WM fibers. An increase in DR is interpreted as a likely consequence of myelin breakdown and an increase in DA is interpreted as probably due to Wallerian degeneration. Thus, DTI data together with ROI data can help in better understanding CC changes in the elderly. Finally, the study of subregional CC modifications and the investigation of mechanisms underlying WM changes may be relevant for both speculative aspects of neurology and for the application of clinical trials in nondisabled elderly who are at risk of developing cognitive imapirment. Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • The corpus callosum (CC) is the most important structure involved in the transmission of interhemispheric information. The callosal fibers have a well-defined topographic organisation, connecting homotopic brain regions between the hemispheres. • Atrophy of the CC, or of its subregions, may lead to interhemispheric disconnection, resulting in functional disability because of reduced hemisphere integration. • The Leukoaraiosis and Disability (LADIS) study cohort is a longitudinal study which focused on CC changes as possible predictor of motor and cognitive dysfunction in elderly people. • The authors observed that CC atrophy, corrected for all confounders, such as age-related white matter changes, general atrophy, age, gender and handedness, is able to predict the development of motor and cognitive dysfunction during a 3-year follow-up. • However, pathophysiological mechanisms other than Wallerian degeneration can explain the CC changes. Thus, the application of different MRI techniques, such as diffusion tensor imaging, may be of help for an improved understanding of white matter callosal modifications.
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