M. Di Paola

Gross morphology and morphometric sequelae in the hippocampus, fornix, and corpus callosum of patients with severe non-missile traumatic brain injury without macroscopically detectable lesions: a T1 weighted MRI study

Objective: The gross morphology and morphometry of the hippocampus, fornix, and corpus callosum in patients with severe non-missile traumatic brain injury (nmTBI) without obvious neuroradiological lesions was examined and the volumes of these structures were correlated with performance on memory tests. In addition, the predictability of the length of coma from the selected anatomical volumes was examined. Method: High spatial resolution T1 weighted MRI scans of the brain (1 mm3) and neuropsychological evaluations with standardised tests were performed at least 3 months after trauma in 19 patients. Results: In comparison with control subjects matched in terms of gender and age, volume reduction in the hippocampus, fornix, and corpus callosum of the nmTBI patients was quantitatively significant. The length of coma correlated with the volume reduction in the corpus callosum. Immediate free recall of word lists correlated with the volume of the fornix and the corpus callosum. Delayed recall of word lists and immediate recall of the Rey figure both correlated with the volume of the fornix. Delayed recall of the Rey figure correlated with the volume of the fornix and the right hippocampus. Conclusion: These findings demonstrate that in severe nmTBI without obvious neuroradiological lesions there is a clear hippocampal, fornix, and callosal volume reduction. The length of coma predicts the callosal volume reduction, which could be considered a marker of the severity of axonal loss. A few memory test scores correlated with the volumes of the selected anatomical structures. This relationship with memory performance may reflect the diffuse nature of the damage, leading to the disruption of neural circuits at multiple levels and the progressive neural degeneration occurring in TBI.

MRI measures of corpus callosum iron and myelin in early Huntington's disease

Increased iron in subcortical gray matter (GM) structures of patients with Huntingtons disease (HD) has been suggested as a causal factor in neuronal degeneration. But how iron content is related to white matter (WM) changes in HD is still unknown. For example, it is not clear whether WM changes share the same physiopathology (i.e. iron accumulation) with GM or whether there is a different mechanism. The present study used MRI to examine iron content in premanifest gene carriers (PreHD, n = 25) and in early HD patients (n = 25) compared with healthy controls (n = 50). 3T MRI acquisitions included high resolution 3D T1, EPI sequences for diffusion tensor imaging (DTI) as an indirect measure of tissue integrity, and T2*‐weighted gradient echo‐planar imaging for MR‐based relaxometry (R2*), which provides an indirect measure of ferritin/iron deposition in the brain. Myelin breakdown starts in the PreHD stage, but there is no difference in iron content values. Iron content reduction manifests later, in the early HD stage, in which we found a lower R2* parameter value in the isthmus. The WM iron reduction in HD is temporally well‐defined (no iron differences in PreHD subjects and iron differences only in early HD patients). Iron level in callosal WM may be regarded as a marker of disease state, as iron does not differentiate PreHD subjects from controls but distinguishes between PreHD and HD. Hum Brain Mapp 35:3143–3151, 2014.

White matter changes in patients with hypoxic amnesia

A deficit of declarative memory is a common sequela after a hypoxic episode. While the role of gray matter changes (i.e., atrophy of hippocampal formation) as mainly responsible for memory loss has been emphasized, the role of the white matter damage has so far been neglected. The present study was aimed at evaluating whether white matter damage, within the neural circuitry responsible for declarative memory functioning, is present in anoxic patients. We assessed, by means of voxel-based morphometry, the integrity of white matter regions in five patients with hypoxic amnesia. When anoxic patients were compared to healthy controls, significantly less white matter density was detected in the fornix, anterior portion of the cingulum bundle and uncinate fasciculus bilaterally. We conclude that cerebral hypoxia may alter, together with the hippocampi, the integrity of white matter fibers throughout the memory-limbic system.

G05 Alterations in iron content in the brain of Huntington disease mutation carriers in comparison with healthy control subjects

Background It has been hypothesised that changes in iron content in the brain may be involved in the pathogenesis of Huntington Disease (HD).1–5 T*2-weighted imaging may be a useful measure to study iron distribution in the brain since a strong linear correlation between chemically determined iron concentration and magnetic susceptibility has been established, specially for grey matter structures.6 7 Increased iron content in the caudate, putamen and specially in the globus pallidus of HD patients and presymptomatic subjects has been described.1–5 Aims To investigate the potential spatial variations in T*2 signal in cerebral structure in Huntington disease mutation carriers. Methods 77 mutation carriers (29 presymptomatic and 48 at early disease stages) and 73 age and gender matched controls underwent T*2 multiecho relaxometry on a 3 Tesla Siemens scanner (Abstract 12361-1 table 1). Six consecutive T*2- weighted gradient-echo whole-brain volumes were acquired using a segmented EPI sequence at different TEs: 6, 12, 20, 30, 45, 60 ms (TR: 5000, bandwidth: 1116 Hz/voxel, matrix size: 128 mm3; voxel size: 1.8 mm3). Image processing was performed combining FSL 4.0 and SPM8 running in Matlab 6.5. Artifacts in the susceptibility maps were avoided by using the first echo data to mask brain tissue. The statistical analysis of the susceptibility maps was carried by a two-sample t-test. The final results were corrected for multiple comparisons using a family wise error (FWE) rate correction set at p<0.05. Results When compared with age and gender-matched control subjects, mutation carriers had increased iron levels in the globus pallidus/putamen bilaterally (p cluster: <0.001 left; <0.01 right; t: 7.41 left; 6.18 right). Furthermore, HD subjects had decreased iron content in occipital and posterior grey matter areas in comparison with control subjects (p cluster: <0.001; t: 6.65). Conclusions The data suggest that iron alterations occur early in the HD process and have a role in the selective striatal degeneration underlying HD pathology. Prospective studies are needed to verify how increased iron levels are involved in HD pathogenesis. References 1. Bartzokis G, Lu PH, Tishler TA, et al. Myelin breakdown and iron changes in Huntingtons disease: pathogenesis and treatment implications. Neurochem Res 2007;32:1655–64. 2. Bartzokis G, Cummings J, Perlman S, et al. Increased basal ganglia iron levels in Huntington disease. Arch Neurol 1999;56:569–74. 3. Rosas HD, Chen YI, Doros G, et al. Alterations in brain transition metals in Huntington disease: an evolving and intricate story. Arch Neurol 2012. In press. 4. Sánchez-Castañeda C, Cherubini A, Elifani F, et al. Seeking huntington disease biomarkers by multimodal, cross-sectional basal ganglia imaging. Hum Brain Mapp 2012. In press. 5. Vymazal J, Klempír J, Jech R, et al. MR relaxometry in Huntingtons disease: correlation between imaging, genetic and clinical parameters. J Neurol Sci 2007;263:20–5. 6. Cherubini A, Péran P, Hagberg GE, et al. Characterisation of white matter fibre bundles with T2* relaxometry and diffusion tensor imaging. Magn Reson Med 2009b;61:1066–72. 7. Langkammer C, Schweser F, Krebs N, et al. Quantitative susceptibility mapping (QSM) as a means to measure brain iron? A post mortem validation study. Neuroimage 2012. In press.

G06 Iron defect is implicated in white matter changes in Huntington disease

Background In normal condition, the concentration of iron in various region of the brain varies greatly. There is a progressive iron accumulation during the brain development (Zecca et al, 2004), with iron concentration increases in the brain until age 40 (Thomas and Jankovic 2004). The iron brain delivery is critical for its effects on fibre myelination, and iron restriction is associated with a general decline of myelin production (Todorich, et al, 2009). Aims To investigate if WM callosal demyelination we have already found in HD (Di Paola et al, 2012) can be related to iron modification. Methods HD patients (n=50) and controls subjects (CS) (n=50) underwent a multi-parameters MRI protocol, including 3D T1 acquisition and six consecutive T2*-weighted gradient echo-planar imaging sequence at different time of echo (Peran et al, 2010). Voxel-based morphometry and relaxometry analyses have been performed. Results When pre-HD subjects were compared to HC, we did not detect any significant volume and iron content difference. When pre-HD subjects were compared to HD patients, callosal volume was reduced in the splenium, isthmus and posterior callosal body in HD, while the reduced iron content extended also more anteriorly involving the callosal body and the rostrum. When HD patients were compared to HC, we found a significantly global reduction of callosal volume with the iron content reduced mainly in the isthmus and part of splenium. Conclusions Our findings suggest that WM damage in our HD subject can be strongly related to iron reduction content. It remains still open if the iron reduction is due to a failure in the repair myelin damage process or it is due to an abnormal brain development and myelination process.