Franco Alessandrini

Assessment of metabolic brain damage and recovery following mild traumatic brain injury: a multicentre, proton magnetic resonance spectroscopic study in concussed patients

Concussive head injury opens a temporary window of brain vulnerability due to the impairment of cellular energetic metabolism. As experimentally demonstrated, a second mild injury occurring during this period can lead to severe brain damage, a condition clinically described as the second impact syndrome. To corroborate the validity of proton magnetic resonance spectroscopy in monitoring cerebral metabolic changes following mild traumatic brain injury, apart from the magnetic field strength (1.5 or 3.0 T) and mode of acquisition, we undertook a multicentre prospective study in which a cohort of 40 athletes suffering from concussion and a group of 30 control healthy subjects were admitted. Athletes (aged 16-35 years) were recruited and examined at three different institutions between September 2007 and June 2009. They underwent assessment of brain metabolism at 3, 15, 22 and 30 days post-injury through proton magnetic resonance spectroscopy for the determination of N-acetylaspartate, creatine and choline-containing compounds. Values of these representative brain metabolites were compared with those observed in the group of non-injured controls. Comparison of spectroscopic data, obtained in controls using different field strength and/or mode of acquisition, did not show any difference in the brain metabolite ratios. Athletes with concussion exhibited the most significant alteration of metabolite ratios at Day 3 post-injury (N-acetylaspartate/creatine: -17.6%, N-acetylaspartate/choline: -21.4%; P < 0.001 with respect to controls). On average, metabolic disturbance gradually recovered, initially in a slow fashion and, following Day 15, more rapidly. At 30 days post-injury, all athletes showed complete recovery, having metabolite ratios returned to values detected in controls. Athletes self-declared symptom clearance between 3 and 15 days after concussion. Results indicate that N-acetylaspartate determination by proton magnetic resonance spectroscopy represents a non-invasive tool to accurately measure changes in cerebral energy metabolism occurring in mild traumatic brain injury. In particular, this metabolic evaluation may significantly improve, along with other clinical assessments, the management of athletes suffering from concussion. Further studies to verify the effects of a second concussive event occurring at different time points of the recovery curve of brain metabolism are needed.

Mapping local hippocampal changes in Alzheimer's disease and normal ageing with MRI at 3 Tesla

Histological studies have suggested differing involvement of the hippocampal subfields in ageing and in Alzheimers disease. The aim of this study was to assess in vivo local hippocampal changes in ageing and Alzheimers disease based on high resolution MRI at 3 Tesla. T(1)-weighted images were acquired from 19 Alzheimers disease patients [age 76 +/- 6 years, three males, Mini-Mental State Examination 13 +/- 4] and 19 controls (age 74 +/- 5 years, 11 males, Mini-Mental State Examination 29 +/- 1). The hippocampal formation was isolated by manual tracing. Radial atrophy mapping was used to assess group differences and correlations by averaging hippocampal shapes across subjects using 3D parametric surface mesh models. Percentage difference, Pearsons r, and significance maps were produced. Hippocampal volumes were inversely correlated with age in older healthy controls (r = 0.56 and 0.6 to the right and left, respectively, P < 0.05, corresponding to 14% lower volume for every 10 years of older age from ages 65 to 85 years). Ageing-associated atrophy mapped to medial and lateral areas of the tail and body corresponding to the CA1 subfield and ventral areas of the head corresponding to the presubiculum. Significantly increased volume with older age mapped to a few small spots mainly located to the CA1 sector of the right hippocampus. Volumes were 35% and 30% smaller in Alzheimers disease patients to the right and left (P < 0.0005). Alzheimers disease-associated atrophy mapped not only to CA1 areas of the body and tail corresponding to those also associated with age, but also to dorsal CA1 areas of the head unaffected by age. Regions corresponding to the CA2-3 fields were relatively spared in both ageing and Alzheimers disease. Hippocampal atrophy in Alzheimers disease maps to areas in the body and tail that partly overlap those affected by normal ageing. Specific areas in the anterior and dorsal CA1 subfield involved in Alzheimers disease were not in normal ageing. These patterns might relate to differential neural systems involved in Alzheimers disease and ageing.

Radiosurgical Treatment of Cavernous Sinus Meningiomas: Experience with 122 Treated Patients

OBJECTIVE To evaluate the efficacy of gamma knife (GK) radiosurgery, in terms of neurological improvement and tumor growth control (TGC), for a large series of patients with cavernous sinus meningiomas. METHODS Between February 1993 and January 2002, 156 patients with cavernous sinus meningiomas (35 male and 121 female patients; mean age, 56.1 yr) were treated with GK radiosurgery in our department. GK radiosurgery was used as a first-choice treatment for 75 of 156 patients and as postoperative adjuvant therapy for 81 of 156 patients (all with Grade I meningiomas). Eligibility criteria for radiosurgery were as follows: symptomatic meningiomas and/or documented tumor progression on magnetic resonance imaging scans, conditions of high operative risk, patient refusal of microsurgery or reoperation, tumor volume of <20 cm3, and location no less than 2 mm from the optic pathways. RESULTS Follow-up data for at least 12 months were available for 122 patients (median follow-up period, 48.9 mo). Clinical conditions were improved or stable for 118 of 122 patients (97%). Neurological recovery was observed for 78.5% of patients treated with GK radiosurgery alone and for 60.5% of patients treated with adjuvant therapy (P < 0.05). Adequate TGC was documented for 119 of 122 tumors (97.5%), with shrinkage/disappearance in 75 of 122 cases (61.5%) and no variation in volume in 44 of 122 cases (36%); the overall actuarial progression-free survival rate at 5 years was 96.5%. Tumor size regression was observed for 80% of patients with follow-up periods of more than 30 months, compared with 43.5% of patients with follow-up periods of less than 30 months (P < 0.0002). Radiosurgical sequelae were transient in 4 of 122 cases (3.0%) and permanent in 1 case (1%). CONCLUSION For the follow-up periods in our series (median, >4 yr), GK radiosurgery seems to be both safe (permanent morbidity rate, 1%) and effective (97% neurological improvement/stability, 97.5% overall TGC, and 96.5% actuarial TGC at 5 yr). GK radiosurgery might be considered a first-choice treatment for selected patients with cavernous sinus meningiomas.

The role of Gamma Knife Radiosurgery in the management of cavernous sinus meningiomas

PURPOSE To evaluate the efficacy of Gamma Knife (GK) radiosurgery in terms of neurologic improvement and tumor growth control (TGC) in a large series of patients with cavernous sinus meningioma (CSM). METHODS AND MATERIALS One hundred thirty-eight patients with CSM (28 males, 110 females; mean age: 56.2 years) were treated with GK between February 1993 and February 2001. GK was used as a first-choice treatment in 68/138 patients and as postoperative adjuvant therapy in 70/138. In 32 patients, it was possible to compare the size of the planned treatment volume to tumor volume using the conformity index (CI); optimal CI values were taken to be < or =1.5 (range: 0.94-2.24). RESULTS A follow-up (FU) period of at least 12 months was available for 111 patients (median: 48.2 months, range: 12.1-84.5 months). Clinical conditions were improved or stable in 107/111 patients (96.5%). Neurologic recovery was observed in 76% of cases treated by GK alone and in 56.5% of adjuvant treatments (p < 0.03). Adequate TGC was documented in 108/111 tumors (97%), with shrinkage/disappearance in 70/111 (63%) and no variation in volume in 38/111 (34%); the overall actuarial progression-free survival rate at 5 years was 96%. Tumor size regression was observed in 79.5% of patients with FU >30 months, compared with 47.5% of patients with FU <30 months (p < 0.001). One hundred percent TGC was shown in treated patients with a CI < or =1.5 (20/32), compared with 92% TGC in cases with a CI >1.5 (p < 0.15, NS). Radiosurgical sequelae were transient in 4/111 cases (3.5%) and permanent in one case (1%). CONCLUSIONS For the FU period of our series (median: >4 years), GK radiosurgery seems to be both safe (permanent morbidity 1%) and effective (96% neurologic improvement/stability, 97% overall TGC, 96% actuarial TGC at 5 years) and might be considered as a first-choice treatment for selected patients with CSM.

Assessment and surgical management of posterior fossa epidermoid tumors: report of 28 cases.

OBJECTIVE The management of a series of 28 patients operated on for posterior fossa epidermoids is reviewed, emphasizing the need for long-term follow-up. We discuss the rationale for a comprehensive classification system that may allow the comparison of results from homogeneous series. METHODS We grouped the tumors to differentiate the surgical management according to various tumor sites and the degree of extension. Twenty patients harbored tumors located in the cerebellopontine angle, five patients harbored tumors in the fourth ventricle, and three patients harbored tumors in the posterior fossa basal. In 17 patients, extensions of tumors outside the posterior fossa included the following regions: the suprasellar/ chiasmatic (n = 5), the parasellar/temporobasal (n = 5), and the mesencephalic/pineal (n = 7). Tumor extension was also defined by the number of regions involved. Pre- and postoperative magnetic resonance imaging and computed tomographic findings collected in 17 and 28 patients, respectively, were carefully evaluated. RESULTS Clinical features and surgical approaches varied according to location and growth pattern. Fifty-seven percent of the tumors were completely removed. A higher total removal rate was achieved in patients with tumors confined to the primary location. One patient (3%) died in the perioperative period. Approximately half of the patients presented with transient mild focal deficit impairments resulting from the manipulation of the nervous structure over a wide area. There was a higher rate of surgical complications with fourth ventricle and mesencephalic extended cerebellopontine angle tumors. The mean follow-up period was 8.6 years. Thirty percent of the patients with subtotal removal experienced symptomatic recurrences after 8.1 years, whereas all patients with total removal were still asymptomatic. The recurrence-free survival rate was 95% at 13 years for patients with total removal compared with 65% for patients with subtotal removal. Problems of identification of tumor regrowth are discussed. CONCLUSION By assessing posterior fossa epidermoids, we determined that location and extension play a major role in the prognosis. Our data suggest that more aggressive surgery is called for at first operation, and that a second operation should be planned when regrowth becomes symptomatic and/or tends to extend outside its original site.

Brain morphometry reproducibility in multi-center 3T MRI studies: A comparison of cross-sectional and longitudinal segmentations

Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation tools. The test-retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test-retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5-2) when possible. We acquired across-session test-retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test-retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.

Microstructural diffusion changes are independent of macrostructural volume loss in moderate to severe Alzheimer's disease.

Although it is established that Alzheimers disease (AD) leads to cerebral macrostructural atrophy, microstructural diffusion changes have also been observed, but it is not yet known whether these changes offer unique information about the disease pathology. Thus, a multi-modal imaging study was conducted to determine the independent contribution of each modality in moderate to severe AD. Seventeen patients with moderate-severe AD and 13 healthy volunteers underwent diffusion-weighted and T1-weighted MR scanning. Images were processed to obtain measures of macrostructural atrophy (gray and white matter volumes) and microstructural damage (fractional anisotropy and mean diffusivity). Microstructural diffusion changes independent of macrostructural loss were investigated using an ANCOVA where macrostructural maps were used as voxel-wise covariates. The reverse ANCOVA model was also assessed, where macrostructural loss was the dependent variable and microstructural diffusion tensor imaging maps were the imaging covariates. Diffusion differences between patients and controls were observed after controlling for volumetric differences in medial temporal, retrosplenial regions, anterior commissure, corona radiata, internal capsule, thalamus, corticopontine tracts, cerebral peduncle, striatum, and precentral gyrus. Independent volumetric differences were observed in the entorhinal cortex, inferior temporal lobe, posterior cingulate cortex, splenium and cerebellum. While it is well known that AD is associated with pronounced volumetric change, this study suggests that measures of microstructure provide unique information not obtainable with volumetric mapping in regions known to be pivotal in AD and in those thought to be spared. As such this work provides great understanding of the topography of pathological changes in AD that can be captured with imaging.

Multisite longitudinal reliability of tract-based spatial statistics in diffusion tensor imaging of healthy elderly subjects

Large-scale longitudinal neuroimaging studies with diffusion imaging techniques are necessary to test and validate models of white matter neurophysiological processes that change in time, both in healthy and diseased brains. The predictive power of such longitudinal models will always be limited by the reproducibility of repeated measures acquired during different sessions. At present, there is limited quantitative knowledge about the across-session reproducibility of standard diffusion metrics in 3T multi-centric studies on subjects in stable conditions, in particular when using tract based spatial statistics and with elderly people. In this study we implemented a multi-site brain diffusion protocol in 10 clinical 3T MRI sites distributed across 4 countries in Europe (Italy, Germany, France and Greece) using vendor provided sequences from Siemens (Allegra, Trio Tim, Verio, Skyra, Biograph mMR), Philips (Achieva) and GE (HDxt) scanners. We acquired DTI data (2 × 2 × 2 mm(3), b = 700 s/mm(2), 5 b0 and 30 diffusion weighted volumes) of a group of healthy stable elderly subjects (5 subjects per site) in two separate sessions at least a week apart. For each subject and session four scalar diffusion metrics were considered: fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial (AD) diffusivity. The diffusion metrics from multiple subjects and sessions at each site were aligned to their common white matter skeleton using tract-based spatial statistics. The reproducibility at each MRI site was examined by looking at group averages of absolute changes relative to the mean (%) on various parameters: i) reproducibility of the signal-to-noise ratio (SNR) of the b0 images in centrum semiovale, ii) full brain test-retest differences of the diffusion metric maps on the white matter skeleton, iii) reproducibility of the diffusion metrics on atlas-based white matter ROIs on the white matter skeleton. Despite the differences of MRI scanner configurations across sites (vendors, models, RF coils and acquisition sequences) we found good and consistent test-retest reproducibility. White matter b0 SNR reproducibility was on average 7 ± 1% with no significant MRI site effects. Whole brain analysis resulted in no significant test-retest differences at any of the sites with any of the DTI metrics. The atlas-based ROI analysis showed that the mean reproducibility errors largely remained in the 2-4% range for FA and AD and 2-6% for MD and RD, averaged across ROIs. Our results show reproducibility values comparable to those reported in studies using a smaller number of MRI scanners, slightly different DTI protocols and mostly younger populations. We therefore show that the acquisition and analysis protocols used are appropriate for multi-site experimental scenarios.

Radiologic and surgical aspects of pure spinal epidural cavernous angiomas: Report on 5 cases and review of the literature

BACKGROUND Cavernous angiomas (CAs) that are localized completely in the spinal epidural space are uncommon vascular malformations. Although they have increasingly been reported in the literature in recent years, diagnostic and surgical features are not clearly defined. METHODS We report five patients with pure spinal epidural cavernous angiomas (PSECAs) and review the literature, focusing on their radiologic and surgical characteristics. We also compare these tumors with other extra-axial CAs as well as with their intra-axial counterparts. RESULTS PSECAs, like all other extra-axial CAs, differ from intra-axial ones on MRI: the hemorrhagic variant is less frequent, hemosiderin rim is rare, the signal is different, and contrast enhancement is the rule. They are very similar to spinal meningiomas but they differ in their growth pattern and morphology, since they infiltrate intervertebral foramina and have an oval shape. In PSECA, intraoperative bleeding is rarely profuse, in contrast to other extra-axial CAs, especially those of the cavernous sinus. CONCLUSIONS On MRI, PSECAs and other extra-axial CAs constitute a homogeneous group since they enhance significantly. At operation, since there is rarely enough bleeding to limit removal, radical excision of PSECAs can be achieved with good results.

Effect of memantine on resting state default mode network activity in Alzheimer's disease.

BackgroundMemantine is an approved symptomatic treatment for moderate to severe Alzheimer’s disease that reduces the excitotoxic effects of hyperactive glutamatergic transmission. However, the exact mechanism of the effect of memantine in Alzheimer’s disease patients is poorly understood. Importantly, the default mode network (DMN), which plays a key role in attention, is hypoactive in Alzheimer’s disease and is under glutamatergic control.ObjectiveTo assess the effect of memantine on the activity of the DMN in moderate to severe Alzheimer’s disease.MethodsFunctional magnetic resonance imaging (MRI) data from 15 patients with moderate to severe Alzheimer’s disease, seven treated with memantine (mean±SD age 77±8 years, mean±SD Mini-Mental State Examination [MMSE] score 16±5) and eight with placebo (mean±SD age 76±6 years, mean±SD MMSE score 13±1), were acquired at baseline (T0) and after 6 months of treatment (T6). Resting state components were extracted after spatial normalization in individual patients with independent component analysis. The consistency of the components was assessed using ICASSO and the DMN was recognized through spatial correlation with a pre-defined template. Voxel-based statistical analyses were performed to study the change in DMN activity from T0 to T6 in the two groups.ResultsAt T0, the two groups showed similar DMN activity except in the precuneus and cuneus, where the patients who started treatment with memantine had slightly greater activity (p <0.05 corrected for familywise error [FWE]). The prospective comparison between T0 and T6 in the treated patients showed increased DMN activation mapping in the precuneus (p <0.05, FWE corrected), while the prospective comparison in the untreated patients did not show significant changes. The treatment×time interaction term was significant at p <0.05, FWE corrected.ConclusionsThe results suggest a positive effect of memantine treatment in patients with moderate to severe Alzheimer’s disease, resulting in an increased resting DMN activity in the precuneus region over 6 months. Future studies confirming the present findings are required to further demonstrate the beneficial effects of memantine on the DMN in Alzheimer’s disease.