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The contribution of the thalamus to the functioning of prospective memory (PM) is currently unknown. Here we report an experimental investigation of the performance of two patients with bilateral infarcts in the anterior-mesial regions of the thalami on an event-based PM paradigm. One patient, G.P., had a pervasive declarative memory impairment but no significant executive deficit. The other patient, R.F., had a memory deficit limited to verbal material with associated behavioral abnormalities (inertia and apathy); she performed poorly on tests of executive functions. Although both patients performed poorly on the PM task, a qualitative analysis of performance revealed different mechanisms at the base of their impaired PM. G.P. had reduced declarative memory for target words compared with normal controls; but, unforgotten words were normally able to elicit his recall of the prospective intention. Conversely, R.F.'s declarative memory for target words was as accurate as that of normal controls, but she presented a dramatically reduced ratio between the number of target words she recalled and the number of times she activated the prospective intention on the PM task, suggesting that her deficit consisted of difficulty in activating the intention despite normal declarative memory for the target events. In conclusion, results of the present study demonstrate that thalamic structures have an important role in PM processes. They also document that damage to the anterior-mesial regions of the thalami affects PM abilities by two different mechanisms, respectively based on the relative disruption of declarative memory or executive processes functioning, which, in turn, is related to the specific intrathalamic structures involved by the lesions. Indeed, while G.P.'s pervasive declarative memory deficit was underlain by bilateral involvement of the mammillo-thalamic tract, R.F.'s executive and behavioral abnormalities were likely related to bilateral damage of the midline, intralaminar, and medio-dorsal nuclei., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Previous studies have shown inconsistent results when reporting brain abnormalities in Williams syndrome (WS). This makes an interpretation of clinical and behavioural data uncertain in terms of anatomical localization of brain tissue changes. In this study we employed voxel based morphometry to directly investigate the regional distribution of grey matter (GM) density as a function of individual neuropsychological profiles in individuals with WS. GM maps were regressed against the neuropsychological measures on which WS individuals performed worse than controls. Results showed an association between the regional GM density in the cerebellum, bilaterally, the right Supplementary Motor Area, the right fusiform gyrus, and measures of morpho-syntactic ability. An association was also found between measures of visuo-spatial and visuo-motor abilities and regional GM density in the left cerebellum, left parietal lobule, right superior and left orbital frontal gyri. The study shows the potential to clarify the anatomical substrate underlying specific cognitive deficits in WS.

A new method to investigate anomalous diffusion in human brain, inspired by the stretched-exponential model proposed by Hall and Barrick, is proposed here, together with a discussion about its potential application to cerebral white matter characterization. Aim of the work was to show the ability of anomalous diffusion indices to characterize white matter structures, whose complexity is only partially accounted by diffusion tensor imaging indices. MR signal was expressed as a stretched-exponential only along the principal axes of diffusion; whereas, in a generic direction, it was modeled as a combination of three stretched-exponentials. Indices to quantify the tissue anomalous diffusion and its anisotropy, independently of the experiment reference frame, were derived. Experimental results, obtained on 10 healthy subjects at 3T, show that the new parameters are highly correlated to intrinsic local geometry when compared with Hall and Barrick indices. Moreover, they offer a different contrast in white matter regions when compared with diffusion tensor imaging. Specifically, the new indices show a higher capability to discriminate among areas of the corpus callosum associated to different distribution in axonal densities, thus offering a new potential tool to detect more specific patterns of brain abnormalities than diffusion tensor imaging in the presence of neurological and psychiatric disorders., (Copyright © 2010 Wiley-Liss, Inc.)

Cognitive reserve (CR), for which formal education represents a proxy index, has been claimed as a factor mitigating the clinical manifestations of Alzheimer disease (AD). The aim of this study was to assess the impact of formal education in modifying the relationship between cerebral grey matter (GM) damage and clinical manifestations in a large cohort of patients with AD or amnesic mild cognitive impairment (a-MCI). We recruited 22 patients with AD and 23 with a-MCI, and we classified them in subjects with high (HEL) or low educational level (LEL). All patients underwent a neuropsychological assessment and magnetic resonance imaging (MRI) scanning at 3T. T1-weighted volumes were analyzed, using voxel-based morphometry, for GM investigation. A 1-year clinical follow-up was available for part of the a-MCI patients. There were no between-groups differences in clinical features, memory, and language functions. Conversely, HEL subjects performed better in all tests assessing visuo-spatial abilities. GM volumes of LEL compared with HEL patients were reduced in the supramarginal gyrus bilaterally and in the right posterior cingulate/precuneus and frontal opercular cortex. Conversely, HEL compared with LEL patients showed reduced GM volumes in the entorhinal cortices and temporal poles, regions typically affected by AD pathology. These results remained unchanged when including in the analysis of only patients with clinically proven AD (AD and a-MCI converters). This study suggests that CR produces selective GM changes that mitigate the clinical impact of AD. Moreover, it supports the idea that CR is based on several "brain reserves" rather than on a generalized increase of brain plasticity.

Previous studies suggest that the clinical manifestations of Alzheimer's disease (AD) are not only associated with regional gray matter damage but also with abnormal functional integration of different brain regions by disconnection mechanisms. A measure of anatomical connectivity (anatomical connectivity mapping or ACM) can be obtained by initiating diffusion tractography streamlines from all parenchymal voxels and then counting the number of streamlines passing through each voxel of the brain. In order to assess the potential of this parameter for the study of disconnection in AD, we computed it in a group of patients with AD (N=9), in 16 patients with amnestic mild cognitive impairment (a-MCI, which is considered the prodromal stage of AD) and in 12 healthy volunteers. All subjects had an MRI scan at 3T, and diffusion MRI data were analyzed to obtain fractional anisotropy (FA) and ACM. Two types of ACM maps, absolute count (ac-ACM) and normalized by brain size count (nc-ACM), were obtained. No between group differences in FA surviving correction for multiple comparison were found, while areas of both decreased (in the supramarginal gyrus) and increased (in the putamen) ACM were found in patients with AD. Similar results were obtained with ac-ACM and nc-ACM. ACM of the supramarginal gyrus was strongly associated with measures of short-term memory in healthy subjects. This study shows that ACM provides information that is complementary to that offered by FA and appears to be more sensitive than FA to brain changes in patients with AD. The increased ACM in the putamen was unexpected. Given the nature of ACM, an increase of this parameter may reflect a change in any of the areas connected to it. One intriguing possibility is that this increase of ACM in AD patients might reflect processes of brain plasticity driven by cholinesterase inhibitors., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The feeling of guilt is a complex mental state underlying several human behaviors in both private and social life. From a psychological and evolutionary viewpoint, guilt is an emotional and cognitive function, characterized by prosocial sentiments, entailing specific moral believes, which can be predominantly driven by inner values (deontological guilt) or by more interpersonal situations (altruistic guilt). The aim of this study was to investigate whether there is a distinct neurobiological substrate for these two expressions of guilt in healthy individuals. We first run two behavioral studies, recruiting a sample of 72 healthy volunteers, to validate a set of stimuli selectively evoking deontological and altruistic guilt, or basic control emotions (i.e., anger and sadness). Similar stimuli were reproduced in a event-related functional magnetic resonance imaging (fMRI) paradigm, to investigate the neural correlates of the same emotions, in a new sample of 22 healthy volunteers. We show that guilty emotions, compared to anger and sadness, activate specific brain areas (i.e., cingulate gyrus and medial frontal cortex) and that different neuronal networks are involved in each specific kind of guilt, with the insula selectively responding to deontological guilt stimuli. This study provides evidence for the existence of distinct neural circuits involved in different guilty feelings. This complex emotion might account for normal individual attitudes and deviant social behaviors. Moreover, an abnormal processing of specific guilt feelings might account for some psychopathological manifestation, such as obsessive-compulsive disorder and depression., (Copyright © 2010 Wiley-Liss, Inc.)

Obstructive sleep apnea (OSA) is accompanied by neurocognitive impairment, likely mediated by injury to various brain regions. We evaluated brain morphological changes in patients with OSA and their relationship to neuropsychological and oximetric data. Sixteen patients affected by moderate-severe OSA (age: 55.8±6.7 years, 13 males) and fourteen control subjects (age: 57.6±5.1 years, 9 males) underwent 3.0 Tesla brain magnetic resonance imaging (MRI) and neuropsychological testing evaluating short- and long-term memory, executive functions, language, attention, praxia and non-verbal learning. Volumetric segmentation of cortical and subcortical structures and voxel-based morphometry (VBM) were performed. Patients and controls differed significantly in Rey Auditory-Verbal Learning test (immediate and delayed recall), Stroop test and Digit span backward scores. Volumes of cortical gray matter (GM), right hippocampus, right and left caudate were smaller in patients compared to controls, with also brain parenchymal fraction (a normalized measure of cerebral atrophy) approaching statistical significance. Differences remained significant after controlling for comorbidities (hypertension, diabetes, smoking, hypercholesterolemia). VBM analysis showed regions of decreased GM volume in right and left hippocampus and within more lateral temporal areas in patients with OSA. Our findings indicate that the significant cognitive impairment seen in patients with moderate-severe OSA is associated with brain tissue damage in regions involved in several cognitive tasks. We conclude that OSA can increase brain susceptibility to the effects of aging and other clinical and pathological occurrences., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Objective: To assess the contribution of regional grey matter (GM) atrophy and functional disconnection in determining the level of cognitive decline in patients with Alzheimer's disease (AD) at different clinical stages., Methods: Ten patients with amnesic mild cognitive impairment (a-MCI), 11 patients with probable AD and 10 healthy controls were recruited. T1 volumes were obtained from each subject and postprocessed according to an optimised voxel based morphometry protocol. Resting state functional MRI data were also collected from the same individuals and analysed to produce connectivity maps after identification of the default mode network (DMN) by independent component analysis., Results: Compared with healthy controls, both AD and a-MCI patients showed a similar regional pattern of brain disconnection between the posterior cingulate cortex (PCC) and the medial prefrontal cortex and the rest of the brain. Conversely, the distribution of GM atrophy was significantly more restricted in a-MCI than in AD patients. Interestingly, the PCC showed reduced connectivity in a-MCI patients in the absence of GM atrophy, which was, in contrast, detectable at the stage of fully developed AD., Conclusions: This study indicates that disconnection precedes GM atrophy in the PCC, which is a critical area of the DMN, and supports the hypothesis that GM atrophy in specific regions of AD brains likely reflects a long term effect of brain disconnection. In this context, our study indicates that GM atrophy in PCC accompanies the conversion from MCI to AD.

Motor impairment represents the main clinical feature of Parkinson's disease (PD). Cognitive deficits are also frequently observed in patients with PD, with a prominent involvement of executive functions and visuo-spatial abilities. We used event-related functional MRI (fMRI) and a paradigm based on visual attention and motor inhibition (Go/NoGO-task) to investigate brain activations in 13 patients with early PD in comparison with 11 healthy controls. The two groups did not report behavioural differences in task performance. During motor inhibition (NoGO-effect), PD patients compared to controls showed an increased activation in the prefrontal cortex and in the basal ganglia. They also showed a reduced and less coherent hemodynamic response in the occipital cortex. These results indicate that specific cortico-subcortical functional changes, involving not only the fronto-striatal network but also the temporal-occipital cortex, are already present in patients with early PD and no clinical evidence of cognitive impairment. We discuss our findings in terms of compensatory mechanisms (fronto-striatal changes) and preclinical signs of visuo-perceptual deficits and visual hallucinations., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Purpose: To assess, by means of magnetic resonance (MR) imaging, the longitudinal changes in white matter (WM) and gray matter (GM) in a cohort of patients with clinically isolated syndrome (CIS) who were followed up for 1 year., Materials and Methods: This prospective, HIPAA-compliant study was approved by the institutional review board. Written informed consent was obtained from all the participants. Changes in GM and WM integrity were respectively investigated by using three-dimensional T1-weighted and diffusion-tensor (DT) imaging sequences and by applying voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses. Thirty-four consecutive patients (21 women, 13 men; mean age, 32.8 years ± 7.7 [standard deviation]) who had CIS were recruited. All the patients underwent a neurologic and an MR examination at baseline and 12 months later; the MR examination consisted of three-dimensional T1-weighted dual-echo turbo spin-echo DT imaging. VBM and TBSS were used to analyze GM volume and WM fractional anisotropy, respectively., Results: After 1 year, multiple sclerosis (MS) was diagnosed in 33 (97%) of 34 patients with CIS. Longitudinal volumetric analysis revealed a significant (P < .001) reduction in global GM volume. The VBM analysis showed the development of regional GM atrophy involving several cortical and subcortical regions in both hemispheres (P < .05). No significant longitudinal change in global or regional WM fractional anisotropy was otherwise observed., Conclusion: WM damage was detectable early and involved most fiber tracts in patients with MS, but it did not worsen significantly during the 1st year after clinical onset. In contrast, GM damage was not detectable at the time of clinical onset, but a significant decrease in cortical and deep GM volume was observed at 1 year., (© RSNA, 2010.)

Deficits in sustained attention may lead to action slips in everyday life as irrelevant action sequences are inappropriately triggered internally or by the environment. While deficits in sustained attention have been associated with damage to the frontal lobes of the brain, little is known about the role of the frontal lobes in the Elevator Counting subtest of the Test of Everyday Attention. In the current study, 55 frontal patients subdivided into medial, orbital and lateral subgroups, 18 patients with posterior lesions and 82 healthy controls performed the Elevator Counting task. The results revealed that patients with medial and left lateral prefrontal lesions were significantly impaired on the task compared to healthy controls. Research suggests that patients with medial lesions are susceptible to competition from task irrelevant schema; whereas the left lateral group in the current study may fail to keep track of the tones already presented., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

We combined bifocal transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) tractography to investigate in humans the contribution of connections originating from different parietal areas in planning of different reaching to grasp movements. TMS experiments revealed that in the left hemisphere functional connectivity between the primary motor cortex (M1) and a portion of the angular gyrus (AG) close to the caudal intraparietal sulcus was activated during early preparation of reaching and grasping movements only when the movement was made with a whole hand grasp (WHG) towards objects in contralateral space. In contrast, a different pathway, linking M1 with a part of the supramarginal gyrus (SMG) close to the anterior intraparietal sulcus, was sensitive only to the type of grasp required (precision grasping) but not to the position of the object in space. A triple coil experiment revealed that inactivation of the ventral premotor area (PMv) by continuous theta burst stimulation interfered with some of these interactions. Anatomical DTI tractography revealed that AG and SMG are strongly connected with PMv and with M1 by different bundles of the superior longitudinal fasciculus (SLF). These results demonstrate the existence of segregated parieto-premotor-motor pathways crucial for preparation of different grasping actions and indicate that these may process information relevant to both the position of the object and the hand shape required to use it., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: To investigate whether, in patients with amnesic mild cognitive impairment (a-MCI), recognition deficits are mainly due to a selective impairment of recollection rather than familiarity., Methods: Nineteen patients with a-MCI and 23 sex-, age-, and education-matched healthy controls underwent two experimental investigations, using the Process Dissociation Procedure (PDP) and the Remember/Know (R/K) procedure, to assess the differential contribution of recollection and familiarity to their recognition performance., Results: Both experimental procedures revealed a selective preservation of familiarity in a-MCI patients. Moreover, the R/K procedure showed a statistically significant impairment of recollection in a-MCI patients for words that were either read or anagrammed during the study phase., Conclusions: A-MCI is known to be commonly associated with a high risk of conversion to Alzheimer's disease (AD). Several previous studies have demonstrated a characteristic impairment of episodic memory in a-MCI, with an early dysfunction of recognition. Our findings are consistent with the knowledge of neurodegeneration occurring in AD, which is characterized, at the earliest disease stages, by a selective involvement of the entorhinal cortex. Moreover, the current study supports the dual process model of recognition, which hypothesizes recollection and familiarity to be independent processes associated with distinct anatomical substrates.

Much debate surrounds the role of the left inferior frontal gyrus (LIFG). Evidence from lesion and neuroimaging studies suggests the LIFG supports a selection mechanism used in single word generation. Single case studies of dynamic aphasic patients with LIFG damage concur with this and extend the finding to selection of sentences at the conceptual preparation stage of language generation. A neuropsychological group with unselected focal frontal and non-frontal lesions is assessed on a sentence generation task that varied the number of possible conceptual propositions available for selection. Frontal patients with LIFG damage when compared to Frontal patients without LIFG damage and Posterior patients were selectively impaired on sentence generation tests only when stimuli activated multiple conceptual propositions that compete with each other for selection. We found that this selective impairment is critical for reduced speech rate, the core deficit of dynamic aphasia, and we would argue it is causative for one form of dynamic aphasia associated with LIFG lesions. These results provide evidence that the LIFG is crucial for selecting among multiple competing conceptual propositions for language generation., (2010. Published by Elsevier Ltd. All rights reserved.)

One possible explanation for the mismatch between tissue damage and preservation of neurological functions in patients with benign multiple sclerosis (BMS) is that the pathophysiology differs from that occurring in other multiple sclerosis (MS) phenotypes. The objective of this study was to identify pathologically specific patterns of tissue integrity/damage characteristics of patients with BMS, and markers of potential prognostic value. The pyramidal system was investigated in 10 BMS patients and 20 controls using voxel-based morphometry to assess grey matter (GM) atrophy, and diffusion tractography and quantitative magnetization transfer to quantify the microstructural damage in the corticospinal tracts (CSTs). Widespread reductions in GM volume were found in patients compared with controls, including the primary motor cortex. A significant decrease was observed in the mean macromolecular pool ratio (F) of both CSTs, with no fractional anisotropy (FA) change. GM volume of the primary motor areas was associated with clinical scores but not with the CST parameters. The mismatch between F and FA suggests the presence of extensive demyelination in the CSTs of patients with BMS, in the absence of axonal damage. The lack of correlation with GM volume indicates a complex interaction between disruptive and reparative mechanisms in BMS.

This study investigates abnormalities of grey (GM) and white matter (WM) in Alzheimer's disease (AD), by modeling the AD pathological process as a continuous course between normal aging and fully developed dementia, with amnesic mild cognitive impairment (aMCI) as an intermediate stage. All subjects (9 AD, 16 aMCI patients, and 13 healthy controls) underwent a full neuropsychological assessment and an MRI examination at 3 Tesla, including a volumetric scan and diffusion tensor (DT)-MRI. The volumes were processed to perform a voxel-based morphometric analysis of GM and WM volume, while DT-MRI data were analyzed using tract based spatial statistics, to estimate changes in fractional anisotropy and mean diffusivity data. GM and WM volume and mean diffusivity and fractional anisotropy were compared across the three groups, and their correlation with cognitive functions was investigated. While AD presented a pattern of widespread GM atrophy, tissue loss was more subtle in patients with aMCI. WM atrophy was mainly located in the temporal lobe, but evidence of WM microscopic damage, assessed by DT-MRI, was also observable in the thalamic radiations and in the corpus callosum. Memory and executive functions correlated with either GM volume or fractional anisotropy in fronto-temporal areas. In conclusion, this study shows a comprehensive assessment of the brain tissue damage across AD evolution, providing insights on different pathophysiological mechanisms (GM atrophy, Wallerian degeneration, and brain disconnection) and their possible association with clinical aspects of cognitive decline.

Purpose: To quantify white matter (WM) and gray matter (GM) damage in patients who presented with clinically isolated syndrome (CIS), which is suggestive of multiple sclerosis (MS), by combining volume-based morphometry (VBM) and tract-based spatial statistics (TBSS)., Materials and Methods: This prospective HIPAA-compliant study was approved by the institutional review board. Written informed consent was obtained from all participants. In this study, 34 consecutive patients (21 women, 13 men; mean age, 31.7 years +/- 7.7 [standard deviation]) who presented with CIS were recruited. The magnetic resonance (MR) examination included dual-echo fast spin-echo, three-dimensional T1, and diffusion-tensor imaging. Sixteen matched healthy volunteers served as control subjects. T2 lesion volumes were assessed with a semiautomatic technique. VBM and TBSS were used for the GM and WM analyses, respectively, to compare regional GM volumes and fractional anisotropy (FA) values in the two groups., Results: TBSS analysis revealed a pattern of diffuse FA reductions in patients with CIS at the cluster level (P < .05). Regions of decreased FA involved most of the WM pathways, including the corticospinal tracts, corpus callosum, and superior and inferior longitudinal fasciculi. There were no significant differences between the two groups in terms of global GM, WM, or cerebrospinal fluid volume or in terms of regional GM volume., Conclusion: Diffuse WM damage not accompanied by any change in GM or WM volume is observed in patients with CIS. This suggests that WM involvement plays a relevant role in the early phases of MS. Subsequently detected GM damage may be secondary to WM alterations.

Behavioral and psychological symptoms of dementia (BPSD) are commonly observed over the course of Alzheimer's disease (AD). However, it is unclear whether BPSD are part of AD neuropathology or rather represent a psychological reaction to cognitive disabilities. Using voxel-based-morphometry (VBM), we aimed to clarify this issue by investigating patients with AD at different clinical stages. Twenty-seven patients with AD (12 early [ADe] and 15 moderate [ADm]), 19 with amnestic mild cognitive impairment (a-MCI), and 23 healthy controls underwent MRI scanning at 3T. Assessment of BPSD was done in each patient using the Neuropsychiatric Inventory-12 (NPI-12). VBM was used to investigate changes in grey matter (GM) atrophy across groups, and associations between regional GM volumes and occurrence and severity of BPSD in patients. Mood disorders, anxiety, and agitation were present in both a-MCI and AD, while psychotic symptoms were observed mainly in AD. As expected, VBM showed only limited areas of GM atrophy in a-MCI patients, with a progressive extension in ADe and ADm patients (PFWE-corrected-values < 0.05). Disinhibition was strongly associated with GM volume in bilateral cingulate and right middle frontal gyri, while delusions were associated with GM volume in right hippocampus (PFWE-corrected-values < 0.05). This study confirms that BPSD are present since the earliest AD stages. Interesting associations were found in regions traditionally implicated by AD neuropathology. This suggests that BPSD are likely to represent clinical features of AD and should be regarded for their diagnostic and prognostic value.

One of the main limitations for BNCT effectiveness is the insufficient intake of (10)B nuclei within tumour cells. This work was aimed at investigating the use of L-DOPA as enhancer for boronophenylalanine (BPA) uptake in the C6 glioma model. The investigation was first performed in vitro, and then extended in vivo to the animal model. BPA accumulation in C6 glioma cells was assessed, using radiowave dielectric spectroscopy (RDS), with and without L-DOPA preloading. C6 glioma cells were also implanted in the brain of 25 rats, randomly assigned to two experimental branches: (1) intra-carotid BPA infusion; (2) intra-carotid BPA infusion after pre-treatment with L-DOPA, administrated 24 h before BPA infusion. All animals were sacrificed, and assessment of BPA concentrations in tumour tissue, normal brain, and blood samples was performed using high performance liquid chromatography (HPLC). L-DOPA preloading induced a massive increase of BPA concentration either in vitro on C6 glioma cells or in vivo in the animal model tumour. Moreover, no significant difference was found in the normal brain and blood samples between the two animal groups. This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT.

This article describes a novel approach for local estimation of the radial diffusion coefficient (D(perpendicular)) in white matter (WM) regions containing well-oriented nervous fibers. The method is based on the assumption that the diffusion process in well-organized WM regions responds to a cylindrical symmetry. The increased precision in the estimation of D(perpendicular) provided by this local approach compared to standard techniques based on diffusion tensor imaging is demonstrated using numerical simulations. An in vivo validation of the technique is also provided, showing its application to the corpus callosum of six healthy volunteers, highlighting the sensitivity of the method. Assuming that D(perpendicular) is sensitive to myelin integrity, our technique has the potential to investigate pathophysiological aspects of several neurological and psychiatric disorders with improved precision in targeted WM tracts.

Several neuroimaging studies in developmental dyslexia (DD) have mainly focused on brain regions subserving phonological processes. However, additional deficits characterize subjects with DD, such as an impairment of visual and rapid stimuli processing and deficits in implicit learning (IL). Little is known about structural abnormalities in brain regions not directly related to phonology and reading processes. The aim of this study was to investigate, using voxel-based morphometry, whether subjects with DD exhibit any structural grey matter (GM) abnormalities in regions that have previously shown abnormal functional magnetic resonance imaging (fMRI) activation during an IL task. Significantly smaller GM volumes were found in the right posterior superior parietal lobule and precuneus and in the right supplementary motor area (SMA) of subjects with DD compared to controls. Moreover, a larger GM volume in parietal cortex was associated with an increase of IL effect in controls but not in subjects with DD. These structural abnormalities are consistent with functional changes and reinforce the hypothesis that an impairment of IL might play a relevant role in learning to read.

Single-process theories assume that familiarity is the sole influence on recognition memory with decisions being made as a continuous process. Dual-process theories claim that recognition involves both recollection and familiarity processes with recollection as a threshold process. Although, the frontal lobes of the brain play an important role in recognition memory, few studies have examined the effect of frontal lobe lesions on recollection and familiarity. In the current study, the nonverbal recognition memory of 24 patients with focal frontal lesions due to tumour or stroke was examined. Recollection and familiarity were estimated using the receiver operating characteristic (ROC) method. A secondary analysis was also conducted using standard signal detection theory methodology. Both analyses led to similar conclusions where only the familiarity component of recognition memory was impaired in frontal patients compared to healthy controls whilst the recollection-type (or variance ratio) processes remained intact.

Background and Purpose: At high altitudes barometric pressure is reduced and, thus, less oxygen is inhaled. Reduced oxygen concentration in brain tissue can lead to cerebral damage and neurological and cognitive deficits. The present study was designed to explore the effects of high-altitude exposure using a quantitative MRI technique, voxel-based morphometry., Methods: We studied nine world-class mountain climbers before (baseline) and after (follow-up) an extremely high-altitude ascent of Everest and K2. We investigated the effects of repeated extremely high-altitude exposures by comparing mountain climbers' scans at baseline with scans of 19 controls. In addition, we measured the effects of a single extremely high-altitude expedition by comparing mountain climbers' scans at baseline and follow-up., Results: A region of reduced white matter density/volume was found in the left pyramidal tract near the primary (BA 4) and supplementary (BA 6) motor cortex when mountain climbers at baseline were compared with controls. Further, when mountain climbers' scans before and after the expedition were compared, a region of reduced grey matter density/volume was found in the left angular gyrus (BA 39)., Conclusion: These findings suggest that extremely high-altitude exposures may cause subtle white and grey matter changes that mainly affect brain regions involved in motor activity.

Purpose: Boron neutron capture therapy (BNCT) is a radiotherapeutic modality based on (10)B(n,alpha)(7)Li reaction, for the treatment of malignant gliomas. One of the main limitations for BNCT effectiveness is the insufficient intake of (10)B nuclei in the tumor cells. This work was aimed at investigating the use of L-DOPA as a putative enhancer for (10)B-drug 4-dihydroxy-borylphenylalanine (BPA) uptake in the C6-glioma model. The investigation was first performed in vitro and then extended to the animal model., Methods and Materials: BPA accumulation in C6-glioma cells was assessed using radiowave dielectric spectroscopy, with and without L-DOPA preloading. Two L-DOPA incubation times (2 and 4 hours) were investigated, and the corresponding effects on BPA accumulation were quantified. C6-glioma cells were also implanted in the brain of 32 rats, and tumor growth was monitored by magnetic resonance imaging. Rats were assigned to two experimental branches: (1) BPA administration; (2) BPA administration after pretreatment with L-DOPA. All animals were sacrificed, and assessments of BPA concentrations in tumor tissue, normal brain, and blood samples were performed using high-performance liquid chromatography., Results: L-DOPA preloading induced a massive increase of BPA concentration in C6-glioma cells only after a 4-hour incubation. In the animal model, L-DOPA pretreatment produced a significantly higher accumulation of BPA in tumor tissue but not in normal brain and blood samples., Conclusions: This study suggests the potential use of L-DOPA as enhancer for BPA accumulation in malignant gliomas eligible for BNCT. L-DOPA preloading effect is discussed in terms of membrane transport mechanisms.

The volume of the brain and of some of its structures can provide insight into the pathological process of several diseases. For this reason, in the recent years we saw a tremendous progress in the development of automated techniques for gaining information about global and regional atrophy. This paper reviews the main methods of analysis to quantify brain volume, and their application to the study of normal aging and the principal forms of degenerative dementias.

Diffusion tensor magnetic resonance imaging (DT-MRI) is a powerful quantitative technique with the ability to detect in vivo microscopic characteristics and abnormalities of brain tissue. It has been successfully applied to a number of neurological conditions, such as stroke, multiple sclerosis and brain tumors, providing information otherwise inaccessible on the pathological substrates. DT-MRI has also been used to study patients with cognitive decline, mainly those with Alzheimer's disease. Several image-analysis approaches have been employed, including region of interest, histogram, voxel-based analyses and DT-MRI-based tractography. Specific patterns of spatial distribution of tissue damage and correlations with neuropsychological measures have been reported. This review focuses on the use of DT-MRI to investigate dementias. The main clinical results and the different methods of image analysis will be overviewed and discussed.

Focal damage confined to the hippocampus may result in recognition deficits characterized by a dissociation between impaired recollection and preserved familiarity. Here, we report a single case of an amnesic patient with bilateral damage to the anterior part of the thalamus, who presented with a neuropsychological profile suggesting such a dissociation. We hypothesized that this focal damage involved the so-called Delay and Brion's circuit, which has been theorized to subserve episodic memory processes, but at a different anatomical level than in patients with hippocampal lesions. Using two independent experimental paradigms (remember/know and confidence receiver operating characteristics [ROC]) and recruiting a sex- and age-matched group of healthy controls, we demonstrated that this patient's recognition deficits were due to a selective impairment of recollection with a normal familiarity process. The patient underwent an ad hoc brain MRI study, and a quantitative analysis of his MR images was performed. Tissue damage extended bilaterally to the mammillo-thalamic tract, with complete preservation of the medio-dorsal thalamic nuclei. Our findings support the idea that the same functional specialization hypothesized for the different sub-regions of the mesial temporal lobe might also extend to the thalamus. This case will be discussed in light of its implications in support of recent theories, which regard recollection and familiarity as independent processes associated with different neural circuits.

Recollection and familiarity represent two processes involved in episodic memory retrieval. We investigated how scopolamine (an antagonist of acetylcholine muscarinic receptors) influenced brain activity during memory retrieval, using a paradigm that separated recollection and familiarity. Eighteen healthy volunteers were recruited in a randomized, placebo-controlled, double-blind design using event-related fMRI. Participants were required to perform a verbal recognition memory task within the scanner, either under placebo or scopolamine conditions. Depending on the subcondition, participants were required to make a simple recognition decision (old/new items) or base their decision on more specific information related to prior experience (target/non-target/new items). We show a drug modulation in left prefrontal and perirhinal cortex during recollection. Such an effect was specifically driven by novelty and showed an inverse correlation with accuracy performance. Additionally, we show a direct correlation between drug-related signal change in left prefrontal and perirhinal cortices. We discuss the findings in terms of acetylcholine mediation of the familiarity/novelty signal through perirhinal cortex and the control of the relative signal strength through prefrontal cortex.

Brain damage in Alzheimer's disease (AD) and mild cognitive impairment (MCI) is widespread with involvement of large portions of the neocortex and the subcortical white matter. A quantitative measure of neuronal damage of the entire brain might be valuable in the context of large-scale, longitudinal studies of these patients. This study investigated the extent of neuroaxonal injury of patients with AD and MCI using a novel unlocalized proton magnetic resonance spectroscopy ((1)H-MRS) technique, which allows quantification of the concentration of N-acetylaspartate from the whole of the brain tissue (WBNAA). Conventional brain MRI and WBNAA were obtained from 28 AD patients, 27 MCI patients and 25 age-matched controls. Normalized brain volume (NBV) was also measured using an automated segmentation technique. WBNAA and NBV showed a significant heterogeneity between groups (P < 0.001). WBNAA concentration was different between controls and MCI patients (P = 0.003), but not between MCI and AD patients (P = 0.33). NBV differed both between controls and MCI patients (P = 0.02) and between MCI and AD patients (P = 0.03). A multivariate regression model retained WBNAA as the best MRI predictor of the Mini Mental State Examination score (P = 0.001). Significant neuronal damage, which is related to the extent of cognitive decline, can be quantified in the whole brain tissue of patients with AD, using a novel (1)H-MRS approach. The demonstration in patients with MCI of MR structural and metabolic findings, intermediate between those of healthy volunteers and those of AD patients, indicates that neuronal damage is already evident and widespread in individuals with MCI before they are clinically demented.

The aim of the present study was to apply diffusion tensor MRI (DT-MRI), a quantitative MRI measure which reflects tissue organization, to dementia with Lewy bodies (DLB). DT-MRI scans were obtained from 15 patients with probable DLB and 10 sex- and age-matched healthy controls. Abnormalities were found in the corpus callosum, pericallosal areas and the frontal, parietal, occipital and, less prominently, temporal white matter of patients compared with controls. Abnormalities were also found in the caudate nucleus and the putamen. The average grey matter volume was lower in patients than in controls. These findings of concomitant grey matter atrophy and white matter abnormalities (as detected by DT-MRI) in regions with a high prevalence of long connecting fibre tracts might suggest the presence of neurodegeneration involving associative cortices. The modest involvement of the temporal lobe fits with the relative preservation of global neuropsychological measures and memory tasks in the early stage of DLB. The selective involvement of parietal, frontal and occipital lobes might explain some of the clinical and neuropsychological features of DLB, providing a possible distinctive marker for this disease. The abnormalities found in the subcortical grey matter may indicate that DLB and Parkinson's disease share a similar nigrostriatal involvement caused by common pathophysiological mechanisms.

Axons produce signals that regulate oligodendrocyte proliferation, survival, terminal differentiation, and myelinogenesis. We review here recent in vitro and in vivo experimental approaches that aim to characterize axonal signals to oligodendroglia and to identify molecular mediators that regulate differentiation of oligodendendrocytes. We propose that the promoters of myelin genes, whose activation during terminal differentiation is modulated by axonal signals, can provide a means to identify molecular mediators of axo-oligodendroglial signals.

Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.

Purpose: To identify the gene disrupted by a de novo reciprocal balanced translocation t(6;8)(q26;q13) in a patient with Duane retraction syndrome (DURS). The break point in chromosome arm 8q is positioned within the DURS1 critical region., Methods: Fluorescence in situ hybridization (FISH) analysis using cosmid and BAC clones covering the DURS1 locus was performed to define the break point position and its relationship with expressed sequence tags (ESTs) in the region. Once the interrupted gene was identified, the full-length cDNA was sequenced and the genomic organization defined. Eighteen patients with sporadic DURS without cytogenetic abnormalities involving the DURS1 region were screened for point mutations in the candidate DURS1 gene., Results: A carboxypeptidase gene (CPAH) was directly interrupted between the first and second exons in a patient with DURS who carried a de novo reciprocal balanced translocation t(6;8)(q26;q13) involving the DURS1 region on chromosome arm 8q13. The gene was transcribed in at least two alternative mRNA forms, with different start and stop codons., Conclusions: The CPAH gene was interrupted in a patient with DURS carrying a translocation break point in the DURS1 region on chromosome 8q13. CPAH is therefore a likely candidate for this abnormality, even if the possibility that other genes are involved, either by direct effects on transcription units present in the first CPAH intron or by position effects, cannot be ruled out. Functional studies of the influence of this gene on the morphogenesis of eye muscles and their innervation may clarify this question.

Congenital hypothyroidism (CH) may cause severe and irreversible neurologic and developmental abnormalities when not recognized early. Many millions of newborns have now been screened and many thousands of patients with CH have been identified. Approximately 80%-85% have defects of thyroid gland development, while 15%-20% have congenital errors of thyroid hormone biosynthesis. An entire population screened for CH over a long period of time, was studied in the present report, using a population-based approach. In particular, two CH phenotypes, both presenting with in situ thyroid gland (patients with either goiter or with thyroid gland volume ranging from normal to hypoplasic) were analyzed. Mutations were searched in some of the most likely candidate genes: thyroperoxidase (TPO) in patients with CH goiter, Pax8 and thyrotropin receptor (TSHR) in the other group. In the former group (n = 8), four TPO gene mutations were identified in three patients. One patient was a compound heterozygous. In two cases an already described mutation (1277(insGGCC)) was present; in two other cases mutations not previously described (1996(G-->T) and 2295(G-->A)), which induced aminoacid variations with a Glu --> Stop and Val --> Ile changes, respectively, were identified. In all patients mutations were inherited from one of the parents. In the case of the compound heterozygous patient, one mutation was inherited from the mother (1277(insGGCC)) and the other from the father (1996(G-->T), Glu --> Stop). In the latter group (n = 8), a patient with a 16-base pair C(T)(13)CC deletion in TSHR gene intron 8, 42-bp distal to exon/intron 8 splice junction, was identified. No mutation was identified in Pax8 gene.

Resistin is overexpressed in human adipose tissue of obese individuals and is likely to modulate insulin sensitivity. Resistin is, therefore, a candidate gene for insulin resistance. We searched for polymorphisms in the resistin gene by single strand conformation polymorphism and direct sequencing. An ATG triplet repeat in the 3'-untranslated region was identified and considered for association with insulin resistance. Three alleles were identified (allele 1: 8 repeats, allele frequency, 0.3%; allele 2: 7 repeats; allele frequency, 94.5%; allele 3: 6 repeats; allele frequency, 5.2%). Two hundred and three unrelated white Caucasian nondiabetic subjects from Sicily and 456 from the Gargano area (center east coast of Italy) were analyzed. Among Sicilians, subjects carrying allele 3 had a lower fasting insulin and insulin resistance index (homeostasis model assessment of insulin resistance; P < 0.001 for both) and glucose (P = 0.025) and insulin (P = 0.002) levels during the oral glucose tolerance test. In subjects from Gargano, those carrying allele 3 had lower fasting plasma glucose levels and serum triglycerides (P = 0.01 for both). When the 2 populations were analyzed together, subjects carrying allele 3 had lower fasting insulin levels (P < 0.005), homeostasis model assessment of insulin resistance (P < 0.005), and serum triglycerides (P = 0.01). In conclusion, our data suggest that subjects carrying allele 3 of the resistin gene are characterized by relatively high insulin sensitivity.

Background: Diffusion-tensor magnetic resonance imaging is sensitive to the more destructive aspects of multiple sclerosis (MS) evolution occurring outside and within T2-visible lesions and, as a consequence, holds promise for providing a more complete picture of primary progressive (PP) MS-related tissue damage than conventional magnetic resonance imaging., Objective: To improve our understanding of PPMS by assessing the extent of occult pathological features in the normal-appearing white and gray matter of the brain using diffusion-tensor magnetic resonance imaging., Methods: Ninety-six patients with PPMS, 47 patients with secondary progressive (SP) MS, and 44 healthy control subjects were studied. T2-hyperintense and T1-hypointense lesion volumes were calculated, and the volume of the whole brain tissue was measured. Diffusion-tensor magnetic resonance imaging scans were postprocessed and analyzed to obtain the mean diffusivity and fractional anisotropy histograms from the brain and from the normal-appearing white and gray matter in isolation., Results: The mean T2-hyperintense and T1-hypointense lesion volumes were lower in patients with PPMS than in patients with SPMS, while the mean absolute brain volumes were similar in the 2 groups. The average lesion diffusivity was significantly higher in patients with SPMS than in patients with PPMS (P<.001). Histogram-derived metrics of the brain tissue and normal-appearing white and gray matter were significantly different between patients with PPMS and healthy subjects (range, P =.004 to <.001). Average diffusivity values were significantly higher in patients with SPMS than in patients with PPMS for all the tissues studied (range, P =.001 to <.001). Fractional anisotropy histogram-derived quantities did not significantly differ between the 2 patient groups (range, P =.94 to.03)., Conclusion: This study confirms that, in patients with PPMS, normal-appearing white and gray matter are not spared by disease-related pathological processes, although they are affected to a lesser degree than in patients with SPMS.

Previous diffusion tensor magnetic resonance imaging (DT-MRI) studies reported mean diffusivity () and fractional anisotropy (FA) changes in lesions and normal-appearing white matter (NAWM) of patients with multiple sclerosis (MS), but neglected the additional information which can be obtained by the analysis of the inter-voxel coherence (C). The present study is based on a large sample of patients with MS and it is aimed at assessing the potential role of C in the quantification of MS-related tissue damage of T2-visible lesions and NAWM. We obtained dual-echo, T1-weighted and DT-MRI scans from 78 patients with relapsing-remitting (RR), secondary progressive (SP), or primary progressive (PP) MS and from 26 healthy volunteers. We calculated, FA and C of T2-hyperintense lesions, T1-isointense lesions, T1-hypointense lesions and several areas of the NAWM. and FA of the majority of NAWM regions studied from MS patients were different from the corresponding quantities of the white matter from controls. NAWM C from patients was lower than white matter C from controls only for the parietal pericallosal areas. SPMS patients had higher corpus callosum and lower corpus callosum FA and C than patients with either RRMS or PPMS. Average lesion was higher, and average FA and C lower than the corresponding quantities measured in the NAWM. Average T1-hypointense lesion was higher and average FA lower than the corresponding quantities of T1-isointense lesions, whereas average C of these two lesion populations were not different. SPMS had higher average lesion than both PPMS and RRMS patients. NAWM and C of the corpus callosum were moderately correlated with disability. This study confirms the role of DT-MRI metrics to identify MS lesions with different amounts of tissue damage and to detect diffuse changes in the NAWM. It also shows that measuring C enables us to obtain additional information about tissue damage, which is complementary to that given by the analysis of and FA.

Objective: To investigate the extent and the nature of white matter tissue damage of patients with Alzheimer's disease using diffusion tensor magnetic resonance imaging (DT-MRI)., Background: Although Alzheimer's disease pathology mainly affects cortical grey matter, previous pathological and MRI studies showed that also the brain white matter of patients is damaged. However, the nature of Alzheimer's disease associated white matter damage is still unclear., Methods: Conventional and DT-MRI scans were obtained from 16 patients with Alzheimer's disease and 10 sex and age matched healthy volunteers. The mean diffusivity (D), fractional anisotropy (FA), and inter-voxel coherence (C) of several white matter regions were measured., Results: D was higher and FA lower in the corpus callosum, as well as in the white matter of the frontal, temporal, and parietal lobes from patients with Alzheimer's disease than in the corresponding regions from healthy controls. D and FA of the white matter of the occipital lobe and internal capsule were not different between patients and controls. C values were also not different between patients and controls for any of the regions studied. Strong correlations were found between the mini mental state examination score and the average overall white matter D (r=0.92, p<0.001) and FA (r=0.78; p<0.001)., Conclusions: White matter changes in patients with Alzheimer's disease are likely to be secondary to wallerian degeneration of fibre tracts due to neuronal loss in cortical associative areas.

Background and Purpose: Increasing evidence exists that cerebral gray matter (GM) from patients with multiple sclerosis (MS) is not spared. This study was performed to quantify in vivo the extent of cerebral GM pathologic abnormality in patients with relapsing-remitting (RR), secondary progressive (SP), and primary progressive MS, by using diffusion tensor (DT) MR imaging., Methods: Dual-echo and DT MR imaging of the brain were performed in 102 patients with MS and 30 healthy volunteers. After GM segmentation using a technique based on diffusion anisotropy thresholding, average diffusivity (D) histograms of the cerebral GM were produced for all participants., Results: All D histogram-derived metrics of the GM were significantly different between control volunteers and the whole MS population. No significant difference was found for any of the D histogram-derived metrics between control volunteers and patients with RRMS, whereas significant differences were found for D and D histogram peak location between control volunteers and patients with PPMS. All the D histogram-derived metrics differed significantly between patients with RRMS and patients with SPMS. Patients with SPMS also had significantly lower D than did patients with PPMS. All D histogram-derived metrics of the GM were strongly correlated with the T2 lesion volume., Conclusions: This study confirms the presence of brain GM changes in patients with MS. It also shows that the extent of such changes is greater during the progressive forms of the disease.

Protein tyrosine phosphatase 1B (PTP1B) inhibits insulin signaling and, when overexpressed, plays a role in insulin resistance (Ahmad et al. 1997). We identified, in the 3' untranslated region of the PTP1B gene, a 1484insG variation that, in two different populations, is associated with several features of insulin resistance: among male individuals, higher values of the insulin resistance HOMA(IR) index (P=.006), serum triglycerides (P=.0002), and total/HDL cholesterol ratio (P=.025) and, among female individuals, higher blood pressure (P=.01). Similar data were also obtained in a family-based association study by use of sib pairs discordant for genotype (Gu et al. 2000). Subjects carrying the 1484insG variant showed also PTP1B mRNA overexpression in skeletal muscle (6,166 plus minus 1,879 copies/40 ng RNA vs. 2,983 plus minus 1,620; P<.01). Finally, PTP1B mRNA stability was significantly higher (P<.01) in human embryo kidney 293 cells transfected with 1484insG PTP1B, as compared with those transfected with wild-type PTP1B. Our data indicate that the 1484insG allele causes PTP1B overexpression and plays a role in insulin resistance. Therefore, individuals carrying the 1484insG variant might particularly benefit from PTP1B inhibitors, a promising new tool for treatment of insulin resistance (Kennedy and Ramachandran 2000).

In patients with primary progressive (PP) multiple sclerosis, brain MRI lesion activity and burden are low, despite the presence of severe neurological impairment. On the contrary, the degree of cord atrophy and diffuse tissue damage in the brain and cervical cord have been found to be associated with clinical disability. Against this background, this study aimed at providing an in vivo indirect assessment of brain and cervical cord pathology in a large cohort of PP multiple sclerosis patients, using conventional MRI and magnetization transfer imaging (MTI). Ninety-one PP multiple sclerosis patients, 36 secondary progressive (SP) multiple sclerosis patients and 30 healthy controls underwent brain and cervical cord MRI scans, using dual echo (brain) or fast short-tau inversion recovery (cervical cord) MTI and T(1)-weighted sequences. For the brain, T(2) hyperintense and T(1) hypointense lesion volumes were calculated and the volume of the whole of the brain tissue measured. For the cervical cord, the number and burden of lesions and the cross-sectional area were assessed. MTI scans were post-processed and analysed to obtain magnetization transfer ratio (MTR) histograms from the whole of the brain and cervical cord tissue and from the normal-appearing brain tissue in isolation. In PP multiple sclerosis patients, brain, normal-appearing brain tissue and cervical cord MTR histogram-derived metrics revealed the presence of diffuse tissue damage whose characteristics did not significantly differ from those of SP multiple sclerosis patients, even though SP multiple sclerosis patients had higher MRI-visible lesion burdens. None of the correlations between MRI or MTI measures obtained from the brain and the cord were significant. PP multiple sclerosis patients' disability was significantly, albeit weakly associated with a composite MR model including measures of loss and intrinsic damage of cervical cord tissue. Our data indicate the presence of a diffuse tissue damage undetectable by conventional MRI in PP multiple sclerosis patients, whose extent seems to match that of SP multiple sclerosis patients with similar levels of disability. They also suggest that the severity of multiple sclerosis pathology in the cervical cord is one of the factors contributing to neurological impairment in PP multiple sclerosis.

Objective: To assess the feasibility of a new technique based on diffusion anisotropy to segment white and grey matter of the brain. To use this technique to measure the mean diffusivity () and magnetisation transfer ratio (MTR) of normal appearing white matter (NAWM) and grey matter (NAGM) from patients with multiple sclerosis., Methods: Dual echo turbo spin echo, MT, and diffusion weighted scans of the brain were obtained from 30 patients with multiple sclerosis and 18 sex and age matched healthy controls. After image coregistration and removal of T2 visible lesions, white and grey matter were segmented from 10 supratentorial slices using diffusion anisotropy thresholds. Histograms of the average MTR and were created for normal white and grey matter of controls and NAWM and NAGM of patients with multiple sclerosis., Results: All the MTR histogram derived metrics of the NAWM from patients with multiple sclerosis were significantly lower than those of white matter from controls. The peak height of the histogram of NAWM from patients with multiple sclerosis was also significantly different from that of normal white matter. The average MTR, the peak location of the MTR histogram, and peak height of the histogram of the NAGM of patients with multiple sclerosis were significantly lower than the corresponding quantities of grey matter from controls., Conclusions: A technique was developed for segmenting white and grey matter with the potential for improving the understanding of the pathophysiology of many neurological conditions. Its application to the study of multiple sclerosis confirms the presence of a diffuse tissue damage in the NAWM of these patients and suggests that subtle changes also occur in the NAGM.

It remains unclear whether brain energetics is disturbed in patients with mitochondrial disease without clinical central nervous system involvement (MDW). The authors used the high temporal and spatial resolution phosphorus magnetic resonance spectroscopy (31P MRS) technique that they developed to study high energy phosphates (HEPs) and intracellular pH (pH) in the visual cortex of 9 normal subjects and 5 MDW patients with single mtDNA deletion at rest, during, and after visual activation. In normal subjects, HEPs remained unchanged during activation but rose significantly (by 17%) during recovery, and pH increased during visual activation with a slow return to rest values. In MDW patients, HEPs were within the normal range at rest and did not change during activation, but fell significantly (by 22%) in the recovery period; pH did not reveal a homogeneous pattern. In the brain of patients with MDW, energy balance remains normal until oxidative metabolism is intensively stressed, as during a postactivation phase. The heterogeneity of the physicochemical environment (that is, pH) suggests various degrees of subclinical brain involvement. The combined use of MRS and brain activation is fundamental for the study of brain energetics and may prove an important diagnostic tool in patients with MDW.

Objectives: To assess (a) whether the changes in the normal appearing brain tissue (NABT), as revealed by magnetisation transfer (MT) histogram analysis, correlates with cognitive dysfunction in patients with multiple sclerosis and (b) the relative contribution of these changes by comparison with that of multiple sclerosis lesions visible on conventional MRI., Methods: Dual echo, T1 weighted and MT scans of the brain were obtained in 12 patients with multiple sclerosis with cognitive impairment and in seven without cognitive impairment. Lesion loads were assessed from T2 and T1 weighted scans. To create MT histograms of the NABT, multiple sclerosis lesion outlines from dual echo scans were superimposed automatically and nulled out from the coregistered and scalp stripped MTR maps. Average lesion MT ratio (MTR) and brain size were also measured., Results: T2 and T1 lesion loads were significantly higher and the average lesion MTR and brain size were significantly lower in the group of cognitively impaired patients. Patients with cognitive deficits also had significantly lower average MTR and peak location of the NABT histogram. Logistic regression analysis showed that 68% of the total variance was explained by average NABT-MTR alone. A multivariable regression model showed that NABT-MTR was the only factor that significantly correlated with cognitive impairment in these patients (p=0.001)., Conclusions: The extent of abnormalities which go undetected when using conventional MRI is relevant in determining cognitive impairment in multiple sclerosis.

Background and Purpose: Previous studies have failed to show significant correlations between the number and extent of T2 spinal cord lesions and the clinical status of multiple sclerosis (MS) patients. We evaluated 1) whether it is feasible to create magnetization transfer-ratio (MTR) histograms of the cervical cord in patients with MS by using two different acquisition schemes, and 2) whether cervical cord MTR histogram metrics were different from those of healthy control subjects and between MS patients with and without locomotor disability., Methods: We obtained two sets of gradient-echo sequences with and without a saturation pulse from 90 MS patients and 20 sex- and age-matched healthy control subjects. One set consisted of 20 axial, contiguous slices with a thickness equal to 5 mm. The other set consisted of 17 sagittal slices with a thickness equal to 3 mm and an interslice gap equal to 0.3 mm. After image coregistration and removal of tissues around the cervical cord, MTR histograms were created. The average MTR, the peak height, and the peak position of the histograms were measured. All of these measurements were from the whole of the cervical cord, thus including both MS lesions and normal-appearing tissue., Results: When comparing the MTR histograms obtained using axial, contiguous, 5-mm-thick slices, MS patients had significantly lower average cervical cord MTR and peak height than did control subjects. When comparing the MTR histograms obtained using sagittal, 3-mm-thick slices, MS patients also had significantly lower average cervical cord MTR and peak location than did control subjects. Patients with locomotor disability had significantly lower average cord MTR and peak location than those without., Conclusion: This study shows that it is feasible to obtain MTR histograms of the cervical cord from MS patients by using different acquisition schemes. Our results also suggest that the assessment of MS cervical cord damage, achieved using MTR histograms, may lead to a better understanding of the clinical manifestations of the disease.