Patrice Péran

Magnetic resonance imaging markers of Parkinson's disease nigrostriatal signature

One objective of modern neuroimaging is to identify markers that can aid in diagnosis, disease progression monitoring and long-term drug impact analysis. In this study, Parkinson-associated physiopathological modifications were characterized in six subcortical structures by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (i.e. volume atrophy, iron deposition and microstructural damage). Thirty patients with Parkinsons disease and 22 control subjects underwent 3-T magnetic resonance imaging with T₂*-weighted, whole-brain T₁-weighted and diffusion tensor imaging scans. The mean R₂* value, mean diffusivity and fractional anisotropy in the pallidum, putamen, caudate nucleus, thalamus, substantia nigra and red nucleus were compared between patients with Parkinsons disease and control subjects. Comparisons were also performed using voxel-based analysis of R₂*, mean diffusivity and fractional anisotropy maps to determine which subregion of the basal ganglia showed the greater difference for each parameter. Averages of each subregion were then used in a logistic regression analysis. Compared with control subjects, patients with Parkinsons disease displayed significantly higher R₂* values in the substantia nigra, lower fractional anisotropy values in the substantia nigra and thalamus, and higher mean diffusivity values in the thalamus. Voxel-based analyses confirmed these results and, in addition, showed a significant difference in the mean diffusivity in the striatum. The combination of three markers was sufficient to obtain a 95% global accuracy (area under the receiver operating characteristic curve) for discriminating patients with Parkinsons disease from controls. The markers comprising discriminating combinations were R₂* in the substantia nigra, fractional anisotropy in the substantia nigra and mean diffusivity in the putamen or caudate nucleus. Remarkably, the predictive markers involved the nigrostriatal structures that characterize Parkinsons physiopathology. Furthermore, highly discriminating combinations included markers from three different magnetic resonance parameters (R₂*, mean diffusivity and fractional anisotropy). These findings demonstrate that multimodal magnetic resonance imaging of subcortical grey matter structures is useful for the evaluation of Parkinsons disease and, possibly, of other subcortical pathologies.

Aging of subcortical nuclei: microstructural, mineralization and atrophy modifications measured in vivo using MRI.

In the present study, we characterized the physiological aging of deep grey matter nuclei by simultaneously measuring quantitative magnetic resonance parameters sensitive to complementary tissue characteristics (volume atrophy, iron deposition, microstructural damage) in seven different structures in 100 healthy subjects. Large age-related variations were observed in the thalamus, putamen and caudate. No significant correlations with age were observed in the hippocampus, amygdala, pallidum, or accumbens. Multiple regression analyses of advanced imaging data revealed that the best predictors of physiological aging were the mean relaxation time (T2*) of the putamen and the volume and mean diffusivity of the thalamus. These three parameters accounted for over 70% of the age variance in a linear model comprising 100 healthy subjects, aged from 20 to 70 years. Importantly, the statistical analyses highlighted characteristic patterns of variation for the measurements in the various structures evaluated in this study. These findings contribute in establishing a baseline for comparison with pathological changes in the basal ganglia and thalamus.

Deficit of verb generation in nondemented patients with Parkinson's disease

Clinical and neuroimaging studies have shown that verb processing suggests a preferential participation of a prefrontal network, which is dysfunctional in Parkinsons disease (PD). To assess a verb processing deficit in PD, we compared noun‐ and verb‐generation tasks for 34 nondemented PD patients (according to the Dementia Rating Scale) with 34 matched normal subjects, using two intracategory tasks (noun/noun and verb/verb generation) and two intercategory tasks (noun/verb and verb/noun generation). PD patients were significantly impaired in the two tasks involving verb production, i.e., verb/verb and noun/verb generation, whereas their performance was similar to those of controls in the two tasks requiring noun production. For the two impaired tasks, we assessed 1) the influence of lexical competition that corresponds to the presence of several candidate words for a given stimulus; 2) the influence of slight cognitive dysfunction; and 3) the influence of motor deficit. Significant correlations were found between DRS scores and performance on the noun/verb task, and no significant correlations were found between lexical competition or motor deficit and performance. The specific deficit for verb production in PD patients is discussed in relation to deficits affecting either action or grammatical representations.

Combined volumetry and DTI in subcortical structures of mild cognitive impairment and Alzheimer's disease patients.

The aim of this work was to investigate the hypothesis that multimodal MRI is able to detect the progressive disruption of volume and microstructure of subcortical structures in patients with amnestic mild cognitive impairment (a-MCI) and mild Alzheimers disease (AD) in comparison with healthy controls (CTRL). We combined volumetric and diffusion tensor imaging (DTI) techniques in a cross-sectional study including 30 a-MCI, 30 AD patients, and 30 age-matched CTRL. We employed a fully automated model-based segmentation algorithm on 3 Tesla MRI anatomical images and accurate coregistration of DTI to anatomical images to extract regional values of DTI parameters. Both the hippocampi significantly and progressively decreased in volume from CTRL through MCI to AD. Both the thalami showed a progressive and significant decrease in volume from CTRL to AD. Mean diffusivity (MD) values increased progressively across the three groups in the bilateral hippocampus, amygdala, and in the right caudate. No differences in fractional anisotropy (FA) values were found. Two distinct but overlapping patterns of progression of structural (i.e., atrophy) and microstructural (i.e., MD increase) damage were observed. Particularly, the pattern of atrophy was mirrored by the increasing value of the averaged MD, which provided a further indicator of subtle tissue disruption in the hippocampal structure in mild AD patients. Combining different MRI modalities can allow identifying sensitive indicators of the subtle pathogenic mechanisms that occur in subcortical areas of AD patients.

Volume and iron content in basal ganglia and thalamus

Magnetic resonance imaging (MRI) studies have highlighted the possibility to investigate brain iron content in vivo. In this study, we combined T2* relaxometry and automatic segmentation of basal ganglia based on T1‐weighted images in healthy subjects, with the aim of characterizing age related changes in volume and iron‐related relaxivity values (R2*) of these structures. Thirty healthy subjects underwent MR imaging at 3 Tesla. Mean R2* values and volumes were calculated for the selected subcortical structures (pallidum, putamen, thalamus and caudate nucleus). Our results showed a correlation between R2* values and iron concentration as calculated from published post‐mortem data. Furthermore, we observed a shrinkage/iron increase with a different pattern in the anatomical regions selected in this work, suggesting that the age‐related changes on these MR parameters are specific to the subcortical structure considered. In particular, the putamen demonstrated a decrease of volume and an increase of iron level, with the posterior region of this structure appearing more disposed to iron deposition. Our work suggests that combining volumetry and iron estimation in MRI permits to investigate in vivo neurophysiological and neuropathological changes of basal ganglia. Hum Brain Mapp 2009.

Developmental topographical disorientation in a healthy subject.

We present the case of F.G., a healthy, normally developed 22-year-old male subject affected by a pervasive disorder in environmental orientation and navigation who presents no history of neurological or psychiatric disease. A neuro-radiological examination showed no evidence of anatomical or structural alterations to the brain. We submitted the subject for a comprehensive neuropsychological assessment of the different cognitive processes involved in topographical orientation to evaluate his ability to navigate the spatial environment. The results confirmed a severe developmental topographical disorder and deficits in a number of specific cognitive processes directly or indirectly involved in navigation. The results are discussed with reference to the sole previously described case of developmental topographical disorientation (Pt1; Iaria et al., 2009). F.G. differs from the former case due to the following: the greater severity of his disorder, his complete lack of navigational skills, the failure to develop compensatory strategies, and the presence of a specific deficit in processing the spatial relationships between the parts of a whole. The present case not only confirms the existence of developmental topographical-skill disorders, but also sheds light on the architecture of topographical processes and their development in human beings.

Voxel-based analysis of R2* maps in the healthy human brain

To develop a voxel‐based analysis of an R2* map of healthy human brain that is automatic, reproducible, and realizable in a single examination on a 3T MR imager. Such a tool could be useful to measure iron accumulation in neurodegenerative diseases.

Characterization of white matter fiber bundles with T2* relaxometry and diffusion tensor imaging

In this study, diffusion tensor imaging (DTI) and T  2* multiecho relaxometry were combined in 30 healthy subjects at 3T, with the aim of characterizing the spatial distribution of relaxation rates in white matter (WM). Region of interest (ROI) analysis was performed in 23 different fiber tracts automatically defined in standard space. Spearman rank analysis was performed on regional values of T  2* , fractional anisotropy (FA), and radial diffusivity (RD). A strong relationship was observed between the location and direction of fiber bundles and relaxation rates, and adjacent fiber bundles with similar orientation showed very different relaxation rates. Moreover, while relaxation rates varied largely between different fiber tracts, variation of the same parameter within the same anatomical fiber bundle across individuals was remarkably limited. The rich variability of relaxation rates in WM and their complex relationship with DTI data suggested that the two techniques might be sensitive to complementary characteristics of myelin structure. This has tremendous potential to allow for a more detailed understanding of brain development and pathology, in particular in the context of age‐related cognitive decline. Magn Reson Med, 2009.

Hippocampi, Thalami, and Accumbens Microstructural Damage in Schizophrenia: A Volumetry, Diffusivity, and Neuropsychological Study

Volumetric abnormalities in the subcortical structures have been described in schizophrenia. However, it still has to be clarified if subtle microstructural damage is also present. Thus, we aimed to detect subcortical volume and mean diffusivity (MD) alterations in 45 patients with diagnosis of schizophrenia compared with 45 age-, gender-, and educational attainment-matched healthy comparison (HC) participants, by using a combined volumetry and diffusion tensor imaging (DTI) method. A secondary aim was to identify the neuropsychological correlates of subcortical abnormalities in the schizophrenic group. We found thalami and hippocampi bilaterally and left accumbens to show MD increase in the schizophrenic group. No volumetric decrease was found. Moreover, significant correlations between the MD values in subcortical structures (right thalamus and hippocampus and left accumbens) and working memory performance were found. Thus, subcortical microstructural alterations are present in schizophrenia even in absence of volumetric abnormalities. Furthermore, microstructural damage in subcortical areas is linked to working memory, suggesting the presence of a subtle microstructural subcortical dysfunction in the pathoetiological mechanism underlying high cognitive load performances in schizophrenia. Finally, our findings indicate that MD is a more sensitive marker of brain tissue deficits than signal intensity variations measured in T1-weighted imaging data, consistently with previous reports. Thus, DTI appears to be an invaluable tool to investigate subcortical pathology in schizophrenia, greatly enhancing the ability to detect subtle brain changes in this complex disorder.

Seeking huntington disease biomarkers by multimodal, cross-sectional basal ganglia imaging

Neurodegeneration of the striatum in Huntington disease (HD) is characterized by loss of medium‐spiny neurons, huntingtin nuclear inclusions, reactive gliosis, and iron accumulation. Neuroimaging allows in vivo detection of the macro‐ and micro‐structural changes that occur from presymptomatic stages of the disease (preHD). The aim of our study was to evaluate the reliability of multimodal imaging as an in vivo biomarker of vulnerability and development of the disease and to characterize macro‐ and micro‐structural changes in subcortical nuclei in HD. Macrostructure (T1‐weighted images), microstructure (diffusion tensor imaging), and iron content (R  2* relaxometry) of subcortical nuclei and medial temporal lobe structures were evaluated by a 3 T scanner in 17 preHD carriers, 12 early‐stage patients and 29 matched controls. We observed a volume reduction and microstructural changes in the basal ganglia (caudate, putamen, and globus pallidus) and iron accumulation in the globus pallidus in both preHD and symptomatic subjects; all these features were significantly more pronounced in patients, in whom degeneration extended to the other subcortical nuclei (i.e., thalamus and accumbens). Mean diffusivity (MD) was the most powerful predictor in models explaining more than 50% of the variability in HD development in the caudate, putamen, and thalamus. These findings suggest that the measurement of MD may further enhance the well‐known predictive value of striatal volume to assess disease progression as it is highly sensitive to tissue microimpairment. Multimodal imaging may detect brain changes even in preHD stages. Hum Brain Mapp, 2013.