Nilo Riva

Divergent brain network connectivity in amyotrophic lateral sclerosis

Using resting state (RS) functional magnetic resonance imaging and independent component analysis, the integrity of brain networks related to cognition and behavior was investigated in 20 nondemented patients with amyotrophic lateral sclerosis (ALS). The association between RS functional connectivity and executive functions was assessed in 16 patients with neuropsychological assessment. ALS patients compared with control subjects showed a decreased connectivity of the right orbitofrontal cortex, and an enhanced connectivity of the left precuneus in the default mode network; a decreased connectivity of the left inferior frontal cortex, and an increased connectivity of the right angular gyrus in the right frontoparietal network; and an increased connectivity of the parietal cortex in the left frontoparietal network. The enhanced parietal connectivity was associated with the clinical and cognitive deficits of the patients. In ALS, an alteration of large-scale functional brain networks associated with cognition does occur, even in the absence of overt dementia. The increased parietal connectivity may have a role in an attempt to maintain cognitive efficiency in the presence of structural frontotemporal injury.

Sensorimotor Functional Connectivity Changes in Amyotrophic Lateral Sclerosis

We investigated whether the functional connections to the primary sensorimotor cortex (SMC) at rest are abnormal in 26 patients with amyotrophic lateral sclerosis (ALS) and whether such changes are related to the corticospinal tract (CST) damage, measured using diffusion tensor magnetic resonance imaging (DT MRI). ALS patients versus controls showed a significantly increased functional connectivity between the left SMC and the right cingulate cortex, parahippocampal gyrus, and cerebellum-crus II. No right SMC connectivity changes were found. The pattern of increased functional connectivity to the left SMC was more widespread when considering only patients with no CST DT MRI abnormalities than the whole group of patients. In this patient group, functional connectivity was also increased between the right SMC and the right parahippocampal gyrus. On the contrary, in ALS patients with CST damage (as assessed using DT MRI) versus controls, functional connectivity was increased between the left SMC and the right cingulate cortex only, while it was decreased between the right SMC and the right cerebellum-lobule VI. In ALS patients, disease severity correlated with reduced SMC functional connectivity. Functional brain changes do occur in ALS with mild disability. These changes might have a role in compensating for (limited) structural damage and might exhaust with increasing burden of disease pathology.

Cognitive Functions and White Matter Tract Damage in Amyotrophic Lateral Sclerosis: A Diffusion Tensor Tractography Study

BACKGROUND AND PURPOSE: ALS is predominantly a disease of the motor system, but cognitive and behavioral symptoms also are observed. DT MR imaging is sensitive to microstructural changes occurring in WM tracts of patients with ALS. In this study, we investigated the association between cognitive functions and extramotor WM tract abnormalities in ALS patients. MATERIALS AND METHODS: DT MR imaging was obtained from 16 nondemented patients with ALS and 15 healthy controls. Patients with ALS underwent a neuropsychologic and behavioral evaluation. DT tractography was used to asses the integrity of the CST, corpus callosum, and the major long-range association tracts. The relationship between DT MR imaging metrics and cognitive functions was tested by using linear model analyses, adjusting for age and clinical disability. RESULTS: Eleven patients (69%) scored below the fifth percentile in at least 1 cognitive test, and 2 of them had a mild executive impairment. Performances at tests assessing attention and executive functions correlated with DT MR imaging metrics of the corpus callosum, CST, and long association WM tracts bilaterally, including the cingulum, inferior longitudinal, inferior fronto-occipital, and uncinate fasciculi. Verbal learning and memory test scores were associated with fornix DT MR imaging values, whereas visual-spatial abilities correlated with left uncinate fractional anisotropy. CONCLUSIONS: WM tract degeneration is associated with neuropsychologic deficits in patients with ALS. DT tractography holds promise to gain insight into the role of the brain WM network abnormalities in the development of cognitive impairment in patients with ALS.

The Cortical Signature of Amyotrophic Lateral Sclerosis

The aim of this study was to explore the pattern of regional cortical thickness in patients with non-familial amyotrophic lateral sclerosis (ALS) and to investigate whether cortical thinning is associated with disease progression rate. Cortical thickness analysis was performed in 44 ALS patients and 26 healthy controls. Group differences in cortical thickness and the age-by-group effects were assessed using vertex-by-vertex and multivariate linear models. The discriminatory ability of MRI variables in distinguishing patients from controls was estimated using the Concordance Statistics (C-statistic) within logistic regression analyses. Correlations between cortical thickness measures and disease progression rate were tested using the Pearson coefficient. Relative to controls, ALS patients showed a bilateral cortical thinning of the primary motor, prefrontal and ventral frontal cortices, cingulate gyrus, insula, superior and inferior temporal and parietal regions, and medial and lateral occipital areas. There was a significant age-by-group effect in the sensorimotor cortices bilaterally, suggesting a stronger association between age and cortical thinning in ALS patients compared to controls. The mean cortical thickness of the sensorimotor cortices distinguished patients with ALS from controls (C-statistic ≥0.74). Cortical thinning of the left sensorimotor cortices was related to a faster clinical progression (r = −0.33, p = 0.03). Cortical thickness measurements allowed the detection and quantification of motor and extramotor involvement in patients with ALS. Cortical thinning of the precentral gyrus might offer a marker of upper motor neuron involvement and disease progression.

Physical activity and amyotrophic lateral sclerosis: A European population-based case–control study

To assess whether physical activity is a risk factor for amyotrophic lateral sclerosis (ALS).

The Topography of Brain Microstructural Damage in Amyotrophic Lateral Sclerosis Assessed Using Diffusion Tensor MR Imaging

BACKGROUND AND PURPOSE: ALS leads to macrostructural (ie, cortical atrophy and hyperintensities along the corticospinal tract) and microstructural (ie, gray matter intrinsic damage) central nervous system abnormalities. We used a multimodal voxelwise imaging approach to assess microstructural changes independent of macrostructural volume loss in patients with ALS compared with HCs. MATERIALS AND METHODS: Twenty-three patients with ALS and 14 HCs were studied. Conventional imaging and DTI were performed. Images were processed by using SPM5 to assess measures of gray and white matter atrophy as well as microstructural damage (ie, MD and FA). DTI alterations independent of volume loss were investigated. RESULTS: When we accounted for both gray and white matter atrophy, patients with ALS showed increased MD values in several gray and white matter areas mainly located in the orbitofrontal and frontotemporal regions bilaterally, in the right genu of the corpus callosum, and in the right posterior limb of the internal capsule. When we accounted for white matter volume loss, patients with ALS showed decreased FA along the corticospinal tract bilaterally and in the left inferior frontal lobe relative to HCs. The MD of the orbitofrontal regions bilaterally was associated significantly with disease duration. CONCLUSIONS: In patients with ALS, DTI detects microstructural changes independent of brain tissue loss. The affected regions included both motor and extramotor areas. The extent of ALS-related DTI abnormalities was greater than that disclosed by the volumetric analysis.

Intrahemispheric and interhemispheric structural network abnormalities in PLS and ALS

Using diffusion tensor (DT) magnetic resonance imaging (MRI), damage to brain intrahemispheric and interhemispheric connections was assessed in 26 sporadic primary lateral sclerosis (PLS) patients compared with 28 sporadic amyotrophic lateral sclerosis (ALS) patients with similar disability and 35 healthy controls. DT MRI diagnostic accuracy in distinguishing the two motor neuron disease (MND) variants was tested. PLS and ALS patients showed a distributed pattern of abnormalities of the motor system, including the corticospinal tracts and corpus callosum (CC). PLS versus ALS patients showed a more severe damage to the motor CC fibers and subcortical white matter (WM) underlying the primary motor cortices. Both patient groups showed an extra‐motor damage, which was more severe in PLS. This did not appear to be driven by longer disease duration in PLS. In PLS patients, damage to the CC mid‐body correlated with the severity of upper motor neuron clinical burden. CC fractional anisotropy values had the highest accuracy in distinguishing PLS from controls and ALS. PLS and ALS share an overlapped pattern of WM abnormalities. This underscores that PLS, despite its distinct clinical phenotype and long survival, still lies within the wider MND spectrum. Whether CC diffusivity may be a novel marker to increase confidence in an early diagnostic separation of PLS from ALS still needs to be investigated. Hum Brain Mapp 35:1710–1722, 2014.

Structural brain correlates of cognitive and behavioral impairment in MND

To assess the structural correlates of cognitive and behavioral impairment in motor neuron diseases (MND) using multimodal MRI.

Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to Unravel Their Pathogenesis

BACKGROUND Charcot-Marie-Tooth (CMT) neuropathies are very heterogeneous disorders from both a clinical and genetic point of view. The CMT genes identified so far encode different proteins that are variably involved in regulating Schwann cells and/or axonal functions. However, the function of most of these proteins still remains to be elucidated. OBJECTIVE To characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of CMT neuropathy. DESIGN A cohort of 131 unrelated patients were screened for mutations in 12 genes responsible for CMT neuropathies. Demyelinating, axonal, and intermediate forms of CMT neuropathy were initially distinguished as usual on the basis of electrophysiological criteria and clinical evaluation. A sural nerve biopsy was also performed for selected cases. Accordingly, patients underwent first-level analysis of the genes most frequently mutated in each clinical form of CMT neuropathy. RESULTS Although our cohort had a particularly high percentage of cases of rare axonal and intermediate CMT neuropathies, we found mutations in 40% of patients. Among identified changes, 7 represented new mutations occurring in the MPZ, GJB1, EGR2, MFN2, NEFL, and HSBP1/HSP27 genes. Histopathological analysis performed in selected cases revealed morphological features, which correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism. CONCLUSION Clinical and pathological analysis of patients with CMT neuropathies contributes to our understanding of the molecular mechanisms of CMT neuropathies.

Peripheral nerve morphogenesis induced by scaffold micropatterning

Several bioengineering approaches have been proposed for peripheral nervous system repair, with limited results and still open questions about the underlying molecular mechanisms. We assessed the biological processes that occur after the implantation of collagen scaffold with a peculiar porous micro-structure of the wall in a rat sciatic nerve transection model compared to commercial collagen conduits and nerve crush injury using functional, histological and genome wide analyses. We demonstrated that within 60 days, our conduit had been completely substituted by a normal nerve. Gene expression analysis documented a precise sequential regulation of known genes involved in angiogenesis, Schwann cells/axons interactions and myelination, together with a selective modulation of key biological pathways for nerve morphogenesis induced by porous matrices. These data suggest that the scaffolds micro-structure profoundly influences cell behaviors and creates an instructive micro-environment to enhance nerve morphogenesis that can be exploited to improve recovery and understand the molecular differences between repair and regeneration.