In patients with progressive supranuclear palsy (PSP), previous reports have shown a severe white matter (WM) damage involving supra and infratentorial regions including cerebellum. In the present study, we investigated potential correlations between WM integrity loss and clinical-cognitive features of patients with PSP. By using magnetic resonance imaging and diffusion tensor imaging with tract based spatial statistic analysis, we analyzed WM volume in 18 patients with PSP and 18 healthy controls (HCs). All patients and HCs underwent a detailed clinical and neuropsychological evaluation. Relative to HCs, patients with PSP showed WM changes encompassing supra and infratentorial areas such as corpus callosum, fornix, midbrain, inferior fronto-occipital fasciculus, anterior thalamic radiation, superior cerebellar peduncle, superior longitudinal fasciculus, uncinate fasciculus, cingulate gyrus, and cortico-spinal tract bilaterally. Among different correlations between motor-cognitive features and WM structural abnormalities, we detected a significant association between fronto-cerebellar WM loss and executive cognitive impairment in patients with PSP. Our findings, therefore, corroborate the hypothesis that cognitive impairment in PSP may result from both "intrinsic" and "extrinsic" frontal lobe dysfunction, likely related to cerebellar disconnection.
The North American Alzheimer's Disease Neuroimaging Initiative (NA-ADNI) was the first program to develop standardized procedures for Alzheimer's disease (AD) imaging biomarker collection. OBJECTIve: We describe the validation of acquisition and processing of structural magnetic resonance imaging (MRI) in different Italian academic AD clinics following NA-ADNI procedures.
Amyotrophic lateral sclerosis (ALS) and behavioral variant frontotemporal dementia (bvFTD) lie on a clinical, pathologic, and genetic continuum. Neuroimaging techniques have proven to be potentially useful to unravel the shared features of these syndromes. Using resting-state functional magnetic resonance imaging (RS-fMRI), we investigated functional connectivity of brain networks in 15 ALS and 15 bvFTD patients in early stages of disease and 15 healthy controls, looking expressly for connectivity pattern divergence or overlap between the 2 disorders. Compared with controls, we found decreased RS-fMRI signals within sensorimotor, right frontoparietal, salience, and executive networks in both patient groups. Within the default mode network (DMN), divergent connectivity patterns were observed, with RS-fMRI signals in the posterior cingulate cortex enhanced in bvFTD patients and suppressed in ALS patients. Our findings confirm that ALS and bvFTD not only broadly share common RS-fMRI connectivity patterns, probably representing different phenotypical expressions of the same neurodegenerative process, but also differ in the DMN, probably reflecting a different stage of neurodegeneration.
Multiple sclerosis (MS) is a complex disease triggered by environmental and genetic agents, and clinically characterized by bout onset (BOMS) or progressive onset (PrMS). We collected clinical and familial aggregation data in a cohort of 518 Italian PrMS patients, and compared with 400 BOMS cases. An increased prevalence of MS in first-degree relatives of Italian PrMS was found. Familial aggregation is not influenced by probands' clinical course, and there is no disease course concordance within MS families. These data are useful in counseling MS patients affected with different clinical courses of the disease.
The discrimination between recurrent glioma and radiation injury is often a challenge on conventional magnetic resonance imaging (MRI). We verified whether adding and combining proton MR spectroscopic imaging ((1)H-MRSI), diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) information at 3 Tesla facilitate such discrimination.
For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of ? interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct ? interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available ? interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ?2 relapses in the last 2 years) were randomly assigned to azathioprine or ? interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n?=?150) were randomized in 2 groups (77 azathioprine, 73 ? interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 ? interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as ? interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 ? interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p?=?0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of ? interferons for patients with relapsing-remitting multiple sclerosis. Considering also the convenience of the oral administration, and the low cost for health service providers, azathioprine may represent an alternative to interferon treatment, while the different side effect profiles of both medications have to be taken into account.
The diagnosis of Parkinson's disease (PD) remains still clinical; nevertheless, in the last decades, the rapid evolution of advanced MRI techniques has made it possible to detect structural and, increasingly, functional brain changes in patients with PD. Indeed, functional MRI (fMRI) techniques have offered the opportunity to directly measure the brain's activity and connectivity in patients with PD both in early and complicated stage of the disease. The aims of the following review are (1) to present an overview of recent fMRI reports investigating the activity and connectivity of sensorimotor areas in patients with PD using both task-related and "resting-state" fMRI analysis (2) to elucidate potential pathophysiological mechanisms underlying dyskinetic motor complications in the advanced stage of PD.
Resting-state functional magnetic resonance imaging (RS-fMRI) has demonstrated disrupted default mode network (DMN) connectivity in a number of pain conditions, including migraine. However, the significance of altered resting-state brain functional connectivity in migraine is still unknown. The present study is aimed to explore DMN functional connectivity in patients with migraine without aura (MwoA) and investigate its clinical significance.
A 62-year-old man presented to our neurology outpatient clinic with a 3-week history of progressive right wrist drop. He had been complaining of generalized asthenia, numbness, and tingling involving the soles of both feet for the last year. He had a history of chronic renal failure due to type II diabetes, for which he was on maintenance hemodialysis. He had hypertension and hyperlipidemia, treated respectively with propranolol and simvastatin. He denied smoking and alcohol abuse.
Migraine pathophysiology is not completely understood and is still a matter of ongoing research. However, functional magnetic resonance imaging studies have provided, over the last few decades, notable insights into neuronal mechanisms underlying migraine. Recently, by using an innovative approach based on repetitive trigeminal painful stimulation, researchers have explored pain processing network functional changes associated with migraine and their correlations with specific migraineous clinical features. These functional changes have been demonstrated during different phases of migraine cycle. However, owing to the complexity of its neurobiology, migraine pathophysiology still has many secrets to be discovered.
Diffusion tensor imaging (DTI) has become a useful tool for investigating early white matter (WM) abnormalities in motor neuron disease. Furthermore, fiber tracking packages that apply multi-tensorial algorithms, such as q-ball imaging (QBI), have been proposed as alternative approaches to overcome DTI limitations in depicting fiber tracts with different orientations within the same voxel. We explored motor and extra-motor WM tract abnormalities in phenotypically heterogeneous amyotrophic lateral sclerosis (ALS) cases aiming to establish a consistent QBI-based WM signature of disease. We performed a whole-brain, QBI tract-based spatial statistics analysis with deterministic tractography of genu, body and splenium of corpus callosum (CC) and corticospinal tracts (CST) in 20 ALS patients (12 classical and 8 lower motor neuron variants) compared to 20 healthy controls. Mean tract length, fiber volume and density, and generalized fractional anisotropy were extracted and related to clinical indices of pyramidal impairment (upper motor neuron score), disease disability (ALS functional rating scale-revised) and progression. ALS patients showed significantly decreased fiber density and volume, and increased tract length in all regions of CC and left CST (p < 0.05, corrected). In CC body, pyramidal impairment was inversely correlated to fiber density (p = 0.01), while in CC splenium, clinical disability (p = 0.01) and progression (p = 0.02) were inversely correlated to tract length. Our findings further suggest that QBI tractography might represent a promising approach for investigating structural alterations in neurodegenerative diseases and confirm that callosal involvement is a consistent feature of most ALS variants, significantly related to both pyramidal dysfunction and disease disability.
Diffusion-weighted magnetic resonance imaging (DWMRI) is used to study white matter (WM) in normal and clinical populations. In DWMRI studies, diffusion tensor imaging (DTI) models the WM anisotropy with one dominant direction, detecting possible pathway abnormalities only in large and highly coherent fiber tracts. However, more general anisotropy models like Q-ball imaging (QBI) may provide more sensitive WM descriptors in single patients. The present study aimed to compare DTI and QBI models in a group-level population analysis, using Amyotrophic Lateral Sclerosis (ALS) as a pathological case model of WM tract degeneration. DWMRI was performed in 19 ALS patients and 19 age and sex-matched healthy controls. DTI and QBI estimates were compared in whole-brain tract-based spatial statistics (TBSS) and volume of interest (VOI) analyses, and correlated with ALS clinical scores of disability. A significant decrease of the QBI-derived generalized fractional anisotropy (GFA) was observed in both motor and extramotor fibers of ALS patients compared to controls. Homologue DTI-derived FA maps were only partially overlapping with GFA maps. Particularly, the left corticospinal tracts resulted more markedly depicted by the QBI than by the DTI model, with GFA predicting ALS disability better than FA. The present findings demonstrate that QBI model is suitable for studying WM tract degeneration in population-level clinical studies. Particularly, group-level studies of fiber integrity may benefit from QBI when DTI is biased towards low values, such as in cases of fiber degeneration, and in regions with more than one dominant fiber direction.
Cortical sources of resting state electroencephalographic (EEG) rhythms are abnormal in subjects with mild cognitive impairment (MCI). Here, we tested the hypothesis that these sources in amnesic MCI subjects further deteriorate over 1 year. To this aim, the resting state eyes-closed EEG data were recorded in 54 MCI subjects at baseline (Mini Mental State Examination I = 26.9; standard error [SE], 0.2) and at approximately 1-year follow-up (13.8 months; SE, 0.5; Mini Mental State Examination II = 25.8; SE, 0.2). As a control, EEG recordings were also performed in 45 normal elderly and in 50 mild Alzheimers disease subjects. EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), and beta2 (20-30 Hz). Cortical EEG sources were estimated using low-resolution brain electromagnetic tomography. Compared with the normal elderly and mild Alzheimers disease subjects, the MCI subjects were characterized by an intermediate power of posterior alpha1 sources. In the MCI subjects, the follow-up EEG recordings showed a decreased power of posterior alpha1 and alpha2 sources. These results suggest that the resting state EEG alpha sources were sensitive-at least at the group level-to the cognitive decline occurring in the amnesic MCI group over 1 year, and might represent cost-effective, noninvasive and widely available markers to follow amnesic MCI populations in large clinical trials.
MRI is highly sensitive in detecting focal white matter lesions in multiple sclerosis (MS). For this reason, it has been formally included in the diagnostic workup of patients with clinically isolated syndromes suggestive of MS, through the definition of ad hoc sets of criteria to show disease dissemination in space and time. MRI is used in virtually all clinical trials of the disease as a surrogate measure of treatment response. Several guidelines have been published to help characterizing the imaging features on conventional MR sequences of "typical" MS lesions and work has also been performed to identify "red flags" which should alert the clinicians to exclude possible alternative conditions. Despite this, the application of the available guidelines and criteria in daily life clinical practice is still limited and varies among and within countries (including Italy) due to regulatory issues and heterogeneity of MRI facilities. It is crucial for neurologists and neuroradiologists to become familiar with these criteria to improve the quality of their diagnostic assessment. In patients with established MS, the main problem is to define standard procedures for monitoring the course of the disease and treatment response. This review aims at providing daily life guidelines to clinicians for a correct application of MRI in the workup of patients suspected of having MS as well as in the monitoring of disease evolution in those with established MS. It also offers clues for the standardization of MRI studies and relative reporting to be applied at a national level.
In amyotrophic lateral sclerosis (ALS), diffusion weighted magnetic resonance imaging (DW-MRI) has produced mounting evidence of a widespread white matter (WM) damage within motor and extramotor pathways. To provide novel information about the degenerative process in ALS, overcoming some of the limitations imposed by diffusion tensor imaging (DTI), we performed a high angular resolution diffusion imaging (HARDI) analysis of DW-MRI data. Generalized fractional anisotropy (GFA) was evaluated in 19 patients with ALS and 19 matched control subjects, and was correlated with clinical scores of disability, pyramidal impairment by upper motor neuron (UMN) score and frontal dysfunction by the Frontal Systems Behaviour (FrSBe) scale. Results demonstrated that ALS patients showed a significant decrease of GFA in the WM tracts underneath the left and right precentral gyri and the body of the corpus callosum (p < 0.05, corrected), where GFA was significantly related to UMN scores (p < 0.001, uncorrected); and in the left superior longitudinal fasciculus (p < 0.05, corrected), where GFA was significantly related to FrSBe scale scores (p < 0.01, uncorrected). In conclusion, this study revealed a pattern of motor and extramotor frontal diffusivity abnormalities (probably related to behavioural and cognitive dysfunctions) showing a spatial distribution similar to what was previously described in ALS - frontotemporal dementia continuum.
There is a broad scientific consensus that amyotrophic lateral sclerosis (ALS), a fatal neuromuscular disease, is caused by gene--environment interactions. In fact, given that only about 10% of all ALS diagnosis has a genetic basis, gene-environmental interaction may give account for the remaining percentage of cases. However, relatively little attention has been paid to environmental and lifestyle factors that may trigger the cascade of motor neuron degeneration leading to ALS, although exposure to chemicals--including lead and pesticides-agricultural environments, smoking, intense physical activity, trauma and electromagnetic fields have been associated with an increased risk of ALS. This review provides an overview of our current knowledge of potential toxic etiologies of ALS with emphasis on the role of cyanobacteria, heavy metals and pesticides as potential risk factors for developing ALS. We will summarize the most recent evidence from epidemiological studies and experimental findings from animal and cellular models, revealing that potential causal links between environmental toxicants and ALS pathogenesis have not been fully ascertained, thus justifying the need for further research.
Advances in imaging have provided further insights into the complex migraine pathophysiology. Functional neuroimaging by means of PET and functional MRI studies have addressed crucial migraine-related issues, improving our understanding of the circuitry that may be involved in the generation, maintenance and recurrence of pain symptoms in migraine. In the last few years, a growing body of imaging literature has also explored pathophysiology of associated migraine symptoms. Of great interest will be the use of advanced imaging techniques to elucidate neural correlates of migraine prodromal, in order to identify clinical subgroups of migrainous subjects. However, the interpretation of the biological significance of these various functional changes could remain incomplete without a combination of expanding genomic information about neurochemical pathways and genetic polymorphisms linked to specific migraine subtypes. Hopefully, a more detailed picture of the migraine neurobiology will emerge from future neuroimaging studies, which may eventually lead to better and more rational treatments.
Brain activity during rest is characterized by slow (0.01-0.1 Hz) fluctuations of blood oxygenation level-dependent functional magnetic resonance imaging signals. These fluctuations are organized as functional connectivity networks called resting-state networks, anatomically corresponding to specific neuronal circuits. As Parkinsons disease is mainly characterized by a dysfunction of the sensorimotor pathways, which can be influenced by levodopa administration, the present study investigated the functional connectivity changes within the sensorimotor resting-state network in drug-naïve patients with Parkinsons disease after acute levodopa administration. Using a double-blind placebo-controlled design, resting-state functional magnetic resonance imaging was carried out in 20 drug-naïve patients with Parkinsons disease, immediately before and 60 min after, oral administration of either levodopa or placebo. Control resting-state functional magnetic resonance imaging data were recorded in 18 age- and sex-matched healthy volunteers. Independent component analysis was performed to extract resting-state network maps and associated time-course spectral features. At the anatomical level, levodopa enhanced the sensorimotor network functional connectivity in the supplementary motor area, a region where drug-naïve patients with Parkinsons disease exhibited reduced signal fluctuations compared with untreated patients. At the spectral frequency level, levodopa stimulated these fluctuations in a selective frequency band of the sensorimotor network. The reported effects induced by levodopa on sensorimotor network topological and spectral features confirm that the sensorimotor system is a target of acute levodopa administration in drug-naïve patients with Parkinsons disease. Moreover, while the regional changes in supplementary motor area reflect the functional improvement in motor function, the rhythm-specific modulation induced by the dopamine precursor discloses a novel aspect of pharmacological stimulation in Parkinsons disease, adding further insight to the comprehension of levodopa action.
Progressive supranuclear palsy is the most common neurodegenerative bradykinetic-rigid syndrome after Parkinsons disease. Several volumetric studies have revealed a widespread cortical and subcortical gray matter atrophy, however the correlations between the pattern of gray matter loss and clinical-cognitive features have been poorly investigated.
Previous studies have shown that affective symptoms are part of the clinical picture in amyotrophic lateral sclerosis (ALS), the most common motor neuron disorder in elderly people. Diffuse neurodegeneration of limbic regions (e.g., prefrontal cortex [PFC], amygdala) was demonstrated in ALS post-mortem, although the mechanisms of emotional dysregulation in ALS in vivo remain unclear. Using functional imaging, we assessed the brain responses to emotional faces in 11 cognitively unimpaired ALS patients and 12 healthy controls (HCs). We tested whether regional activities and connectivity patterns in the limbic system differed between ALS patients and HCs and whether the variability in clinical measures modulated the neuroimaging data. Relative to HCs, ALS patients displayed greater activation in a series of PFC areas and altered left amygdala-PFC connectivity. Anxiety modulated the right amygdala-PFC connectivity in HCs but not in ALS patients. Reduced right premotor cortex activity and altered left amygdala-supplementary motor area connectivity were associated with longer disease duration and greater disease severity, respectively. Our findings demonstrate dysfunctions of the limbic system in ALS patients at early stages of the disease, and extend our knowledge about the interplay between emotional brain areas and the regions traditionally implicated in motor control.
Resting State fMRI (RS-fMRI) represents an emerging and powerful tool to explore brain functional connectivity (FC) changes associated with neurologic disorders. Compared to activation/task-related fMRI, RS-fMRI has the advantages that (i) BOLD fMRI signals are self-generated and independent of subjects performance during the task and (ii) a single dataset is sufficient to extract a set of RS networks (RSNs) that allows to explore whole brain FC. According to these features RS-fMRI appears particularly suitable for the study of FC changes related to multiple sclerosis (MS). In the present review we will first give a brief description of RS-fMRI methodology and then an overview of most relevant studies conducted so far in MS by using this approach. The most interesting results, in particular, regard the default-mode network (DMN), whose FC changes have been correlated with cognitive status of MS patients, and the visual RSN (V-RSN) whose FC changes have been correlated with visual recovery after optic neuritis. The executive control network (ECN), the lateralized frontoparietal network (FPN), and the sensory motor network (SMN) have also been investigated in MS, showing significant FC rearrangements. All together, RS-fMRI studies conducted so far in MS suggest that prominent RS-FC changes can be detected in many RSNs and correlate with clinical and/or structural MRI measures. Future RS-fMRI studies will further clarify the dynamics and clinical impact of RSNs changes in MS.
Multiple Sclerosis associated neuropsychiatric disorders include major depression (MD), obsessive-compulsive disorder (OCD), bipolar affective disorder, euphoria, pseudobulbar affect, psychosis, and personality change. Magnetic Resonance Imaging (MRI) studies focused mainly on identifying morphostructural correlates of MD; only a few anecdotal cases on OCD associated to MS (OCD-MS), euphoria, pseudobulbar affect, psychosis, personality change, and one research article on MRI abnormalities in OCD-MS have been published. Therefore, in the present review we will report mainly on neuroimaging abnormalities found in MS patients with MD and OCD. All together, the studies on MD associated to MS suggest that, in this disease, depression is linked to a damage involving mainly frontotemporal regions either with discrete lesions (with those visible in T1 weighted images playing a more significant role) or subtle normal appearing white matter abnormalities. Hippocampal atrophy, as well, seems to be involved in MS related depression. It is conceivable that grey matter pathology (i.e., global and regional atrophy, cortical lesions), which occurs early in the course of disease, may involve several areas including the dorsolateral prefrontal cortex, the orbitofrontal cortex, and the anterior cingulate cortex whose disruption is currently thought to explain late-life depression. Further MRI studies are necessary to better elucidate OCD pathogenesis in MS.
The hormone adiponectin exerts beneficial pleiotropic effects on biological and metabolic processes. Although a well-recognized insulin sensitizer, its characteristic has yet to be clearly defined. Myotonic dystrophy type 1 (DM1) is a rare genetic disorder that features muscle wasting and metabolic comorbidity, and patients have an increased risk of developing type 2 diabetes. We analyzed circulating levels of adiponectin and its oligomers to determine whether their expression correlates with metabolic alterations in DM1 patients.
A possible definition of clinical, educational and organizing aspects of emergency neurology in Italy is reported in this position paper of Emergency Neurology Intersociety Group, created in 2008 among the two neurological Societies in Italy: Società Italiana di Neurologia and Società di Neuroscienze Ospedaliere. The aim of this Group has been the evaluation of the role of neurologist in the emergency setting of Italian hospitals, as well as of the description of different scenarios in which a ward dedicated to a semi-intensive care of neurological emergencies could have a role in the actual organization of academic or general hospitals in our Country. The actual great relevance of neurologist activity in the inpatients treatment, in fact, is actually misleaded as it is the considerable significance of neurological expertise, techniques and support in hospital care pathways also involving neurological manifestations throughout the course of other diseases. Finally, the possible contents of educational programs orienting neurological specialty towards a better comprehension and management of emergency neurological problems either in terms of specific formation or of techniques to be learned by emergency neurologist, are reported as a results of the Consensus Workshop hold in Castiglioncello (LI) in September 12th, 2009.
Fused in sarcoma (FUS) or translocation in liposarcoma (TLS), a DNA/RNA-binding protein, causes a dominant autosomal inherited form of amyotrophic lateral sclerosis (ALS), ALS 6. Its main role in neurodegeneration is highlighted by the presence of cytoplasmic accumulation of its mutant protein form in ALS patients. To further define the frequency and spectrum of FUS gene mutations, we have performed a molecular screening of a cohort of 327 Italian patients from Southern Italy with sporadic ALS (SALS). We identified 4 patients carrying 3 different missense mutations and several polymorphisms. Two different substitutions occurring in the same amino acidic position have been observed in 2 patients: R521G and R521C respectively; P525L mutation has been found in 2 additional cases. Most of the patients with FUS mutations showed early symptom onset and had short disease survival. We also detected 4 different polymorphic variants (3-untranslated region [UTR] variant, c.*41G>A; c.523+3ins[GAGGTG]; c.335-15del[TTTT]; and rs13331793) in 9 patients from within our cohort. This study underlines the importance of population-based mutation screening of newly identified genes.
The aim of our study was to explore the pain processing network in patients with migraine during trigeminal nociceptive stimulation. Sixteen patients with episodic migraine without aura and 16 healthy controls performed functional magnetic resonance imaging during thermal stimuli (at 41, 51 and 53°C). Patients with migraine showed a greater activation in the perigenual part of anterior cingulate cortex at 51°C and less activation in the bilateral somatosensory cortex at 53°C compared to healthy controls. There were no differences in experimental pain perception between groups. Our findings demonstrate a functional reorganization of cerebral areas known to be involved in pain processing in patients with migraine.
Spontaneous intracranial hypotension is an uncommon cause of sudden and persistent headache: associated symptoms are common, among which there are cranial nerve palsies, especially of the abducens nerve. We report a case of a 21-year-old man with a transient and isolated third nerve palsy due to spontaneous intracranial hypotension. To our knowledge, there are only few reports in the literature of such association.
Knowledge of the exact spatial distribution of brain tissues in images acquired by magnetic resonance imaging (MRI) is necessary to measure and compare the performance of segmentation algorithms. Currently available physical phantoms do not satisfy this requirement. State-of-the-art digital brain phantoms also fall short because they do not handle separately anatomical structures (e.g. basal ganglia) and provide relatively rough simulations of tissue fine structure and inhomogeneity. We present a software procedure for the construction of a realistic MRI digital brain phantom. The phantom consists of hydrogen nuclear magnetic resonance spin-lattice relaxation rate (R1), spin-spin relaxation rate (R2), and proton density (PD) values for a 24 × 19 × 15.5 cm volume of a "normal" head. The phantom includes 17 normal tissues, each characterized by both mean value and variations in R1, R2, and PD. In addition, an optional tissue class for multiple sclerosis (MS) lesions is simulated. The phantom was used to create realistic magnetic resonance (MR) images of the brain using simulated conventional spin-echo (CSE) and fast field-echo (FFE) sequences. Results of mono-parametric segmentation of simulations of sequences with different noise and slice thickness are presented as an example of possible applications of the phantom. The phantom data and simulated images are available online at http://lab.ibb.cnr.it/.
Brain activity during resting wakefulness is characterized by slow (<0.1Hz) fluctuations of blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) signals that are topographically organized in discrete functional connectivity networks (resting-state networks, RSNs). The present study aimed at revealing possible network-specific alcohol-induced changes in resting-state fMRI (RS-fMRI) signals. RS-fMRI was carried out on eight healthy subjects in four consecutive 6-min sessions, one before and three after a 0.7 g/kg dose of ethyl alcohol. Control experiments were carried out in different days without alcohol administration. Independent component analysis (ICA) was performed on all experimental and control scans to extract individual and group-level RSN maps in a dynamic network analysis. Alcohol administration significantly increased the overall strength of the visual network ICA component, reaching the peak at 90 min. Within the visual network, the alcohol-induced increase was more pronounced in the primary regions of the occipital cortex and less pronounced in the secondary regions of the occipito-temporal cortex. Other major RSN components, such as the default-mode, the fronto-parietal, the sensori-motor, the self-referential and the auditory components, did not exhibit alcohol-induced changes during the same time window. Alcohol-induced effects on the resting-state functional connectivity of the visual network observed in the present study demonstrate that the visual system is a selective and primary target of acute alcohol administration. The strong enhancement of spontaneous BOLD fluctuations in the primary visual cortex in an acute alcoholic state may impair the normal activation response to visual stimuli and affect visual perception.
Hemiparkinsonism with hemiatrophy syndrome is defined by the occurrence of a body hemiatrophy with features of an early onset, slowly progressive, asymmetric parkinsonism more prominent on the side of the hemiatrophy. The underlying pathogenesis is not well understood but perinatal cerebral insults seem to play a crucial role. We describe the case of a 52-year-old woman who presented with a two year history of slowness and stiffness of left arm and leg with dystonic posturing of the ipsilateral hand. When examined, she had a left body hemiatrophy which was present since early childhood. Clinical and imaging findings supported the diagnosis of hemiparkinsonism with hemiatrophy syndrome with a good response to dopamine agonist therapy. This case report further characterizes this heterogeneous form of parkinsonism which deserves attention for clinical management and prognostic evaluation.
We assessed the spontaneous blood-oxygen-level-dependent signal fluctuations in the resting-state brain networks of amyotrophic lateral sclerosis patients and their relation to physiologically sensitive and disease modified functional magnetic resonance imaging parameters. Resting-state functional magnetic resonance imaging was performed at 3 Tesla on 20 amyotrophic lateral sclerosis patients with minimal frontal cognitive dysfunction and 20 age- and sex-matched healthy volunteers. Resting-state network maps were extracted with independent component analysis and group-level statistical analyses were performed to detect disease and disease-by-age interaction effects. Whole-brain global and regional atrophy measures were obtained from same-session structural scans. The sensori-motor network showed significant disease effects, with signals suppressed in patients bilaterally in the primary motor cortex. The default-mode network showed a significant disease-by-age interaction in the posterior cingulate cortex, where signals correlated with age positively in patients and negatively in controls. Both disease and disease-by-age interaction effects were detected in the right fronto-parietal network. Although global atrophy did not show significant differences, regions of reduced gray matter volume were detected in patients compared with controls adjacent to regions of reduced functional connectivity. Our results confirm that resting-state functional magnetic resonance imaging signals in the sensori-motor network are suppressed in amyotrophic lateral sclerosis. A similar suppression is evident in the right fronto-parietal network, possibly reflecting the patients frontal dysfunction and right-lateralized patterns of regional atrophy. The interaction between disease and aging in the default-mode network unravels a possible mechanism of compensation between motor and extramotor systems emerging as a supplementary functional push to help motor disturbances.
A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing-remitting multiple sclerosis patients, aged 18-50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 microg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.
Mutations in the FUS gene have recently been described as a cause of familial amyotrophic lateral sclerosis (ALS), but their role in the pathogenesis of sporadic ALS is unclear. We undertook mutational screening of all coding exons of FUS in 228 sporadic ALS cases, and, as previous reports suggest that exon 15 represents a mutational hotspot, we sequenced this exon in an additional 1295 sporadic cases. Six variants in six different cases were found, indicating that FUS mutations can underlie apparently sporadic ALS, but account for less than 1% of this form of disease.
Hyperhomocysteinaemia was reported in patients with Parkinsons disease (PD) treated with l-Dopa. The increase in plasma concentration of this sulfur compound arises from the massive methylation of the drug operated by the enzyme catechol-O-methyltransferase (COMT), which acts as a powerful sink of methyl groups. The contemporary occurrence of C677T polymorphism in homozygosity, leading to a temperature-labile variant of the MTHFR enzyme, induces an even more marked increase in tHcy. Here we show that l-Dopa administration in hyperhomocysteinemic PD patients is able to lower intracellular concentration of S-Adenosylmethionine (AdoMet) in erythrocytes (RBC), while the occurrence of hyperhomocysteinaemia causes a significant increase in S-Adenosylhomocysteine (AdoHcy) level. In patients with PD treated with l-Dopa and hyperhomocysteinemic, the remarkable decrease in AdoMet and the concurrent increase in AdoHcy concentration both contribute to significantly lower the transmethylation potential ([AdoMet]/[AdoHcy]), a useful index of the effectiveness of methyl group transfer by methyltransferases. This decrease could indeed contribute to partly attenuate, through a self-limiting kinetic mechanism, the tendency of developing drug resistance, partly mediated in these patients by COMT upregulation. Our results also support the conclusion that COMT inhibitors (entacapone or tolcapone), when administered in PD patients treated with l-Dopa, may potentiate the endogenous AdoHcy-dependent COMT inhibition mechanism already operative in a variable fashion.
Mutations in the Cu/Zn superoxide dismutase 1 (SOD1) gene have been reported to cause adult-onset autosomal dominant amyotrophic lateral sclerosis (FALS). In sporadic cases (SALS), de novo mutations in the SOD1 gene have occasionally been observed. All the SOD1 mutations are autosomal dominantly inherited with the exception of D90A. To date, in Italy, only two sporadic ALS cases carrying the D90A mutation have been reported in a homozygous state. We investigated for the presence of this mutation in 169 unrelated ALS patients from southern Italy. The genetic analysis revealed three ALS patients (1.8%) with mild phenotype carrying the homozygous D90A mutation.
The congenital form of myotonic dystrophy type 1 (CDM1) has an almost exclusively maternal transmission and is characterized by mental retardation and by moderate/severe ventriculomegaly and white matter hyperintensities on brain magnetic resonance imaging (MRI). We report a 20-year-old case of CDM1 with paternal inheritance showing mental retardation and normal brain MRI, and presenting at birth with hypotonia, facial weakness and feeding difficulties. We reviewed the literature for studies addressing the brain neuroimaging in paternally transmitted CDM1 and found four studies reporting diffuse cerebral, frontal lobe or mild parietal cortical atrophy, or mild ventricular dilatation, without white matter abnormalities. To our knowledge, this is the first report describing normal brain MRI in a mentally retarded CDM1 patient with paternal transmission.
The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown, but genetic factors are thought to play a significant role in determining susceptibility to motor neuron degeneration. To identify genetic variants altering risk of ALS, we undertook a two-stage genome-wide association study (GWAS): we followed our initial GWAS of 545 066 SNPs in 553 individuals with ALS and 2338 controls by testing the 7600 most associated SNPs from the first stage in three independent cohorts consisting of 2160 cases and 3008 controls. None of the SNPs selected for replication exceeded the Bonferroni threshold for significance. The two most significantly associated SNPs, rs2708909 and rs2708851 [odds ratio (OR) = 1.17 and 1.18, and P-values = 6.98 x 10(-7) and 1.16 x 10(-6)], were located on chromosome 7p13.3 within a 175 kb linkage disequilibrium block containing the SUNC1, HUS1 and C7orf57 genes. These associations did not achieve genome-wide significance in the original cohort and failed to replicate in an additional independent cohort of 989 US cases and 327 controls (OR = 1.18 and 1.19, P-values = 0.08 and 0.06, respectively). Thus, we chose to cautiously interpret our data as hypothesis-generating requiring additional confirmation, especially as all previously reported loci for ALS have failed to replicate successfully. Indeed, the three loci (FGGY, ITPR2 and DPP6) identified in previous GWAS of sporadic ALS were not significantly associated with disease in our study. Our findings suggest that ALS is more genetically and clinically heterogeneous than previously recognized. Genotype data from our study have been made available online to facilitate such future endeavors.
Functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) represent brain activity in terms of a reliable anatomical localization and a detailed temporal evolution of neural signals. Simultaneous EEG-fMRI recordings offer the possibility to greatly enrich the significance and the interpretation of the single modality results because the same neural processes are observed from the same brain at the same time. Nonetheless, the different physical nature of the measured signals by the two techniques renders the coupling not always straightforward, especially in cognitive experiments where spatially localized and distributed effects coexist and evolve temporally at different temporal scales. The purpose of this article is to illustrate the combination of simultaneously recorded EEG and fMRI signals exploiting the principles of EEG distributed source modeling. We define a common source space for fMRI and EEG signal projection and gather a conceptually unique framework for the spatial and temporal comparative analysis. We illustrate this framework in a graded-load working-memory simultaneous EEG-fMRI experiment based on the n-back task where sustained load-dependent changes in the blood-oxygenation-level-dependent (BOLD) signals during continuous item memorization co-occur with parametric changes in the EEG theta power induced at each single item. In line with previous studies, we demonstrate on two single-subject cases how the presented approach is capable of colocalizing in midline frontal regions two phenomena simultaneously observed at different temporal scales, such as the sustained negative changes in BOLD activity and the parametric EEG theta synchronization. We discuss the presented approach in relation to modeling and interpretation issues typically arising in simultaneous EEG-fMRI studies.
The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.
To investigate functional connectivity of the visual resting-state network (V-RSN) in normal-sighted relapsing-remitting multiple sclerosis (RRMS) patients with and without previous optic neuritis (ON).
Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease principally affecting motor neurons. Besides motor symptoms, a subset of patients develop cognitive disturbances or even frontotemporal dementia (FTD), indicating that ALS may also involve extramotor brain regions. Both neuropathological and neuroimaging findings have provided further insight on the widespread effect of the neurodegeneration on brain connectivity and the underlying neurobiology of motor neurons degeneration. However, associated effects on motor and extramotor brain networks are largely unknown. Particularly, neuropathological findings suggest that ALS not only affects the frontotemporal network but rather is part of a wide clinicopathological spectrum of brain disorders known as TAR-DNA binding protein 43 (TDP-43) proteinopathies. This paper reviews the current state of knowledge concerning the neuropsychological and neuropathological sequelae of TDP-43 proteinopathies, with special focus on the neuroimaging findings associated with cognitive change in ALS.
Migraine is a complex and often disabling brain disorder that affects about 15 % of the population. The diagnosis of migraine is based on clinical features as proposed by the International Headache Society criteria but they are somewhat subjective and arbitrary. Functional neuroimaging of patients with migraine has been recently employed to study the underlying pathophysiology of headache. These studies have suggested that migraine involves functional and structural plasticity of both central and peripheral nervous system. Insights into the fundamental physiology of migraine have been limited by the lack of methods available to detect the pathophysiological background of critical moment of migraine attack onset that is greatly different from the onset of pain or pain phase of a migraine attack. In order to overcome methodological caveats in detecting "migraine origin" or a "migraine generator", functional brain imaging has been lately dominated by experimental acute-pain research. Along this research line functional imaging using experimental pain stimulation have greatly improved our knowledge about physiological or dysfunctional neuronal activity pattern in patients with migraine, but at the same time, it is important to emphasize that experimental pain is different from spontaneous migraine pain.
Migraine is a common, multifactorial disorder, typically characterized by recurrent attacks of throbbing unilateral headache, autonomic nervous system dysfunction and, in approximately one-third of cases, neurological transient symptoms (migraineous aura). The diagnosis of primary headaches is exclusively a clinical task but, for this reason, it is sometimes subjective and arbitrary. However, until today no single diagnostic tool is able to define, ensure or differentiate idiopathic headache syndromes, although, in the clinical setting, conventional neuroimaging techniques are often widely and improperly used in headache patients. Recent years have seen rapid growth of neuroimaging methodology which has provided new insights into functional brain organization of migraine patients. Although functional magnetic resonance imaging has today little or no value in clinical practice, clinicians role is crucial since without a proper clinical selection neuroimaging studies could generate inconclusive results. Likewise, functional neuroimaging is crucial for clinicians in order to further elucidate pathophysiological mechanisms underlying this complex and often disabling disease and to provide new therapeutical approaches for migraine patients.
Freezing of gait is a common cause of disability and falls in patients with Parkinsons disease. We studied brain functional connectivity, by means of resting-state functional magnetic resonance imaging, in patients with Parkinsons disease and freezing of gait.
It has been recently reported that a large proportion of patients with familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are associated with a hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72. We have assessed 1757 Italian sporadic ALS cases, 133 from Sardinia, 101 from Sicily, and 1523 from mainland Italy. Sixty (3.7%) of 1624 mainland Italians and Sicilians and 9 (6.8%) of the 133 Sardinian sporadic ALS cases carried the pathogenic repeat expansion. None of the 619 regionally matched control samples (1238 chromosomes) carried the expansion. Twenty-five cases (36.2%) had behavioral FTD in addition to ALS. FTD or unspecified dementia was also detected in 19 pedigrees (27.5%) in first-degree relatives of ALS patients. Cases carrying the C9ORF72 hexanucleotide expansion survived 1 year less than cases who did not carry this mutation. In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population, representing by far the most common mutation in Italy and the second most common in Sardinia.
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents [children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003]. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
We explored the functional pattern of the pain-processing network in patients with migraine, in the interictal periods, during trigeminal noxious stimulation. Contact heat evoked potential stimulation induced thermal pain and functional magnetic resonance imaging were used to measure whole-brain activation in 16 patients with episodic migraine without aura and 16 age- and gender-matched healthy controls in response to a severe (53°C) noxious, a moderate (51°C) noxious, and a control (41°C) stimulus applied to the maxillary skin. When comparing the fMRI activation over the entire brain, patients with migraine, with respect to healthy controls, showed a significantly greater activation in the perigenual part of anterior cingulate cortex at 51°C and less activation in the bilateral secondary somatosensory cortex at 53°C. A group-by-stimulus interaction analysis revealed a region in the pons showing a divergent response in patients and healthy controls. Correlation analyses demonstrated that the pons activation correlated with higher headache-related disability in patients. Our findings demonstrate increased antinociceptive activity in patients with migraine, which may represent a compensatory reorganization to modulate pain perception at the same intensity of healthy controls.
Cortical gray matter volume and resting state cortical electroencephalographic rhythms are typically abnormal in subjects with amnesic mild cognitive impairment (MCI) and Alzheimers disease (AD). Here we tested the hypothesis that in amnesic MCI and AD subjects, abnormalities of EEG rhythms are a functional reflection of cortical atrophy across the disease. Eyes-closed resting state EEG data were recorded in 57 healthy elderly (Nold), 102 amnesic MCI, and 108 AD patients. Cortical gray matter volume was indexed by magnetic resonance imaging recorded in the MCI and AD subjects according to Alzheimers disease neuroimaging initiative project (http://www.adni-info.org/). EEG rhythms of interest were delta (2-4 Hz), theta (4-8 Hz), alpha1 (8-10.5 Hz), alpha2 (10.5-13 Hz), beta1 (13-20 Hz), beta2 (20-30 Hz), and gamma (30-40 Hz). These rhythms were indexed by LORETA. Compared with the Nold, the MCI showed a decrease in amplitude of alpha 1 sources. With respect to the Nold and MCI, the AD showed an amplitude increase of delta sources, along with a strong amplitude reduction of alpha 1 sources. In the MCI and AD subjects as a whole group, the lower the cortical gray matter volume, the higher the delta sources, the lower the alpha 1 sources. The better the score to cognitive tests the higher the gray matter volume, the lower the pathological delta sources, and the higher the alpha sources. These results suggest that in amnesic MCI and AD subjects, abnormalities of resting state cortical EEG rhythms are not epiphenomena but are strictly related to neurodegeneration (atrophy of cortical gray matter) and cognition.
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