Maria Consuelo Valentini

Brain hypermetabolism in amyotrophic lateral sclerosis: a FDG PET study in ALS of spinal and bulbar onset

PurposeTo identify the neurobiological traits of amyotrophic lateral sclerosis (ALS) and to elucidate functional differences between ALS of spinal and bulbar onset. We hypothesized that glucose metabolism distribution might vary between groups.MethodsThe study groups comprised 32 patients with ALS of either bulbar (n = 13) or spinal (n = 19) onset and 22 subjects as controls. They were investigated by [18F]fluorodeoxyglucose (FDG) positron emission tomography (FDG PET), comparing the patient groups with each other and with the controls by statistical parametric mapping.ResultsHighly significant relative increases in glucose metabolism distribution were found in the group comprising all 32 ALS patients as compared with the controls in the bilateral amygdalae, midbrain, pons and cerebellum. Relative hypermetabolism was also found in patients with spinal onset as compared with the controls in the right midbrain. In patients with bulbar onset compared with the controls and with patients with spinal onset, large relatively hypometabolic areas were found in the bilateral frontal cortex, right insula, anterior cingulate, precuneus and inferior parietal lobe. Patients with spinal onset had significantly higher scores in a neuropsychological test assessing verbal fluency compared with patients with bulbar onset.ConclusionThis large FDG PET investigation provided unprecedented evidence of relatively increased metabolism in the amygdalae, midbrain and pons in ALS patients as compared with control subjects, possibly due to local activation of astrocytes and microglia. Highly significant relative decreases in metabolism were found in large frontal and parietal regions in the bulbar onset patients as compared with the spinal onset patients and the controls, suggesting a differential metabolic and neuropsychological state between the two conditions.

Functional pattern of brain FDG-PET in amyotrophic lateral sclerosis

Objective: We investigated a large sample of patients with amyotrophic lateral sclerosis (ALS) at rest in order to assess the value of 18F-2-fluoro-2-deoxy-d-glucose (18F-FDG) PET as a biomarker to discriminate patients from controls. Methods: A total of 195 patients with ALS and 40 controls underwent brain 18F-FDG-PET, most within 5 months of diagnosis. Spinal and bulbar subgroups of ALS were also investigated. Twenty-five bilateral cortical and subcortical volumes of interest and cerebellum were taken into account, and 18F-FDG uptakes were individually normalized by whole-brain values. Group analyses investigated the ALS-related metabolic changes. Discriminant analysis investigating sensitivity and specificity was performed using the 51 volumes of interest as well as age and sex. Metabolic connectivity was explored by voxel-wise interregional correlation analysis. Results: Hypometabolism was found in frontal, motor, and occipital cortex and hypermetabolism in midbrain, temporal pole, and hippocampus in patients with ALS compared to controls. A similar metabolic pattern was also found in the 2 subgroups. Discriminant analysis showed a sensitivity of 95% and a specificity of 83% in separating patients from controls. Connectivity analysis found a highly significant positive correlation between midbrain and white matter in corticospinal tracts in patients with ALS. Conclusions: 18F-FDG distribution changes in ALS showed a clear pattern of hypometabolism in frontal and occipital cortex and hypermetabolism in midbrain. The latter might be interpreted as the neurobiological correlate of diffuse subcortical gliosis. Discriminant analysis resulted in high sensitivity and specificity in differentiating patients with ALS from controls. Once validated by diseased-control studies, the present methodology might represent a potentially useful biomarker for ALS diagnosis. Classificaton of evidence: This study provides Class III evidence that 18F-FDG-PET accurately distinguishes patients with ALS from normal controls (sensitivity 95.4%, specificity 82.5%).

Accuracy of 18F-FDG-PET/CT for staging of oral squamous cell carcinoma

This study prospectively assessed 2‐[F18]‐fluoro‐2‐deoxy‐D‐glucose–positron emission tomography (18F‐FDG‐PET)/CT (PET/CT) in oral squamous cell carcinoma.

A Distinct MR Imaging Phenotype in Amyotrophic Lateral Sclerosis: Correlation between T1 Magnetization Transfer Contrast Hyperintensity along the Corticospinal Tract and Diffusion Tensor Imaging Analysis

BACKGROUND AND PURPOSE: In the search for a diagnostic marker in ALS, we focused our attention on the hyperintense signal intensity in T1 MTC MR images along the CST, detected in some patients and not found in other patients with ALS and in control subjects. The aim of this study was to investigate the relationship between the hyperintense signal intensity in T1 MTC images and white matter damage. To this purpose, we studied potential heterogeneities in DTI values within our patients by using TBSS without a priori anatomic information. MATERIALS AND METHODS: In 43 patients with ALS and 43 healthy control subjects, the presence or absence of T1 MTC hyperintense signal intensity was evaluated. With a DTI analysis with a TBSS approach, differences in FA distribution between the 2 groups (patients with T1 MTC hyperintense signal intensity and patients without it) compared with each other and with control subjects were investigated. RESULTS: We found regional differences in white matter FA between patients with T1 MTC hyperintense signal intensity (37.2%) and patients without it. Patients with T1 MTC abnormal signal intensity showed lower FA strictly limited to the motor network and the posterior aspect of the body of the CC without extramotor FA reductions, whereas patients without this sign showed FA reductions in several confluent regions within and outside the CST and in the whole CC. CONCLUSIONS: T1 MTC hyperintense signal intensity in the CST and posterior CC, when present, is specific for ALS and represents, among patients with ALS, a possible distinct phenotype of presentation of the disease with prominent UMN involvement.

Role of PET and SPECT in the Study of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis has been defined as a “heterogeneous group of neurodegenerative syndromes characterized by progressive muscle paralysis caused by the degeneration of motor neurons allocated in primary motor cortex, brainstem, and spinal cord.” A comprehensive diagnostic workup for ALS usually includes several electrodiagnostic, clinical laboratory and genetic tests. Neuroimaging exams, such as computed tomography, magnetic resonance imaging and spinal cord myelogram, may also be required. Nuclear medicine, with PET and SPECT, may also play a role in the evaluation of patients with ALS, and provide additional information to the clinicians. This paper aims to offer to the reader a comprehensive review of the different radiotracers for the assessment of the metabolism of glucose (FDG), the measurement of cerebral blood flow (CBF), or the evaluation of neurotransmitters, astrocytes, and microglia by means of newer and not yet clinically diffuse radiopharmaceuticals.

Astroblastoma: beside being a tumor entity, an occasional phenotype of astrocytic gliomas?

The diagnosis of astroblastoma is based on a typical histological aspect with perivascular distribution of cells sending cytoplasmic extensions to the vessels and vascular hyalinization. These criteria are useful for standardizing the identification of the tumor, but, in spite of this, there are discrepancies in the literature concerning the age distribution and the benign or malignant nature of the tumor. Three cases are discussed in this study: Case 1 was a typical high-grade astroblastoma; Case 2 was an oligodendroglioma at the first intervention and an oligoastrocytoma at the second intervention with typical perivascular arrangements in the astrocytic component; Case 3 was a gemistocytic glioma with malignant features and typical perivascular arrangements. Genetic analysis showed genetic alterations that are typical of gliomas of all malignancy grades. Using the neurosphere assay, neurospheres and adherent cells were found to have developed in Case 1, while adherent cells only developed in Case 2, in line with the stemness potential of the tumors. The cases are discussed in relation to their diagnostic assessment as astroblastoma, and it is hypothesized that the typical perivascular distribution of cells may not indicate a separate and unique tumor entity, but may be a peculiarity that can be acquired by astrocytic gliomas when an unknown cause from the tumor microenvironment influences the relationship between vessels and tumor cells.

Neural correlates underlying the comprehension of deceitful and ironic communicative intentions

Neuroimaging studies have shown that a left fronto-temporo-parietal cerebral network is recruited in the comprehension of both deceitful and ironic speech acts. However, no studies to date have directly compared neural activation during the comprehension of these pragmatic phenomena. We used fMRI to investigate the existence of common and specific neural circuits underlying the comprehension of the same speech act, uttered with different communicative intentions, i.e., of being sincere, deceitful or ironic. In particular, the novelty of the present study is that it explores the existence of a specific cerebral area involved in the recognition of irony versus deceit. We presented 23 healthy participants with 48 context stories each followed by a target sentence. For each story we designed different versions eliciting, respectively, different pragmatic interpretations of the same target sentence - literal, deceitful or ironic-. We kept the semantic and syntactic complexity of the target sentence constant across the conditions. Our results showed that the recognition of ironic communicative intention activated the left temporo-parietal junction (lTPJ), the left inferior frontal gyrus (lIFG), the left middle frontal gyrus (lMFG), the left middle temporal gyrus (lMTG), and the left dorsolateral prefrontal cortex (lDLPFC). Comprehension of deceitful communicative intention activated the lIFG, the lMFG, and the lDLPFC. fMRI analysis revealed that a left fronto-temporal network-including the inferior frontal gyrus (IFG), the dorsolateral prefrontal cortex (DLPFC) and the middle frontal gyrus (MFG)-is activated in both irony and deceit recognition. The original result of the present investigation is that the lMTG was found to be more active in the comprehension of ironic versus deceitful communicative intention, thus suggesting its specific role in irony recognition. To conclude, our results showed that common cerebral areas are recruited in the comprehension of both pragmatic phenomena, while the lMTG has a key role in the recognition of ironic versus deceitful communicative intention.

A familial ALS case carrying a novel p.G147C SOD1 heterozygous missense mutation with non-executive cognitive impairment

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease causing progressive muscle weakness and wasting. Death usually occurs within 3–5 years from respiratory failure. Approximately 10% of cases are familial (fALS).The frequency of SOD1 gene mutations in patients with fALS varies among populations, from 0% in Ireland to 13.6% in Italy and 23.5% in Scandinavia.1 SOD1 encodes for the Cu/Zn Superoxide Dismutase 1. Mutations are usually autosomal dominant, but the p.D90A and the p.D96N may be autosomal recessive.2 Performing the genetic screening of an Italian fALS series, we found a novel c.442g>t heterozygous missense mutation of SOD1 gene leading to a substitution of cysteine for glycine (p.G147C). Such mutation was absent in healthy controls (n=130). The patient provided written informed consent. The index case displayed progressive weakness and wasting of both hands when he was 52 years old. One year after the onset he also exhibited tongue hypotrophy with fasciculations, spastic paraparesis, impairment of feet extension and brisk jaw jerk and lower limbs reflexes. Plantar response was absent bilaterally. He referred diffuse cramps and fasciculations. Dysphagia, dysarthria, dysphonia and dyspnoea were absent. The amyotrophic lateral sclerosis funcional rating scale revised (ALSFRS-R) was 44/48. Needle electromyography (EMG) showed chronic and active denervation in bulbar and spinal regions. Forced vital capacity was 106%. The neuropsychological evaluation showed an impaired performance in the Rey-Osterrieth Complex Figure (ROCF) Test, in copy and recall task, while other tests had normal scores. Brain MRI showed selective atrophy of the right supramarginal gyrus (figure 1 …

Group Membership Modulates the Neural Circuitry Underlying Third Party Punishment

This research aims to explore the neural correlates involved in altruistic punishment, parochial altruism and anti-social punishment, using the Third-Party Punishment (TPP) game. In particular, this study considered these punishment behaviors in in-group vs. out-group game settings, to compare how people behave with members of their own national group and with members of another national group. The results showed that participants act altruistically to protect in-group members. This study indicates that norm violation in in-group (but not in out-group) settings results in increased activity in the medial prefrontal cortex and temporo-parietal junction, brain regions involved in the mentalizing network, as the third-party attempts to understand or justify in-group members’ behavior. Finally, exploratory analysis during anti-social punishment behavior showed brain activation recruitment of the ventromedial prefrontal cortex, an area associated with altered regulation of emotions.

Glioblastoma Stem Cells: Conversion or Reprogramming from Tumor Non-Stem Cells?

It is widely accepted that gliomas origin from immature glia and the most important hypothesis is that this origin is from glioblastoma stem cells (GSCs). GSCs are responsible for tumor growth, proliferation, therapy resistance and recurrence. They may represent transformed normal neural stem cells (NSCs), embryonically regressed adult glia or, simply, a functional status that could be regulated by the tumor microenvironment. Objective of the work is to interpret all the immunohistochemical, genetic and in vitro culture features of primary tumors and cell lines in favor of the above mentioned hypothesis on the functional status and microenvironment. A series of glioblastomas (GBMs) have been studied after stereotactic biopsies for expression of stemness and differentiation antigens, genetic aberrations and stem cell generation potential by immunohistochemical, immunofluorescence, molecular genetics methods. Perivascular and perinecrotic niches are the crucial points where microenvironment exerts its influence. The most malignant regions of GBM contain hyperproliferating areas expressing stemness antigens, such as Nestin, SOX2, CD133 and almost no differentiation antigens and show a high proliferation index. Circumscribed necroses develop within these areas by ischemia due to the imbalance between the high proliferation rate of tumor cells and the low one of endothelial cells. Perinecrotic GSCs are interpreted as elicited by hypoxia through HIF-1/2 constituting thus a niche. The hypothesis can be formulated that the stem cell status is a functional one that can be reached by dedifferentiated tumor cells through embryonic regression and that GSCs surrounding circumscribed necroses may of course represent a niche, but they are the residue of GCSs/progenitors originally populating the hyperproliferating areas. A conversion of tumor non-stem cells into tumor stem cells is possible, as well as reprogramming of tumor cells due to the microenvironment regulation through its intrinsic and extrinsic signaling. This hypothesis could influence the therapeutic strategies addressed to annihilate GSCs.