The metabolic signature of C9ORF72-related ALS: FDG PET comparison with nonmutated patients

Purpose Recently, a GGGGCC hexanucleotide repeat expansion in the C9ORF72 gene, located on chromosome 9p21 has been demonstrated to be the commonest cause of familial amyotrophic lateral sclerosis (ALS) and to account for 5 to 10 % of apparently sporadic ALS. Relatively little is known about the brain metabolism profile of patients carrying the expansion. Our aim was to identify the [18F]FDG PET profile in ALS patients with the C9ORF72 expansion (C9ORF72-ALS). Methods Fifteen C9ORF72-ALS patients were compared with 12 patients with ALS and comorbid frontotemporal dementia (FTD) without the C9ORF72 expansion (ALSFTD) and 30 cognitively normal patients with ALS without mutations of ALS-related genes (sALS). The three groups were then cross-matched to 40 neurologically normal controls. All patients underwent FDG PET within 4 months of diagnosis. Results The C9ORF72-ALS patients compared with the sALS patients showed significant hypometabolism in the anterior and posterior cingulate cortex, insula, caudate and thalamus, the left frontal and superior temporal cortex, and hypermetabolism in the midbrain, bilateral occipital cortex, globus pallidus and left inferior temporal cortex. The ALS FTD patients compared with the sALS patients showed more limited hypometabolic areas, including the orbitofrontal, prefrontal, anterior cingulate and insular cortex, and hypermetabolic areas, including the bilateral occipital cortex, the left precentral and postcentral cortex and superior temporal gyrus. The C9ORF72-ALS patients compared with the ALS-FTD patients showed hypometabolism in the left temporal cortex. Conclusion ALS patients with the C9ORF72 hexanucleotide repeat expansion had a more widespread central nervous system involvement than ALS patients without genetic mutations, with or without comorbid FTD, consistent with their more severe clinical picture

Molecular Chaperones in the Pathogenesis of Amyotrophic Lateral Sclerosis: The Role of HSPB1

open15siGenetic discoveries in amyotrophic lateral sclerosis (ALS) have a significant impact on deciphering molecular mechanisms of motor neuron degeneration but, despite recent advances, the etiology of most sporadic cases remains elusive. Several cellular mechanisms contribute to the motor neuron degeneration in ALS, including RNA metabolism, cellular interactions between neurons and nonneuronal cells, and seeding of misfolded protein with prion-like propagation. In this scenario, the importance of protein turnover and degradation in motor neuron homeostasis gained increased recognition. In this study, we evaluated the role of the candidate gene HSPB1, a molecular chaperone involved in several proteome-maintenance functions. In a cohort of 247 unrelated Italian ALS patients, we identified two variants (c.570G>C, p.Gln190His and c.610dupG, p.Ala204Glyfs*6). Functional characterization of the p.Ala204Glyfs*6 demonstrated that the mutant protein alters HSPB1 dynamic equilibrium, sequestering the wild-type protein in a stable dimer and resulting in a loss of chaperone-like activity. Our results underline the relevance of identifying rare but pathogenic variations in sporadic neurodegenerative diseases, suggesting a possible correlation between specific pathomechanisms linked to HSPB1 mutations and the associated neurological phenotype. Our study provides additional lines of evidence to support the involvement of HSPB1 in the pathogenesis of sporadic ALS.openCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; Bandettini di Poggio, Monica; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, VincentCapponi, Simona; Geuens, Thomas; Geroldi, Alessandro; Origone, Paola; Verdiani, Simonetta; Cichero, Elena; Adriaenssens, Elias; De Winter, Vicky; BANDETTINI DI POGGIO, MONICA LAURA; Barberis, Marco; Chiò, Adriano; Fossa, Paola; Mandich, Paola; Bellone, Emilia; Timmerman, Vincen

What is the role of the placebo effect for pain relief in neurorehabilitation? Clinical implications from the Italian consensus conference on pain in neurorehabilitation

Background: It is increasingly acknowledged that the outcomes of medical treatments are influenced by the context of the clinical encounter through the mechanisms of the placebo effect. The phenomenon of placebo analgesia might be exploited to maximize the efficacy of neurorehabilitation treatments. Since its intensity varies across neurological disorders, the Italian Consensus Conference on Pain in Neurorehabilitation (ICCP) summarized the studies on this field to provide guidance on its use. Methods: A review of the existing reviews and meta-analyses was performed to assess the magnitude of the placebo effect in disorders that may undergo neurorehabilitation treatment. The search was performed on Pubmed using placebo, pain, and the names of neurological disorders as keywords. Methodological quality was assessed using a pre-existing checklist. Data about the magnitude of the placebo effect were extracted from the included reviews and were commented in a narrative form. Results: 11 articles were included in this review. Placebo treatments showed weak effects in central neuropathic pain (pain reduction from 0.44 to 0.66 on a 0-10 scale) and moderate effects in postherpetic neuralgia (1.16), in diabetic peripheral neuropathy (1.45), and in pain associated to HIV (1.82). Moderate effects were also found on pain due to fibromyalgia and migraine; only weak short-term effects were found in complex regional pain syndrome. Confounding variables might have influenced these results. Clinical implications: These estimates should be interpreted with caution, but underscore that the placebo effect can be exploited in neurorehabilitation programs. It is not necessary to conceal its use from the patient. Knowledge of placebo mechanisms can be used to shape the doctor-patient relationship, to reduce the use of analgesic drugs and to train the patient to become an active agent of the therapy

Exploiting mutual information for the imputation of static and dynamic mixed-type clinical data with an adaptive k-nearest neighbours approach

Clinical registers constitute an invaluable resource in the medical data-driven decision making context. Accurate machine learning and data mining approaches on these data can lead to faster diagnosis, definition of tailored interventions, and improved outcome prediction. A typical issue when implementing such approaches is the almost unavoidable presence of missing values in the collected data. In this work, we propose an imputation algorithm based on a mutual information-weighted k-nearest neighbours approach, able to handle the simultaneous presence of missing information in different types of variables. We developed and validated the method on a clinical register, constituted by the information collected over subsequent screening visits of a cohort of patients affected by amyotrophic lateral sclerosis

Systems biology analysis of the proteomic alterations in Parkinson's disease: Common and disease-specific pathways

Objectives: Many biochemical mechanisms have been proposed to play a role in different neurodegenerative disorders. To distinguish what is disease-specific from what is generically linked to a neurodegenerative state is essential to better describe Parkinson's disease (PD) pathogenesis. PD and Amyotrophic Lateral Sclerosis (ALS) share some common mechanisms. Moreover, a high incidence of comorbidity may be explained by common biochemical altered pathways. Methods: We performed a bioinformatics meta-analysis of all the proteomic investigations of neuronal alterations in PD, ALS and Alzheimer's disease (AD), used as control (non-motor neurodegenerative disease). We combined these data with genes found in a curated disease-gene database (DisGeNET). Moreover, we are currently going to analyze Peripheral Blood Mononuclear Cells samples coming from 20 ALS patients, 20 PD patients and 20 comorbid ALS/PD patients by two-dimensional electrophoresis. Results: From our bioinformatics analysis some proteins were associated uniquely to PD, whereas others were associated to both diseases. Biological processes mostly associated to PD turned out to be chromatin organization, mitochondrion organization and protein folding. In addition, we found common dysregulated pathways, i.e., translation, SRP-dependent protein targeting to membrane and protein transport. Conclusions: PD and ALS pathogenesis have some common mechanisms, due to the fact that they are both neurodegenerative diseases. The combination of bioinformatics tools and proteomic analysis of samples coming from comorbid patients will allow u also to highlight the disease-specific pathways, which may justify the degeneration of different neuron populations

A Dynamic Bayesian Network model for simulation of disease progression in Amyotrophic Lateral Sclerosis patients

Background. Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily affecting upper and lower motor neurons in the brain and spinal cord. The heterogeneity in the course of ALS clinical progression and ultimately survival, coupled with the rarity of this disease, make predicting disease outcome at the level of the individual patient very challenging. Besides, stratification of ALS patients has been known for years as a question of great importance to clinical practice, research and drug development. Methods. In this work, we present a Dynamic Bayesian Network (DBN) model of ALS progression to detect probabilistic relationships among variables included in the Pooled Resource Open-Access ALS Clinical Trials Database (PRO-ACT), which provides records of over 10,700 patients from different clinical trials, and with over 2,869,973 longitudinally collected data measurements. Results. Our model unravels new dependencies among clinical variables in relation to ALS progression, such as the influence of basophil count and creatine kinase on patients’ clinical status and the respiratory functional state, respectively. Furthermore, it provided an indication of ALS temporal evolution, in terms of the most probable disease trajectories across time at the level of both patient population and individual patient. Conclusions. The risk factors identified by out DBN model could allow patients' stratification based on velocity of disease progression and a sensitivity analysis on this latter in response to changes in input variables, i.e. variables measured at diagnosis.</jats:p

C9ORF72 and parkinsonism: Weak link, innocent bystander, or central player in neurodegeneration?

Highlights \u2022C9ORF72-associated diseases may vary from ALS-FTD complex to movement disorders. \u2022We describe an atypical DOPA-responsive parkinsonism carrying C9orf72 expansion. \u2022Penetrance, genotype-phenotype correlations and DOPA-responsiveness are discussed

Prognostic power of the human psoas muscles FDG metabolism in amyotrophic lateral sclerosis

In Amyotrophic Lateral Sclerosis (ALS) spinal cord (SC) showed a moderate increase in FDG uptake with respect to healthy subjects. The main aim of our study is to integrate the information concerning the divergent behavior of SC with skeletal muscle metabolism improving the informative potential of 18F-fluoro-2-deoxy-glucose (FDG) PET/CT imaging regarding specific pathophysiological mechanisms underlying ALS progression. We analyzed 50 ALS patients with spinal onset consecutively submitted to FDG PET/CT imaging. Obtained data were compared to the corresponding findings in 36 age and sex-matched controls. A computational method was used to extract psoas volume and attenuation coefficient from CT images. Psoas volume was normalized for patient ideal body weight (IBW). In co-registered PET images, FDG accumulation was defined by average normalized standardized uptake value (N-SUV). Average Hounsfield values (AVH) in the psoas were similar in patients and controls (39\ub18 AHV vs 39\ub111 AHV, respectively, p=ns). By contrast, ALS was associated with a significant reduction in psoas volume normalized for IBW (8.8\ub12.9 mL/Kg IBW vs 10.3\ub12.7 mL/Kg IBW, respectively, p&lt;0.05). More interestingly, N-SUV was significantly higher in patients than in controls (0.44\ub10.19 vs 0.29\ub10.09; p&lt;0.001). These SUV values predicted overall survival rate at Kaplan-Meyer analysis (p&lt;0.05) with a predictive power that was confirmed by univariate as well as by multivariate Cox analysis (p&lt;0.02). ALS is therefore associated with a psoas reduction in volume and increase in FDG uptake. The intensity of FDG uptake within this muscular district is related to disease aggressiveness

TDP-43 real-time quaking induced conversion reaction optimization and detection of seeding activity in CSF of amyotrophic lateral sclerosis and frontotemporal dementia patients

The pathological deposition of the transactive response DNA-binding protein of 43\u2009kDa occurs in the majority ( 3c97%) of amyotrophic lateral sclerosis and in around 45% of frontotemporal lobar degeneration cases. Amyotrophic lateral sclerosis and frontotemporal lobar degeneration clinically overlap, presenting a continuum of phenotypes. Both amyotrophic lateral sclerosis and frontotemporal lobar degeneration lack treatments capable of interfering with the underlying pathological process and early detection of transactive response DNA-binding protein of 43\u2009kDa pathology would facilitate the development of disease-modifying drugs. The real-time quaking-induced conversion reaction showed the ability to detect prions in several peripheral tissues of patients with different forms of prion and prion-like diseases. Despite transactive response DNA-binding protein of 43\u2009kDa displays prion-like properties, to date the real-time quaking-induced conversion reaction technology has not yet been adapted to this protein. The aim of this study was to adapt the real-time quaking-induced conversion reaction technique for the transactive response DNA-binding protein of 43\u2009kDa substrate and to exploit the intrinsic ability of this technology to amplify minute amount of mis-folded proteins for the detection of pathological transactive response DNA-binding protein of 43\u2009kDa species in the cerebrospinal fluid of amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. We first optimized the technique with synthetic transactive response DNA-binding protein of 43\u2009kDa-pre-formed aggregates and with autopsy-verified brain homogenate samples and subsequently analysed CSF samples from amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients and controls. Transactive response DNA-binding protein of 43\u2009kDa real-time quaking-induced conversion reaction was able to detect as little as 15\u2009pg of transactive response DNA-binding protein of 43\u2009kDa aggregates, discriminating between a cohort of patients affected by amyotrophic lateral sclerosis and frontotemporal lobar degeneration and age-matched controls with a total sensitivity of 94% and a specificity of 85%. Our data give a proof-of-concept that transactive response DNA-binding protein of 43\u2009kDa is a suitable substrate for the real-time quaking-induced conversion reaction. Transactive response DNA-binding protein of 43\u2009kDa real-time quaking-induced conversion reaction could be an innovative and useful tool for diagnosis and drug development in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The cerebrospinal fluid detection of transactive response DNA-binding protein of 43\u2009kDa pathological aggregates may be exploited as a disease biomarker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients