ORCID Profile
0000-0002-4788-1875
Current Organisations
Shizuoka University
,
Istituti Clinici Scientifici Maugeri SpA IRCCS Milano
,
Università degli Studi di Palermo
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Publisher: Springer Science and Business Media LLC
Date: 12-2021
DOI: 10.1038/S41588-021-00973-1
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 in iduals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Cold Spring Harbor Laboratory
Date: 15-03-2021
DOI: 10.1101/2021.03.12.21253159
Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced in iduals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.
Publisher: Cold Spring Harbor Laboratory
Date: 02-01-2020
DOI: 10.1101/2020.01.01.892513
Abstract: We studied fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 in iduals) with associated geography (1,422 in iduals). We applied ChromoPainter/fineSTRUCTURE, identifying 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. Despite superexponential population growth, north-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.
Publisher: Elsevier BV
Date: 03-2018
Publisher: Springer Science and Business Media LLC
Date: 07-06-1111
DOI: 10.1038/S41598-017-02811-Z
Abstract: This study aimed to evaluate muscle oxidative function during exercise in amyotrophic lateral sclerosis patients (pALS) with non-invasive methods in order to assess if determinants of reduced exercise tolerance might match ALS clinical heterogeneity. 17 pALS, who were followed for 4 months, were compared with 13 healthy controls (CTRL). Exercise tolerance was assessed by an incremental exercise test on cycle ergometer measuring peak O 2 uptake ( $$\\dot{{\\rm{V}}}$$ V ̇ O 2peak ), vastus lateralis oxidative function by near infrared spectroscopy (NIRS) and breathing pattern ( $$\\dot{{\\rm{V}}}$$ V ̇ E peak ). pALS displayed: (1) 44% lower $$\\dot{{\\rm{V}}}$$ V ̇ O 2peak vs . CTRL (p 0.0001), paralleled by a 43% decreased peak skeletal muscle oxidative function (p 0.01), with a linear regression between these two variables (r 2 = 0.64, p 0.0001) (2) 46% reduced $$\\dot{{\\rm{V}}}$$ V ̇ E peak vs . CTRL (p 0.0001), achieved by using an inefficient breathing pattern (increasing respiratory frequency) from the onset until the end of exercise. Inefficient skeletal muscle O 2 function, when flanking the impaired motor units recruitment, is a major determinant of pALS clinical heterogeneity and working capacity exercise tolerance. CPET and NIRS are useful tools for detecting early stages of oxidative deficiency in skeletal muscles, disclosing in idual impairments in the O 2 transport and utilization chain.
Publisher: BMJ
Date: 21-08-2019
Abstract: We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case–control studies and explored the independent effects of intensity, duration and time-since-quitting. ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models. Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (p trend =0.001) rather than intensity (p trend =0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (p trend .0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration. Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
Publisher: Bentham Science Publishers Ltd.
Date: 26-10-2027
Publisher: Springer Science and Business Media LLC
Date: 21-03-2017
DOI: 10.1038/NCOMMS14774
Abstract: We have previously shown higher-than-expected rates of schizophrenia in relatives of patients with amyotrophic lateral sclerosis (ALS), suggesting an aetiological relationship between the diseases. Here, we investigate the genetic relationship between ALS and schizophrenia using genome-wide association study data from over 100,000 unique in iduals. Using linkage disequilibrium score regression, we estimate the genetic correlation between ALS and schizophrenia to be 14.3% (7.05–21.6 P =1 × 10 −4 ) with schizophrenia polygenic risk scores explaining up to 0.12% of the variance in ALS ( P =8.4 × 10 −7 ). A modest increase in comorbidity of ALS and schizophrenia is expected given these findings (odds ratio 1.08–1.26) but this would require very large studies to observe epidemiologically. We identify five potential novel ALS-associated loci using conditional false discovery rate analysis. It is likely that shared neurobiological mechanisms between these two disorders will engender novel hypotheses in future preclinical and clinical studies.
Publisher: American Medical Association (AMA)
Date: 10-2021
Publisher: Elsevier BV
Date: 2019
DOI: 10.2139/SSRN.3399502
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.CORTEX.2014.01.002
Abstract: Amyotrophic Lateral Sclerosis (ALS) is associated in about half of the cases with behavioral and cognitive disorders, including impairments in socio-emotional processing, considered as key-features for the diagnosis of the behavioral variant of frontotemporal dementia (bv-FTD). The neurostructural bases of emotional deficits in ALS, however, still remain largely unexplored. Here we aim to assess emotion recognition in non-demented sporadic ALS patients compared with healthy controls, and to explore for the first time its microstructural white-matter correlates. Twenty-two subjects with either probable or definite diagnosis of ALS and 55 age-, gender-, and education-matched healthy controls were recruited in the study. All participants performed the Ekman 60-Faces Test, assessing the recognition of six basic emotions (i.e., anger, disgust, fear, sadness, surprise and happiness). A subgroup of subjects, comprising 19 patients and 20 healthy controls, also underwent a Diffusion Tensor Imaging scanning. Behavioral analysis highlighted a significant decline of emotion recognition skills in patients compared to controls, particularly affecting the identification of negative emotions. Moreover, the Diffusion Tensor Imaging analyses revealed a correlation between this impairment and the alteration of white-matter integrity along the right inferior longitudinal fasciculus and inferior fronto-occipital fasciculus. Our findings indicate the presence of an early emotion recognition deficit in non-demented sporadic ALS patients, associated with microstructural changes in ventral associative bundles connecting occipital, temporo-limbic and orbitofrontal regions in the right hemisphere. These changes may represent a frontotemporal-limbic microstructural marker of socio-emotional impairment in ALS.
Publisher: Wiley
Date: 13-03-2019
DOI: 10.1002/ANA.25431
Publisher: Springer Science and Business Media LLC
Date: 25-07-2016
DOI: 10.1038/NG.3622
Location: Italy
No related grants have been discovered for Christian Lunetta.