ALS phenotype is influenced by age, sex, and genetics

Chiò, Adriano; Moglia, Cristina; Canosa, Antonio; Manera, Umberto; D’Ovidio, Fabrizio; Vasta, Rosario; Grassano, Maurizio; Brunetti, Maura; Barberis, Marco; Corrado, Lucia; D’Alfonso, Sandra; Iazzolino, Barbara; Peotta, Laura; Sarnelli, Maria Francesca; Solara, Valentina; Zucchetti, Jean Pierre; Marchi, Fabiola De; Mazzini, Letizia; Mora, Gabriele; Calvo, Andrea

doi:10.1212/wnl.0000000000008869

Cited by 120 publications

(115 citation statements)

References 30 publications

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“…Methodological differences can explain these discrepancies. Again, in any of these studies, no covariables such as comorbidities, progression rate or phenotype were considered (22). Our study shows that sex has neither an independent effect in the diagnostic delay, nor in any of its subprocesses.…”

Section: Sexmentioning

confidence: 67%

“…Some studies proposed that aged patients have longer diagnostic delays (1,5,13), another (13) found the opposite and others did not find an effect (8,11). None of these studies included covariables that vary with age such as the progression rate, comorbidities, or phenotypes (22). In our study, after adjusting for these and other covariables, an independent effect of age was not found in any of the studied time frames: the time symptoms-neurologist, the time neurologist-diagnosis, nor the diagnostic delay.…”

Section: Unmodifiable Factorsmentioning

confidence: 99%

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Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

et al. 2020

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Objective: To analyze those factors contributing to the diagnostic delay in ALS.Methods: Consecutive ALS patients were categorized as those studied in departmental hospitals and those studied in a referral ALS center. Demographic and clinical variables, together with data of the diagnostic pathway were collected. Multivariable models were used to assess their effect in the time between symptoms onset and the first neurologist visit (time symptoms-neurologist), in the time between the first neurologist visit and the diagnosis (time neurologist-diagnosis) and in the diagnostic delay.Results: 166 ALS patients with a median diagnostic delay of 11.53 months (IQR: 6.68, 15.23) were included. The median diagnostic delay was 8.57 months (5.16, 11.61) in the referral center vs. 12.08 months (6.87, 16.8) in departmental centers. Bulbar onset, fast progression rate, upper motor neuron predominant phenotype and an early referral to the neurologist were associated with a shorter time between symptoms–neurologist. Being studied in a referral center was associated with a shorter time between neurologist–diagnosis. Comorbidities, familial ALS, bulbar onset, early referral to the neurologist and being studied in a referral center were associated with a shorter diagnostic delay. For patients studied in departmental hospitals, fast progression rate was also strongly associated with a shorter time between neurologist–diagnosis and diagnostic delay.Conclusion: Unmodifiable factors (comorbidities, familial ALS, bulbar onset, and progression rate) as well as modifiable factors (early referral to the neurologist and the evaluation in an ALS referral center) have an independent effect in the diagnostic delay. The universalization of ALS Units is probably the most efficient measure to reduce the diagnostic delay.

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Section: Sexmentioning

confidence: 67%

Section: Unmodifiable Factorsmentioning

confidence: 99%

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

et al. 2020

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“…Thus, a genetic component may play a causative role in sporadic cases as well, making the distinction between fALS and sALS not straightforward 15 . The penetrance of many ALS genes is age dependent and a large variability in clinical manifestations and prognosis is observed in fALS 16,17 Recent evidence suggests that in the multistep pathogenic process which leads to the development of ALS, genetic background is dynamically interacting with specific environmental factors, reducing the number of steps necessary to start neurodegeneration and favoring disease onset 18 …”

Section: Introductionmentioning

confidence: 99%

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Tondo

Iaccarino

Cerami

et al. 2020

Ann Clin Transl Neurol

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Objective Neuroinflammation is considered a key driver for neurodegeneration in several neurological diseases, including amyotrophic lateral sclerosis (ALS). SOD1 mutations cause about 20% of familial ALS, and related pathology might generate microglial activation triggering neurodegeneration. 11C‐PK11195 is the prototypical and most validated PET radiotracer, targeting the 18‐kDa translocator protein which is overexpressed in activated microglia. In this study, we investigated microglia activation in asymptomatic (ASYM) and symptomatic (SYM) SOD1 mutated carriers, by using 11C‐PK11195 and PET imaging. Methods We included 20 subjects: 4 ASYM‐carriers, neurologically normal, 6 SYM‐carriers with probable ALS, and 10 healthy controls. A receptor parametric mapping procedure estimated 11C‐PK11195 binding potentials and voxel‐wise statistical comparisons were performed at group and single‐subject levels. Results Both the SYM‐ and ASYM‐carriers showed significant microglia activation in cortical and subcortical structures, with variable patterns at individual level. Clusters of activation were present in occipital and temporal regions, cerebellum, thalamus, and medulla oblongata. Notably, SYM‐carriers showed microglia activation also in supplementary and primary motor cortices and in the somatosensory regions. Interpretation In vivo neuroinflammation occurred in all SOD1 mutated cases since the presymptomatic stages, as shown by a significant cortical and subcortical microglia activation. The involvement of sensorimotor cortex became evident at the symptomatic disease stage. Although our data indicate the role of in vivo PET imaging for assessing resident microglia in the investigation of SOD1‐ALS pathophysiology, further studies are needed to clarify the temporal and spatial dynamics of microglia activation and its relationship with neurodegeneration.

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“…DNA samples were available for 11 out of 35 ALS patients belonging to Tesauro et al Environmental Research xxx (xxxx) xxx-xxx Briga area, and for 42 out of 71 patients from the rest of Novara province, enrolled from the previous incidence study (Tesauro et al, 2017). Regarding the Briga area, we found only one mutation in 1 patient, namely the GGGGCC pathological expansion in C9ORF72 gene, representing the most common mutation in sporadic and familial ALS cases in the Piedmont region (Chiò et al, 2012(Chiò et al, , 2020 as well as worldwide (Brown and Al-Chalabi, 2017). In the larger reference group of patients living outside the Briga area, 6 patients carried the GGGGCC pathological expansion in C9ORF72 gene, 1 patient carried a known missense mutation (p.L144F) in SOD1 and 3 patients carried intermediate alleles (>30 CAG repeats) at ATXN2 CAG repeat locus.…”

Section: Genetic Analysesmentioning

confidence: 87%

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

Tesauro

Bruschi

Filippini

et al. 2021

Environmental Research

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Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder of the motor system. The etiology is still unknown and the pathogenesis remains unclear. ALS is familial in the 10% of cases with a Mendelian pattern of inheritance. In the remaining sporadic cases, a multifactorial origin is supposed in which several predisposing genes interact with environmental factors. The etiological role of environmental factors, such as pesticides, exposure to electromagnetic fields, and metals has been frequently investigated, with controversial findings. Studies in the past two decades have highlighted possible roles of metals, and ionic homeostasis dysregulation has been proposed as the main trigger to motor-neuron degeneration. This study aims at evaluating the possible role of environmental factors in etiopathogenesis of ALS, with a particular attention on metal contamination, focusing on the industrial Briga area in the province of Novara (Piedmont region, North Italy), characterized by: i) a higher incidence of sporadic ALS (sALS) in comparison with the entire province, and ii) the reported environmental pollution. Environmental data from surface, ground and discharge waters, and from soils were collected and specifically analyzed for metal content. Considering the significance of genetic mechanisms in ALS, a characterization for the main ALS genes has been performed to evaluate the genetic contribution for the sALS patients living in the area of study. The main findings of this study are the demonstration that in the Briga area the most common metal contaminants are Cu, Zn, Cr, Ni (widely used in tip-plating processes), that are above law limits in surface waters, discharge waters, and soil. In addition, other metals and metalloids, such as Cd, Pb, Mn, and As show a severe contamination in the same area. Results of genetic analyses show that sALS patients in the Briga area do not carry recurrent mutations or an excess of mutations in the four main ALS causative genes (SOD1, TARDBP, FUS, C9ORF72) and for ATXN2 CAG repeat locus. This study supports the hypothesis that the higher incidence of sALS in Briga area may be related to environmental metal(loid)s contamination, along with other environmental factors. Further studies, implementing analysis of genetic polymorphisms, as well as investigation with long term follow-up, may yield to key aspects into the etiology of ALS. The interplay between different approaches (environmental, chemical, epidemiological, genetic) of our work provides new insights and methodology to the comprehension of the disease etiology.

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ALS phenotype is influenced by age, sex, and genetics

Cited by 120 publications

References 30 publications

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

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ALS phenotype is influenced by age, sex, and genetics

Cited by 120 publications

References 30 publications

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

Early Referral to an ALS Center Reduces Several Months the Diagnostic Delay: A Multicenter-Based Study

11C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis

Metal(loid)s role in the pathogenesis of amyotrophic lateral sclerosis: Environmental, epidemiological, and genetic data

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¹¹C‐PK11195 PET–based molecular study of microglia activation in SOD1 amyotrophic lateral sclerosis