Publications by authors named "Cristina Moglia"

96 Publications

Italian adaptation of the Beaumont Behavioral Inventory (BBI): psychometric properties and clinical usability.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jul 19:1-6. Epub 2021 Jul 19.

"Rita Levi Montalcini" Department of Neuroscience, University of Turin, ALS Centre, Turin, Italy.

Up to 50% of patients affected by amyotrophic lateral sclerosis (ALS) show behavioral changes within the of frontotemporal degeneration (FTD). Behavioral dysfunctions in ALS patients negatively impact on management, prognosis and survival. It is, thus, crucial to develop ALS-specific psychometric tools for early detecting alterations in behavior. This study aimed at investigating psychometric properties and feasibility of the Beaumont Behavioral Impairment (BBI), a proxy-report questionnaire designed to screen for FTD-like behavioral symptoms in ALS patients. Ninety ALS patients were compared to 100 healthy participants (HPs) on the BBI. ALS patients underwent clinical, cognitive, mood/anxiety and further behavioral (Frontal System Behavior Scale, FrSBe; Frontal Behavioral Inventory, FBI) evaluation. Validity, reliability, sensitivity and specificity of the BBI were assessed. The BBI was significantly related to FrSBe and FBI scores, whereas not to other measures. A Principal Component Analysis yielded a mono-component structure; Cronbach's α was .93. The BBI proved to be sensitive to changes in behavior as well as to discriminate between different degrees of dysfunction. By addressing the FrSBe as the gold standard, the BBI reached optimal sensitivity (85.7%) and specificity (79.7%) at a cutoff of 10.5. Moreover, the BBI proved to be more accurate than the FrSBe and the FBI in clinical classifications. The BBI showed high internal consistency, as well as good construct, convergent and divergent validity. Its clinical usability is encouraged in ALS patients as being able to sensitively and specifically detect FTD-like behavioral changes.
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http://dx.doi.org/10.1080/21678421.2021.1946085DOI Listing
July 2021

What is amyotrophic lateral sclerosis prevalence?

Amyotroph Lateral Scler Frontotemporal Degener 2021 Jun 21:1-6. Epub 2021 Jun 21.

Department of Neuroscience "Rita Levi Montalcini", ALS Center, University of Turin, Turin, Italy.

To assess amyotrophic lateral sclerosis (ALS) prevalence and to analyze how this estimate vary according to the historical depth of data collection. Data from the PARALS register have been used. Crude prevalence ratio was estimated on 31 December 2015 for the period 2015-2013 and then repeated extending the time interval by 3 years each time. For each time interval, prevalence ratio was calculated globally and stratified by sex, age at diagnosis, and phenotype. Prevalence was also calculated considering patients who underwent tracheostomy during the same study period. Prevalence ratios increased proportionally to the length of the time period considered, ranging from 6 (95% CI 5.3-6.7) for a 3-year period to 12.1 (95% CI 11.1-13.1) per 100,000 population for a 21-year period. Prevalence ratio increase was inversely proportional to age at diagnosis, being null in the >85 years class and maximal in the 25-35 age class (+1700%). Among phenotypes, predominant UMN showed the highest increase (from 0.5, 95% CI 0.3-0.8, to 2.1, 95% CI 1.7 - 2.6, +320%). : Because of the variability of ALS survival, prevalence ratio strongly depends on the length of the follow-up period. A 12-year period should be sufficient to get a reliable estimate of ALS prevalence including long-survival patients.
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http://dx.doi.org/10.1080/21678421.2021.1936557DOI Listing
June 2021

A novel splice site mutation in a familial ALS case: effects on protein expression.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Apr 21:1-9. Epub 2021 Apr 21.

"Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Turin, Turin, Italy.

To investigate the impact of a novel heterozygous mutation in the acceptor splice site of intron 14 (c.1542 - 1 g > t) on protein expression in Peripheral Blood Mononuclear Cells (PBMC) from a familial ALS patient. : PBMC were isolated for mRNA analysis (cDNA synthesis, sequencing and one-step RT-PCR), Western Immunoblot (WI), and Immunofluorescence (IF). : cDNA analysis revealed the skipping of exon 15 and a premature stop codon at c.228. RT-PCR showed reduced FUS mRNA by more than half compared to a healthy control (HC) and an ALS patient without genetic mutations (wtALS). In WI FUS band intensity in the proband was 30-50% compared to HC and wtALS. An antibody expected to detect only the wild-type protein did not reveal any reduction of FUS band intensity compared to the other antibodies. IF showed no difference among HC, wtALS, and the proband. : The reduction of FUS mRNA and protein in PBMC suggests the absence of the truncated protein, probably due to nonsense-mediated decay, leading to loss of function.
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http://dx.doi.org/10.1080/21678421.2021.1909065DOI Listing
April 2021

Amyotrophic lateral sclerosis caregiver burden and patients' quality of life during COVID-19 pandemic.

Amyotroph Lateral Scler Frontotemporal Degener 2021 Apr 16:1-3. Epub 2021 Apr 16.

"Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.

To assess patients Quality of life (QoL) and the burden of their caregivers during Covid-19 pandemic and specifically the impact of two-month lockdown period. : In April 2020, a total of 60 patients and 59 caregivers were administered by phone scales assessing patients' QoL (McGill QoL Questionnaire), general health status (EQ-5D-5L), and caregiver burden (Zarit Burden Interview). The administration was repeated one month after the end of lockdown measures, with the addition of a qualitative questionnaire (COVID-QoL Questionnaire) exploring family reorganization and personal perception of lock down. : QoL and perceived health status did not worsen during lockdown, while caregiver burden increased ( = 0.01). Patient's QoL and caregiver burden were inversely correlated at T1 (ZBI total score mildly correlated with Mc Gill existential subscore,  = 0.02, rho = 0.30 and with Mc Gill total score,  = 0.05, rho = 0.265). No significant correlations were found at T2. According to the COVID-QoL questionnaire, caregivers perceived lower family help compared to patients ( < 0.001). : Restricted measures of lockdown period during COVID-19 pandemic did not result in a significant reduction of QoL in our cohort of ALS patients, while caregiver burden significantly increased. ALS motor impairment may have played a role in the unchanged life conditions of patients. Instead, the restriction of family help for primary caregivers could be responsible of their increased burden, reflecting the importance of a wide social support in the management of this clinical condition.
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http://dx.doi.org/10.1080/21678421.2021.1912772DOI Listing
April 2021

The heterozygous deletion c.1509_1510delAG in exon 14 of FUS causes an aggressive childhood-onset ALS with cognitive impairment.

Neurobiol Aging 2021 Jul 3;103:130.e1-130.e7. Epub 2021 Feb 3.

Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health (DINOGMI) University of Genoa and IRCCS Policlinico San Martino, Genoa, Italy; IRCCS Policlinico San Martino, Genoa, Italy.

We report a case of childhood-onset ALS with a FUS gene mutation presenting cognitive impairment and a rapid clinical progression. The patient, an 11-year-old girl, presented with right distal upper limb weakness and mild intellectual disability at the Griffith Mental Development Scales. The disease rapidly worsened and the patient became tetraplegic and bed-ridden 2 years after symptom onset. A c.1509_1510delAG mutation in exon 14 of the FUS gene was detected, resulting in a predicted truncated protein, p.G504Wfs*12, lacking the nuclear localization signal. The levels of FUS mRNA in the proband were not significantly different compared to controls. Western immunoblot analysis showed that one antibody (500-526) detected in the proband ~50% of the amount of FUS protein compared to controls, while 3 other antibodies (2-27, 400-450 and FUS C-terminal), which recognize both wild type and the mutated FUS, detected 60% to 75% of the amount of the protein. These findings indicate that p.G504Wfs*12 FUS is more prone to undergo post-translational modification respect to wild type FUS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2021.01.029DOI Listing
July 2021

Do ecological factors influence the clinical presentation of amyotrophic lateral sclerosis?

J Neurol Neurosurg Psychiatry 2021 Feb 9. Epub 2021 Feb 9.

ALS Center, 'Rita Levi Montalcini' Department of Neurosciences, University of Turin, Torino, Italy.

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http://dx.doi.org/10.1136/jnnp-2020-325625DOI Listing
February 2021

The interplay among education, brain metabolism, and cognitive impairment suggests a role of cognitive reserve in Amyotrophic Lateral Sclerosis.

Neurobiol Aging 2021 02 19;98:205-213. Epub 2020 Nov 19.

Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy; Department of Medical Radiation Physics and Nuclear Medicine, Karolinska University Hospital, Stockholm, Sweden.

We tested the Cognitive Reserve (CR) hypothesis in Amyotrophic Lateral Sclerosis (ALS), enrolling 111 patients, using education as CR proxy, F-FDG-PET to assess brain damage, and ECAS to measure cognition. Education was regressed out against brain metabolism, including age, sex, spinal/bulbar onset, ALSFRS-R, and ECAS as covariates. Clusters showing a significant correlation were used as seed regions in an interregional correlation analysis (IRCA) in the ALS group and in 40 controls. In the ALS group, we found a negative correlation between brain metabolism and education in the right anterior cingulate and bilateral medial frontal gyrus. In the IRCA in the ALS group, the medial frontal cluster metabolism positively correlated with that of frontotemporal regions (right > left), bilateral caudate nuclei, and right insula, and negatively correlated with that of corticospinal tracts, cerebellum, and pons. In controls, the IRCA showed significant positive correlations in the same regions but less extended. Our results agree with the CR hypothesis. The negative correlation between the medial frontal cluster and the cerebellum found only in ALS patients might reflect cerebellar compensation.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.11.010DOI Listing
February 2021

Neck flexor weakness at diagnosis predicts respiratory impairment in amyotrophic lateral sclerosis.

Eur J Neurol 2021 Apr 29;28(4):1181-1187. Epub 2020 Dec 29.

ALS Centre, Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy.

Background And Purpose: The purpose was to assess the prognostic role of neck muscle weakness at diagnosis in amyotrophic lateral sclerosis (ALS) patients with respect to survival and respiratory impairment.

Methods: A retrospective cohort study was conducted. All ALS patients seen in the Turin ALS Centre from 2007 to 2014 were included. Muscle strength at diagnosis was evaluated using the Medical Research Council (MRC) scale. Survival was considered as the time from diagnosis to death or tracheostomy; time to respiratory impairment was considered as the interval from diagnosis to the first event amongst an ALS Functional Rating Scale revised item 10 <4, forced vital capacity <70%, start of non-invasive ventilation or tracheostomy. Time from diagnosis to dysarthria, dysphagia and walking impairment were considered as secondary outcomes. Cox proportional hazard regression models adjusted for sex, age at diagnosis, diagnostic delay, onset site, genetics status and the MRC scores of other muscle groups were used to assess the prognostic role of neck muscles.

Results: A total of 370 patients were included in the study. Fifty-nine (15.9%) patients showed neck flexor weakness at diagnosis; MRC values were mostly in agreement for neck extensors. Neck flexors were the only muscles able to predict survival (hazard ratio 0.49, 95% confidence interval 0.28-0.86; p = 0.01). Furthermore, neck flexor normal strength decreased the risk of respiratory impairment (hazard ratio 0.46, 95% confidence interval 0.22-0.96; p = 0.04) but did not influence any secondary outcomes.

Discussion: Neck flexor weakness at diagnosis predicts survival and respiratory impairment in ALS. This result could be valuable for both planning of patients' interventions and clinical trials' design.
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http://dx.doi.org/10.1111/ene.14676DOI Listing
April 2021

Comorbidity of Cervical Spondylogenic Myelopathy and Amyotrophic Lateral Sclerosis: When Electromyography Makes the Difference in Diagnosis.

Eur Neurol 2020 9;83(6):626-629. Epub 2020 Dec 9.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy,

Cervical spondylogenic myelopathy (CSM) represents a common differential diagnosis for spinal onset Amyotrophic Lateral Sclerosis (ALS). Identifying occurrence of ALS in patients with CSM may be challenging. We evaluated the accuracy of Awaji criteria in the diagnosis of ALS in a cohort of patients with CSM. We screened all patients attending Turin ALS Center during the 2006-2018 period. We selected only patients for whom cervical cord MRI showed radiological signs of CSM. All patients underwent electromyography (EMG), and Awaji criteria were used for diagnosis of clinically probable ALS. All patients were followed up clinically for at least 6 months, and ALS diagnosis was eventually confirmed according to El-Escorial revised criteria, based on disease progression. Of 2,059 patients screened, in 42 cases, MRI showed signs of CSM; CSM incidence and prevalence risks were 0.16 and 2.04%, respectively. Based on clinical progression, 72.7% of patients were diagnosed as CSM and 27.3% as CSM + ALS. At EMG 6 (18.2%) patients fulfilled the criteria for ALS, 5 of them (83.3%) during clinical follow-up were diagnosed as clinical definite ALS + CSM. Accuracy of Awaji criteria in diagnosing ALS was good (AUC = 0.757, p = 0.03). Sensitivity and specificity of Awaji criteria were, respectively, 55.6 and 95.8%. Positive predictive value was 83.3%, while negative predictive value was 85.2%. CSM-ALS comorbidity is a relatively common problem in clinical practice. To better choose patients who could benefit from surgery, EMG should be performed in CSM patients, due to its good accuracy in recognizing ALS.
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http://dx.doi.org/10.1159/000512269DOI Listing
May 2021

Metabolic brain changes across different levels of cognitive impairment in ALS: a F-FDG-PET study.

J Neurol Neurosurg Psychiatry 2020 Nov 23. Epub 2020 Nov 23.

"Rita Levi Montalcini" Department of Neuroscience, University of Turin, ALS Centre, Turin, Italy.

Objective: To identify the metabolic changes related to the various levels of cognitive deficits in amyotrophic lateral sclerosis (ALS) using F-2-fluoro-2-deoxy-D-glucose positron emission tomography (F-FDG-PET) imaging.

Methods: 274 ALS patients underwent neuropsychological assessment and brain F-FDG-PET at diagnosis. According to the criteria published in 2017, cognitive status was classified as ALS with normal cognition (ALS-Cn, n=132), ALS with behavioural impairment (ALS-Bi, n=66), ALS with cognitive impairment (ALS-Ci, n=30), ALS with cognitive and behavioural impairment (ALS-Cbi, n=26), ALS with frontotemporal dementia (ALS-FTD, n=20). We compared each group displaying some degree of cognitive and/or behavioural impairment to ALS-Cn patients, including age at PET, sex and ALS Functional Rating Scale-Revised as covariates.

Results: We identified frontal lobe relative hypometabolism in cognitively impaired patients that resulted more extensive and significant across the continuum from ALS-Ci, through ALS-Cbi, to ALS-FTD. ALS-FTD patients also showed cerebellar relative hypermetabolism. ALS-Bi patients did not show any difference compared with ALS-Cn.

Conclusions: These data support the concept that patients with cognitive impairment have a more widespread neurodegenerative process compared with patients with a pure motor disease: the more severe the cognitive impairment, the more diffuse the metabolic changes. Otherwise, metabolic changes related to pure behavioural impairment need further characterisation.
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http://dx.doi.org/10.1136/jnnp-2020-323876DOI Listing
November 2020

Mutational Analysis of Known ALS Genes in an Italian Population-Based Cohort.

Neurology 2021 01 18;96(4):e600-e609. Epub 2020 Nov 18.

From "Rita Levi Montalcini" Department of Neuroscience (M.G., A. Calvo, C.M., A. Canosa, U.M., R.V., A. Chiò), University of Turin, Italy; Biocomputational Group (J.D., R.J.G.) and Neuromuscular Diseases Research Section (M.G., R.C., B.J.T.), Laboratory of Neurogenetics, National Institute on Aging, NIH, Porter Neuroscience Research Center, Bethesda, MD; Laboratory of Genetics, Department of Clinical Pathology (M. Brunetti, M. Barberis, L.S.), Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont; ALS Center (L.M.), Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy; Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics (S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda; Department of Neurology (S.W.S., B.J.T.), Johns Hopkins University Medical Center; Department of Anatomy, Physiology & Genetics (C.D.), and The American Genome Center, Collaborative Health Initiative Research Program (C.D.), Uniformed Services University of the Health Sciences, Bethesda, MD; and Institute of Cognitive Sciences and Technologies (A. Chiò), National Council of Research, Rome, Italy.

Objective: To assess the burden of rare genetic variants and to estimate the contribution of known amyotrophic lateral sclerosis (ALS) genes in an Italian population-based cohort, we performed whole genome sequencing in 959 patients with ALS and 677 matched healthy controls.

Methods: We performed genome sequencing in a population-based cohort (Piemonte and Valle d'Aosta Registry for ALS [PARALS]). A panel of 40 ALS genes was analyzed to identify potential disease-causing genetic variants and to evaluate the gene-wide burden of rare variants among our population.

Results: A total of 959 patients with ALS were compared with 677 healthy controls from the same geographical area. Gene-wide association tests demonstrated a strong association with , whose rare variants are the second most common cause of disease after expansion. A lower signal was observed for , proving that its effect on our cohort is driven by a few known causal variants. We detected rare variants in other known ALS genes that did not surpass statistical significance in gene-wise tests, thus highlighting that their contribution to disease risk in our cohort is limited.

Conclusions: We identified potential disease-causing variants in 11.9% of our patients. We identified the genes most frequently involved in our cohort and confirmed the contribution of rare variants in disease risk. Our results provide further insight into the pathologic mechanism of the disease and demonstrate the importance of genome-wide sequencing as a diagnostic tool.
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http://dx.doi.org/10.1212/WNL.0000000000011209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905787PMC
January 2021

Brain metabolic correlates of apathy in amyotrophic lateral sclerosis: An 18F-FDG-positron emission tomography stud.

Eur J Neurol 2021 Mar 3;28(3):745-753. Epub 2020 Dec 3.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.

Background And Purpose: The aim of this study was to evaluate brain metabolic correlates of apathy in amyotrophic lateral sclerosis (ALS).

Methods: A total of 165 ALS patients underwent F-2-fluoro-2-deoxy-D-glucose positron emission tomography ( F-FDG-PET) and Frontal Systems Behaviour Scale (FrSBe) evaluation. FrSBe provides "before" and "after" apathy subscores, referring to premorbid and morbid conditions. "After" apathy subscore and "before-after" gap, i.e. the difference between "before" and "after" subscores, were regressed against whole-brain metabolism. Among patients with a pathological "after" apathy subscore (i.e., ≥65), we compared patients with "before" apathy subscores ≥65 and <65, and patients with "before-after" gaps of <22 and ≥22.

Results: In the whole sample, the "after" apathy subscore negatively correlated with metabolism in the dorsolateral prefrontal cortex (DLPFC), dorsomedial prefrontal cortex (DMPFC), ventrolateral prefrontal cortex (VLPFC), premotor cortex (PMC) and anterior cingulate cortex (ACC), and insula bilaterally. A positive correlation was found in the cerebellum and pons. The "before-after" gap negatively correlated with metabolism in bilateral DLPFC, DMPFC and PMC, and left VLPFC and ACC, and positively correlated with cerebellar and pontine clusters. Among patients with an "after" apathy subscore ≥65, we found no difference between those with "before" apathy subscores ≥65 and <65. Patients with a "before-after" gap ≥22, compared to patients with a gap <22, showed relative hypometabolism in bilateral DLPFC and DMPFC, and left ACC and PMC, and relative cerebellar and pontine hypermetabolism.

Conclusion: No studies on brain F-2-fluoro-2-deoxy-D-glucose positron emission tomography correlates of apathy have been performed in ALS. We found that FrSBe "after" apathy subscore correlated with metabolic changes in brain regions known as neuroanatomical correlates of apathy. Furthermore, our findings support the relevance of the gap between premorbid and morbid conditions to detect behavioural changes due to the neurodegenerative process underlying ALS.
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http://dx.doi.org/10.1111/ene.14637DOI Listing
March 2021

Differential Neuropsychological Profile of Patients With Amyotrophic Lateral Sclerosis With and Without Mutation.

Neurology 2021 01 26;96(1):e141-e152. Epub 2020 Oct 26.

From the ALS Center, 'Rita Levi Montalcini' Department of Neuroscience (B.I., L.P., J.P.Z., A. Canosa, U.M., R.V., M.G., F.P., M. Brunetti, C.M., A. Calvo, A. Chiò), University of Torino; Medical Genetic Unit (M. Barberis, L.S.) and Neurology 1 (A. Canosa, M. Brunetti, C.M., A. Calvo, A. Chiò), Azienda Ospedaliero-Universitaria Città della Salute e della Scienza of Torino, Turin; and Institute of Cognitive Sciences and Technologies (A. Chiò), National Research Council, Rome, Italy.

Objective: To determine whether the neuropsychological profiles of patients with amyotrophic lateral sclerosis (ALS) with (ALSC9+) and without (ALSC9-) expansion are different, we administered a battery of neuropsychological tests to 741 patients with ALS (68 ALSC9+ and 673 ALSC9-) and 129 controls.

Methods: The study population includes 741 patients with ALS who were consecutively diagnosed at the Turin ALS expert center in the 2010-2018 period and who underwent both cognitive/behavioral and genetic testing. Patients' neuropsychological patterns were compared (1) at the same degree of cognitive and behavioral deficit according to the revised ALS-Frontotemporal Dementia Consensus Criteria and (2) at the same level of motor impairment according to the King staging system.

Results: Despite being about 7 years younger, ALSC9+ patients had significantly lower scores in tests exploring executive function and verbal memory both when classified as cognitively normal and when diagnosed in the intermediate cognitive categories. Considering the clinical perspective, ALSC9+ patients showed significantly lower scores compared to ALSC9- patients at King stage 1 and 3 in almost all the examined neuropsychological domains; at King stage 2, ALSC9+ patients were more severely affected only in the verbal memory domain. Behavioral function was comparably impaired in the 2 cohorts.

Conclusions: ALSC9+ patients show a different neuropsychological profile compared to ALSC9- patients, being more impaired in executive functions and verbal memory domains at all King stages. Verbal memory emerged as a particularly vulnerable function in ALSC9+, with worse performances even when patients were still classified as cognitively normal.
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http://dx.doi.org/10.1212/WNL.0000000000011093DOI Listing
January 2021

Brain metabolic changes across King's stages in amyotrophic lateral sclerosis: a F-2-fluoro-2-deoxy-D-glucose-positron emission tomography study.

Eur J Nucl Med Mol Imaging 2021 04 7;48(4):1124-1133. Epub 2020 Oct 7.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Via Cherasco 15, 10126, Turin, Italy.

Purpose: To assess the brain metabolic correlates of the different regional extent of ALS, evaluated with the King's staging system, using brain F-2-fluoro-2-deoxy-D-glucose-PET (F-FDG-PET).

Methods: Three hundred ninety ALS cases with King's stages 1, 2, and 3 (n = 390), i.e., involvement of 1, 2, and 3 body regions respectively, underwent brain F-FDG-PET at diagnosis. King's stage at PET was derived from ALSFRS-R and was regressed out against whole-brain metabolism in the whole sample. The full factorial design confirmed the hypothesis that differences among groups (King's 1, King's 2, King's 3, and 40 healthy controls (HC)) existed overall. Comparisons among stages and between each group and HC were performed. We included age at PET and sex as covariates.

Results: Brain metabolism was inversely correlated with stage in medial frontal gyrus bilaterally, and right precentral and postcentral gyri. The full factorial design resulted in a significant main effect of groups. There was no significant difference between stages 1 and 2. Comparing stage 3 to stage 1+2, a significant relative hypometabolism was highlighted in the former in the left precentral and medial frontal gyri, and in the right medial frontal, postcentral, precentral, and middle frontal gyri. The comparisons between each group and HC showed the extension of frontal metabolic changes from stage 1 to stage 3, with the larger metabolic gap between stages 2 and 3.

Conclusions: Our findings support the hypothesis that in ALS, the propagation of neurodegeneration follows a corticofugal, regional ordered pattern, extending from the motor cortex to posterior and anterior regions.
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http://dx.doi.org/10.1007/s00259-020-05053-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041703PMC
April 2021

Broadening the clinical spectrum of FUS mutations: a case with monomelic amyotrophy with a late progression to amyotrophic lateral sclerosis.

Neurol Sci 2021 03 1;42(3):1207-1209. Epub 2020 Oct 1.

ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy.

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http://dx.doi.org/10.1007/s10072-020-04751-5DOI Listing
March 2021

The Characteristics of Cognitive Impairment in ALS Patients Depend on the Lateralization of Motor Damage.

Brain Sci 2020 Sep 19;10(9). Epub 2020 Sep 19.

Faculty of Psychology, eCampus University, 22060 Novedrate, Italy.

(1) Background: Cognitive features of patients with amyotrophic lateral sclerosis (ALS) have never been specifically analyzed according to the lateralization of motor impairment. In the present study we investigated the cognitive performances of ALS patients to describe the relationship between motor and cognitive dysfunction, according to site and side of disease onset. (2) Methods: Six-hundred and nine ALS patients underwent a comprehensive neuropsychological evaluation at diagnosis in Turin ALS Centre Tests included-mini-mental state examination (MMSE), frontal assessment battery (FAB), trail-making test A/B (TMT A-B), digit span forward and backward (digit span FW/digit span BW), letter fluency test (FAS), category fluency test (CAT), Rey auditory verbal learning test (RAVLT), Babcock story recall test (BSRT), Rey-Osterrieth complex figure test (ROCFT), Wisconsin card sorting test (WCST), Raven's coloured progressive matrices (CPM47). Cognitive performances of patients, grouped by side and site of onset, were statistically compared using -scores, as appropriate. (3) Results: Bulbar patients and bilateral spinal onset patients (S) were generally characterized by lower cognitive performances in most neuropsychological tests, when compared to patients with lateralized onset (right-side spinal onset, S and left-side spinal onset, S). Digit span backward and visual memory task (ROCFT) median -scores were significantly higher, reflecting a better cognitive performance, in S patients when compared to bulbar/S patients, while verbal memory tasks (RAVLT and BRST) resulted in significantly higher scores in S patients. Our results are in keeping with hemispheric functional lateralization of language and visuospatial abilities. (4) Conclusions: In ALS patients, as in other neurodegenerative diseases, we found a direct relationship between lateralized motor and cognitive features.
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http://dx.doi.org/10.3390/brainsci10090650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563934PMC
September 2020

Telemedicine for patients with amyotrophic lateral sclerosis during COVID-19 pandemic: an Italian ALS referral center experience.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 12;22(3-4):308-311. Epub 2020 Sep 12.

ALS Center, 'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Turin, Italy and.

We describe the telemedicine experience of an Italian ALS tertiary Center during COVID-19 pandemic. A total of 144 visits were scheduled between 6th March and 6th April 2020. These mostly consisted of neurological or psychological visits (139, 96.5%). One hundred thirty-nine (96.5%) visits were performed as telemedicine and mostly via phone call (112, 80.6%). Three (2.1%) visits were considered as urgent and maintained as outpatient care. Additionally, patients were still able to telephone, being put through directly to their neurologists. Many requests of contact were addressed at getting information about the scheduled visits or examinations (45, 43.3%). Globally, patients and caregivers were satisfied with the telemedicine service. However, the majority (85, 65.9%) would prefer a face-to-face visit. In conclusion, telemedicine could be considered a good complement to face-to-face care, even after social restrictions have been eased.
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http://dx.doi.org/10.1080/21678421.2020.1820043DOI Listing
May 2021

Structural and functional brain connectome in motor neuron diseases: A multicenter MRI study.

Neurology 2020 11 10;95(18):e2552-e2564. Epub 2020 Sep 10.

From the Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, (S.B., F.A., C.C., E.G.S., V.C., E.C., M.F.), Neurorehabilitation Unit (N.R.), Neurology Unit (Y.F., M.F.), Neurophysiology Unit (M.F.), and Department of Neuroradiology and CERMAC (A.F.), IRCCS San Raffaele Scientific Institute; Vita-Salute San Raffaele University (F.A., C.C., E.G.S., V.C., Y.F., A.F., M.F.), Milan; Department of Advanced Medical and Surgical Sciences (F.T., C.F., M.R.M., G.T.), University of Campania "Luigi Vanvitelli," Naples; and ALS Center (C.M., A.C.), "Rita Levi Montalcini" Department of Neuroscience, University of Torino, Italy.

Objective: To investigate structural and functional neural organization in amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), and progressive muscular atrophy (PMA).

Methods: A total of 173 patients with sporadic ALS, 38 patients with PLS, 28 patients with PMA, and 79 healthy controls were recruited from 3 Italian centers. Participants underwent clinical, neuropsychological, and brain MRI evaluations. Using graph analysis and connectomics, global and lobar topologic network properties and regional structural and functional brain connectivity were assessed. The association between structural and functional network organization and clinical and cognitive data was investigated.

Results: Compared with healthy controls, patients with ALS and patients with PLS showed altered structural global network properties, as well as local topologic alterations and decreased structural connectivity in sensorimotor, basal ganglia, frontal, and parietal areas. Patients with PMA showed preserved global structure. Patient groups did not show significant alterations of functional network topologic properties relative to controls. Increased local functional connectivity was observed in patients with ALS in the precentral, middle, and superior frontal areas, and in patients with PLS in the sensorimotor, basal ganglia, and temporal networks. In patients with ALS and patients with PLS, structural connectivity alterations correlated with motor impairment, whereas functional connectivity disruption was closely related to executive dysfunction and behavioral disturbances.

Conclusions: This multicenter study showed widespread motor and extramotor network degeneration in ALS and PLS, suggesting that graph analysis and connectomics might represent a powerful approach to detect upper motor neuron degeneration, extramotor brain changes, and network reorganization associated with the disease. Network-based advanced MRI provides an objective in vivo assessment of motor neuron diseases, delivering potential prognostic markers.
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http://dx.doi.org/10.1212/WNL.0000000000010731DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682834PMC
November 2020

Validation of the Italian version of self-administered ALSFRS-R scale.

Amyotroph Lateral Scler Frontotemporal Degener 2021 02 28;22(1-2):151-153. Epub 2020 Aug 28.

ALS Centre, Department of Neuroscience "Rita Levi Montalcini", University of Torino, Turin, Italy and.

Objectives: To validate and assess the reliability of the Italian version of self-administered ALSFRS-R, considering patients' clinical and cognitive features and caregiver's help. During the COVID-19 pandemic, by analyzing the results of 70 paired self-administered vs standard telephone-administered ALSFRS-R, we calculated overall score, single item scores, ALSFRS-R domain scores, King's and MiToS stage inter-rater agreement and reliability using different validated methods. We created the Italian version of self-administered ALSFRS-R following ENCALS recommendation. Correlation between the two scales was 0.94 and no systematic directional bias was found. The intraclass correlation coefficient (ICC) was very high (>0.90) for the vast majority of the considered classification criteria, especially King's total score (0.96) and MiToS score (0.94). A higher ICC was found when the patients answered the questionnaire with the caregiver's help (0.95). Online self-administered ALSFRS-R scale is a valid tool to stratify ALS patients into clinical stages and to implement telemedicine monitoring.
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http://dx.doi.org/10.1080/21678421.2020.1813307DOI Listing
February 2021

Acute, Hemorrhagic, Necrotizing Pancreatitis Associated With Riluzole Treatment in a Patient With Amyotrophic Lateral Sclerosis.

Am J Ther 2020 Aug 3. Epub 2020 Aug 3.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy.

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http://dx.doi.org/10.1097/MJT.0000000000001217DOI Listing
August 2020

Lifetime sport practice and brain metabolism in Amyotrophic Lateral Sclerosis.

Neuroimage Clin 2020 12;27:102312. Epub 2020 Jun 12.

Institute of Cognitive Sciences and Technologies, C.N.R., Rome, Italy; Department of Nuclear Medicine, Karolinska Hospital, Stockholm, Sweden.

Objective: To evaluate the metabolic correlates of lifetime sport practice in ALS through brain F-FDG-PET.

Methods: 131 patients completed a questionnaire about lifetime exposures, including physical activity related to sports, hobbies and occupations, and underwent brain F-FDG-PET. Exposure to sports was expressed as MET (Metabolic Equivalent of Task). We considered only regular practice (at least 2 h/week, for at least three months). We compared brain metabolism between two groups: subjects who did not report regular sport practice during life (N-group) and patients who did (Y-group). The resulting significant clusters were used in each group as seed regions in an interregional correlation analysis (IRCA) to evaluate the impact of lifetime sport practice on brain networks typically involved by the neurodegenerative process of ALS. Each group was compared to healthy controls (HC, n = 40).

Results: We found a significant, relative cerebellar hypermetabolism in the N-group compared to the Y-group. The metabolism of such cerebellar cluster resulted correlated to more significant and widespread metabolic changes in areas known to be affected by ALS (i.e. frontotemporal regions and corticospinal tracts) in the N-group as compared to the Y-group, despite the same level of disability as expressed by the ALS FRS-R. Such findings resulted independent of age, sex, site of onset (bulbar/spinal), presence/absence of C9ORF72 expansion, cognitive status and physical activity related to hobbies and occupations. When compared to HC, the N-group showed more widespread metabolic changes than the Y-group in cortical regions known to be relatively hypometabolic in ALS patients as compared to HC.

Conclusions: We hypothesize that patients of the N-group might cope better with the neurodegenerative process, since they show more widespread metabolic changes as compared to the Y-group, despite the same level of disability. Nevertheless, further studies are necessary to corroborate this hypothesis.
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http://dx.doi.org/10.1016/j.nicl.2020.102312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334468PMC
June 2021

The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis.

J Neurol 2020 Nov 17;267(11):3258-3267. Epub 2020 Jun 17.

"Rita Levi Montalcini" Department of Neuroscience, ALS Centre, University of Turin, Via Cherasco 15, 10126, Turin, Italy.

Objectives: The aim of the study is to analyze the ALS disease progression and respiratory function of Italian patients treated with edaravone (EVN), as well as the adherence to, and the effects of, the therapy.

Methods: We performed an observational study of patients treated with EVN from May 2017 to May 2019, in 39 Italian ALS Centers. Taking into account ALS patients with at least 12 months of EVN treatment, we compared the decline of ALSFRS-R and FVC with a group of matched historical controls from the Pooled Resource Open-Access ALS Clinical Trials (PRO-ACT) database, using both descriptive and survival analysis approaches.

Results: A total of 331 ALS Italian patients treated with EVN and 290 matched historical controls were recruited in this study. No significant differences on disease progression or respiratory function were found comparing the two cohorts in both descriptive and survival analyses. The EVN treatment was overall well tolerated.

Conclusions: The study showed that EVN treatment was well tolerated. No significant differences were reported in ALS patients treated and not treated with EVN, in terms of both disease progression and respiratory function. These findings prove that further studies are required to better clarify whether EVN could be considered an effective treatment for ALS disease.
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http://dx.doi.org/10.1007/s00415-020-09993-zDOI Listing
November 2020

Decline of cognitive and behavioral functions in amyotrophic lateral sclerosis: a longitudinal study.

Amyotroph Lateral Scler Frontotemporal Degener 2020 08 2;21(5-6):373-379. Epub 2020 Jun 2.

ALS Center, Department of Neurology, Azienda Ospedaliera Universitaria Maggiore della Carità, Novara, Italy.

: A cognitive impairment, ranging from frontotemporal dementia (FTD) to milder forms of dysexecutive or behavioral dysfunction, is detected in 30-50% of patients affected by amyotrophic lateral sclerosis (ALS) at diagnosis. Such condition considerably influences the prognosis, and possibly impacts on the decision-making process with regards to end-of-life choices. The aim of our study is to examine the changes of cognitive and behavioral impairment in a large population of ALS from the time of diagnosis to a 6-month follow-up (IQR 5.5-9.0 months), and to examine to what extent the progression of cognitive impairment affects survival time and rate of disease progression.: We recruited 146 ALS patients classified according to revised criteria of ALS and FTD spectrum disorder. In a multidisciplinary setting, during two subsequent visits we examined clinical features with ALSFRS-r score, FVC% and BMI, and cognitive status with an extensive neuropsychological evaluation.: At second examination, one-third of patients showed a worsening of cognitive impairment, namely 88% of ALSbi, 27% of ALSci, 40% of ALScbi, and, interestingly, also 24% of cognitive normal ALS developed a significant cognitive dysfunction. We find that those who changed their cognitive status presented a lower ALSFRS-r score at t1 and a shorter survival time compared to those who did not change, regardless of the type of cognitive impairment.: We show how cognitive disorders in ALS patients can not only be present at diagnosis, but also manifest during disease and influence the progression of motor deficit and the prognosis.
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http://dx.doi.org/10.1080/21678421.2020.1771732DOI Listing
August 2020

A familial amyotrophic lateral sclerosis pedigree discordant for a novel p.Glu46Asp heterozygous OPTN variant and the p.Ala5Val heterozygous SOD1 missense mutation.

J Clin Neurosci 2020 May 27;75:223-225. Epub 2020 Mar 27.

ALS Centre, "Rita Levi Montalcini" Department of Neuroscience, University of Turin, Turin, Italy; Azienda Ospedaliero Universitaria Città della Salute e della Scienza, SC Neurologia 1U, Turin, Italy.

About 10% of Amyotrophic Lateral Sclerosis (ALS) cases are familial (FALS), mainly related to mutations in C9ORF72, SOD1, TARDBP, and FUS genes. Recent data revealed the presence of multiple variants in ALS-associated genes in FALS in excess of what is to be expected by chance. FALS patients not carrying a pathogenic genetic mutation detected in their kindred have been reported. We report a FALS case, who did not carry the p.Ala5Val heterozygous SOD1 mutation that had been detected in other affected subjects of his kindred. He underwent Next-Generation Sequencing, revealing a novel p.Glu46Asp heterozygous OPTN variant of uncertain significance (VUS). Discordant genetic test results in FALS cases within the same family and the detection of variants of uncertain significance increase the complexities of genetic counselling.
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http://dx.doi.org/10.1016/j.jocn.2020.03.032DOI Listing
May 2020

G-CSF (filgrastim) treatment for amyotrophic lateral sclerosis: protocol for a phase II randomised, double-blind, placebo-controlled, parallel group, multicentre clinical study (STEMALS-II trial).

BMJ Open 2020 03 24;10(3):e034049. Epub 2020 Mar 24.

'Rita Levi Montalcini' Department of Neuroscience, University of Turin, Torino, Piemonte, Italy.

Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurological disorder characterised by a selective degeneration of motor neurons (MNs). Stem cell transplantation is considered as a promising strategy in neurological disorders therapy and the possibility of inducing bone marrow cells (BMCs) to circulate in the peripheral blood is suggested to investigate stem cells migration in degenerated ALS nerve tissues where potentially repair MN damage. Granulocyte-colony stimulating factor (G-CSF) is a growth factor which stimulates haematopoietic progenitor cells, mobilises BMCs into injured brain and it is itself a neurotrophic factor for MN. G-CSF safety in humans has been demonstrated and many observations suggest that it may affect neural cells. Therefore, we decided to use G-CSF to mobilise BMCs into the peripheral circulation in patients with ALS, planning a clinical trial to evaluate the effect of G-CSF administration in ALS patients compared with placebo.

Methods And Analysis: STEMALS-II is a phase II multicentre, randomised double-blind, placebo-controlled, parallel group clinical trial on G-CSF (filgrastim) and mannitol in ALS patients. Specifically, we investigate safety, tolerability and efficacy of four repeated courses of intravenous G-CSF and mannitol administered in 76 ALS patients in comparison with placebo (indistinguishable glucose solution 5%). We determine increase of G-CSF levels in serum and cerebrospinal fluid as CD34 cells and leucocyte count after treatment; reduction in ALS Functional Rating Scale-Revised Score, forced vital capacity, Scale for Testing Muscle Strength Score and quality of life; the adverse events/reactions during the treatment; changes in neuroinflammation biomarkers before and after treatment.

Ethics And Dissemination: The study protocol was approved by the Ethics Committee of Azienda Ospedaliera Universitaria 'Città della Salute e della Scienza', Torino, Italy. Results will be presented during scientific symposia or published in scientific journals.

Trial Registration Number: Eudract 2014-002228-28.
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http://dx.doi.org/10.1136/bmjopen-2019-034049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202695PMC
March 2020

Prognostic role of slow vital capacity in amyotrophic lateral sclerosis.

J Neurol 2020 Jun 12;267(6):1615-1621. Epub 2020 Feb 12.

Department of Neuroscience, ALS Center, "Rita Levi Montalcini", University of Turin, Via Cherasco 15, 1026, Turin, Italy.

Objectives: To compare the prognostic role of FVC and SVC at diagnosis in amyotrophic lateral sclerosis (ALS) patients.

Methods: We included all patients from the Piemonte and Valle D'Aosta ALS register (PARALS) who had been diagnosed with ALS between 1995 and 2015 and underwent spirometry at diagnosis. Survival was considered as time to death/tracheostomy; to assess the prognostic value in typical trial timeframes, survival at 12 and 18 months was calculated too. Cox proportional hazard regression models adjusted by sex, age at diagnosis, diagnostic delay, onset site, and ALSFRS-R total score at the moment of diagnosis were used to assess the prognostic role of FVC and SVC.

Results: A total of 795 ALS patients underwent spirometry at diagnosis during the study period. Four hundred and sixteen (52.3%) performed both FVC and SVC, whereas the others performed FVC only. FVC and SVC values were highly correlated (r = 0.92, p < 0.001) in the overall population and slightly less correlated in patients with bulbar onset (r = 0.86, p < 0.001). Both FVC and SVC proved to have a prognostic role with comparable hazard ratios (HRs) (HR 1.83, 95% CI 1.48-2.27 and 1.88, 95% CI 1.51-2.33, respectively). When considering typical trial timeframes, HRs remained similar and were inversely proportional to FVC and SVC values.

Discussion: FVC and SVC at diagnosis can be used interchangeably as independent predictors of survival in both clinical and research settings.
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http://dx.doi.org/10.1007/s00415-020-09751-1DOI Listing
June 2020

ALS phenotype is influenced by age, sex, and genetics: A population-based study.

Neurology 2020 02 6;94(8):e802-e810. Epub 2020 Jan 6.

From the ALS Center (A. Chiò, C.M., A. Canosa, U.M., F.D., R.V., M.G., M. Brunetti, M. Barberis, B.I., L.P., J.P.Z., A. Calvo), "Rita Levi Montalcini" Department of Neuroscience, University of Torino; Azienda Ospedaliero-Universitaria Città della Salute e della Scienza of Torino (A. Chiò, C.M., A. Calvo), Turin; Institute of Cognitive Sciences and Technologies (A. Chiò), National Research Council, Rome; Department of Health Sciences Interdisciplinary Research Center of Autoimmune Diseases (L.C., S.D.), "Amedeo Avogadro" University of Eastern Piedmont, Novara; ALS Center, Department of Neurology (M.F.S., V.S., F.D.M., L.M.), Azienda Ospedaliera Universitaria Maggiore della Carità, Novara; and Istituti Clinici Scientifici Maugeri (G.M.), IRCCS Milano, Milan, Italy.

Objective: To assess the determinants of amyotrophic lateral sclerosis (ALS) phenotypes in a population-based cohort.

Methods: The study population included 2,839 patients with ALS diagnosed in Piemonte, Italy (1995-2015). Patients were classified according to motor (classic, bulbar, flail arm, flail leg, predominantly upper motor neuron [PUMN], respiratory) and cognitive phenotypes (normal, ALS with cognitive impairment [ALSci], ALS with behavioral impairment [ALSbi], ALSci and ALSbi combined [ALScbi], ALS-frontotemporal dementia [FTD]). Binary logistic regression analysis was adjusted for sex, age, and genetics.

Results: Bulbar phenotype correlated with older age ( < 0.0001), women were more affected than men at increasing age ( < 0.0001), classic with younger age ( = 0.029), men were more affected than women at increasing age ( < 0.0001), PUMN with younger age ( < 0.0001), flail arm with male sex ( < 0.0001) and younger age ( = 0.04), flail leg with male sex with increasing age ( = 0.008), and respiratory with male sex ( < 0.0001). expansions correlated with bulbar phenotype ( < 0.0001), and were less frequent in PUMN ( = 0.041); mutations correlated with flail leg phenotype ( < 0.0001), and were less frequent in bulbar ( < 0.0001). ALS-FTD correlated with ( < 0.0001) and bulbar phenotype ( = 0.008), ALScbi with PUMN ( = 0.014), and ALSci with older age ( = 0.008).

Conclusions: Our data suggest that the spatial-temporal combination of motor and cognitive events leading to the onset and progression of ALS is characterized by a differential susceptibility to the pathologic process of motor and prefrontal cortices and lower motor neurons, and is influenced by age, sex, and gene variants. The identification of those factors that regulate ALS phenotype will allow us to reclassify patients into pathologically homogenous subgroups, responsive to targeted personalized therapies.
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http://dx.doi.org/10.1212/WNL.0000000000008869DOI Listing
February 2020

Regional spreading of symptoms at diagnosis as a prognostic marker in amyotrophic lateral sclerosis: a population-based study.

J Neurol Neurosurg Psychiatry 2020 03 23;91(3):291-297. Epub 2019 Dec 23.

Department of Neuroscience 'Rita Levi Montalcini', ALS Centre, University of Turin, Torino, Piemonte, Italy.

Objective: The lack of prognostic biomarkers in patients with amyotrophic lateral sclerosis (ALS) induced researchers to develop clinical evaluation tools for stratification and survival prediction. We assessed the correlation between patterns of functional involvement, considered as a cumulative number of body regions involved, and overall survival in a population-based series of patients with ALS (PARALS).

Methods: We derived the functional involvement of four body regions at diagnosis using ALSFRS-R subscores for bulbar, upper limbs, lower limbs and respiratory/thoracic regions. We analysed the effect of number of body regions involved (NBRI) at diagnosis on overall survival, adjusting for age at onset, sex, site of onset, diagnostic delay, forced vital capacity, body mass index, mutational status, cognition and comparing it with King's staging system.

Results: The NBRI was strongly related to survival, with a progressive increase of death/tracheostomy risk among groups (two body regions HR=1.24, 95% CI 1.06 to 1.45, p=0007; three body regions HR=1.65, 95% CI 1.38 to 1.98, p<0.001; four body regions HR=2.68, 95% CI 2.11 to 3.39, p<0.001). Using ALSFRS-R score, the consistency between the number of regions involved and King's clinical stage at diagnosis was very high (81%). The evaluation of respiratory/thoracic region and cognition allowed to subdivide patients into different prognostic categories. Regional spreading of the disease is associated with survival, independently from the initial region involved.

Conclusions: The evaluation of NBRI, with the inclusion of initial respiratory/thoracic involvement and cognition, can be useful in many research fields, improving the stratification of patients. Our findings highlight the importance of the spatial spreading of functional impairment in the prediction of ALS outcome.
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http://dx.doi.org/10.1136/jnnp-2019-321153DOI Listing
March 2020
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