Publications by authors named "Nicola Ticozzi"

75 Publications

Identification of the Raman Salivary Fingerprint of Parkinson's Disease Through the Spectroscopic- Computational Combinatory Approach.

Front Neurosci 2021 26;15:704963. Epub 2021 Oct 26.

IRCCS Fondazione Don Carlo Gnocchi ONLUS, Milan, Italy.

Despite the wide range of proposed biomarkers for Parkinson's disease (PD), there are no specific molecules or signals able to early and uniquely identify the pathology onset, progression and stratification. Saliva is a complex biofluid, containing a wide range of biological molecules shared with blood and cerebrospinal fluid. By means of an optimized Raman spectroscopy procedure, the salivary Raman signature of PD can be characterized and used to create a classification model. Raman analysis was applied to collect the global signal from the saliva of 23 PD patients and related pathological and healthy controls. The acquired spectra were computed using machine and deep learning approaches. The Raman database was used to create a classification model able to discriminate each spectrum to the correct belonging group, with accuracy, specificity, and sensitivity of more than 97% for the single spectra attribution. Similarly, each patient was correctly assigned with discriminatory power of more than 90%. Moreover, the extracted data were significantly correlated with clinical data used nowadays for the PD diagnosis and monitoring. The preliminary data reported highlight the potentialities of the proposed methodology that, once validated in larger cohorts and with multi-centered studies, could represent an innovative minimally invasive and accurate procedure to determine the PD onset, progression and to monitor therapies and rehabilitation efficacy.
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http://dx.doi.org/10.3389/fnins.2021.704963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576466PMC
October 2021

Emotional Processing and Experience in Amyotrophic Lateral Sclerosis: A Systematic and Critical Review.

Brain Sci 2021 Oct 15;11(10). Epub 2021 Oct 15.

Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, 20149 Milan, Italy.

Even though increasing literature describes changes in emotional processing in Amyotrophic Lateral Sclerosis (ALS), efforts to summarize relevant findings are lacking in the field. A systematic literature review was performed to provide a critical and up-to-date account of emotional abilities in ALS. References were identified by searches of PubMed, Web of Science and Scopus (1980-2021, English literature), with the following key terms: ("Amyotrophic Lateral Sclerosis" or "Primary Lateral Sclerosis" or "Motor Neuron") and "Emotion*" and ("Processing" or "Attribution" or "Elaboration" or "Perception" or "Recognition"). Studies concerning only caregivers, pseudobulbar affect, and social cognition were excluded. Forty-one articles were included, all concerning ALS, and seven topics were identified: Emotion recognition, Emotional responsiveness, Emotional reactivity, Faces approachability rating, Valence rating, Memory for emotional materials and Alexithymia. The majority of these aspects have only been sparsely addressed. The evidence confirms altered emotional processing in ALS. The most consistent findings regard the recognition of facial expressions for negative emotions, but also alterations in the subjective responsiveness to emotional stimuli (arousal, valence and approachability), in psychophysiological and cerebral reactivity and in emotional memory, together with alexithymia traits, were reported. According to this evidence, emotional abilities should be included in the clinical assessment and therapeutic interventions.
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http://dx.doi.org/10.3390/brainsci11101356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8534224PMC
October 2021

Association of Clinically Evident Eye Movement Abnormalities With Motor and Cognitive Features in Patients With Motor Neuron Disorders.

Neurology 2021 Nov 9;97(18):e1835-e1846. Epub 2021 Sep 9.

From the Department of Neurology (B.P., L.C., A.D., E.C., S.T., A.M., F.G., F.V., C.M., V.S., N.T.), Istituto Auxologico Italiano IRCCS; Department of Pathophysiology and Transplantation (F.S., F.V., V.S., N.T.), Dino Ferrari Center and Department of Health Sciences (R.F.), Aldo Ravelli Center for Neurotechnology and Experimental Brain Therapeutics, Universitá degli Studi di Milano; Neuromuscular Omnicenter (L.G., F.C., A.L., C.L.), Fondazione Serena Onlus; Department of Materials Science and COMiB Research Center (F.C.), Università degli Studi di Milano-Bicocca; ASST Santi Paolo e Carlo (R.F.), Neurology Clinic III; and IRCCS Ca Granda Foundation Maggiore Policlinico Hospital (R.F.), Milan, Italy.

Background And Objectives: Although oculomotor abnormalities (OMAs) are not usually considered prominent features of amyotrophic lateral sclerosis (ALS), they may represent potential clinical markers of neurodegeneration, especially when investigated together with cognitive and behavioral alterations. The aim of our study was to identify patterns of clinically evident OMAs in patients with ALS and to correlate such findings with cognitive-behavioral data.

Methods: Three consecutive inpatient cohorts of Italian patients with ALS and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided into a discovery cohort and a replication cohort. Controls included a cohort of cognitively impaired individuals and patients with Alzheimer disease (AD). Participants underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed with a standard neuropsychological battery (discovery ALS cohort and AD cohort) and the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS) (replication ALS cohort).

Results: We recruited 864 individuals with ALS (635 discovery, 229 replication), 798 who were cognitively unimpaired and 171 with AD. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls ( = 1.2 × 10) and 11.4% of patients with AD ( = NS). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMA frequency was higher in patients with bulbar onset, prominent upper motor neuron signs, and advanced disease stages. Cognitive dysfunction was significantly more frequent in patients with OMAs in both ALS cohorts ( = 1.1 × 10). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathologic scores at the ECAS ALS-specific domains. Last, OMAs could be observed in 35.0% of cognitively impaired patients with ALS vs 11.4% of patients with AD ( = 6.4 × 10), suggesting a possible involvement of frontal oculomotor areas in ALS.

Conclusion: Patients with ALS showed a range of clinically evident OMAs, and these alterations were significantly correlated with cognitive, but not behavioral, changes. OMAs may be a marker of neurodegeneration, and bedside assessment represents a rapid, highly specific tool for detecting cognitive impairment in ALS.
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http://dx.doi.org/10.1212/WNL.0000000000012774DOI Listing
November 2021

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis.

JAMA Neurol 2021 Oct;78(10):1236-1248

Maurice Wohl Clinical Neuroscience Institute, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom.

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.

Objective: To identify the genetic variants associated with juvenile ALS.

Design, Setting, And Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.

Main Outcomes And Measures: De novo variants present only in the index case and not in unaffected family members.

Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.

Conclusions And Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.
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http://dx.doi.org/10.1001/jamaneurol.2021.2598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406220PMC
October 2021

A preliminary comparison between ECAS and ALS-CBS in classifying cognitive-behavioural phenotypes in a cohort of non-demented amyotrophic lateral sclerosis patients.

J Neurol 2021 Aug 19. Epub 2021 Aug 19.

Neuromuscular Omnicentre (NEMO), Fondazione Serena Onlus, Piazza Ospedale Maggiore, 3, 20162, Milan, Italy.

To define the presence and type of frontotemporal dysfunction in amyotrophic lateral sclerosis (ALS), different screening tools have been created. Currently, the most used screening tests are the Edinburgh cognitive and behavioural ALS screen (ECAS) and the ALS cognitive behavioural screen (ALS-CBS). The objective of this study was to compare the ability of ECAS and ALS-CBS in classifying non-demented ALS patients according to Strong criteria. One-hundred and fifty-four in- and out-patients with an age > 18 and a definite or probable ALS diagnosis were recruited between September 2019 and February 2020 at NeMO Clinical Centre and at Istituto Auxologico Italiano in Milan and underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and the ALS Cognitive Behavioural Screen (ALS-CBS). Exclusion criteria involved patients with a diagnosis of FTD, with a severe cognitive deterioration and/or an important behavioural impairment, with a significant psychiatric disorder or with the co-presence of another significant illness. The distribution of patients according to Strong criteria was different for ECAS and ALS-CBS and the degree of agreement between the two tests in terms of Cohen's Kappa coefficient resulted equal to 0.2047 with a 95% confidence limits interval between 0.1122 and 0.2973. This study for the first time compares the ability of ECAS and ALS-CBS in stratifying ALS patients. Further studies will be conducted to better understand the reasons underlying the differences between these two tests in classifying the different subtypes of fronto-temporal dysfunction in ALS.
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http://dx.doi.org/10.1007/s00415-021-10753-wDOI Listing
August 2021

Attachment, Personality and Locus of Control: Psychological Determinants of Risk Perception and Preventive Behaviors for COVID-19.

Front Psychol 2021 9;12:634012. Epub 2021 Jul 9.

Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy.

The understanding of factors that shape risk perception is crucial to modulate the perceived threat and, in turn, to promote optimal engagement in preventive actions. An on-line, cross-sectional, survey was conducted in Italy between May and July 2020 to investigate risk perception for COVID-19 and the adoption of preventive measures. A total of 964 volunteers participated in the study. Possible predictors of risk perception were identified through a hierarchical multiple linear regression analysis, including sociodemographic, epidemiological and, most of all, psychological factors. A path analysis was adopted to probe the possible mediating role of risk perception on the relationship between the independent variables considered and the adoption of preventive measures. Focusing on the psychological predictors of risk perception, high levels of anxiety, an anxious attachment, and an external locus of control predicted higher perceived risk. Conversely, high levels of openness personality and of avoidant attachment predicted a lower perception of risk. In turn, the higher was the perceived risk the higher was the adoption of precautionary measures. Furthermore, psychological factors influenced the adoption of preventive behaviors both directly and indirectly through their effect on risk perception. Our findings might be taken into high consideration by stakeholders, who are responsible for promoting a truthful perception of risk and proper compliance with precautionary measures.
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http://dx.doi.org/10.3389/fpsyg.2021.634012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299752PMC
July 2021

Epileptic Capgras-Like Delusions in a Patient with Right Frontal Meningioma: Case Report.

Case Rep Neurol 2021 May-Aug;13(2):284-288. Epub 2021 May 27.

Department of Neurology, Istituto Auxologico Italiano IRCCS, Milan, Italy.

Capgras syndrome is a condition characterized by the belief that a relative has been replaced by an almost identical imposter. The disorder has been reported in several neurological diseases. We describe the uncommon case of a transient Capgras syndrome manifesting as focal temporal seizures in a woman with a right frontal meningioma. Our patient represents an exceptional case of Capgras syndrome for several reasons, namely, the association with meningioma, very rarely reported before, the transient manifestation of symptoms, and, most importantly, the epileptic etiology of reduplicative paramnesias. Lastly, our report also confirms the importance of frontal and right hemisphere dysfunction in generating Capgras syndrome-like delusions.
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http://dx.doi.org/10.1159/000513675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8215999PMC
May 2021

Testing olfactory dysfunction in acute and recovered COVID-19 patients: a single center study in Italy.

Neurol Sci 2021 Jun 26;42(6):2183-2189. Epub 2021 Mar 26.

Department of Neurology and Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milan, Italy.

Background: Olfactory dysfunction in coronavirus disease 2019 (COVID-19) is common during acute illness and appears to last longer than other symptoms. The aim of this study was to objectively investigate olfactory dysfunction in two cohorts of patients at two different stages: during acute illness and after a median recovery of 4 months.

Methods: Twenty-five acutely ill patients and 26 recovered subjects were investigated. Acute patients had a molecular diagnosis of COVID-19; recovered subjects had a positive antibody assay and a negative molecular test. A 33-item psychophysical olfactory identification test tailored for the Italian population was performed.

Results: Median time from symptoms onset to olfactory test was 33 days in acute patients and 122 days in recovered subjects. The former scored a significantly higher number of errors at psychophysical testing (median [IQR]: 8 [13] vs 3 [2], p < 0.001) and were more frequently hyposmic (64% vs 19%, p = 0.002). Recovered subjects reported a variable time to subjective olfactory recovery, from days up to 4 months. Participants included in the study reported no significant nasal symptoms at olfactory testing. Among recovered subject who reported olfactory loss during acute COVID-19, four (27%) were still hyposmic. Demographic and clinical characteristics did not show significant associations with olfactory dysfunction.

Conclusion: Moderate-to-severe hospitalized patients showed a high level and frequency of olfactory dysfunction compared to recovered subjects. In the latter group, subjects who reported persisting olfactory dysfunction showed abnormal scores on psychophysical testing, indicating that, at least in some subjects, persistent hyposmia may represent a long-term sequela of COVID-19.
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http://dx.doi.org/10.1007/s10072-021-05200-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994059PMC
June 2021

Genetics of primary lateral sclerosis.

Amyotroph Lateral Scler Frontotemporal Degener 2020 11;21(sup1):28-34

Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, Milano, Italy.

With the exception of rare, juvenile-onset, autosomal recessive cases, primary lateral sclerosis (PLS) has long been considered an exclusively sporadic motor neuron disease. However, the identification of PLS cases within pedigrees with familial amyotrophic lateral sclerosis (ALS), together with the clinical and neuropathological overlap with other neurodegenerative disease with strong genetic component such as ALS and hereditary spastic paraparesis (HSP), suggest the existence of a genetic component in PLS as well. Here we will review the genetics of juvenile PLS-like syndromes and the contribution of mutations in ALS and HSP-associated genes to PLS pathogenesis.
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http://dx.doi.org/10.1080/21678421.2020.1837177DOI Listing
November 2020

Ocular Involvement Occurs Frequently at All Stages of Amyotrophic Lateral Sclerosis: Preliminary Experience in a Large Italian Cohort.

J Clin Neurol 2021 Jan;17(1):96-105

Neuromuscular Omnicentre (NEMO), Fondazione Serena Onlus, Milan, Italy.

Background And Purpose: The study aimed to obtain optometric findings of amyotrophic lateral sclerosis (ALS) patients in different stages of the disease, and to determine the relation between ocular data and ALS-related features; that is, functional and cognitive impairment and staging.

Methods: The optometric protocol included tests of the ocular motility [broad-H test and Northeastern State University College of Optometry (NSUCO) test], near point of convergence (NPC), error refraction, best-corrected visual acuity, and binocular visual alignment, and an ocular symptoms questionnaire. The functional measures included the Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-r) and Milano-Torino staging (MiToS), and cognitive impairment was assessed using the Edinburgh Cognitive and Behavioural ALS Screen (ECAS). Demographic and clinical features were also collected, including whether the patients used an eye-tracking communication device (ETCD).

Results: Two-hundred consecutive ALS patients (median age of 64 years, 118 males and 82 females) in different stages of disease were recruited. Nearly 70% of patients reported at least one ocular symptom, and the use of an ETCD was found to be significantly related to the presence of most symptoms. Moreover, the severely symptomatic group was characterized by significantly lower ALSFRS-r total and subscale scores, and higher MiToS. Abnormal NPC values were significantly related to lower ALSFRS-r total and bulbar-subscale scores. Patients with acceptable NSUCO test values exhibited significantly higher ECAS scores.

Conclusions: The presence of ocular alteration in patients in different stages of ALS supports the idea that this is a multisystem disorder and emphasizes the importance of optometric evaluations in multidisciplinary assessments to address ocular impairment early in the disease process.
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http://dx.doi.org/10.3988/jcn.2021.17.1.96DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7840315PMC
January 2021

The Effect of SMN Gene Dosage on ALS Risk and Disease Severity.

Ann Neurol 2021 04 15;89(4):686-697. Epub 2021 Jan 15.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Objective: The role of the survival of motor neuron (SMN) gene in amyotrophic lateral sclerosis (ALS) is unclear, with several conflicting reports. A decisive result on this topic is needed, given that treatment options are available now for SMN deficiency.

Methods: In this largest multicenter case control study to evaluate the effect of SMN1 and SMN2 copy numbers in ALS, we used whole genome sequencing data from Project MinE data freeze 2. SMN copy numbers of 6,375 patients with ALS and 2,412 controls were called from whole genome sequencing data, and the reliability of the calls was tested with multiplex ligation-dependent probe amplification data.

Results: The copy number distribution of SMN1 and SMN2 between cases and controls did not show any statistical differences (binomial multivariate logistic regression SMN1 p = 0.54 and SMN2 p = 0.49). In addition, the copy number of SMN did not associate with patient survival (Royston-Parmar; SMN1 p = 0.78 and SMN2 p = 0.23) or age at onset (Royston-Parmar; SMN1 p = 0.75 and SMN2 p = 0.63).

Interpretation: In our well-powered study, there was no association of SMN1 or SMN2 copy numbers with the risk of ALS or ALS disease severity. This suggests that changing SMN protein levels in the physiological range may not modify ALS disease course. This is an important finding in the light of emerging therapies targeted at SMN deficiencies. ANN NEUROL 2021;89:686-697.
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http://dx.doi.org/10.1002/ana.26009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048961PMC
April 2021

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

Brain Commun 2020 14;2(2):fcaa142. Epub 2020 Sep 14.

Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Laboratory of Prion Biology, Trieste, Italy.

The pathological deposition of the transactive response DNA-binding protein of 43 kDa occurs in the majority (∼97%) 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 kDa 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 kDa 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 kDa 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 kDa 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 kDa-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 kDa real-time quaking-induced conversion reaction was able to detect as little as 15 pg of transactive response DNA-binding protein of 43 kDa 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 kDa is a suitable substrate for the real-time quaking-induced conversion reaction. Transactive response DNA-binding protein of 43 kDa 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 kDa pathological aggregates may be exploited as a disease biomarker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.
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http://dx.doi.org/10.1093/braincomms/fcaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566418PMC
September 2020

Advance care planning and mental capacity in ALS: a current challenge for an unsolved matter.

Neurol Sci 2020 Oct 20;41(10):2997-2998. Epub 2020 May 20.

Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Milan, Italy.

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http://dx.doi.org/10.1007/s10072-020-04462-xDOI Listing
October 2020

Sorting Rare ALS Genetic Variants by Targeted Re-Sequencing Panel in Italian Patients: , , and Variants Account for 3% of Rare Genetic Forms.

J Clin Med 2020 Feb 3;9(2). Epub 2020 Feb 3.

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease due to motor neuron loss variably associated with frontotemporal dementia (FTD). Next generation sequencing technology revealed an increasing number of rare and novel genetic variants and interpretation of their pathogenicity represents a major challange in the diagnosis of ALS. We selected 213 consecutive patients with sporadic or familial (16%) ALS, tested negative for , , , and mutations. To reveal rare forms of genetic ALS, we performed a comprehensive multi-gene panel screening including 46 genes associated with ALS, hereditary motor neuronopathies, spastic paraplegia, and FTD. Our study allowed the identification of pathogenic or likely pathogenic variants in 4.2% of patients. The genes with the highest percentage of pathogenic variants were (1%), VCP (1%) , , , and ) genes. We also found 49 novel or rare gene variants of unknown significance in 30 patients (14%), 44 unlikely pathogenic variants (39%), and 48 variants in ALS susceptibility genes. The results of our study suggest the screening of , , and genes in routine diagnostic investigations for both sporadic and familial cases, and confirm the importance of diagnosis and couselling for patients and their relative family members.
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http://dx.doi.org/10.3390/jcm9020412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073901PMC
February 2020

Comparative Analysis of and Sporadic Disease in a Large Multicenter ALS Population: The Effect of Male Sex on Survival of Positive Patients.

Front Neurosci 2019 17;13:485. Epub 2019 May 17.

Department of Advanced Medical and Surgical Sciences, MRI Research Center SUN-FISM, University of Campania "Luigi Vanvitelli", Naples, Italy.

We investigated whether the repeat expansion is associated with specific clinical features, comorbidities, and prognosis in patients with amyotrophic lateral sclerosis (ALS). A cohort of 1417 ALS patients, diagnosed between January 1, 2009 and December 31, 2013 by 13 Italian ALS Referral Centers, was screened for the repeat expansion, and the analyses were performed comparing patients carrying this expansion (ALS-C9Pos) to those negative for this and other explored ALS-related mutations (ALS without genetic mutations, ALSwoGM). Compared to the ALSwoGM group, ALS-C9Pos patients ( = 84) were younger at disease onset, at the first clinical observation and at diagnosis ( < 0.001). After correcting for these differences, we found that ALS-C9Pos patients had higher odds of bulbar onset, diagnosis of frontotemporal dementia (FTD) and family history of ALS, FTD, and Alzheimer's disease and had lower odds of spinal onset, non-invasive ventilation, hypertension and psychiatric diseases than ALSwoGM patients. Among these variables, those related to shorter survival time were: bulbar onset, presence of FTD, hypertension, psychiatric disease, and family history of ALS ( < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33, = 0.021), but not in women ( > 0.05) as well as in the whole sample ( > 0.05). When compared to ALSwoGM, ALS-C9Pos showed an earlier disease onset, no significant diagnostic delay and a higher odds of bulbar onset, FTD and family history of ALS and dementia. Moreover, male sex drove the negative effect of expanded variant on survival, confirming the hypothesis that sex is likely to be a crucial factor in the biology of -related disease.
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http://dx.doi.org/10.3389/fnins.2019.00485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534038PMC
May 2019

Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder.

Front Neurosci 2019 11;13:175. Epub 2019 Mar 11.

Department of Neuroscience, Azienda Ospedaliera Universitaria Modena, St. Agostino- Estense Hospital, Modena, Italy.

The historical view that Amyotrophic Lateral Sclerosis (ALS) as a pure motor disorder has been increasingly challenged by the discovery of cognitive and behavioral changes in the spectrum of Frontotemporal Dementia (FTD). Less recognized and still significant comorbidities that ALS patients may present are prior or concomitant psychiatric illness, such as psychosis and schizophrenia, or mood disorders. These non-motor symptoms disturbances have a close time relationship with disease onset, may constitute part of a larger framework of network disruption in motor neuron disorders, and may impact ALS patients and families, with regards to ethical choices and end-of-life decisions. This review aims at identifying the most common psychiatric alterations related to ALS and its prognosis, looking at a common genetic background and shared structural brain pathology.
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http://dx.doi.org/10.3389/fnins.2019.00175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6421303PMC
March 2019

PON1 is a disease modifier gene in amyotrophic lateral sclerosis: association of the Q192R polymorphism with bulbar onset and reduced survival.

Neurol Sci 2019 Jul 22;40(7):1469-1473. Epub 2019 Mar 22.

Department of Neurology - Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Piazzale Brescia 20, 20149, Milan, Italy.

Introduction: Previous studies have associated single-nucleotide polymorphisms (SNPs) in the gene encoding the detoxifying enzyme paraoxonase 1 (PON1) to the risk of sporadic ALS. Here, we aimed to assess the role of the coding rs662 (Q192R) SNP as a modifier of ALS phenotype.

Materials And Methods: We genotyped a cohort of 409 patients diagnosed with ALS at our Center between 2002 and 2009 (269 males and 140 females; mean age at onset, 58.3 ± 37.5 years).

Results: We found PON1 to be a disease modifier gene in ALS, with the minor allele G associated both with bulbar onset (30.9% vs. 24.6%, p = 0.013) and independently with reduced survival (OR = 1.38, p = 0.012) under a dominant model. No association was found with gender or age at onset.

Discussion: As this SNP is known to modify the detoxifying activity of paraxonase 1 with respect to different substrates as well as other activities of the protein, we hypothesize that the identified association might reflect specific motor neuron vulnerability to certain exogenous toxic substances metabolized less efficiently by the 192R alloenzyme, or to detrimental endogenous pathophysiological processes such as oxidative stress. Further exploration of this possible metabolic susceptibility could deepen our knowledge of ALS pathomechanisms.
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http://dx.doi.org/10.1007/s10072-019-03834-2DOI Listing
July 2019

Sexuality and intimacy in ALS: systematic literature review and future perspectives.

J Neurol Neurosurg Psychiatry 2019 06 11;90(6):712-719. Epub 2018 Dec 11.

Department of Neurology and Laboratory of Neuroscience, Istituto Auxologico Italiano, IRCCS, Milan, Italy

Several features of amyotrophic lateral sclerosis (ALS) impact on sexuality and intimate relationship; however, the issue has received poor attention so far. We performed a systematic literature review in order to provide an up-to-date account of sexuality in ALS. References were identified by searches of PubMed, Web of Science, Scopus and PsycINFO (1970-2017, English literature). The following were the key terms: 'sexual' OR 'sexuality' OR 'intimacy' OR 'marital' AND 'ALS' OR 'Amyotrophic Lateral Sclerosis' OR 'Motor Neuron Disease' OR 'MND'. Titles and abstracts were screened for relevance and a full-text analysis was performed on the selected articles. Studies were included if they referred to sexual well-being/activities/functions or intimate relationship between patients and their partners and management of such topic by clinicians. Eligibility assessment was performed independently by two reviewers. A thematic and level of evidence classification of studies was performed. Studies' design, objectives, measurements and outcomes were summarised. Thirty articles were included and four topics were identified: intimacy in the dyads; sexual activities in patients and with their partners; sexual function disturbances; and sexuality and cognitive-behavioural alterations. The quality of the studies varies, with globally poor level of evidence. Some sexuality issues have been only sparsely addressed, such as gender-related differences, same-sex relationships and sexual activities other than intercourse. Sexuality in ALS is still not adequately considered by clinicians and researchers. We present preliminary recommendations for improving sexuality and intimacy at any ALS multidisciplinary clinics.
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http://dx.doi.org/10.1136/jnnp-2018-319684DOI Listing
June 2019

Response to the commentary "The effect of C9orf72 intermediate repeat expansions in neurodegenerative and autoimmune diseases" by Biasiotto G and Zanella I..

Mult Scler Relat Disord 2019 01 14;27:79-80. Epub 2018 Oct 14.

Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, 20149 Milan, Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, 20122 Milan, Italy.

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http://dx.doi.org/10.1016/j.msard.2018.10.007DOI Listing
January 2019

No C9orf72 repeat expansion in patients with primary progressive multiple sclerosis.

Mult Scler Relat Disord 2018 Oct 1;25:192-195. Epub 2018 Aug 1.

Istituto Auxologico Italiano, IRCCS, Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Milan 20145, Italy; Department of Pathophysiology and Transplantation, "Dino Ferrari" Center, Università degli Studi di Milano, Milan 20122, Italy. Electronic address:

Pathological repeat expansion (RE) of the C9orf72 hexanucleotide sequence is associated to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia disease continuum, although other heterogeneous clinical phenotypes have been documented. The occurrence of multiple sclerosis (MS) in some C9orf72 carriers with a more severe ALS disease course has suggested a possible modifying role for MS. However, C9orf72 RE seems not to play a role in MS pathogenesis. In this study, we screened C9orf72 in 189 Italian patients with primary progressive MS (PPMS), a rare clinical form characterized by less inflammation over neurodegenerative features. We failed to detect C9orf72 RE, but a significant representation of intermediate alleles (≥ 20 units) was observed in our PPMS cohort (2.1%) compared to healthy controls (0%, p < 0.05). In the normal range, allele distribution showed a trimodal pattern (2,5,8-repeat units) in PPMS and healthy controls with no significant difference. Our findings further demonstrate that C9orf72 RE is not genetically associated to MS spectrum, but suggest that intermediate alleles may represent risk factors as already reported for Parkinson disease.
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http://dx.doi.org/10.1016/j.msard.2018.07.047DOI Listing
October 2018

The Arrows and Colors Cognitive Test (ACCT): A new verbal-motor free cognitive measure for executive functions in ALS.

PLoS One 2018 9;13(8):e0200953. Epub 2018 Aug 9.

Department of Neurology and Laboratory of Neuroscience-IRCCS Istituto Auxologico Italiano, Milan, Italy.

Background And Objective: The presence of executive deficits in patients with Amyotrophic Lateral Sclerosis is well established, even if standardized measures are difficult to obtain due to progressive physical disability of the patients. We present clinical data concerning a newly developed measure of cognitive flexibility, administered by means of Eye-Tracking (ET) technology in order to bypass verbal-motor limitations.

Methods: 21 ALS patients and 21 age-and education-matched healthy subjects participated in an ET-based cognitive assessment, including a newly developed test of cognitive flexibility (Arrows and Colors Cognitive Test-ACCT) and other oculomotor-driven measures of cognitive functions. A standard screening of frontal and working memory abilities and global cognitive efficiency was administered to all subjects, in addition to a psychological self-rated assessment. For ALS patients, a clinical examination was also performed.

Results: ACCT successfully discriminated between patients and healthy controls, mainly concerning execution times obtained at different subtests. A qualitative analysis performed on error distributions in patients highlighted a lower prevalence of perseverative errors, with respect to other type of errors. Correlations between ACCT and other ET-based frontal-executive measures were significant and involved different frontal sub-domains. Limited correlations were observed between ACCT and standard 'paper and pencil' cognitive tests.

Conclusions: The newly developed ET-based measure of cognitive flexibility could be a useful tool to detect slight frontal impairments in non-demented ALS patients by bypassing verbal-motor limitations through the oculomotor-driven administration. The findings reported in the present study represent the first contribution towards the development of a full verbal-motor free executive test for ALS patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0200953PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6084851PMC
January 2019

ALS-associated missense and nonsense TBK1 mutations can both cause loss of kinase function.

Neurobiol Aging 2018 11 25;71:266.e1-266.e10. Epub 2018 Jun 25.

Department of Neurology, University of Massachusetts Medical School, Worcester, MA.

Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983933PMC
November 2018

Cognitive-behavioral longitudinal assessment in ALS: the Italian Edinburgh Cognitive and Behavioral ALS screen (ECAS).

Amyotroph Lateral Scler Frontotemporal Degener 2018 08 26;19(5-6):387-395. Epub 2018 May 26.

a Department of Neurology and Laboratory of Neuroscience , IRCCS Istituto Auxologico Italiano , Milan , Italy.

Objective: The study presents data on the longitudinal administration of the Italian Edinburgh Cognitive and Behavioral ALS Screen (ECAS). We investigated cognitive-behavioral performance in a group of ALS patients over time and the feasibility of repeating the ECAS longitudinally compared with standard neuropsychological tests. Finally, correlations between clinical/genetic and cognitive/behavioral data were considered.

Methods: One hundred and sixty-eight ALS patients were tested at baseline (T). Among these, 48 patients performed the ECAS after 6 months (T), 18 patients performed it at T (12 months), and five patients were assessed after 24 months (T). Participants were also administered two cognitive test (FAB; MoCA) and psychological questionnaires (BDI; STAI/Y). The FBI was carried out with caregivers.

Results: No cognitive deterioration was found across follow-ups. In contrast, although scores did not change between T and T, scores improved significantly for ECAS Total/ALS Non-specific and Memory domains when the ECAS was repeated on three occasions (T, T, T). Apathy/Inertia was the most common behavioral symptom, but no worsening of behavioral scores was detected over time. After 12-24 months, patients were still able to perform the ECAS in total, in contrast to FAB and MoCA, which were only partially administrable.

Conclusions: The significant improvement of some ECAS scores over time supports the presence of possible practice effects, particularly in the memory domain, highlighting the need to accommodate for these in longitudinal assessments, through healthy controls groups or alternate versions. This work represents the first Italian ECAS follow-up study and confirms ECAS feasibility in patients with increasing physical disability.
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http://dx.doi.org/10.1080/21678421.2018.1473443DOI Listing
August 2018

The Complex Interplay Between Depression/Anxiety and Executive Functioning: Insights From the ECAS in a Large ALS Population.

Front Psychol 2018 5;9:450. Epub 2018 Apr 5.

Laboratory of Neuroscience, Department of Neurology, Istituto Auxologico Italiano - Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy.

The observed association between depressive symptoms and cognitive performances has not been previously clarified in patients with amyotrophic lateral sclerosis (pALS). In fact, the use of cognitive measures often not accommodating for motor disability has led to heterogeneous and not conclusive findings about this issue. The aim of the present study was to evaluate the relationship between cognitive and depressive/anxiety symptoms by means of the recently developed Edinburgh Cognitive and Behavioral ALS Screen (ECAS), a brief assessment specifically designed for pALS. Sample included 168 pALS (114 males, 54 females); they were administered two standard cognitive screening tools (FAB; MoCA) and the ECAS, assessing different cognitive domains, including ALS-specific (executive functions, verbal fluency, and language tests) and ALS non-specific subtests (memory and visuospatial tests). Two psychological questionnaires for depression and anxiety (BDI; STAI/Y) were also administered to patients. Pearson's correlation coefficient was used to assess the degree of association between cognitive and psychological measures. Depression assessment negatively correlated with the ECAS, more significantly with regard to the executive functions subdomain. In particular, Sentence Completion and Social Cognition subscores were negatively associated with depression levels measured by BDI total score and Somatic-Performance symptoms subscore. Conversely, no significant correlations were observed between depression level and cognitive functions as measured by traditional screening tools for frontal abilities (FAB) and global cognition (MoCA) assessment. Finally, no significant correlations were observed between state/trait anxiety and the ECAS. This represents the first study focusing on the relationship between cognitive and psychological components in pALS by means of the ECAS, the current gold standard for ALS cognitive-behavioral assessment. If confirmed by further investigations, the observed association between depression and executive functions suggests the need for a careful screening and treatment of depression, to avoid overestimation of cognitive involvement and possibly improve cognitive performances in ALS.
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http://dx.doi.org/10.3389/fpsyg.2018.00450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895754PMC
April 2018

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.

Neuron 2018 03;97(6):1268-1283.e6

Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.
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http://dx.doi.org/10.1016/j.neuron.2018.02.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867896PMC
March 2018

The LRRK2 Variant E193K Prevents Mitochondrial Fission Upon MPP+ Treatment by Altering LRRK2 Binding to DRP1.

Front Mol Neurosci 2018 28;11:64. Epub 2018 Feb 28.

Dulbecco Telethon Institute, CIBIO, Università degli Studi di Trento, Trento, Italy.

Mutations in leucine-rich repeat kinase 2 gene () are associated with familial and sporadic Parkinson's disease (PD). LRRK2 is a complex protein that consists of multiple domains, including 13 putative armadillo-type repeats at the N-terminus. In this study, we analyzed the functional and molecular consequences of a novel variant, E193K, identified in an Italian family. E193K substitution does not influence LRRK2 kinase activity. Instead it affects LRRK2 biochemical properties, such as phosphorylation at Ser935 and affinity for 14-3-3ε. Primary fibroblasts obtained from an E193K carrier demonstrated increased cellular toxicity and abnormal mitochondrial fission upon 1-methyl-4-phenylpyridinium treatment. We found that E193K alters LRRK2 binding to DRP1, a crucial mediator of mitochondrial fission. Our data support a role for LRRK2 as a scaffolding protein influencing mitochondrial fission.
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http://dx.doi.org/10.3389/fnmol.2018.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5835904PMC
February 2018

Characterization of the c9orf72 GC-rich low complexity sequence in two cohorts of Italian and Turkish ALS cases.

Amyotroph Lateral Scler Frontotemporal Degener 2018 08 28;19(5-6):426-431. Epub 2018 Feb 28.

a Department of Health Sciences, Interdisciplinary Research Center of Autoimmune Diseases , Universita' del Piemonte Orientale , Novara , Italy.

Large expansions of a noncoding GGGGCC repeat in the C9orf72 gene are the main cause of amyotrophic lateral sclerosis (ALS). The GGGGCC repeat is contiguous with another GC-rich region. Recent studies reported a significantly higher frequency of insertions/deletions within the GC-rich region in patients carrying the GGGGCC expansion. A GTGGT motif comprised within the GC-rich region, which joins two 100% GC sequences, was frequently deleted, supporting the hypothesis that these deletions could make the region more prone to slippage and pathological expansion. To confirm this hypothesis, we sequenced the GC-rich region adjacent the GGGGCC repeat in ALS patients, 116 C9orf72 expansion carriers, 219 non-carriers, and 223 healthy controls, from Italian and Turkish cohorts. Deletions were significantly more frequent in C9orf72 expansion carriers (6%) compared to non-carrier ALS patients (0.46%, OR =14.00, 95% CI =1.71-306.59, p = 0.003), to controls (0%, OR =16.29, 95% CI =2.12-725.99, p = 4.86 × 10) and to the whole cohort of non-carriers (0.2%, OR =28.51, 95% CI =3.47-618.91, p = 9.58 × 10). Among expansion carriers, deletions with or without the GTGGT motif were equally distributed (4 vs. 3). The frequency of insertions was not statistically different between C9orf72 expansion carriers and any other group including the whole cohort of non-carriers (p = 0.439, Fisher's exact test). Our data confirmed the association between deletions within GC-rich region and the GGGGCC expansion in Italian and Turkish cases, although we did not confirm a role of the GTGGT element deletion. Further studies will be therefore necessary to assess the causal relationships between contiguous deletions of the GC-rich region and the GGGGCC expansion.
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http://dx.doi.org/10.1080/21678421.2018.1440407DOI Listing
August 2018

Elevated Global DNA Methylation Is Not Exclusive to Amyotrophic Lateral Sclerosis and Is Also Observed in Spinocerebellar Ataxia Types 1 and 2.

Neurodegener Dis 2018 9;18(1):38-48. Epub 2018 Feb 9.

Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), Molecular Biology and Genetics Department, Boğaziçi University, Istanbul, Turkey.

Adult-onset neurological disorders are caused and influenced by a multitude of different factors, including epigenetic modifications. Here, using an ELISA kit selected upon careful testing, we investigated global 5-methylcytosine (5-mC) levels in sporadic and familial amyotrophic lateral sclerosis (sALS and fALS), spinocerebellar ataxia types 1 and 2 (SCA1 and SCA2), Huntington's disease, Friedreich's ataxia, and myotonic dystrophy type 1. We report a significant elevation in global 5-mC levels of about 2-7% on average for sALS (p < 0.01 [F(1, 243) = 9.159, p = 0.0027]) and various forms of fALS along with SCA1 (p < 0.01 [F(1, 83) = 11.285], p = 0.0012) and SCA2 (p < 0.001 [F(1, 122) = 29.996, p = 0.0001]) when compared to age- and sex-matched healthy controls. C9orf72 expansion carrier ALS patients exhibit the highest global 5-mC levels along with C9orf72 promoter hypermethylation. We failed to measure global 5-hydroxymethylcytosine (5-hmC) levels in blood, probably due to the very low levels of 5-hmC and the limitations of the commercially available ELISA kits. Our results point towards a role for epigenetics modification in ALS, SCA1, and SCA2, and help conclude a dispute on the global 5-mC levels in sALS blood.
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http://dx.doi.org/10.1159/000486201DOI Listing
January 2019
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