Publications by authors named "Federico Verde"

26 Publications

  • Page 1 of 1

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

Neurology 2021 Sep 9. Epub 2021 Sep 9.

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

Objective: 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 ALS patients and to correlate such findings with cognitive-behavioral data.

Methods: three consecutive, inpatient cohorts of Italian ALS patients and controls were retrospectively evaluated to assess the frequency of OMAs and cognitive-behavioral alterations. The ALS population was divided in a discovery and a replication cohort. Controls included a cohort of cognitively impaired individuals and of patients with Alzheimer's disease (AD). Subjects underwent bedside eye movement evaluation to determine the presence and pattern of OMAs. Cognitive assessment was performed using 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 ALS (635 discovery, 229 replication), 798 cognitively unimpaired, and 171 AD subjects. OMAs were detected in 10.5% of our ALS cohort vs 1.6% of cognitively unimpaired controls (p=1.2x10) and 11.4% of AD patients (p=ns). The most frequent deficits were smooth pursuit and saccadic abnormalities. OMAs 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 (p=1.1x10). Furthermore, OMAs significantly correlated with the severity of cognitive impairment and with pathological scores at the ECAS ALS-specific domains. Lastly, OMAs could be observed in 35.0% of cognitively impaired ALS vs 11.4% of AD patients (p=6.4x10), suggesting a possible involvement of frontal oculomotor areas in ALS.

Discussion: ALS patients 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
September 2021

Comparison of CSF and serum neurofilament light and heavy chain as differential diagnostic biomarkers for ALS.

J Neurol Neurosurg Psychiatry 2021 Aug 20. Epub 2021 Aug 20.

Neurology, University of Ulm, Ulm, Germany

Objective: Elevated levels of neurofilament light (NfL) and heavy (NfH) chain in amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) and serum reflect neuro-axonal degeneration and are used as diagnostic biomarkers. However, studies comparing the differential diagnostic potential for ALS of all four parameters are missing. Here, we measured serum NfL/NfH and CSF NfL/NfH in a large cohort of ALS and other neurological disorders and analysed the differential diagnostic potential.

Methods: In total CSF and serum of 294 patients were analysed. The diagnostic groups comprised: ALS (n=75), frontotemporal lobar degeneration (FTLD) (n=33), Alzheimer's disease (n=20), Parkinson's disease (dementia) (n=18), Creutzfeldt-Jakob disease (n=11), non-neurodegenerative controls (n=77) (Con) and 60 patients who were seen under the direct differential diagnosis of a patient with ALS (Con.DD).

Results: CSF and serum NfL and NfH showed significantly increased levels in ALS (p<0.0001) compared with Con and Con.DD. The difference between ALS and FTLD was markedly stronger for NfH than for NfL. CSF and serum NfL demonstrated a stronger correlation (r=0.84 (95% CI 0.80 to 0.87), p<0.001) than CSF and serum NfH (r=0.68 (95% CI 0.61 to 0.75), p<0.0001). Comparing ALS and Con.DD, receiver operating characteristic analysis revealed the best area under the curve (AUC) value for CSF NfL (AUC=0.94, 95% CI 0.91 to 0.98), followed by CSF NfH (0.93, 95% CI 0.88 to 0.98), serum NfL (0.93, 95% CI 0.89 to 0.97) and serum NfH (0.88, 95% CI 0.82 to 0.94).

Conclusion: Our results demonstrate that CSF NfL and NfH as well as serum NfL are equally suited for the differential diagnosis of ALS, whereas serum NfH appears to be slightly less potent.
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http://dx.doi.org/10.1136/jnnp-2021-327129DOI Listing
August 2021

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Front Neurosci 2021 21;15:679199. Epub 2021 Jun 21.

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

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper and lower motor neurons causing relentless paralysis of voluntary muscles, whereas in FTD, progressive atrophy of the frontal and temporal lobes of the brain results in deterioration of cognitive functions, language, personality, and behavior. In contrast to Alzheimer's disease (AD), ALS and FTD still lack a specific neurochemical biomarker reflecting neuropathology . However, in the past 10 years, considerable progress has been made in the characterization of neurofilament light chain (NFL) as cerebrospinal fluid (CSF) and blood biomarker for both diseases. NFL is a structural component of the axonal cytoskeleton and is released into the CSF as a consequence of axonal damage or degeneration, thus behaving in general as a relatively non-specific marker of neuroaxonal pathology. However, in ALS, the elevation of its CSF levels exceeds that observed in most other neurological diseases, making it useful for the discrimination from mimic conditions and potentially worthy of consideration for introduction into diagnostic criteria. Moreover, NFL correlates with disease progression rate and is negatively associated with survival, thus providing prognostic information. In FTD patients, CSF NFL is elevated compared with healthy individuals and, to a lesser extent, patients with other forms of dementia, but the latter difference is not sufficient to enable a satisfying diagnostic performance at individual patient level. However, also in FTD, CSF NFL correlates with several measures of disease severity. Due to technological progress, NFL can now be quantified also in peripheral blood, where it is present at much lower concentrations compared with CSF, thus allowing less invasive sampling, scalability, and longitudinal measurements. The latter has promoted innovative studies demonstrating longitudinal kinetics of NFL in presymptomatic individuals harboring gene mutations causing ALS and FTD. Especially in ALS, NFL levels are generally stable over time, which, together with their correlation with progression rate, makes NFL an ideal pharmacodynamic biomarker for therapeutic trials. In this review, we illustrate the significance of NFL as biomarker for ALS and FTD and discuss unsolved issues and potential for future developments.
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http://dx.doi.org/10.3389/fnins.2021.679199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8255624PMC
June 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

Association between renin-angiotensin-aldosterone system inhibitors and risk of dementia: A meta-analysis.

Pharmacol Res 2021 04 24;166:105515. Epub 2021 Feb 24.

Biostatistic Unit, IRCCS Istituto Auxologico Italiano, Milan, Italy; Department of Statistics and Quantitative Methods, University of Milano-Bicocca, Milan, Italy.

Objective: To evaluate the association of all RAAS inhibitors, ACE inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) on dementia onset (any dementia, Alzheimer's disease and vascular dementia) using a meta-analytic approach.

Methods: A systematic MEDLINE search was carried out to identify all observational studies published up to the 30th September 2020 evaluating the association between RAAS inhibitors and risk of dementia. Studies were included if original investigations considering incident dementia cases, with ACEIs and/or ARBs as exposure and other antihypertensives (AHs) use as reference, and if reporting association estimates and relative variability measures. Random effect pooled relative risks (pRR) and the corresponding 95% confidence intervals (95%CI) were calculated according to DerSimonian and Laird's (DL) or to Hartung Knapp Sidik Jonkman (HKSJ) method depending on the number of studies and between-studies heterogeneity. A linear mixed meta-regression model (MM) was applied to take into account correlation among association estimates from the same study.

Results: 15 studies were included in the meta-analysis. ARBs but not ACEIs' use led to a significant reduction of the risk of any dementia (pRR 0.78, 95%CI 0.70-0.87) and Alzheimer's disease (pRR 0.73, 95%CI 0.60-0.90). Moreover, when compared to ACEIs, ARBs reduced of 14% the risk of any dementia (pRR 0.86, 95%CI 0.79-0.94).

Conclusions: ARBs but not ACEIs led to a reduction in the risk of any dementia. The difference between ARBs and ACEIs in terms of preventive effectiveness could be due to distinct profiles of antagonism towards independent receptor pathways or to differential influences on amyloid metabolism.
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http://dx.doi.org/10.1016/j.phrs.2021.105515DOI Listing
April 2021

Chitotriosidase as biomarker for early stage amyotrophic lateral sclerosis: a multicenter study.

Amyotroph Lateral Scler Frontotemporal Degener 2021 05 12;22(3-4):276-286. Epub 2021 Feb 12.

Department of Neurology, Ulm University, Ulm, Germany.

Levels of chitotriosidase (CHIT1) are increased in the cerebrospinal fluid (CSF) of amyotrophic lateral sclerosis (ALS) patients reflecting microglial activation. Here, we determine the diagnostic and prognostic potential of CHIT1 for early symptomatic ALS. : Overall, 275 patients from 8 European neurological centers were examined. We included ALS with <6 and >6 months from symptom onset, other motoneuron diseases (oMND), ALS mimics (DCon) and non-neurodegenerative controls (Con). CSF CHIT1 levels were analyzed for diagnostic power and association with progression and survival in comparison to the benchmark neurofilament. The 24-bp duplication polymorphism of CHIT1 was analyzed in a subset of patients ( = 65). Homozygous CHIT1 duplication mutation carriers (9%) invariably had undetectable CSF CHIT1 levels, while heterozygous carriers had similar levels as patients with wildtype CHIT1 ( = 0.414). In both early and late symptomatic ALS CHIT1 levels was increased, did not correlate with patients' progression rates, and was higher in patients diagnosed with higher diagnostic certainty. Neurofilament levels correlated with CHIT1 levels and prevailed over CHIT1 regarding diagnostic performance. Both CHIT1 and neurofilaments were identified as independent predictors of survival in late but not early symptomatic ALS. Evidence is provided that CHIT1 predicts progression in El Escorial diagnostic category in the group of ALS cases with a short duration. : CSF CHIT1 level may have additional value in the prognostication of ALS patients with a short history of symptoms classified in diagnostic categories of lower clinical certainty. To fully interpret apparently low CHIT1 levels knowledge of CHIT1 genotype is needed.
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http://dx.doi.org/10.1080/21678421.2020.1861023DOI Listing
May 2021

Next-generation sequencing application to investigate skeletal muscle channelopathies in a large cohort of Italian patients.

Neuromuscul Disord 2021 04 14;31(4):336-347. Epub 2020 Dec 14.

Neurology IV Unit, Neuroimmunology and Neuromuscular Diseases, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A, 3 in both CLCN1 and SCN4A, 1 in ATP2A1, 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1, p.K1302R in SCN4A, p.L208P in ATP2A1 and c.280-1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis.
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http://dx.doi.org/10.1016/j.nmd.2020.12.003DOI Listing
April 2021

Neurochemical biomarkers in amyotrophic lateral sclerosis.

Curr Opin Neurol 2019 10;32(5):747-757

Department of Neurology, University of Ulm, Ulm, Germany.

Purpose Of Review: The diagnosis of amyotrophic lateral sclerosis (ALS) still relies mainly on clinical criteria. In present review we will provide an overview of neurochemical ALS biomarkers, which are in the most advanced position on the way towards inclusion into the clinical work-up.

Recent Findings: The field of ALS neurology still lacks a neurochemical marker for routine clinical use. However, this is urgently needed, because it would help in diagnosis, prognostic stratification, and monitoring of drug response. Despite this lack of a routinely used biomarker, in the last decade significant progress has been made in the field. In particular, two molecules have been extensively studied - the light chain and the phosphorylated form of the heavy chain of neurofilaments, NFL and pNFH, respectively - which have demonstrated a high diagnostic performance and promising prognostic value and are therefore ready to be introduced into the clinical scenario. On the other hand, we still lack a neurochemical cerebrospinal fluid or blood biomarker reflecting TDP-43 pathology.

Summary: Neurofilaments seem to be ready for clinical use in the early and differential diagnosis of ALS. We also highlight still unresolved issues which deserve further investigation.
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http://dx.doi.org/10.1097/WCO.0000000000000744DOI Listing
October 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

Neurofilament light chain in serum for the diagnosis of amyotrophic lateral sclerosis.

J Neurol Neurosurg Psychiatry 2019 02 11;90(2):157-164. Epub 2018 Oct 11.

Department of Neurology, University of Ulm, Ulm, Germany

Objective: To determine the diagnostic and prognostic performance of serum neurofilament light chain (NFL) in amyotrophic lateral sclerosis (ALS).

Methods: This single-centre, prospective, longitudinal study included the following patients: 124 patients with ALS; 50 patients without neurodegenerative diseases; 44 patients with conditions included in the differential diagnosis of ALS (disease controls); 65 patients with other neurodegenerative diseases (20 with frontotemporal dementia, 20 with Alzheimer's disease, 19 with Parkinson's disease, 6 with Creutzfeldt-Jakob disease (CJD)). Serum NFL levels were measured using the ultrasensitive single molecule array (Simoa) technology.

Results: Serum NFL levels were higher in ALS in comparison to all other categories except for CJD. A cut-off level of 62 pg/mL discriminated between ALS and all other conditions with 85.5% sensitivity (95% CI 78% to 91.2%) and 81.8% specificity (95% CI 74.9% to 87.4%). Among patients with ALS, serum NFL correlated positively with disease progression rate (r=0.336, 95% CI 0.14 to 0.506, p=0.0008), and higher levels were associated with shorter survival (p=0.0054). Serum NFL did not differ among patients in different ALS pathological stages as evaluated by diffusion-tensor imaging, and in single patients NFL levels were stable over time.

Conclusions: Serum NFL is increased in ALS in comparison to other conditions and can serve as diagnostic and prognostic biomarker. We established a cut-off level for the diagnosis of ALS.
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http://dx.doi.org/10.1136/jnnp-2018-318704DOI Listing
February 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

Chromogranin A levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis.

Neurobiol Aging 2018 07 27;67:21-22. Epub 2018 Feb 27.

Department of Neurology, Ulm University, Ulm, Germany. Electronic address:

Chromogranin A (CgA) is a protein found in large dense-core vesicles of neuroendocrine cells and neurons and regulating secretion. A relevance to amyotrophic lateral sclerosis (ALS) was suggested as its overexpression accelerates disease onset in model systems and it interacts with mutant forms of SOD1. Recently, increased cerebrospinal fluid (CSF) CgA levels have been reported in ALS patients relative to controls. With the aim of confirming this finding, we measured CgA and phosphorylated neurofilament heavy chain (pNFH), an established ALS biomarker, in the CSF of 32 ALS patients and 32 disease controls. ALS patients had clearly increased pNFH levels (p < 0.0001), while CgA levels were only modestly lower relative to controls (p = 0.0265), with wide value overlap and consequently poor discriminative performance. CgA did not correlate with any disease parameters among ALS patients. Our findings suggest that CgA is not a promising clinical biomarker for ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2018.02.017DOI Listing
July 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 multisystem degeneration amyotrophic lateral sclerosis - neuropathological staging and clinical translation.

Arch Ital Biol 2017 Dec;155(4):118-130

Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany - Email:

Amyotrophic lateral sclerosis (ALS) is traditionally considered a disease affecting exclusively motor neurons. However, much evidence points towards additional involvement of brain systems other than the motor. As much as half of ALS patients display cognitive-behavioral disturbances. ALS shares with a considerable proportion of FTD cases the same neuropathological substrate, namely, inclusions of abnormally phosphorylated protein TDP-43 (pTDP-43). In analogy with pathological staging systems elaborated in the past decades for Alzheimer's disease (AD) and Parkinson's disease (PD), a model of staging of pTDP-43 pathology in sporadic ALS (sALS) has been recently proposed. According to it, 4 stages can be recognized, where pTDP-43 inclusions are found in the agranular motor cortex and α-motor neurons of the brain stem and spinal cord (stage 1), in prefrontal neocortex (middle frontal gyrus), reticular formation, and precerebellar nuclei (stage 2), in further areas of the prefrontal neocortex (gyrus rectus and orbitofrontal gyri), postcentrally located sensory cortex, and basal ganglia (stage 3), and in the anteromedial temporal lobe including the hippocampus (stage 4). Based on this staging effort, a corticofugal axonal model for spreading of pathology can be hypothesized, whereby pathology starts in the primary motor cortex and spreads from there via axonal projections to lower motor neurons and to subcortical structures. Recent neuroradiological evidence seems to support the proposed staging system. From the clinical standpoint, a proportion of ALS patients display extramotor deficits (namely cognitive-behavioural disturbances, impaired ocular movements, and extrapyramidal alterations), which seem to correspond to the pathological involvement of the relevant cerebral structures. This review describes neuropathological sALS staging and addresses clinical evidence corresponding to this staging, pointing towards the concept of ALS as a multisystem brain degeneration disorder instead of a disease confined to motor neurons.
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http://dx.doi.org/10.12871/00039829201746DOI Listing
December 2017

Multicenter evaluation of neurofilaments in early symptom onset amyotrophic lateral sclerosis.

Neurology 2018 01 6;90(1):e22-e30. Epub 2017 Dec 6.

From the Nuffield Department of Clinical Neurosciences (E.F., E.G., M.R.T.), University of Oxford, UK; Department of Neurology (P.O., P.S., F.V., J.H.W., P.W., A.C.L., M.O.), Ulm University Hospital, Germany; Department of Pathophysiology and Transplantation (F.V., V.S.), Università degli Studi di Milano; Department of Neurology-Stroke Unit and Laboratory of Neuroscience (F.V., C.M., V.S.), IRCCS Istituto Auxologico Italiano, Milan, Italy; Neurologic Clinic and Policlinic, Departments of Medicine, Clinical Research, and Biomedicine (C.B., J.K.), University Hospital and University of Basel, Switzerland; Department of Neurology (P.V.D.) and Laboratory of Molecular Neurobiomarker Research and Laboratory Medicine (K.P.), University Hospitals Leuven; KU Leuven-University of Leuven (P.V.D.); Department of Neurosciences (P.V.D.), VIB-Center for Brain & Disease Research, Leuven, Belgium; Department of Neurology (J.G., P.M., B.S.), Jena University Hospital, Germany; Department of Metabolic Biochemistry (C.J., F.L.) and Neurological Diseases Department (M.d.M.A., F.S.), Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix, Paris, France; Department of Neurology (S.K., S.P.), Hannover Medical School; Institute for Epidemiology and Medical Biometry (B.M.) Ulm University, Germany; Donders Institute for Brain, Cognition and Behaviour, Department of Neurology (J.R., M.M.V.), and Radboud Alzheimer Center, Department of Laboratory Medicine (M.M.V.), Radboud University Medical Center, Nijmegen, the Netherlands; and Department of Neurodegenerative Disease and Gerontopsychiatry/Neurology (P.W.), Bonn University Hospital, Germany.

Objective: To examine neurofilament (Nf) concentrations according to symptom onset and clinical diagnostic certainty categories of amyotrophic lateral sclerosis (ALS).

Methods: We measured Nf light chain (NfL) and phosphorylated Nf heavy chain (pNfH) CSF and NfL serum levels in patients with ALS with first symptom onset ≤6 months (n = 54) or >6 months (n = 135) from sampling, and patients with other neurologic diseases, differential diagnoses of a motor neuron disease (MND mimics), and other MND variants to determine the diagnostic accuracy in patients with ALS with early symptom onset. Samples were received multicentric and analyzed by ELISA and Simoa platform and related to other clinical measures.

Results: NfL and pNfH in CSF and NfL in serum were increased in early and later symptomatic phase ALS ( < 0.0001). CSF and serum NfL and CSF pNfH discriminated patients with ALS with early symptom onset from those with other neurologic diseases and MND mimics with high sensitivity (94%, 88%, 98%, and 89%, 100%, 78%) and specificity (86%, 92%, 91%, and 94%, 90%, 98%) and did not vary between clinical diagnostic categories of ALS in the early symptomatic phase group. Baseline NfL and pNfH levels were not significantly different in patients with ALS with clinical progression to definite or probable ALS at follow-up.

Conclusion: The measurement of Nf has potential to enhance diagnostic accuracy of ALS in those presenting soon after symptom onset, and is measurable across multiple centers.

Classification Of Evidence: This study provides Class II evidence that CSF and serum Nf concentrations discriminate ALS with early symptom onset from other neurologic diseases.
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http://dx.doi.org/10.1212/WNL.0000000000004761DOI Listing
January 2018

Chitotriosidase (CHIT1) is increased in microglia and macrophages in spinal cord of amyotrophic lateral sclerosis and cerebrospinal fluid levels correlate with disease severity and progression.

J Neurol Neurosurg Psychiatry 2018 03 15;89(3):239-247. Epub 2017 Nov 15.

Department of Neurology, University of Ulm, Ulm, Germany.

Objectives: Neurochemical markers of amyotrophic lateral sclerosis (ALS) that reflect underlying disease mechanisms might help in diagnosis, staging and prediction of outcome. We aimed at determining the origin and differential diagnostic and prognostic potential of the putative marker of microglial activation chitotriosidase (CHIT1).

Methods: Altogether 316 patients were included, comprising patients with sporadic ALS, ALS mimics (disease controls (DCo)), frontotemporal lobar degeneration (FTLD), Creutzfeldt-Jakob disease (CJD), Alzheimer's disease (AD), Parkinson's disease (PD) and healthy controls (Con). CHIT1 and neurofilament levels were determined in cerebrospinal fluid (CSF) and blood and analysed with regard to diagnostic sensitivity and specificity and prognostic performance. Additionally, postmortem tissue was analysed for CHIT1 expression.

Results: In ALS, CHIT1 CSF levels were higher compared with Con (p<0.0001), DCo (p<0.05) and neurodegenerative diseases (AD p<0.05, PD p<0.01, FTLD p<0.0001) except CJD. CHIT1 concentrations were correlated with ALS disease progression and severity but not with the survival time, as did neurofilaments. Serum CHIT1 levels were not different in ALS compared with any other study group. In the spinal cord of patients with ALS, but not Con, AD or CJD cases, CHIT1 was expressed in the corticospinal tract and CHIT1 staining colocalised with markers of microglia (IBA1) and macrophages (CD68).

Conclusions: CHIT1 concentrations in the CSF of patients with ALS may reflect the extent of microglia/macrophage activation in the white matter of the spinal cord. CHIT1 could be a potentially useful marker for differential diagnosis and prediction of disease progression in ALS and, therefore, seems suitable as a supplemental marker for patient stratification in therapeutic trials.
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http://dx.doi.org/10.1136/jnnp-2017-317138DOI Listing
March 2018

A novel nonsense pathogenic variant in a family exhibiting a variable occipital horn syndrome phenotype.

Mol Genet Metab Rep 2017 Dec 21;13:14-17. Epub 2017 Jul 21.

Neurology Unit and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Ospedale San Luca, piazzale Brescia 20, 20149 Milan, Italy.

We report on a family with occipital horn syndrome (OHS) diagnosed in the proband's late fifties. A novel pathogenic variant (c.4222A > T, p.(Lys1408*)), representing the first nonsense variant and the second late truncation causing OHS rather than classic Menkes disease, was found to segregate in the family. The predicted maintenance of transmembrane domains is consistent with a residual protein activity, which may explain the mild clinical presentation.
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http://dx.doi.org/10.1016/j.ymgmr.2017.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522958PMC
December 2017

The role of de novo mutations in the development of amyotrophic lateral sclerosis.

Hum Mutat 2017 11 3;38(11):1534-1541. Epub 2017 Aug 3.

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

The genetic basis combined with the sporadic occurrence of amyotrophic lateral sclerosis (ALS) suggests a role of de novo mutations in disease pathogenesis. Previous studies provided some evidence for this hypothesis; however, results were conflicting: no genes with recurrent occurring de novo mutations were identified and different pathways were postulated. In this study, we analyzed whole-exome data from 82 new patient-parents trios and combined it with the datasets of all previously published ALS trios (173 trios in total). The per patient de novo rate was not higher than expected based on the general population (P = 0.40). We showed that these mutations are not part of the previously postulated pathways, and gene-gene interaction analysis found no enrichment of interacting genes in this group (P = 0.57). Also, we were able to show that the de novo mutations in ALS patients are located in genes already prone for de novo mutations (P < 1 × 10 ). Although the individual effect of rare de novo mutations in specific genes could not be assessed, our results indicate that, in contrast to previous hypothesis, de novo mutations in general do not impose a major burden on ALS risk.
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http://dx.doi.org/10.1002/humu.23295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599399PMC
November 2017

Mutations in the vesicular trafficking protein annexin A11 are associated with amyotrophic lateral sclerosis.

Sci Transl Med 2017 05;9(388)

Department of Genome Analysis, University of Amsterdam, Academic Medical Centre, P.O. Box 22700, 1100DE Amsterdam, Netherlands.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases ( = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
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http://dx.doi.org/10.1126/scitranslmed.aad9157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599403PMC
May 2017

NEK1 variants confer susceptibility to amyotrophic lateral sclerosis.

Nat Genet 2016 09 25;48(9):1037-42. Epub 2016 Jul 25.

Neurogenetics Group, Division of Brain Sciences, Imperial College London, London, UK.

To identify genetic factors contributing to amyotrophic lateral sclerosis (ALS), we conducted whole-exome analyses of 1,022 index familial ALS (FALS) cases and 7,315 controls. In a new screening strategy, we performed gene-burden analyses trained with established ALS genes and identified a significant association between loss-of-function (LOF) NEK1 variants and FALS risk. Independently, autozygosity mapping for an isolated community in the Netherlands identified a NEK1 p.Arg261His variant as a candidate risk factor. Replication analyses of sporadic ALS (SALS) cases and independent control cohorts confirmed significant disease association for both p.Arg261His (10,589 samples analyzed) and NEK1 LOF variants (3,362 samples analyzed). In total, we observed NEK1 risk variants in nearly 3% of ALS cases. NEK1 has been linked to several cellular functions, including cilia formation, DNA-damage response, microtubule stability, neuronal morphology and axonal polarity. Our results provide new and important insights into ALS etiopathogenesis and genetic etiology.
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http://dx.doi.org/10.1038/ng.3626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5560030PMC
September 2016

The validation of the Italian Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

Amyotroph Lateral Scler Frontotemporal Degener 2016 Oct - Nov;17(7-8):489-498. Epub 2016 May 24.

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

This study presents the Italian validation of the recently developed Edinburgh Cognitive and Behavioural ALS Screen (ECAS), a short screen for cognitive/behavioural alterations in patients with amyotrophic lateral sclerosis (ALS). We evaluated the psychometric properties of the ECAS Italian version in terms of reliability and convergent validity for both cognitive and behavioural features. Furthermore, we investigated the relationship with affective and clinical variables, in addition to ECAS usability and patients' insight into cognitive/behaviour changes. Finally, correlations between genetic and cognitive/behavioural data were analysed. We recruited 107 patients with ALS. Normative data were collected on 248 healthy subjects. Participants were administered the ECAS and two standard cognitive screening tools (FAB, MoCA), two psychological questionnaires (BDI, STAI/Y) and an ad hoc usability questionnaire. The FBI was also carried out with caregivers. Results showed that the ECAS Italian version discriminated well between patients and controls. The most prevalent deficit occurred in executive functions and fluency. Correlations were observed between the ECAS and standard cognitive screening tools and between the ECAS carer interview and the FBI, supporting its full convergent validity. In conclusion, the ECAS Italian version provides clinicians with a rapid, feasible and sensitive tool, useful to identify different profiles of cognitive-behavioural impairment in ALS.
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http://dx.doi.org/10.1080/21678421.2016.1183679DOI Listing
October 2017

MRI abnormalities found 1 year prior to symptom onset in a case of Creutzfeldt-Jakob disease.

J Neurol 2016 Mar 12;263(3):597-9. Epub 2016 Feb 12.

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

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http://dx.doi.org/10.1007/s00415-016-8022-6DOI Listing
March 2016

An old woman with pressure ulcer, rigidity, and opisthotonus: never forget tetanus!

Lancet 2014 Dec 19;384(9961):2266. Epub 2014 Dec 19.

Università degli Studi di Milano, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(14)61832-8DOI Listing
December 2014

Analysis of hnRNPA1, A2/B1, and A3 genes in patients with amyotrophic lateral sclerosis.

Neurobiol Aging 2013 Nov 2;34(11):2695.e11-2. Epub 2013 Jul 2.

Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Via Zucchi 18, 20095 Cusano Milanino, Milan, Italy.

Mutations in the prion-like domain (PrLD) of hnRNPA1 and A2/B1 genes were recently identified in 2 families with inclusion body myopathy associated with Paget disease of bone, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis, and in ALS patients. These mutations were shown to increase the propensity of hnRNPA1 and A2/B1 proteins, which are TDP-43-binding partners, to self-aggregate. hnRNPA3 protein contains a similar PrLD and was recently described in the p62-positive/TDP-43-negative inclusions in affected tissues of C9orf72-mutated ALS/FTD patients. We screened hnRNPA1, A2/B1, and A3 genes in a cohort of 113 familial ALS (FALS) individuals without mutations in other known ALS-causative genes. We extended our analysis to 108 FALS with mutations in other ALS-associated genes and to 622 sporadic cases by screening specifically the PrLDs of hnRNPA1, A2/B1, and A3. We failed to find variants in each cohort. Our results suggest that mutations in hnRNPA1, A2/B1, and A3 genes are a rare finding in ALS.
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http://dx.doi.org/10.1016/j.neurobiolaging.2013.05.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6591723PMC
November 2013

Oligoclonal bands in the cerebrospinal fluid of amyotrophic lateral sclerosis patients with disease-associated mutations.

J Neurol 2013 Jan 1;260(1):85-92. Epub 2012 Jul 1.

Department of Neurology and Laboratory of Neuroscience, IRCCS Istituto Auxologico Italiano, Piazzale Brescia 20, 20149 Milan, Italy; Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, 'Dino Ferrari' Center, Università degli Studi di Milano, 20122 Milan, Italy.

In amyotrophic lateral sclerosis (ALS) cerebrospinal fluid (CSF) analysis is usually performed to exclude inflammatory processes of the central nervous system. Although in a small subset of patients an intrathecal synthesis of IgG is detectable, usually there is no clear explanation for this evidence. This study investigates the occurrence of oligoclonal bands (OCBs) in the CSF of a large series of ALS patients, attempting a correlation with genotype data. CSF was collected from 259 ALS patients. CSF parameters were measured according to standard procedures, and detection of OCBs performed by isoelectric focusing. The patients were screened for mutations in SOD1, FUS, TARDBP, ANG, OPTN, and C9ORF72. We observed the presence of OCBs in the CSF of 9/259 ALS patients (3.5 %), and of disease-associated mutations in 12 cases. OCBs were significantly more frequent in mutation carriers compared to the remaining cohort (3/12 vs 6/247; p < 0.01). Among patients with OCBs, two patients had the TARDBP p.A382T mutation (one of which in homozygous state), and one the ANG p.P-4S variant. Both patients carrying the p.A382T mutation had an atypical phenotype, one of them manifesting signs suggestive of a cerebellar involvement, and the other presenting neuroradiological findings suggestive of an inflammatory disorder of the central nervous system. Our results suggest that ALS patients with OCBs may harbor mutations in disease-causing genes. We speculate that mutations in both TARDBP and ANG genes may disrupt the blood-brain barrier (BBB), promoting local immune responses and neuroinflammation. The role of mutant TARDBP and ANG genes on BBB integrity of ALS patients warrants further investigation.
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http://dx.doi.org/10.1007/s00415-012-6589-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196642PMC
January 2013
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