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INTRODUCTION: We assessed TAR DNA-binding protein 43 (TDP-43) seeding activity and aggregates detection in olfactory mucosa of patients with frontotemporal lobar degeneration with TDP-43-immunoreactive pathology (FTLD-TDP) by TDP-43 seeding amplification assay (TDP43-SAA) and immunocytochemical analysis. METHODS: The TDP43-SAA was optimized using frontal cortex samples from 16 post mortem cases with FTLD-TDP, FTLD with tau inclusions, and controls. Subsequently, olfactory mucosa samples were collected from 17 patients with FTLD-TDP, 15 healthy controls, and three patients carrying MAPT variants. RESULTS: TDP43-SAA discriminated with 100% accuracy post mortem cases presenting or lacking TDP-43 neuropathology. TDP-43 seeding activity was detectable in the olfactory mucosa, and 82.4% of patients with FTLD-TDP tested positive, whereas 86.7% of controls tested negative (P < 0.001). Two out of three patients with MAPT mutations tested negative. In TDP43-SAA positive samples, cytoplasmatic deposits of phosphorylated TDP-43 in the olfactory neural cells were detected. DISCUSSION: TDP-43 aggregates can be detectable in olfactory mucosa, suggesting that TDP43-SAA might be useful for identifying and monitoring FTLD-TDP in living patients.
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Demência Frontotemporal , Degeneração Lobar Frontotemporal , Humanos , Demência Frontotemporal/genética , Degeneração Lobar Frontotemporal/genética , Degeneração Lobar Frontotemporal/patologia , Proteínas tau/genética , Proteínas tau/metabolismo , Lobo Frontal/metabolismo , Neurônios/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Morphologically distinct TDP-43 aggregates occur in clinically different FTLD-TDP subtypes, yet the mechanism of their emergence and contribution to clinical heterogeneity are poorly understood. Several lines of evidence suggest that pathological TDP-43 follows a prion-like cascade, but the molecular determinants of this process remain unknown. We use advanced microscopy techniques to compare the seeding properties of pathological FTLD-TDP-A and FTLD-TDP-C aggregates. Upon inoculation of patient-derived aggregates in cells, FTLD-TDP-A seeds amplify in a template-dependent fashion, triggering neoaggregation more efficiently than those extracted from FTLD-TDP-C patients, correlating with the respective disease progression rates. Neoaggregates are sequentially phosphorylated with N-to-C directionality and with subtype-specific timelines. The resulting FTLD-TDP-A neoaggregates are large and contain densely packed fibrils, reminiscent of the pure compacted fibrils present within cytoplasmic inclusions in postmortem brains. In contrast, FTLD-TDP-C dystrophic neurites show less dense fibrils mixed with cellular components, and their respective neoaggregates are small, amorphous protein accumulations. These cellular seeding models replicate aspects of the patient pathological diversity and will be a useful tool in the quest for subtype-specific therapeutics.
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Demência Frontotemporal , Príons , Encéfalo/metabolismo , Demência Frontotemporal/metabolismo , Humanos , Corpos de Inclusão/metabolismo , Príons/metabolismoRESUMO
PURPOSE: In amyotrophic lateral sclerosis, functional alterations within the brain have been intensively assessed, while progression of lower motor neuron damage has scarcely been defined. The aim of the present study was to develop a computational method to systematically evaluate spinal cord metabolism as a tool to monitor disease mechanisms. METHODS: A new computational three-dimensional method to extract the spinal cord from (18)F-FDG PET/CT images was evaluated in 30 patients with spinal onset amyotrophic lateral sclerosis and 30 controls. The algorithm identified the skeleton on the CT images by using an extension of the Hough transform and then extracted the spinal canal and the spinal cord. In these regions, (18)F-FDG standardized uptake values were measured to estimate the metabolic activity of the spinal canal and cord. Measurements were performed in the cervical and dorsal spine and normalized to the corresponding value in the liver. RESULTS: Uptake of (18)F-FDG in the spinal cord was significantly higher in patients than in controls (p < 0.05). By contrast, no significant differences were observed in spinal cord and spinal canal volumes between the two groups. (18)F-FDG uptake was completely independent of age, gender, degree of functional impairment, disease duration and riluzole treatment. Kaplan-Meier analysis showed a higher mortality rate in patients with standardized uptake values above the fifth decile at the 3-year follow-up evaluation (log-rank test, p < 0.01). The independence of this value was confirmed by multivariate Cox analysis. CONCLUSION: Our computational three-dimensional method enabled the evaluation of spinal cord metabolism and volume and might represent a potential new window onto the pathophysiology of amyotrophic lateral sclerosis.
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Esclerose Lateral Amiotrófica/diagnóstico por imagem , Esclerose Lateral Amiotrófica/metabolismo , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Medula Espinal/diagnóstico por imagem , Medula Espinal/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Neuroimagem/métodos , Especificidade de Órgãos , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
BACKGROUND/AIMS: Apathy is the most common initial symptom of frontotemporal dementia (FTD) and has been linked to frontal-subcortical dopaminergic system dysfunction. No pharmacological therapy has been approved for the treatment of apathy, but, on the basis of its physiopathological mechanism, we suspected that increasing prefrontal dopaminergic innervation could improve this disabling symptom. METHODS: We evaluated a group of 24 nondepressed patients with a diagnosis of the behavioral variant of FTD, in order to determine the effectiveness on apathy of agomelatine, an antidepressant with MT1 and MT2 receptor agonism and 5-HT2C receptor antagonism; the latter leads to an increase in prefrontal dopaminergic and noradrenergic tone. To try to tease out the effects of 5-HT2C antagonism on apathy, patients were randomized, using a cross-over design, to receive either agomelatine 50 mg/day or sustained release melatonin 10 mg/day for 10 weeks in a double-blind procedure. At the end of the follow-up period, subjects receiving melatonin switched to agomelatine for the following 10 weeks. RESULTS: Agomelatine, but not melatonin, was associated with a significant reduction of apathy in FTD subjects and of caregiver distress due to patients' apathy. The switch from melatonin to agomelatine was associated with a reduction in apathetic behavior. Agomelatine was well-tolerated by all enrolled subjects. CONCLUSIONS: Our data, albeit preliminary, suggest that agomelatine could represent a novel useful approach to the treatment of apathy in FTD patients.
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Acetamidas/uso terapêutico , Antidepressivos/uso terapêutico , Apatia/efeitos dos fármacos , Demência Frontotemporal/psicologia , Acetamidas/administração & dosagem , Antidepressivos/administração & dosagem , Método Duplo-Cego , Feminino , Demência Frontotemporal/complicações , Humanos , Masculino , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Receptor MT1 de Melatonina/agonistas , Receptor MT2 de Melatonina/agonistas , Antagonistas do Receptor 5-HT2 de Serotonina/administração & dosagem , Antagonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Resultado do TratamentoAssuntos
Braço/fisiopatologia , Perna (Membro)/fisiopatologia , Doença dos Neurônios Motores/diagnóstico , Doença dos Neurônios Motores/fisiopatologia , Neurônios Motores/patologia , Idade de Início , Idoso , Feminino , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Doença dos Neurônios Motores/patologia , Fenótipo , Estudos Retrospectivos , Fatores SexuaisRESUMO
OBJECTIVE: This article presents an updated analysis of the LIGALS register, a prospective study conducted over a ten-year period (2009-2018) in Liguria, Italy, aimed at evaluating the incidence, prevalence, clinical presentation, and management of amyotrophic lateral sclerosis (ALS). METHODS: We calculated the mean annual crude incidence rate of ALS, assessed the point prevalence of ALS on January 1, 2018, and analyzed demographic factors, clinical characteristics, and clinical management strategies. Data analysis included Cox regression analysis to identify predictors of survival. RESULTS: The mean annual crude incidence rate of ALS was 3.16/100,000 per year (CI 95%) while the point prevalence of ALS on January 1, 2018, was 9.31/100,000 population (CI 95%). Among the patients, 6.5% were familial ALS, while 93.5% were sporadic cases. Clinical management strategies, including percutaneous endoscopic gastrostomy (PEG) and noninvasive ventilation (NIV), were employed. The study observed a stable frequency of NIV initiation and PEG placement over time, with a growing trend toward earlier PEG positioning. The mean survival from symptom onset was 39 months, whereas from diagnosis, it was 26 months. Cox regression analysis identified several predictors of survival, including gender, age at onset and diagnosis, site of onset, diagnostic category, phenotype, and diagnostic delay. CONCLUSIONS: This comprehensive analysis provides valuable insights into the long-term trends in ALS epidemiology and clinical management in Liguria, Italy. It underscores the importance of continued research efforts in understanding and addressing the challenges posed by ALS, particularly in terms of early diagnosis and optimizing clinical interventions to improve patient outcomes.
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Esclerose Lateral Amiotrófica , Humanos , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Esclerose Lateral Amiotrófica/terapia , Seguimentos , Estudos Prospectivos , Diagnóstico Tardio , Itália/epidemiologiaRESUMO
TDP-43 is the primary or secondary pathological hallmark of neurodegenerative diseases, such as amyotrophic lateral sclerosis, half of frontotemporal dementia cases, and limbic age-related TDP-43 encephalopathy, which clinically resembles Alzheimer's dementia. In such diseases, a biomarker that can detect TDP-43 proteinopathy in life would help to stratify patients according to their definite diagnosis of pathology, rather than in clinical subgroups of uncertain pathology. For therapies developed to target pathological proteins that cause the disease a biomarker to detect and track the underlying pathology would greatly enhance such undertakings. This article reviews the latest developments and outlooks of deriving TDP-43-specific biomarkers from the pathophysiological processes involved in the development of TDP-43 proteinopathy and studies using biosamples from clinical entities associated with TDP-43 pathology to investigate biomarker candidates.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Proteinopatias TDP-43 , Humanos , Esclerose Lateral Amiotrófica/metabolismo , Demência Frontotemporal/patologia , Biomarcadores , Proteínas de Ligação a DNA/metabolismoRESUMO
OBJECTIVE: To verify the safety and potential effect on ALS progression of a low-intensity immunosuppressive regimen followed by autologous hematopoietic stem cell transplantation (aHSCT) in amyotrophic lateral sclerosis (ALS) patients. METHODS: ALS eligible patients underwent a set of clinical and laboratory evaluations at T-4 (screening), T-1 (pre-treatment visit), and for the 12 consecutive months after treatment (T3, T6, T9, T12). We evaluated the tolerability of the procedure, its efficacy on clinical course and quality of life (QoL). RESULTS: Eight of the 11 ALS patients enrolled received the established immunoablative protocol. The procedure was well tolerated and side effects were those expected. One patient died 4 months after the conditioning regimen and another patient underwent tracheotomy just before T3 for a sudden respiratory failure, but he is still alive 4 years after the procedure without being ventilated any more. A third patient died 10 months after conditioning. In the other cases, there was no statistical difference in all functional measures and QoL pre- and post-treatment; however, a transitory slopes' reduction of ALSFRS-R and seated SVC% after the conditioning procedures was reported. Moreover, although not statistically significant, trends of reduction of CD4 + and increment of CD8 + were found. CONCLUSIONS: aHSCT was overall well tolerated, but it was not followed by any significant modification in disease progression. Considering the negative results of this small trial, further studies aimed to evaluate the possible efficacy of the aHSCT using a higher-intensity regimen should be carefully and with caution evaluated.
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Esclerose Lateral Amiotrófica , Transplante de Células-Tronco Hematopoéticas , Esclerose Lateral Amiotrófica/cirurgia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Qualidade de Vida , Condicionamento Pré-Transplante/métodos , Transplante AutólogoAssuntos
Doença de Alzheimer/diagnóstico , Amiloidose/diagnóstico , Demência Frontotemporal/diagnóstico , Idoso , Doença de Alzheimer/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Demência Frontotemporal/diagnóstico por imagem , Humanos , Testes Neuropsicológicos/estatística & dados numéricosRESUMO
Cytoplasmic aggregation of the primarily nuclear TAR DNA-binding protein 43 (TDP-43) affects neurons in most amyotrophic lateral sclerosis (ALS) and approximately half of frontotemporal lobar degeneration (FTLD) cases. The cellular prion protein, PrPC, has been recognized as a common receptor and downstream effector of circulating neurotoxic species of several proteins involved in neurodegeneration. Here, capitalizing on our recently adapted TDP-43 real time quaking induced reaction, we set reproducible protocols to obtain standardized preparations of recombinant TDP-43 fibrils. We then exploited two different cellular systems (human SH-SY5Y and mouse N2a neuroblastoma cells) engineered to express low or high PrPC levels to investigate the link between PrPC expression on the cell surface and the internalization of TDP-43 fibrils. Fibril uptake was increased in cells overexpressing either human or mouse prion protein. Increased internalization was associated with detrimental consequences in all PrP-overexpressing cell lines but was milder in cells expressing the human form of the prion protein. As described for other amyloids, treatment with TDP-43 fibrils induced a reduction in the accumulation of the misfolded form of PrPC, PrPSc, in cells chronically infected with prions. Our results expand the list of misfolded proteins whose uptake and detrimental effects are mediated by PrPC, which encompass almost all pathological amyloids involved in neurodegeneration.
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Proteínas de Ligação a DNA/metabolismo , Proteínas PrPC/genética , Proteínas PrPC/metabolismo , Proteínas Priônicas/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Sobrevivência Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/farmacologia , Humanos , Camundongos , Proteínas PrPC/classificação , Proteínas Priônicas/genéticaRESUMO
Neurodegenerative disorders are associated with intra- or extra-cellular deposition of aggregates of misfolded insoluble proteins. These deposits composed of tau, amyloid-ß or α-synuclein spread from cell to cell, in a prion-like manner. Novel evidence suggests that the circulating soluble oligomeric species of these misfolded proteins could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Recent convincing data support the proposition that the cellular prion protein, PrPC, act as a toxicity-inducing receptor for amyloid-ß oligomers. As a consequence, several studies focused their investigations to the role played by PrPC in binding other protein aggregates, such as tau and α-synuclein, for its possible common role in mediating toxic signalling. The biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, could lead to relevant therapeutic implications. Here we describe the structure of PrPC and the proposed interplay with its pathological counterpart PrPSc and then we recapitulate the most recent findings regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins.
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Doenças Neurodegenerativas/metabolismo , Doenças Neurodegenerativas/patologia , Proteínas Priônicas/metabolismo , Agregação Patológica de Proteínas/metabolismo , Transdução de Sinais , Animais , Humanos , alfa-Sinucleína/toxicidade , Proteínas tau/toxicidadeRESUMO
Neurodegenerative disorders are invariably associated with intra- or extra-cellular deposition of aggregates composed of misfolded insoluble proteins. These deposits composed of tau, amyloid-ß or α-synuclein spread from cell to cell, in a prion-like manner. Emerging evidence suggests that the circulating soluble species of these misfolded proteins (usually referred as oligomers) could play a major role in pathology, while insoluble aggregates would represent their protective less toxic counterparts. Convincing data support the hypothesis that the cellular prion protein, PrPC, act as a toxicity-transducing receptor for amyloid-ß oligomers. As a consequence, several studies extended investigations to the role played by PrPC in binding aggregates of proteins other than Aß, such as tau and α-synuclein, for its possible common role in mediating toxic signaling. A better characterization of the biological relevance of PrPC as key ligand and potential mediator of toxicity for multiple proteinaceous aggregated species, prions or PrPSc included, would bring relevant therapeutic implications. Here we will first describe the structure of the prion protein and the hypothesized interplay with its pathological counterpart PrPSc and then we will recapitulate the most relevant discoveries regarding the role of PrPC in the interaction with aggregated forms of other neurodegeneration-associated proteins.
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Doenças Neurodegenerativas/patologia , Proteínas Priônicas/metabolismo , Agregados Proteicos , Transdução de Sinais , Peptídeos beta-Amiloides/toxicidade , Animais , Humanos , Proteínas Priônicas/química , Proteínas Priônicas/toxicidade , alfa-Sinucleína/toxicidadeRESUMO
The pathological deposition of the transactive response DNA-binding protein of 43 kDa occurs in the majority (â¼97%) 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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Increasing evidence suggests that neurodegenerative disorders share a common pathogenic feature: the presence of deposits of misfolded proteins with altered physicochemical properties in the Central Nervous System. Despite a lack of infectivity, experimental data show that the replication and propagation of neurodegenerative disease-related proteins including amyloid-ß (Aß), tau, α-synuclein and the transactive response DNA-binding protein of 43 kDa (TDP-43) share a similar pathological mechanism with prions. These observations have led to the terminology of "prion-like" to distinguish between conditions with noninfectious characteristics but similarities with the prion replication and propagation process. Prions are considered to adapt their conformation to changes in the context of the environment of replication. This process is known as either prion selection or adaptation, where a distinct conformer present in the initial prion population with higher propensity to propagate in the new environment is able to prevail over the others during the replication process. In the last years, many studies have shown that prion-like proteins share not only the prion replication paradigm but also the specific ability to aggregate in different conformations, i.e., strains, with relevant clinical, diagnostic and therapeutic implications. This review focuses on the molecular basis of the strain phenomenon in prion and prion-like proteins.
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Doenças Neurodegenerativas/patologia , Proteínas Priônicas/genética , Príons/genética , Príons/patogenicidade , Peptídeos beta-Amiloides/genética , Animais , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Humanos , Camundongos , Dobramento de Proteína , Proteínas tau/genéticaRESUMO
We investigated whether the C9orf72 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 C9orf72 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 (n = 84) were younger at disease onset, at the first clinical observation and at diagnosis (p < 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 (p < 0.05). Cox proportional hazards regression multivariate analysis suggested that carrying the C9orf72 repeat expansion was an independent factor negatively impacting on survival time in men (HR 1.58, 95% CI 1.07-2.33, p = 0.021), but not in women (p > 0.05) as well as in the whole sample (p > 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 C9orf72-related disease.
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Spinal cord atrophy is one of the hallmarks of amyotrophic lateral sclerosis (ALS); however, it is not routinely assessed in routine clinical practice. In the present study, we evaluated whether spinal cord cross-sectional area measured at the foramen magnum level using a magnetic resonance imaging head scan represents a clinically meaningful measure to be added to the whole-brain volume assessment. Using an active surface approach, we measured the cord area at the foramen magnum and brain parenchymal fraction on T1-weighted three-dimensional spoiled gradient recalled head scans in two groups of subjects: 23 patients with ALS (males/females, 13/10; mean ± standard deviation [SD] age 61.7 ± 10.3 years; median ALS Functional Rating Scale-Revised score 39, range 27-46) and 18 age- and sex-matched healthy volunteers (mean ± SD age 55.7 ± 10.2 years). Spinal cord area at the foramen magnum was significantly less in patients than in control subjects and was significantly correlated with disability as measured with the ALS Functional Rating Scale-Revised (ρ = 0.593, p < 0.005). This correlation remained significant after taking into account inter-individual differences in brain parenchymal fraction (ρ = 0.684, p < 0.001). Our data show that spinal cord area at the foramen magnum correlates with disability in ALS independently of whole-brain atrophy, thus indicating its potential as a disease biomarker.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease with a heterogeneous genetic background. Because mutation analysis by Sanger sequencing is costly and time-consuming, in recent years, next-generation sequencing (NGS) techniques have become of much interest. This study analyses the results of 20 years of molecular analyses in ALS patients in our laboratory using traditional methods and NGS. Almost 300 ALS patients underwent genetic analysis with Sanger sequencing of 7 genes or with an NGS panel of 23 genes. The C9orf72 expansion was tested by fragment size analysis. Sanger sequencing revealed mutations in 23.8% of familial and 3.8% of sporadic cases, whereas NGS detected potentially pathogenic variants in 45.5% of familial and 5.4% of sporadic cases and variants of unknown significance in 30.3% of patients. In 11.8% of patients, potentially causative mutations were found in 2 or more ALS genes. Compared to traditional methods, NGS is more effective in revealing possibly causal variants, but counseling patients becomes more complicated due to frequent variants of unknown significance and potentially oligogenic cases.
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Esclerose Lateral Amiotrófica/genética , Estudos de Associação Genética/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/tendências , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise Mutacional de DNA/métodos , Expansão das Repetições de DNA , Feminino , Variação Genética , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto JovemRESUMO
The aim of this multicenter, retrospective study is to investigate the role of clinical characteristics and therapeutic intervention on ALS prognosis. The study included patients diagnosed from January 1, 2009 to December 31, 2013 in 13 Italian referral centers for ALS located in 10 Italian regions. Caring neurologists collected a detailed phenotypic profile and follow-up data until death into an electronic database. One center collected also data from a population-based registry for ALS. 2648 incident cases were collected. The median survival time from onset to death/tracheostomy was 44 months (SE 1.18, CI 42-46). According to univariate analysis, factors related to survival from onset to death/tracheostomy were: age at onset, diagnostic delay, site of onset, phenotype, degree of certainty at diagnosis according to revised El Escorial criteria (R-EEC), presence/absence of dementia, BMI at diagnosis, patients' provenance. In the multivariate analysis, age at onset, diagnostic delay, phenotypes but not site of onset, presence/absence of dementia, BMI, riluzole use, R-EEC criteria were independent prognostic factors of survival in ALS. We compared patients from an ALS Registry with patients from tertiary centers; the latter ones were younger, less frequently bulbar, but more frequently familial and definite at diagnosis. Our large, multicenter study demonstrated the role of some clinical and demographic factors on ALS survival, and showed some interesting differences between referral centers' patients and the general ALS population. These results can be helpful for clinical practice, in clinical trial design and to validate new tools to predict disease progression.
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Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Idade de Início , Idoso , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Índice de Massa Corporal , Diagnóstico Tardio , Feminino , Seguimentos , Humanos , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Estudos Retrospectivos , Centros de Atenção TerciáriaRESUMO
To assess the association, at diagnosis, between amyotrophic lateral sclerosis (ALS) and dementia in a large cohort of well-characterized Italian patients. We investigated the phenotypic profile of 1638 incident patients with definite, probable or laboratory-supported probable ALS, diagnosed from January 2009 to December 2013 in 13 Italian Referral Centers, located in 10 Italian Regions, and classified in two independent subsamples accounting for presence or not of dementia. The collected ALS features, including survival and other follow-up data, were compared between the two subgroups using a one-way analysis of variance and Chi-square test, as appropriate, logistic regression models and Kaplan-Meier survival analysis. Between-subgroup comparisons showed an older age at clinical observation (p = .006), at onset and at diagnosis (p = .002) in demented versus non demented ALS patients. After adjustment for these variables, diagnosis of dementia was significantly associated with higher odds of family history of ALS (p = .001) and frontotemporal dementia (p = .003) and of bulbar onset (p = .004), and lower odds of flail leg phenotype (p = .019) and spinal onset (p = .008). The median survival time was shorter in demented versus non-demented patients, especially in case of classical, bulbar and flail limb phenotypes and both bulbar and spinal onset. Our multicenter study emphasized the importance of an early diagnosis of comorbid dementia in ALS patients, which may have clinical impact and prognostic relevance. Moreover, our results may give further inputs to validation of ALS-specific tools for the screening of cognitive impairment in clinical practice.