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.

The pathological deposition of the transactive response DNA-binding protein of 43 kDa (TDP-43) 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 able to interfere with the underlying pathological process and early detection of TDP-43 pathology would facilitate the development of disease modifying drugs. The Real Time Quaking Induced Conversion reaction (RT-QuIC) showed the ability to detect prions in several peripheral tissues of patients with different forms of prion and prion-like diseases. Despite TDP-43 displays prion-like properties, to date the RT-QuIC technology has not yet been adapted to this protein. The aim of this study was to adapt the RT-QuIC technique for the TDP-43 substrate and to exploit the intrinsic ability of this technology to amplify minutes amount of misfolded proteins for the detection of pathological TDP-43 species in the CSF of amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. We first optimized the technique with synthetic TDP-43 preformed aggregates and with autopsy-verified brain homogenate samples and subsequently analyzed CSF samples from amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients and controls. TDP-43 RT-QuIC was able to detect as little as 15 picograms of TDP-43 aggregates, discriminating between a cohort of subjects 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 TDP-43 is a suitable substrate for the RT-QuIC. TDP-43 RT-QuIC could be an innovative and useful tool for diagnosis and drug development in amyotrophic lateral sclerosis and frontotemporal lobar degeneration. CSF detection of TDP-43 pathological aggregates may be exploited as a disease biomarker for amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients.

PurposeIn 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.MethodsA new computational three-dimensional method to extract the spinal cord from 18F-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, 18F-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.ResultsUptake of 18F-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. 18F-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.ConclusionOur 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.

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-β (Aβ), 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.

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.

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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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.