Cerebrospinal fluid phosphorylated neurofilament heavy chain and chitotriosidase in primary lateral sclerosis
Federico VerdeGloria ZainaCaterina BodioMaría Orietta BorghiDavide SorannaSilvia PeverelliNicola TicozziClaudia MorelliAlberto DorettiStefano MessinaLuca MadernaClaudia ColombritaValentina GuminaCinzia TilocaPier Luigi MeroniAntonella ZambonAntonia RattiVincenzo Silani
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Abstract:
Primary lateral sclerosis (PLS) is a rare degenerative disease of upper motor neurons (UMNs) manifesting with progressive spasticity. Disease progression is definitely slower than in amyotrophic lateral sclerosis (ALS). Clinical distinction between PLS and ALS can be challenging, as the UMN-dominant form of ALS may sometimes not manifest lower motor neuron (LMN) signs for a long time after symptom onset.1 Therefore, traditional PLS diagnostic criteria allowed diagnosis only after 3 or 4 years of documented absence of LMN signs,2 which poses a psychological burden on patients, hinders correct clinical management and prevents enrolment in clinical trials. In order to overcome these issues, new diagnostic criteria have been recently formulated, shortening the time required for a diagnosis of probable PLS to 2 years.1
Diagnostic uncertainties in PLS are complicated by the lack of specific neurochemical biomarkers. Whereas cerebrospinal fluid (CSF) neurofilament levels are clearly increased in ALS, making them a well-established ALS biomarker reflecting axonal degeneration, few studies reported lower increases in PLS3; a similar pattern was observed for the putative ALS microglial biomarker chitotriosidase (Chit1).4 Here we measured phosphorylated neurofilament heavy chain (pNFH) and Chit1 in the CSF of patients with PLS, ALS and non-neurodegenerative neurological conditions, focusing on the ability of each biomarker to distinguish PLS from controls and from ALS.
### Patients
In this retrospective study we included those 10 patients (5 men, 5 women) from our consecutive PLS series (n=52) whose CSF was stored in our biobank. They all fulfilled—at the time of sampling or on later evaluations—the recently published diagnostic criteria for definite (n=9) or probable (n=1) PLS.1 Patients with ALS and neurological controls (NCs) were selected randomly from our biobank to form two cohorts with sex and age distributions similar to PLS. Patients with ALS (n=28; 16 men, 12 women) fulfilled …Keywords:
Neurofilament
Cytoskeletal proteins have a characteristic distribution within neurons when immunocytochemical techniques are used on conventional paraffin sections. For example, phosphorylated neurofilaments are located within axons but are not normally present in the majority of perikarya of the central nervous system. This pattern can be altered in disease, and neurofilaments that accumulate within perikarya can be phosphorylated inappropriately. To determine whether retained neurofilaments were phosphorylated inappropriately, we used immunocytochemical techniques to examine several diseases in animals in which neurofilaments accumulate within neuronal perikarya. Our investigations of diseases with disparate etiologies show that, whenever neurofilaments are retained within the neuronal perikarya, they are phosphorylated. These results suggest that phosphorylation of neurofilaments in an inappropriate location, i.e. perikarya, may be a nonspecific disease-related response of neurons that can be initiated by a variety of cellular injuries.
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ALS : amyotrophic lateral sclerosis UMN : upper motor neuron LMN : lower motor neuron fALS : familial amyotrophic lateral sclerosis sALS : sporadic amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) reflects a heterogeneous group of neurodegenerative disorders unified by
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In 47 patients with multiple sclerosis and 10 with other diseases of the nervous system determinations of haptoglobin were performed in the serum and cerebrospinal fluid by the method of Owen et al. The Hp level in the serum of multiple sclerosis patients was normal. Its level in the cerebrospinal fluid was higher in multiple sclerosis patients than in cases of other nervous system diseases (statistically significant difference, p less than 0.001). Raised value of the Hp/IgG index in the cerebrospinal fluid of multiple sclerosis patients points to increased permeability of the blood-brain barrier. The so called normal Hp/IgG index was found in multiple sclerosis patients with high Hp and IgG level. Low Hp/IgG index suggested the possibility of IgG synthesis in the brain of patients with this disease. The comparison of the protein level and protein indexes showed that raised IgG level in the cerebrospinal fluid was present in 80% of multiple sclerosis cases, raised Kabat index in 50%, and low Hp/IgG index in 48%.
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Abstract Various studies have suggested that a neurotoxic cerebrospinal fluid profile could be implicated in amyotrophic lateral sclerosis. Here, we systematically review the evidence for cerebrospinal fluid cytotoxicity in amyotrophic lateral sclerosis and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to cerebrospinal fluid from amyotrophic lateral sclerosis patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarized. Twenty-eight studies were included in our analysis. Both participant characteristics and study conditions including cerebrospinal fluid concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to cerebrospinal fluid from patients with amyotrophic lateral sclerosis, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between cerebrospinal fluid cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that cerebrospinal fluid cytotoxicity is a feature of sporadic and possibly also of familial forms of amyotrophic lateral sclerosis. Further research is, however, required to better characterize its underlying mechanisms and to establish its possible contribution to amyotrophic lateral sclerosis pathophysiology.
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Experimental structural alterations were studied in neurofilaments isolated from rat peripheral nerve. Structural alterations were induced in vitro by prolonged incubations of neurofilament-rich fractions in 0.1 M KCI prior to fixation and examination of neurofilaments by negative staining techniques. Neurofilaments appeared to retain their structural integrity during the first week of incubation. Subsequently, a progressive reduction in the numbers of intact neurofilaments coincided with the increasing appearance of neurofilamentous breakdown products. During the period of neurofilament breakdown, an increasing number of altered neurofilaments were observed. These abnormal neurofilaments were characterized primarily by axial enlargements with diameters frequently occurring in the 150–200 Å range but measuring up to 250 Å. Enlarged neurofilaments also showed a greater irregularity of their lateral margins and less ridigity in their linear course. A striking feature of enlarged neurofilaments was their tendency to display twisting deformations along their longitudinal axes. Twists occurred most frequently along neurofilaments of greatest diameter. The largest abnormal neurofilaments reveal multiple periodic twists, sometimes occurring at 800–1000 Å intervals. These enlarged and twisted neurofilaments resembled the abnormal filaments described in neurofibrillary tangles and plaques. The demonstration of neurofilament plasticity as well as the resemblance of neurofilaments deformed in vitro to the abnormal filamentous structures of neurofibrillary tangles and plaques has led to the suggestion that the latter structures may be derived from alterations of normally-formed neurofilaments. Furthermore, it is proposed that the enlarged and twisted filaments of neurofibrillary pathology may arise from alterations in the turnover of neurofilaments or, more specifically, from deficiencies in the degradative processes by which these organelles are broken down.
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Antibody‐mediated inflammation is believed to contribute to tissue injury in multiple sclerosis (MS). The majority of patients with MS have oligoclonal bands (OCB), corresponding to antibodies against a variety of antigens, in their cerebrospinal fluid (CSF). The relation of CSF OCB and disease progression in MS is uncertain. To investigate whether there is a relation between CSF OCB and a more aggressive disease course of MS, 143 patients with definite MS according to the Poser diagnostic criteria and CSF analysis at time of diagnosis were followed over a period of 5 years. There were no differences in presence or number of CSF OCB between patients with significant worsening of disability and stable patients. There were no differences in presence or number of CSF OCB between patients with stable relapsing‐remitting MS and patients developing secondary progression during follow‐up. The presence or number of CSF OCB does not seem to influence early disease progression in MS.
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