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Background and purpose: Cerebrospinal fluid (CSF) kappa free light chains (FLCs) may be a more sensitive marker of intrathecal immunoglobulin (Ig)G synthesis compared with oligoclonal bands (OCBs). Our aim was to retrospectively determine the additional value of the kappa and lambda index (CSF FLC/serum FLC)/(CSF albumin/serum albumin) in predicting a multiple sclerosis (MS) diagnosis in a group of OCB‐negative patients with suspected MS. Methods: The CSF and serum kappa and lambda FLCs were tested using the Freelite kit (serum) and Freelite Mx (CSF) assay (The Binding Site Group, Bimingham, UK) in 391 OCB‐negative patients with suspected/possible MS and in 54 OCB‐positive patients with MS. Results: The CSF kappa FLC levels were below the detection limit (0.27 mg/L) in 61% of patients. Using quantitative data, we found the best kappa index cut‐off value for the prediction of MS to be 5.8. A kappa index ≥5.8 was present in 25% of OCB‐negative MS (23/92) and in 98% of OCB‐positive patients with MS. Using a qualitative approach and a kappa index cut‐off of 5.9, based on literature data, we likewise found that 24% of OCB‐negative patients with MS had a kappa index ≥5.9, compared with 5.4% of OCB‐negative patients without MS (P < 0.001). No reliable data could be obtained for the lambda index; lambda FLCs were below the detection limit (0.68 mg/L) in 90% of CSF samples. Conclusions: The kappa index could contribute to the identification of OCB‐negative patients with a high probability of an MS diagnosis. Using more sensitive techniques might even improve the diagnostic performance of the kappa index and better define the role of the lambda index. [ABSTRACT FROM AUTHOR]

Background: A few studies have suggested that light at night (LAN) exposure, i.e. lighting during night hours, may increase dementia risk. We evaluated such association in a cohort of subjects diagnosed with mild cognitive impairment (MCI)., Methods: We recruited study participants between 2008 and 2014 at the Cognitive Neurology Clinic of Modena Hospital, Northern Italy and followed them for conversion to dementia up to 2021. We collected their residential history and we assessed outdoor artificial LAN exposure at subjects' residences using satellite imagery data available from the Visible Infrared Imaging Radiometer Suite (VIIRS) for the period 2014-2022. We assessed the relation between LAN exposure and cerebrospinal fluid biomarkers. We used a Cox-proportional hazards model to compute the hazard ratio (HR) of dementia with 95% confidence interval (CI) according to increasing LAN exposure through linear, categorical, and non-linear restricted-cubic spline models, adjusting by relevant confounders., Results: Out of 53 recruited subjects, 34 converted to dementia of any type and 26 converted to Alzheimer's dementia. Higher levels of LAN were positively associated with biomarkers of tau pathology, as well as with lower concentrations of amyloid β 1-42 assessed at baseline. LAN exposure was positively associated with dementia conversion using linear regression model (HR 1.04, 95% CI 1.01-1.07 for 1-unit increase). Using as reference the lowest tertile, subjects at both intermediate and highest tertiles of LAN exposure showed increased risk of dementia conversion (HRs 2.53, 95% CI 0.99-6.50, and 3.61, 95% CI 1.34-9.74). In spline regression analysis, the risk linearly increased for conversion to both any dementia and Alzheimer's dementia above 30 nW/cm 2 /sr of LAN exposure. Adding potential confounders including traffic-related particulate matter, smoking status, chronic diseases, and apolipoprotein E status to the multivariable model, or removing cases with dementia onset within the first year of follow-up did not substantially alter the results., Conclusion: Our findings suggest that outdoor artificial LAN may increase dementia conversion, especially above 30 nW/cm 2 /sr, although the limited sample size suggests caution in the interpretation of the results, to be confirmed in larger investigations., Competing Interests: Declarations. Ethics approval and consent to participate: This study was approved by Modena Ethics Committee (no. 84/2015) and all participants signed written consent form. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Alterations in factors involved in cholesterol homeostasis are critical in Alzheimer's disease (AD), but the stage of occurrence, their specific association, and a possible relationship with the APOE4 genotype are not clarified., Objective: We aimed to quantify and correlate specific lipid factors in patients with different degrees of cognitive decline, namely patients with AD and patients with mild cognitive impairment due to AD (MCI-AD), carriers or non-carriers of the APOE4 genotype., Methods: We evaluated Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9), cholesterol and the oxidative metabolites 24-, 25-, 27-hydroxycholesterol (HC) in the cerebrospinal fluid (CSF) and serum of AD (n = 28) and MCI-AD (n = 27) patients., Results: CSF and serum PCSK9 and lipids were similar, except for higher serum PCSK9 and triglycerides in MCI-AD compared to AD. In CSF, AD APOE4 carriers showed higher PCSK9 and 24-HC (+61.3%, p  = 0.027 and +32.7%, p  = 0.037), compared to non-carriers. There was a negative association between CSF PCSK9 and 27-HC in AD (r = -0.444, p  = 0.049) and, exclusively among AD APOE4 carriers, a negative association between CSF PCSK9 and 24-HC (r = -0.786, p  = 0.028). A positive correlation was observed between CSF and serum PCSK9 in AD (r = 0.520, p  = 0.004), driven by APOE4 carriers (r = 0.544, p  = 0.038), suggesting PCSK9 exchange between brain and periphery. A positive correlation was detected between serum and CSF 27-HC (r = 0.465, p  = 0.039) in AD. None of these results were found in MCI-AD patients., Conclusions: PCSK9 and 24-HC might be specific markers of ApoE4-associated lipid alterations in AD, possibly contributing to clinical progression in the AD continuum., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The author FB has been granted by Amgen Inc. (Amgen's PSCK9 Competitive Grant Program 2018, grant number 9406917) with a project entitled: EXplorIng the paThophysological role of PCSK9 in Alzheimer's Disease: focus on inflammation and lipid metabolism (EXIT-AD).

Objective: Neurofilament light chain proteins (NfLs) are considered a promising biomarker of neuroaxonal damage in several neurological diseases. Their measurement in the serum and cerebrospinal fluid (CSF) of patients with dementia may be especially useful. Our aim was to compare the NfL measurement performance of two advanced technologies, specifically the Ella™ microfluidic platform and the Lumipulse™ fully automated system, in patients with cognitive disorders., Methods: Thirty subjects with neurodegenerative cognitive disorders (10 with Alzheimer's Disease, 10 with Frontotemporal Dementia, and 10 with non-progressive Mild Cognitive Impairment) seen at the Cognitive Neurology Clinic of Modena University Hospital (Italy) underwent CSF and serum NfL measurement with both the Ella™ microfluidic platform (Bio-Techne, Minneapolis, MN, USA)) and the Lumipulse™ fully automated system for the CLEIA (Fujirebio Inc., Ghent, Belgium). Correlation and regression analyses were applied to assess the association between NfL concentrations obtained with the two assays in CSF and serum. The Passing-Bablok regression method was employed to evaluate the agreement between the assays., Results: There were high correlations between the two assays (r = 0.976, 95% CI. 0.950-0.989 for CSF vs. r = 0.923, 95% CI 0.842-0.964 for serum). A Passing-Bablok regression model was estimated to explain the relationship between the two assays, allowing us to switch from one to the other when only one assay was available., Conclusions: We found a good degree of correlation between the two methods in patients with neurocognitive disorders. We also established a method that will allow comparisons between results obtained with either technique, allowing for meta-analyses and larger sample sizes.

Background: The presence of inflammatory changes in the cerebrospinal fluid (CSF), including immunoglobulin intrathecal synthesis (IS), can support the diagnosis of autoimmune encephalitis (AE) and allow prompt treatment. The main aim of our study was to calculate the Kappa index as a marker of IS, in patients with AE., Methods: Charts of patients undergoing a diagnostic work-up for suspected AE between 2009 and 2023 were reviewed and the Graus criteria applied. CSF and serum kappa free light chains were determined using the Freelite assay (The Binding Site Group) and the turbidimetric Optilite analyzer., Results: We identified 34 patients with "definite" AE (9 anti-NMDAR AE and 25 limbic AE) and nine patients with "possible" AE. Five patients (15%) with definite AE had pleocytosis and twelve (34%) showed CSF-restricted oligoclonal bands (OCB) at isoelectric focusing. The Kappa index was >6 in 29.4% and > 3 in 50% of the definite AE patients. It was elevated (>3) in 36.4% of patients with definite AE who resulted negative to OCB testing and was the only altered parameter suggestive of an ongoing inflammatory process in the CNS in three definite AE patients with otherwise normal CSF findings (i.e. normal cell count and protein levels, no OCBs). In the possible AE group, one patient had a Kappa index >3 in the absence of OCB., Conclusions: The Kappa index could be useful, as a more sensitive marker of IS and as a supportive marker of neuroinflammation, in the diagnostic work-up of suspected AE., Competing Interests: Declaration of competing interest DF's institution has received kappa free light chain assays (Freelite) for research purposes from Binding Site (Birmingham). GDN, MG, PN, RB, SM, AMS, MS, FV, KS, MC and SM have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting the brain and spinal cord motor neurons. On 25 April 2023, the drug tofersen, an antisense oligonucleotide, received the US Food and Drug Administration approval for treating ALS in adults carrying mutations of the SOD1 gene. We aimed at assessing whether cerebrospinal fluid concentrations of selenium, an element of both toxicological and nutritional interest possibly involved in disease etiology and progression, are modified by tofersen administration. We determined concentrations of selenium species by anion exchange chromatography hyphenated to inductively coupled plasma-dynamic reaction cell-mass spectrometry and overall selenium by using inductively coupled plasma sector-field mass spectrometry, at baseline and 6 months after active tofersen treatment in ten Italian ALS patients carrying the SOD1 gene mutation. Concentrations of total selenium and many selenium species substantially increased after the intervention, particularly of inorganic (tetravalent and hexavalent) selenium and of the organic species selenomethionine and a compound co-eluting with the selenocystine standard. Overall, these findings suggest that tofersen treatment markedly alters selenium status and probably the redox status within the central nervous system, possibly due to a direct effect on neurons and/or the blood-brain barrier. Further studies are required to investigate the biological and clinical relevance of these findings and how they might relate to the pharmacological effects of the drug and to disease progression., (© 2024. The Author(s).)

Considering the growing age of the world population, the incidence of epilepsy in older adults is expected to increase significantly. It has been suggested that late-onset temporal lobe epilepsy (LO-TLE) may be neurodegenerative in origin and overlap with Alzheimer's Disease (AD). Herein, we aimed to characterize the pattern of cortical atrophy and cerebrospinal fluid (CSF) biomarkers of AD (total and phosphorylated tau, and β-amyloid) in a selected population of LO-TLE of unknown origin. We prospectively enrolled individuals with temporal lobe epilepsy onset after the age of 50 and no cognitive impairment. They underwent a structural MRI scan and CSF biomarkers measurement. Imaging and biomarkers data were compared to three retrospectively collected groups: (i) age-sex-matched healthy controls, (ii) patients with Mild Cognitive Impairment (MCI) and abnormal CSF AD biomarkers (MCI-AD), and (iii) patients with MCI and normal CSF AD biomarkers (MCI-noAD). From a pool of 52 patients, twenty consecutive eligible LO-TLE patients with a mean disease duration of 1.8 years were recruited. As control populations, 25 patients with MCI-AD, 25 patients with MCI-noAD, and 25 healthy controls were enrolled. CSF biomarkers returned normal values in LO-TLE, significantly different from patients with MCI due to AD. There were no differences in cortico-subcortical atrophy between epilepsy patients and healthy controls, while patients with MCI demonstrated widespread injuries of cortico-subcortical structures. Individuals with a late-onset form of temporal lobe epilepsy, characterized by short disease duration and normal CSF β-amyloid and tau protein levels, showed patterns of cortical thickness and subcortical volumes not significantly different from healthy controls, but highly different from patients with MCI, either due to Alzheimer's Disease or not., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: SerpinA1, a serine protease inhibitor, is involved in the modulation of microglial-mediated inflammation in neurodegenerative diseases. We explored SerpinA1 levels in cerebrospinal fluid (CSF) and serum of amyotrophic lateral sclerosis (ALS) patients to understand its potential role in the pathogenesis of the disease., Methods: SerpinA1, neurofilament light (NfL) and heavy (NfH) chain, and chitinase-3-like protein-1 (CHI3L1) were determined in CSF and serum of ALS patients (n = 110) and healthy controls (n = 10) (automated next-generation ELISA), and correlated with clinical parameters, after identifying three classes of progressors (fast, intermediate, slow). Biomarker levels were analyzed for diagnostic power and association with progression and survival., Results: SerpinA1 serum was significantly decreased in ALS (median: 1032 μg/mL) compared with controls (1343 μg/mL) (p = 0.02). SerpinA1 CSF was elevated only in fast progressors (8.6 μg/mL) compared with slow (4.43 μg/mL, p = 0.01) and intermediate (4.42 μg/mL, p = 0.03) progressors. Moreover, SerpinA1 CSF correlated with neurofilament and CHI3L1 levels in CSF. Contrarily to SerpinA1 CSF , neurofilament and CHI3L1 concentrations in CSF correlated with measures of disease progression in ALS, while SerpinA1 serum mildly related with time to generalization (rho = 0.20, p = 0.04). In multivariate analysis, the ratio between serum and CSF SerpinA1 (SerpinA1 ratio) and NfH CSF were independently associated with survival., Conclusions: Higher SerpinA1 CSF levels are found in fast progressors, suggesting SerpinA1 is a component of the neuroinflammatory mechanisms acting upon fast-progressing forms of ALS. Both neurofilaments or CHI3L1 CSF levels outperformed SerpinA1 at predicting disease progression rate in our cohort, and so the prognostic value of SerpinA1 alone as a measure remains inconclusive., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Purpose: The study aimed to identify predictors of respiratory failure leading to mechanical ventilation (MV) and tracheostomy in Guillain-Barré syndrome (GBS)., Methods: Two hundred and thirty adult cases admitted to the Neurology Unit of Modena, Italy, between January 2000 and December 2021 were studied. A cut-off of MV starting within 8 weeks from onset of weakness was used. Univariable, multivariable logistic and Cox regression analyses were used to determine which pre-specified clinical and diagnostic characteristics were capable of predicting MV and tracheostomy, due to weaning failure. The model was internally validated within the full cohort. The Erasmus GBS Respiratory Insufficiency Score was retrospectively applied., Results: One hundred and seventy-six cases (76.5%) were classified as classical sensorimotor GBS and 54 (23.4%) as variants. Thirty-two patients (13.9%) needed MV: 84.3% required respiratory support within 7 days. Independent predictors of respiratory failure and MV were older age, facial, bulbar, neck flexor weakness, dysautonomia, axonal electrophysiological subtype, cardiovascular comorbidities and higher disability score at entry. There was no association with abnormal spinal fluid parameters nor with positive serology for recent infections. Twenty-two patients (68.7%) were ventilated for more than 7 days; 4.7% died within 8 weeks. The patients who required MV were treated more often with plasma exchange. Independent predictors of tracheostomy due to weaning trial failure were facial, bulbar, neck flexor weakness, autonomic dysfunction, associated cardiovascular morbidities and axonal electrophysiological subtype on nerve conduction study., Conclusions: Our study indicates distinct predictors of MV and tracheostomy in GBS patients., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Based on epidemiologic and laboratory studies, exposure to air pollutants has been linked to many adverse health effects including a higher risk of dementia. In this study, we aimed to evaluate the effect of long-term exposure to outdoor air pollution on risk of conversion to dementia in a cohort of subjects with mild cognitive impairment (MCI)., Methods: We recruited 53 Italian subjects newly-diagnosed with MCI. Within a geographical information system, we assessed recent outdoor air pollutant exposure, by modeling air levels of particulate matter with equivalent aerodynamic diameter ≤10 μm (PM 10 ) from motorized traffic at participants' residence. We investigated the relation of PM 10 concentrations to subsequent conversion from MCI to any type of dementia. Using a Cox-proportional hazards model combined with a restricted cubic spline model, we computed the hazard ratio (HR) of dementia with its 95% confidence interval (CI) according to increasing PM 10 exposure, adjusting for sex, age, and educational attainment., Results: During a median follow up of 47.3 months, 34 participants developed dementia, in 26 cases diagnosed as Alzheimer's dementia. In non-linear restricted spline regression analysis, mean and maximum annual PM 10 levels positively correlated with cerebrospinal fluid total and phosphorylated tau proteins concentrations, while they were inversely associated with β-amyloid. Concerning the risk of dementia, we found a positive association starting from above 10 μg/m 3 for mean PM 10 levels and above 35 μg/m 3 for maximum PM 10 levels. Specific estimates for Alzheimer's dementia were substantially similar. Adding other potential confounders to the multivariable model or removing early cases of dementia onset during the follow-up had little effect on the estimates., Conclusions: Our findings suggest that exposure to outdoor air pollutants, PM 10 in particular, may non-linearly increase conversion from MCI to dementia above a certain ambient air concentration., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The last ILAE definition of Status Epilepticus (SE) highlights that the persistence of the epileptic activity per se could determine irreversible brain damages that could be responsible for long-term consequences. The measurement of neuro-glial injury biomarkers could help in the identification of those patients who will eventually develop short- and long-term consequences of SE. At present none of the already studied biomarkers has been validated to be used in everyday clinical practice. In this study, we explore the role of NfL and S100B as a prognostic biomarkers to identify patients who will develop short-term disability after an episode of SE., Methods: This is a retrospective assessment of the serum levels of both NfL and S100B in a cohort of 87 adult patients with SE prospectively collected in our SE registry (Modena Status Epilepticus Registry - MoSER -) at Baggiovara Civil Hospital (Modena, Italy). All samples were acquired during SE within 72 hours of SE diagnosis. The comparison groups were: healthy controls (HC, n = 27) and patients with epilepsy (PWE, n = 30). Demographic, clinical, and therapeutical information and thirty-days follow-up information regarding disability development were acquired for every included patient and analyzed in relation to NfL and S100B values., Results: Serum levels of NfL were significantly higher in SE compared to those of PWE (median 7.35 pg/ml, IQR 6.4, p < 0.001) and HC (median 6.57 pg/ml, IQR 9.1, p < 0.001); S100B serum levels were higher in SE (median 0.11 ug/L, IQR 0.18) compared to PWE (median 0.03 ug/L, IQR 0.03, p < 0.001) and HC (median 0.02 ug/L, IQR 0.008, p < 0.001). However, only NfL serum levels were found to be an independent predictor of 30 days functional outcome whereas S100B levels did not., Conclusions: Our results suggest that NfL measurement in serum during SE could help predict the short-term functional outcome. This paper was presented at the 8th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures held in September 2022., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Progranulin protein (GRN) is a growth factor, encoded by the GRN (Granulin precursor) gene, involved in several functions including inflammation, wound repair, signal transduction, proliferation, and tumorigenesis. Mutations in GRN gene are usually the genetic etiology of frontotemporal dementia (FTD), but different studies reported GRN mutations in Alzheimer 's disease (AD) patients., Objective: Here, we analyzed FTD linked gene GRN in 23 patients with a clinical diagnosis of AD and a family history of AD (FAD), not carrying mutations in AD candidate genes (PSEN 1, PSEN 2, and APP). In addition, Microtubule-associated protein tau (MAPT) gene was studied too. All patients underwent an extensive neuropsychological battery., Methods: Genetic analyses were performed thought PCR assay and sequencing. Variants were annotated with ANNOVAR and allele frequency was checked on population databases. In silico prediction tools were consulted to check nonsynonymous variants and their effect on protein function and structure. The clinical data were retrospectively collected from medical records., Results: Genetic screening of MAPT and GRN in 23 FAD patients highlighted two rare different variants in two probands (2/23 = 8,7%) located in GRN gene: R433W (p.Arg433Trp) and C521Y (p.Cys521Tyr). The R433W and C521Y are variants with uncertain significant, that are predicted to affect GRN protein structure and function, with a possible damaging effect., Conclusions: Our data provide evidence of the importance of GRN genetic analysis also in the study of familial AD.