Neurofilament light chain and glial fibrillary acid protein levels are elevated in post-mild COVID-19 or asymptomatic SARS-CoV-2 cases.

Given the huge impact of the COVID-19 pandemic, it appears of paramount importance to assess the cognitive effects on the population returning to work after COVID-19 resolution. Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) represent promising biomarkers of neuro-axonal damage and astrocytic activation. In this cohort study, we explored the association between sNfL and sGFAP concentrations and cognitive performance in a group of 147 adult workers with a previous asymptomatic SARS-CoV-2 infection or mild COVID-19, one week and, in 49 of them, ten months after SARS-Cov2 negativization and compared them to a group of 82 age and BMI-matched healthy controls (HCs). sNfL and sGFAP concentrations were assessed using SimoaTM assay Neurology 2-Plex B Kit. COVID-19 patients were interviewed one-on-one by trained physicians and had to complete a list of questionnaires, including the Cognitive Failure Questionnaire (CFQ). At the first assessment (T0), sNfL and sGFAP levels were significantly higher in COVID-19 patients than in HCs (p < 0.001 for both). The eleven COVID-19 patients with cognitive impairment had significantly higher levels of sNfL and sGFAP than the others (p = 0.005 for both). At the subsequent follow-up (T1), sNfL and sGFAP levels showed a significant decrease (median sNfL 18.3 pg/mL; median sGFAP 77.2 pg/mL), although they were still higher than HCs (median sNfL 7.2 pg/mL, median sGFAP 63.5 pg/mL). Our results suggest an ongoing damage involving neurons and astrocytes after SARS-Cov2 negativization, which reduce after ten months even if still evident compared to HCs.

Familial Alzheimer's disease associated with heterozygous NPC1 mutation.

INTRODUCTION: NPC1 mutations are responsible for Niemann-Pick disease type C (NPC), a rare autosomal recessive neurodegenerative disease. Patients harbouring heterozygous NPC1 mutations may rarely show parkinsonism or dementia. Here, we describe for the first time a large family with an apparently autosomal dominant late-onset Alzheimer's disease (AD) harbouring a novel heterozygous NPC1 mutation. METHODS: All the five living siblings belonging to the family were evaluated. We performed clinical evaluation, neuropsychological tests, assessment of cerebrospinal fluid markers of amyloid deposition, tau pathology and neurodegeneration (ATN), structural neuroimaging and brain amyloid-positron emission tomography. Oxysterol serum levels were also tested. A wide next-generation sequencing panel of genes associated with neurodegenerative diseases and a whole exome sequencing analysis were performed. RESULTS: We detected the novel heterozygous c.3034G>T (p.Gly1012Cys) mutation in NPC1, shared by all the siblings. No other point mutations or deletions in NPC1 or NPC2 were found. In four siblings, a diagnosis of late-onset AD was defined according to clinical characterisation and ATN biomarkers (A+, T+, N+) and serum oxysterol analysis showed increased 7-ketocholesterol and cholestane-3ß,5α,6ß-triol. DISCUSSION: We describe a novel NPC1 heterozygous mutation harboured by different members of a family with autosomal dominant late-onset amnesic AD without NPC-associated features. A missense mutation in homozygous state in the same aminoacidic position has been previously reported in a patient with NPC with severe phenotype. The alteration of serum oxysterols in our family corroborates the pathogenic role of our NPC1 mutation. Our work, illustrating clinical and biochemical disease hallmarks associated with NPC1 heterozygosity in patients affected by AD, provides relevant insights into the pathogenetic mechanisms underlying this possible novel association.

Clinically relevant increases in serum neurofilament light chain and glial fibrillary acidic protein in patients with Susac syndrome.

BACKGROUND AND PURPOSE: Serum levels of neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising neuro-axonal damage and astrocytic activation biomarkers. Susac syndrome (SS) is an increasingly recognized neurological condition and biomarkers that can help assess and monitor disease evolution are highly needed for the adequate management of these patients. sNfL and sGFAP levels were evaluated in patients with SS and their clinical relevance in the relapse and remission phase of the disease was assessed. METHODS: As part of a multicentre study that enrolled patients diagnosed with SS from six international centres, sNfL and sGFAP levels were assessed in 22 SS patients (nine during a relapse and 13 in remission) and 59 age- and sex-matched healthy controls using SimoaTM assay Neurology 2-Plex B Kit. RESULTS: Serum NfL levels were higher than those of healthy controls (p < 0.001) in SS patients and in both subgroups of patients in relapse and in remission (p < 0.001 for both), with significantly higher levels in relapse than in remission (p = 0.008). sNfL levels showed a negative correlation with time from the last relapse (r = -0.663; p = 0.001). sGFAP levels were slightly higher in the whole group of patients than in healthy controls (p = 0.046) and were more pronounced in relapse than in remission (p = 0.013). CONCLUSION: In SS patients, both sNFL and sGFAP levels increased compared with healthy controls. Both biomarkers had higher levels during clinical relapse and much lower levels in remission. sNFL was shown to be time sensitive to clinical changes and can be useful to monitor neuro-axonal damage in SS.

Brain neuronal and glial damage during acute COVID-19 infection in absence of clinical neurological manifestations.

BACKGROUND: To assess whether SARS-CoV-2 infection may affect the central nervous system, specifically neurons and glia cells, even without clinical neurological involvement. METHODS: In this single centre prospective study, serum levels of neurofilament light chain (sNfL) and glial fibrillar acidic protein (sGFAp) were assessed using SimoaTM assay Neurology 2-Plex B Assay Kit, in 148 hospitalised patients with COVID-19 without clinical neurological manifestations and compared them to 53 patients with interstitial pulmonary fibrosis (IPF) and 108 healthy controls (HCs). RESULTS: Age and sex-corrected sNfL levels were higher in patients with COVID-19 (median log10-sNfL 1.41; IQR 1.04-1.83) than patients with IPF (median log10-sNfL 1.18; IQR 0.98-1.38; p<0.001) and HCs (median log10-sNfL 0.89; IQR 0.72-1.14; p<0.001). Likewise, age and sex-corrected sGFAP levels were higher in patients with COVID-19 (median log10-sGFAP 2.26; IQR 2.02-2.53) in comparison with patients with IPF (median log10-sGFAP 2.15; IQR 1.94-2.30; p<0.001) and HCs (median log10-sGFAP 1.87; IQR 0.64-2.09; p<0.001). No significant difference was found between patients with HCs and IPF (p=0.388 for sNfL and p=0.251 for sGFAp). In patients with COVID-19, a prognostic model with mortality as dependent variable (26/148 patients died during hospitalisation) and sNfl, sGFAp and age as independent variables, showed an area under curve of 0.72 (95% CI 0.59 to 0.84; negative predictive value (NPV) (%):80,positive predictive value (PPV)(%): 84; p=0.0008). CONCLUSION: The results of our study suggest that neuronal and glial degeneration can occur in patients with COVID-19 regardless of overt clinical neurological manifestations. With age, levels of sNfl and GFAp can predict in-hospital COVID-19-associated mortality and might be useful to assess COVID-19 patient prognostic profile.

B Lymphocytes in Alzheimer's Disease-A Comprehensive Review.

Alzheimer's disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-ß (Aß) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of "inflammaging", which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aß in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aß and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications.

Primary familial brain calcification with mild phenotype due to a new PDGFB mutation.

INTRODUCTION: Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder that presents cognitive and movement impairment. To diagnose PFBC, both brain calcium accumulations visible at computed tomography (CT) and autosomal dominant or recessive inherited genetic mutation(s) in one of the known genes have to be detected. We describe the case of a female patient aging 62, who presents marked calcifications at brain CT, not due to vitamin D deficiency. These data generated the suspect of PFBC. The patient has two young sons. MATERIALS AND METHODS: The patient first, and her two sons later, underwent clinical and neurological examinations, brain CT, and blood draw for genetic analysis at our clinic. RESULTS: Patient's neurological exams detected gait impairment and tremor of the hands. Brain CT showed calcification of the basal ganglia, cerebellar dentate nuclei, and white matter. Laboratory exams identified high serum parathormone (PTH) and low plasmatic levels of vitamin D; supplementation with vitamin D normalized PTH values. Genetic analysis of the known PFBC-causing genes uncovered a new pathogenic mutation in PDGFB. The same calcifications and genetic variant were found in her younger son. DISCUSSION: Our report presents the case of a patient mildly affected by PFBC due to a novel PDGFB mutation that could have been mistaken with hyperparathyroidism if any further investigations had not been performed. Her younger asymptomatic son bore the same calcification and mutation of the mother, highlighting the importance of family pedigree collection and early diagnosis for prevention of symptoms' onset with future treatments.

Vitamin D in Neurological Diseases.

Vitamin D may have multiple effects on the nervous system and its deficiency can represent a possible risk factor for the development of many neurological diseases. Recent studies are also trying to clarify the different effects of vitamin D supplementation over the course of progressive neurological diseases. In this narrative review, we summarise vitamin D chemistry, metabolism, mechanisms of action, and the recommended daily intake. The role of vitamin D on gene transcription and the immune response is also reviewed. Finally, we discuss the scientific evidence that links low 25-hydroxyvitamin D concentrations to the onset and progression of severe neurological diseases, such as multiple sclerosis, Parkinson's disease, Alzheimer's disease, migraine, diabetic neuropathy and amyotrophic lateral sclerosis. Completed and ongoing clinical trials on vitamin D supplementation in neurological diseases are listed.

Co-occurrence of DMPK expansion and CLCN1 mutation in a patient with myotonia.

INTRODUCTION: Myotonic disorders are a group of diseases affecting the muscle, in different ways. Myotonic dystrophy type 1 (DM1) is related to (CTG)n expansion in the 3-untranslated region of the dystrophia myotonica protein kinase (DMPK) gene and is the most frequent and disabling form, causing muscular, visibility, respiratory, and cardiac impairment. Non-dystrophic myotonias (NDMs) affect the skeletal muscle alone. In particular, mutations in the chloride channel (CLCN1) gene cause myotonia congenita (MC), which can have autosomal dominant or recessive inheritance. CASE REPORT: We describe a patient with a family history of asymptomatic or paucisymptomatic myotonia, who presented handgrip myotonia which sharply reduced after mexiletine administration. Molecular analysis showed both a paternally inherited DMPK expansion and a maternally inherited CLCN1 mutation. CONCLUSIONS: Only one other similar case was reported so far; however, the segregation of the two mutations and the characteristics of the muscle were not studied. Since our patient lacked the classical phenotypical and muscle histopathological characteristics of DM1 and showed mild splicing alterations despite a pathogenic DMPK expansion and the nuclear accumulation of toxic RNA, we may speculate that the co-occurrence of a CLCN1 mutation could have attenuated the severity of DM1 phenotype.

Gordon Holmes syndrome caused by two novel mutations in the PNPLA6 gene.

Gordon Holmes syndrome (GHS) is an autosomal recessive disease characterized by cerebellar ataxia and hypogonadotropic hypogonadism. Among the genes associated with this syndrome, mutations in PNPLA6 have been detected and correlated with the phenotype of GHS. We report a case of a patient affected with GHS, confirmed by physical, neurological, laboratory and genetic analyses. Two compound heterozygous missense mutations on the PNPLA6 gene described as probably damaging/damaging in multiple in silico predictive tools have been detected with massive multigene sequencing. Interestingly, brain MRI uncovered abnormalities in the periventricular white matter, which so far have not been associated with GHS caused by PNPLA6 mutations.