UNASSIGNED: The hepatitis E virus (HEV) can cause acute viral hepatitis with or without neurological manifestations, and occasionally progresses to chronic infection in immunocompromised individuals. The management of chronic HEV infection in cancer patients may be challenging due to the complex immunological constellation. Furthermore, the diagnostic workflow and the impact on quality of life of neurological HEV manifestations in immunocompromised patients have not been sufficiently delineated previously.
UNASSIGNED: A 61-year-old male with systemically treated chronic lymphocytic leukemia (CLL) experienced a slowly progressive atrophy of the spinal cord due to a chronic HEV infection. Despite continuous antiviral treatment with ribavirin, the patient\'s neurological condition continued to deteriorate, particularly following subsequent attempts to treat CLL. Treatment with obinutuzumab resulted in acute bowel and urinary retention and a further deterioration of motor skills, prompting the discontinuation of obinutuzumab. The patient\'s neurological status improved after the administration of intravenous immunoglobulins.
UNASSIGNED: This case study provides a comprehensive long-term follow-up of a cancer patient with chronic HEV infection and associated CNS involvement, which resulted in progressive neurological disability over several years. The challenges faced in diagnosing new neurological symptoms in patients undergoing immunosuppressive cancer treatment underscore the need for an interdisciplinary diagnostic approach that includes HEV testing. We propose a diagnostic pathway for future validation in immunocompromised cohorts presenting with neurological symptoms, emphasizing its potential to enhance clinical outcomes.

OBJECTIVE: This study aims to assess the association between APOE genotype and biomarkers of neurodegeneration in Alzheimer\'s disease (AD).
METHODS: We performed a retrospective observational study at the University Hospital \"P. Giaccone\" in Palermo, Italy. We enrolled patients with cognitive decline, including AD. For each patient, we measured amyloid beta (Aβ)42, Aβ40, tau protein phosphorylated at threonine 181 (pTau), total tau (tTau), neurogranin, alpha-synuclein, and neurofilament light chain (NfL) in cerebrospinal fluid (CSF).
RESULTS: The study population consisted of 194 patients (123 AD and 71 non-AD). AD patients have significantly lower Aβ42 levels and Aβ42/40 ratio and higher pTau, tTau, and NfLs levels than non-AD patients. In AD patients, the APOEε4 allele is associated with a significantly lower Aβ42/40 ratio and higher levels of pTau, tTau, neurogranin, and alpha-synuclein. This association is not observed in non-AD patients.
CONCLUSIONS: This study provides evidence of the significant impact of the APOE ε4 allele on neurodegenerative biomarkers in AD patients, highlighting its role in exacerbating amyloid and tau pathology as well as synaptic degeneration.

UNASSIGNED: Antiretroviral therapy (ART)-conferred suppression of HIV replication limits neuronal injury and inflammation. ART interruption tests efficacy in HIV cure trials and viral rebound after ART interruption may induce neuronal injury. We investigated the impact of protocol-defined ART interruption, commenced during primary HIV-1 infection (PHI) on a biomarker of neuro-axonal injury (neurofilament light protein (NfL)), and its associations with inflammation (D-dimer and interleukin-6 (IL-6)) and HIV-1 reservoir size (total HIV-1 DNA).
UNASSIGNED: Retrospective study measuring plasma NfL in 83 participants enrolled in SPARTAC randomised to receive 48-weeks ART initiated during PHI, followed by ART interruption.
UNASSIGNED: NfL (Simoa immunoassay, Quanterix™) was measured before ART, after 48 weeks on ART, and 12 weeks after stopping ART. Plasma D-dimer and IL-6, and total HIV-1 DNA in peripheral CD4+ T-cells results were available in a subset of participants. Longitudinal NfL changes were assessed using mixed models, and associations with clinical and laboratory parameters using linear regression.
UNASSIGNED: NfL decreased following 48-weeks ART (geometric mean 6.9 to 5.8 pg/mL, p = 0.006) with no further significant change up to 12-weeks post-stopping ART despite viral rebound in the majority of participants (median 1.7 to 3.9 plasma HIV-1 RNA log10 copies/mL). Higher baseline NfL was independently associated with higher plasma HIV-1 RNA (p = 0.020) and older age (p = 0.002). While NfL was positively associated with D-dimer (n = 48; p = 0.002), there was no significant association with IL-6 (n = 48) or total HIV-1 DNA (n = 51).
UNASSIGNED: Using plasma NfL as a surrogate marker, a decrease in neuro-axonal injury was observed in a cohort of participants following ART initiation during PHI, with no evidence of neuro-axonal injury rebound following ART interruption for up to 12 weeks, despite viral rebound in the majority of participants.

OBJECTIVE: The aim was to investigate whether neurofilament light chain (NfL) and profilin-1 (PFN-1) might qualify as surrogate disease and treatment-response biomarkers by correlating their concentrations dynamic with clinical status in a cohort of 30 adult spinal muscular atrophy type 3 patients during nusinersen therapy up to 34 months.
METHODS: Neurofilament light chain was measured in cerebrospinal fluid at each drug administration with a commercial enzyme-linked immunosorbent assay (ELISA); PFN-1 concentrations were tested in serum sampled at the same time points with commercial ELISA assays. Functional motor scores were evaluated at baseline, at the end of the loading phase and at each maintenance dose and correlated to biomarker levels. The concurrent effect of age and clinical phenotype was studied.
RESULTS: Neurofilament light chain levels were included in the reference ranges at baseline; a significant increase was measured during loading phase until 1 month. PFN-1 was higher at baseline than in controls and then decreased during therapy until reaching control levels. Age had an effect on NfL but not on PFN-1. NfL was partially correlated to functional scores at baseline and at last time point, whilst no correlation was found for PFN-1.
CONCLUSIONS: Cerebrospinal fluid NfL levels did not qualify as an optimal surrogate treatment biomarker in adult spinal muscular atrophy patients with a long disease duration, whilst PFN-1 might to a greater extent represent lower motor neuron pathological processes. The observed biomarker level variation during the first 2 months of nusinersen treatment might suggest a limited effect on axonal remodeling or rearrangement.

UNASSIGNED: While John Cunningham virus (JCV) is known to cause neuronal damage in progressive multifocal leukoencephalopathy (PML) among natalizumab-treated MS patients, its association with axonal loss in non-PML conditions remains unclear.
UNASSIGNED: In a cohort of 128 natalizumab-treated MS patients, serum neurofilament (sNfL) levels and JCV antibody titres were measured.
UNASSIGNED: Among 128 patients (mean age = 38.4 years, 71.9% female), 51 (40%) were JCV positive. NfL levels increased by 15.3% for JCV index <0.7 (95% confidence interval [CI] = 0.963-1.381), by 18.6% for index 0.7-1.5 (95% CI = 1.009-1.394) and by 21.1% for index >1.5 (95% CI = 1.040-1.409) compared to JCV negative patients.
UNASSIGNED: These findings indicate a potential link between JCV burden and neuroaxonal degeneration in natalizumab-treated MS patients.

Biallelic variants in the SPG11 gene account for the most common form of autosomal recessive hereditary spastic paraplegia characterized by motor and cognitive impairment, with currently no therapeutic option. We previously observed in a Spg11 knockout mouse that neurodegeneration is associated with accumulation of gangliosides in lysosomes. To test whether a substrate reduction therapy could be a therapeutic option, we downregulated the key enzyme involved in ganglioside biosynthesis using an AAV-PHP.eB viral vector expressing a miRNA targeting St3gal5. Downregulation of St3gal5 in Spg11 knockout mice prevented the accumulation of gangliosides, delayed the onset of motor and cognitive symptoms, and prevented the upregulation of serum levels of neurofilament light chain, a biomarker widely used in neurodegenerative diseases. Importantly, similar results were observed when Spg11 knockout mice were administrated venglustat, a pharmacological inhibitor of glucosylceramide synthase expected to decrease ganglioside synthesis. Downregulation of St3gal5 or venglustat administration in Spg11 knockout mice strongly decreased the formation of axonal spheroids, previously associated with impaired trafficking. Venglustat had similar effect on cultured human SPG11 neurons. In conclusion, this work identifies the first disease-modifying therapeutic strategy in SPG11, and provides data supporting its relevance for therapeutic testing in SPG11 patients.

Frontotemporal lobar degeneration (FTLD) encompasses behavioral variant frontotemporal dementia (bvFTD), progressive supranuclear palsy, corticobasal syndrome/degeneration, and primary progressive aphasias (PPAs). We cross-validated fluid biomarkers and neuroimaging.
Seven fluid biomarkers from cerebrospinal fluid and serum were related to atrophy in 428 participants including these FTLD subtypes, logopenic variant PPA (lvPPA), Alzheimer\'s disease (AD), and healthy subjects. Atrophy was assessed by structural magnetic resonance imaging and atlas-based volumetry.
FTLD subtypes, lvPPA, and AD showed specific profiles for neurofilament light chain, phosphorylated heavy chain, tau, phospho-tau, amyloid beta1-42 from serum/cerebrospinal fluid, and brain atrophy. Neurofilaments related to regional atrophy in bvFTD, whereas progranulin was associated with atrophy in semantic variant PPA. Ubiquitin showed no effects.
Results specify biomarker and atrophy patterns in FTLD and AD supporting differential diagnosis. They identify neurofilaments and progranulin in interaction with structural imaging as promising candidates for monitoring disease progression and therapy.
Study cross-validated neuroimaging and fluid biomarkers in dementia. Five kinds of frontotemporal lobar degeneration and two variants of Alzheimer\'s disease. Study identifies disease-specific fluid biomarker and atrophy profiles. Fluid biomarkers and atrophy interact in a disease-specific way. Neurofilaments and progranulin are proposed as biomarkers for diagnosis and therapy.

Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition\'s clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound\'s putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease that represents a leading cause of non-traumatic disability among young and middle-aged adults. MS is characterized by neurodegeneration caused by axonal injury. Current clinical and radiological markers often lack the sensitivity and specificity required to detect inflammatory activity and neurodegeneration, highlighting the need for better approaches. After neuronal injury, neurofilament light chains (NfL) are released into the cerebrospinal fluid, and eventually into blood. Thus, blood-based NfL could be used as a potential biomarker for inflammatory activity, neurodegeneration, and treatment response in MS. The objective of this study was to determine the value contribution of blood-based NfL as a biomarker in MS in Spain using the Multi-Criteria Decision Analysis (MCDA) methodology.
A literature review was performed, and the results were synthesized in the evidence matrix following the criteria included in the MCDA framework. The study was conducted by a multidisciplinary group of six experts. Participants were trained in MCDA and scored the evidence matrix. Results were analyzed and discussed in a group meeting through reflective MCDA discussion methodology.
MS was considered a severe condition as it is associated with significant disability. There are unmet needs in MS as a disease, but also in terms of biomarkers since no blood biomarker is available in clinical practice to determine disease activity, prognostic assessment, and response to treatment. The results of the present study suggest that quantification of blood-based NfL may represent a safe option to determine inflammation, neurodegeneration, and response to treatments in clinical practice, as well as to complement data to improve the sensitivity of the diagnosis. Participants considered that blood-based NfL could result in a lower use of expensive tests such as magnetic resonance imaging scans and could provide cost-savings by avoiding ineffective treatments. Lower indirect costs could also be expected due to a lower impact of disability consequences. Overall, blood-based NfL measurement is supported by high-quality evidence.
Based on MCDA methodology and the experience of a multidisciplinary group of six stakeholders, blood-based NfL measurement might represent a high-value-option for the management of MS in Spain.

UNASSIGNED: Multiple sclerosis (MS) is one of the most common demyelinating diseases of the central nervous system. We aimed to investigate serum and cerebrospinal fluid levels of different laboratory inflammatory biomarkers in patients with MS.
UNASSIGNED: A total of 120 subjects participated in the study, 60 of whom were diagnosed with MS, 30 with the final diagnosis of non-inflammatory diseases of the central nervous system (CNS), and 30 healthy subjects representing the control group. Regarding the progression of radiological findings after 2 years from the initial diagnosis, the MS group was divided into stationary radiological findings (n=30) and radiologically proven disease progression (n=30). In all patients, we analyzed levels of laboratory inflammatory biomarkers: C reactive protein (CRP), Neutrophil-to-lymphocyte ratio (NLR), Growth differentiation factor 15 (GDF15) in serum samples, and neurofilaments (NFs) in cerebrospinal fluid (CSF). NFs and GDF15 were analyzed initially, while CRP and NLR values were analyzed initially and after two years.
UNASSIGNED: We found statistically lower GDF15 values and initial CRP values in the MS group regarding the group with non-inflammatory diseases of the CNS (p<0.0001). On the other side, we determined a significant elevation of laboratory markers CRP and NLR, initially and after a two-year period, in the MS subgroup with the progression of magnetic resonance imaging (MRI) findings (p<0.0001 and p=0.050, respectively). Also, we found a positive correlation between CRP and NFs (r=0.243, p=0.04), as well as a positive correlation between CRP and GDF15 in patients with MS (r=0.769, p<0.0001).
UNASSIGNED: We found a significant elevation of laboratory markers of systemic inflammation, CRP, and NLR in MS patients who developed disease progression based on MRI findings. There is a need for further studies to validate current parameters to be considered as useful markers of MS activity and disability.
UNASSIGNED: Multipla skleroza je jedna od najčešćih demijelinizujućih bolesti centralnog nervnog sistema. Cilj rada je bio da se ispitaju vrednosti različitih laboratorijskih inflamatornih biomarkera u serumu i cerebrospinalnoj tečnosti kod pacijenata sa multiplom sklerozom (MS).
UNASSIGNED: U istraživanju je učestvovalo ukupno 120 ispitanika, od kojih je 60 sa dijagnozom MS, 30 sa konačnom dijagnozom neinflamatornih bolesti centralnog nervnog sistema (CNS) i 30 zdravih ispitanika koji su činili kontrolnu grupu. U pogledu progresije radioloških nalaza nakon 2 godine od inicijalne dijagnoze, MS grupa je podeljena u podgrupe: sa stacionarnim radiološkim nalazom (n=30) i sa radiološki dokazanom progresijom bolesti (n=30). Kod svih pacijenata smo analizirali vrednosti laboratorijskih inflamatornih biomarkera: C reaktivni protein (CRP), NLR (odnos neutrofila i limfocita), faktor diferencijacije rasta 15 (GDF15) u uzorcima seruma i neurofilamenti (NFs) iz cerebrospinalne tečnosti (CSF). Vrednosti NFs i GDF15 su analizirane inicijalno, dok su vrednosti CRP i NLR analizirane inicijalno i nakon dve godine.
UNASSIGNED: Rezultati studije ukazuju na statistički niže vrednosti GDF15 i vrednosti CRP inicijalno merenog u grupi sa MS u odnosu na grupu sa neinflamatornim oboljenjima CNS (p<0.0001). Sa druge strane, utvrdili smo signifikantno više vrednosti CRP i NLR, inicijalno i nakon dvogodišnjeg perioda, u MS podgrupi sa progresijom MRI nalaza (p<0.0001 i p=0,050, respektivno). Takođe smo utvrdili pozitivnu korelaciju CRP i NFs (r=0,243, p=0,04), kao i pozitivnu korelaciju CRP i GDF15 kod pacijenata sa MS (r=0,769, p<0.0001).
UNASSIGNED: Kod pacijenata sa dijagnozom MS kod kojih je došlo do progresije bolesti na osnovu nalaza MRI uoćava se značajno povećanje laboratorijskih markera sistemske inflamacije, CRP i NLR. Postoji potreba za daljim ispitivanjima kako bi se navedeni parametri potvrdili korisnim markerima aktivnosti i progresije obolelih od multiple skleroze.