Search Results (199)

Prion diseases are fatal neurological disorders characterized by abnormal protein accumulation in the brain, leading to neurodegeneration, dementia, and ataxia. Sporadic Creutzfeldt–Jakob disease (sCJD), the most common form, accounts for 80–90% of cases and progresses rapidly, with most patients surviving <6 months to a year after symptom onset, indicating the importance of early diagnosis. The disease is classified into six subtypes based on PRNP gene polymorphisms, with differences in protein degradation patterns contributing to the diversity of clinical symptoms. However, diagnosis remains challenging because of the variability in clinical presentation and disease duration. Traditional diagnostic criteria established by the World Health Organization (WHO) rely on clinical findings, electroencephalogram, and cerebrospinal fluid tests, such as the 14-3-3 protein assay. However, these criteria require pathological confirmation, often delaying diagnosis. The recently proposed Hermann’s criteria represent a significant advancement by incorporating newer biomarkers, including magnetic resonance imaging, real-time quaking-induced conversion assay, tau protein, and neurofilament light chain. These criteria improve diagnostic sensitivity and specificity but have a slightly higher risk of false positives. This review compares the effectiveness of these biomarkers with the WHO criteria and highlights the importance of early diagnosis for improving patient care. Full article

Cognitive impairment induced by chronic methamphetamine (METH) exposure exhibits similarities to neurodegenerative disorders and is associated with blood–brain barrier (BBB) dysfunction. However, the potential involvement of β-catenin in maintaining BBB integrity during METH exposure remains unexplored. In this study, Y-maze and novel object recognition tests were conducted to assess cognitive impairment in mice exposed chronically to methamphetamine for 2 and 4 weeks. Gd-DTPA and Evans blue leakage tests revealed disruption of the BBB in the hippocampus, while chronic METH exposure for 2 and 4 weeks significantly decreased β-catenin levels along with its transcriptionally regulated protein, claudin5. Additionally, various neural injury-related proteins, such as APP, Aβ1–42, p-tau (Thr181) and p-tau (Ser396), as well as neuroinflammation-related proteins, such as IL-6, IL-1β, and TNF-α, exhibited increased levels following chronic METH exposure. Furthermore, plasma analysis indicated elevated levels of p-Tau (total), neurofilament light chain, and GFAP. In vitro experiments demonstrated that exposure to METH resulted in dose-dependent and time-dependent reductions in cellular activity and connectivity of bEnd.3 and hcmec/D3 cells. Furthermore, β-catenin exhibited decreased levels and altered subcellular localization, transitioning from the cell membrane to the cytoplasm and nucleus upon METH exposure. Overexpression of β-catenin was found to alleviate endothelial toxicity and attenuate junctional weakening induced by METH. The aforementioned findings underscore the crucial involvement of β-catenin in endothelial cells during chronic METH exposure-induced disruption of the BBB, thereby presenting a potential novel target for addressing METH-associated cerebrovascular dysfunction and cognitive impairment. Full article

Background: The Notch signaling pathway is an important regulator of stem cell activity in various tissues, including the central nervous system. It has been implicated in neurodevelopmental processes, including neuronal differentiation and synaptic plasticity. Research suggests that its expression may be associated with certain epileptogenic lesions, particularly those with neurodevelopmental origin. The aim of this study was to investigate the expression of Notch-1 in brain biopsies from various cases of pharmacoresistant epilepsy. Methods: Here, we used immunohistochemistry staining to retrospectively analyze 128 developmental lesions associated with pharmacoresistant epilepsy, including 13 cases with focal cortical dysplasia (FCD) type I, 39 with FCD type II, 37 with hippocampal sclerosis (HS), 23 with FCD IIIc, 9 with mild malformations of cortical development (MCD), 4 cases with mild malformation of cortical development with oligodendroglial hyperplasia and epilepsy (MOGHE), and 3 with tuberous sclerosis (TS). The tissues were stained for Neurofilament protein, Vimentin, S-100 protein, NeuN, and GFAP, as well as the stem cell marker Notch-1. Tissue that stained positively for Notch-1 was further characterized. Results: A positive Notch-1 reaction was found in all cases of FCD type IIb and TS, where it appeared in balloon cells but not in dysmorphic neurons, and in a single case of meningioangiomatosis (FCD IIIc), where it stained spider-like cells. Notch-1-positive cells showed a stem-like, glio-neuronal precursor immunophenotype. No staining was observed in the remaining cases with FCD type I, type III, HS, mild MCD, and MOGHE. Conclusions: Notch-1 displays a distinct pattern of expression in some epileptogenic lesions, potentially highlighting a stem cell-like origin or neurodevelopmental abnormalities contributing to pharmacoresistant epilepsy; however, it is not a general marker of such lesions. Its differential expression may prove useful in distinguishing between different types of FCD or other cortical malformations, which could assist in both their diagnosis and potentially in the development of more targeted therapeutic approaches. Further studies with different stem cell markers are needed in this direction. Full article

Anti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer’s disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity. Full article

Plasma biomarkers are promising tools for the screening and diagnosis of dementia in clinical settings. We analyzed plasma levels of Alzheimer’s core biomarkers, neurofilament light chain (NfL) and glial fibrillary acid protein (GFAP), through single-molecule Array in 108 patients with Alzheimer’s (AD, cerebrospinal fluid with an amyloid+ tau+ neurodegeneration+ profile), 73 patients with frontotemporal dementia (FTD, 24 with genetic diagnosis), and 54 controls. The best area under the curve (AUC) was used to assess the discriminative power. Patients with AD had lower Aß42/40 ratios and NfL levels, along with higher levels of p-tau181 and GFAP, compared with FTD patients. Single biomarkers discriminated well between dementia patients and controls: the Aß42/40 ratio (AUC:0.86) or GFAP (AUC:0.83) was found for AD, and the NfL (AUC:0.84) was found for FTD patients. However, a combination of two (NfL with p-tau181, or the GFAP/NfL ratio, AUCs ~0.87) or three biomarkers (NfL, P-tau181, and Aß42/40 ratio, AUC: 0.90) was required to distinguish between AD and FTD. Biomarker profiles were similar across different FTD phenotypes, except for carriers of PGRN mutations, who had higher levels of NfL than C9orf72 expansion carriers. In our series, NfL alone provided the best distinction between FTD and controls, while a combination of two or three biomarkers was required to obtain good discrimination between AD and FTD. Full article

The coordination of cytoskeletal proteins shapes cell architectures and functions. Age-related changes in cellular mechanical properties have been linked to decreased cellular and tissue dysfunction. Studies have also found a relationship between mitochondrial function and the cytoskeleton. Cytoskeleton inhibitors impact mitochondrial quality and function, including motility and morphology, membrane potential, and respiration. The regulatory properties of the cytoskeleton on mitochondrial functions are involved in the pathogenesis of several diseases. Disassembly of the axon’s cytoskeleton and the release of neurofilament fragments have been documented during neurodegeneration. However, these changes can also be related to mitochondrial impairments, spanning from reduced mitochondrial quality to altered bioenergetics. Herein, we discuss recent research highlighting some of the pathophysiological roles of cytoskeleton disassembly in aging, neurodegeneration, and neuromuscular diseases, with a focus on studies that explored the relationship between intermediate filaments and mitochondrial signaling as relevant contributors to cellular health and disease. Full article

Background: The prognosis of people with multiple sclerosis (MS) has improved substantially in recent decades due to advances in diagnosis and treatment. Due to the unpredictable course and heterogenous treatment response in MS, there is a clear need for biomarkers that reflect disease activity in the clinical follow-up of these patients. We conducted a systematic review with Bayesian network meta-analysis with the aim of analyzing the effects of physical exercise on neurofilaments (NfL) and glial fibrillary acidic protein (GFAP) levels in patients with MS. Methods: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, starting with a PICO (patient/population, intervention, comparison, and outcome) question: what are the clinical effects of physical exercise (with independence of the type) on NfL and/or GFAP levels in patients with MS compared with other interventions or no intervention whatsoever? A systematically comprehensive literature search was conducted from January to March 2024 to identify original studies that answered the PICO question, using the main data sources. The quality of the studies included was assessed using the Quality Index of Downs & Black. For studies included in the systematic review that followed a randomized controlled trial (RCT) design, the methodological quality of each paper was assessed using the Physiotherapy Evidence Database (PEDro) Scale. Risk of bias was also explored by two independent reviewers. Finally, all articles were classified according to the levels of evidence and grades of recommendation for diagnosis studies established by the Oxford Center for Evidence-Based Medicine. For continuous outcome measures with enough comparisons and a methodological quality greater than or equal to good according to the PEDro scale, a Bayesian network meta-analysis (NMA) was applied. The statistical analyses were performed in R (version 4.1.3, R Core Team 2023) using the “BUGSnet” and “gemtc” packages. Bayesian NMA can be used to obtain a posterior probability distribution of all the relative treatment effects, which allows us to quantify the uncertainty of parameter estimates and to rank all the treatments in the network. Results: Eight studies were included in this systematic review and six articles in the NMA, and they were appraised for quality. The characteristics of the included studies, types of training and described protocols, methodological quality, risk of bias, and clinical effects on the studied biomarkers were outlined. Qualitative synthesis, effects of different exercise modalities in NfL with the Bayesian NMA, selection of the final model and model assessment, and ranking of interventions are also shown. Conclusions: Our findings indicated that moderate-intensity exercise is more likely to reduce NfL concentration compared to high-intensity exercise, and, in turn, high-intensity exercise is more likely to reduce NfL concentration than low-intensity exercise. However, the effects of high-intensity exercise on GFAP levels were inconclusive. Full article

Neurodegenerative disorders (NDs) cause progressive neuronal loss and are a significant public health concern, with NDs projected to become the second leading global cause of death within two decades. Huntington’s disease (HD) is a rare, progressive ND caused by an autosomal-dominant mutation in the huntingtin (HTT) gene, leading to severe neuronal loss in the brain and resulting in debilitating motor, cognitive, and psychiatric symptoms. Given the complex pathology of HD, biomarkers are essential for performing early diagnosis, monitoring disease progression, and evaluating treatment efficacy. However, the identification of consistent HD biomarkers is challenging due to the prolonged premanifest HD stage, HD’s heterogeneous presentation, and its multiple underlying biological pathways. This study involves a 10-year bibliometric analysis of HD biomarker research, revealing key research trends and gaps. The study also features a comprehensive literature review of emerging HD biomarkers, concluding the need for better stratification of HD patients and well-designed longitudinal studies to validate HD biomarkers. Promising candidate wet HD biomarkers— including neurofilament light chain protein (NfL), microRNAs, the mutant HTT protein, and specific metabolic and inflammatory markers— are discussed, with emphasis on their potential utility in the premanifest HD stage. Additionally, biomarkers reflecting brain structural deficits and motor or behavioral impairments, such as neurophysiological (e.g., motor tapping, speech, EEG, and event-related potentials) and imaging (e.g., MRI, PET, and diffusion tensor imaging) biomarkers, are evaluated. The findings underscore that the discovery and validation of reliable HD biomarkers urgently require improved patient stratification and well-designed longitudinal studies. Reliable biomarkers, particularly in the premanifest HD stage, are crucial for optimizing HD clinical management strategies, enabling personalized treatment approaches, and advancing clinical trials of HD-modifying therapies. Full article

Background: Mild cognitive impairment is increasingly recognized as a precursor to more severe neurodegenerative conditions, particularly in the context of aging. Recent studies have highlighted the intersection of hearing loss and cognitive decline, suggesting that auditory deficits may exacerbate cognitive impairments in older adults, proposing the use of hearing aids to mitigate cognitive decline, and indicating that early intervention in hearing loss could be crucial for preserving cognitive function. The underlying mechanisms of the relationship between hearing and cognitive impairment may involve neuroinflammatory processes and neurodegeneration. Recent studies have evidenced the role of tau proteins and neurofilaments as biomarkers in the onset and progression of neurodegenerative diseases. Methods: We selected 30 subjects with age-related hearing loss, and we evaluated their cognitive status through the administration of screening tests, which also measured neurofilament light chain and phospho-tau 181 serum levels as biomarkers of neurodegeneration. The subjects were re-evaluated six months after the hearing aid fitting. Results: Patients with hearing impairment presented slightly altered results on cognitive tests, typical of a mild cognitive impairment. At the same time, serum levels of neurofilament light chain and phospho-tau 181 were significantly increased compared to the matched control group. After the hearing aids fitting, auditory, cognitive, and serum values results improved. Conclusions: The results of the study highlight the cognitive involvement in patients with hearing impairment and identify neurofilament light chain and phospho-tau 181 as serum biomarkers of neurodegeneration useful in monitoring the pathology. Full article

Impaired renal function can influence biomarker levels through mechanisms involving blood–brain barrier integrity and clearance pathways; however, the impact of variations within normal renal function remains unclear. The main aim of this study was to determine whether adjustment for the specific level of renal function is necessary when renal function remains within physiological levels. We studied n = 183 patients (NID n = 122; other neurological diseases n = 39; somatoform controls n = 22) who underwent lumbar puncture at University Hospital Frankfurt. Serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), total tau protein (tTAU), and ubiquitin C-terminal hydrolase-L1 (UCHL1) were measured using the single molecule array (SIMOA) technique. Estimated glomerular filtration rate (eGFR) correlated negatively with CSF GFAP (r = −0.217, p = 0.004) and serum NfL (r = −0.164, p = 0.032). Patients with impaired renal function exhibited higher CSF NfL (p = 0.036) and CSF GFAP (p = 0.026) levels. However, these findings did not remain significant after adjusting for BMI and age. Importantly, in patients with normal renal function, no significant correlations with eGFR and biomarker levels were observed after adjustment. Our findings indicate that serum and CSF concentrations of NfL, GFAP, tTAU, and UCHL1 are not significantly affected by fluctuations in physiological kidney function but emphasize the importance of considering comorbidities in impaired renal function when interpreting biomarker levels. Full article

Despite significant efforts, there is still an existing need to identify diagnostic tools that would enable fast and reliable detection of the progressive stage of multiple sclerosis (MS) and help in monitoring the disease course and/or treatment effects. The aim of this prospective study in a group of people with progressive MS was to determine whether changes in the levels of selected serum biomarkers and in cognitive function may predict disease progression, and therefore refine the decision-making process in the evaluation of MS patients. Forty two (42) patients with progressive MS completed all the study procedures; the mean duration of follow-up was 12.97 months. During the observation period, serum concentration of chitinase-3 like-protein-1 (CHI3L1/YKL-40) decreased significantly in the whole study group (from 4034.95 ± 262.62 to 2866.43 ± 173.37; p = 0.0005), as well as in subgroups of people with secondary progressive and primary progressive MS (SPMS: from 3693.81 ± 388.68 to 2542.76 ± 256.59; p = 0.0207; and PPMS: from 4376.09 ± 353.27 to 3190.09 ± 233.22; p = 0.0089, respectively). A significant worsening of Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scores was detected in the whole study group (from 1.18 ± 0.14 to 1.34 ± 0.15; p = 0.0331) as well as in the PPMS subgroup (from 1.04 ± 0.18 to 1.26 ± 0.20; p = 0.0216). No correlations between the analyzed molecular parameters or the results of neuropsychological tests and physical disability were observed. In conclusion, an emphasis should be placed on furthering the search for multimodal biomarkers of disease progression, especially in the PMS population, based on simultaneous analysis of several factors, such as blood biomarkers and cognitive profiles. Full article

Prion diseases, including Creutzfeldt–Jakob disease (CJD), are deadly neurodegenerative disorders characterized by the buildup of abnormal prion proteins in the brain. This accumulation disrupts neuronal functions, leading to the rapid onset of psychiatric symptoms, ataxia, and cognitive decline. The urgency of timely diagnosis for effective treatment necessitates the identification of strongly correlated biomarkers in bodily fluids, which makes our research crucial. In this study, we employed a fully automated multiplex ELISA (Ella^®) to measure the concentrations of 14-3-3 protein, total tau protein, and neurofilament light chain (NF-L) in cerebrospinal fluid (CSF) and serum samples from patients with prion disease and analyzed their link to disease prognosis. However, in North American and European cases, we did not confirm a correlation between NF-L levels and survival time. This discrepancy is believed to stem from differences in treatment policies and measurement methods between Japan and the United States. Nonetheless, our findings suggest that NF-L concentrations could be an early diagnostic marker for CJD patients with further enhancements. The potential impact of our findings on the early diagnosis of CJD patients is significant. Future research should focus on increasing the number of sCJD cases studied in Japan and gathering additional evidence using next-generation measurement techniques. Full article

Severe mental disorders (SMDs), such as schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD), are heterogeneous psychiatric diseases that impose a significant societal burden due to their chronic disabling nature. There are no objective and reliable diagnostic tests for SMDs; thus, there is an urgent need for specific biomarkers to improve diagnosis, treatment, and resource allocation. Neurofilaments, found in cerebrospinal fluid and blood, offer reliable diagnostic and prognostic potential. This review discusses the link between neurofilament light chain (NfL) involvement in psychiatric and neurodegenerative diseases and gives insights into the diagnostic and prognostic value of NfL in SMDs. This systematic review searched PubMed, Scopus, and Web of Science databases to answer the research question “Are NfL levels higher in individuals with SMDs compared to healthy controls?” using terms related to neurofilament, SMDs, SZ, BD, and depression. Of 8577 initial papers, 115 were relevant. After exclusions and manual additions, 17 articles were included. Studies indicate elevated NfL levels in SMDs compared to healthy controls, suggesting its potential as a biomarker for SMDs and for distinguishing neurodegenerative diseases from psychiatric disorders. However, further longitudinal research is needed to confirm its reliability for differential diagnosis, disease prediction, and treatment assessment in psychiatry. Full article

Background/Objectives: Military aviators can be exposed to extreme physiological stressors, including decompression stress, G-forces, as well as intermittent hypoxia and/or hyperoxia, which may contribute to neurobiological dysfunction/damage. This study aimed to investigate the levels of neurological biomarkers in military aviators to assess the potential risk of long-term brain injury and neurodegeneration. Methods: This cross-sectional study involved 48 Canadian Armed Forces (CAF) aviators and 48 non-aviator CAF controls. Plasma samples were analyzed for biomarkers of glial activation (GFAP), axonal damage (NF-L, pNF-H), oxidative stress (PRDX-6), and neurodegeneration (T-tau), along with S100b, NSE, and UCHL-1. The biomarker concentrations were quantified using multiplexed immunoassays. Results: The aviators exhibited significantly elevated levels of GFAP, NF-L, PRDX-6, and T-tau compared to the CAF controls (p < 0.001), indicating increased glial activation, axonal injury, and oxidative stress. Trends toward higher levels of S100b, NSE, and UCHL-1 were observed but were not statistically significant. The elevated biomarker levels suggest cumulative brain damage, raising concerns about potential long-term neurological impairments. Conclusions: Military aviators are at increased risk for neurobiological injury, including glial and axonal damage, oxidative stress, and early neurodegeneration. These findings emphasize the importance of proactive monitoring and further research to understand the long-term impacts of high-altitude flight on brain health and to develop strategies for mitigating cognitive decline and neurodegenerative risks in this population. Full article

Background: A limited number of studies have investigated the role of environmental chemicals in the etiology of mild cognitive impairment (MCI). We performed a cross-sectional study of the association between exposure to selected trace elements and the biomarkers of cognitive decline. Methods: During 2019–2021, we recruited 128 newly diagnosed patients with MCI from two Neurology Clinics in Northern Italy, i.e., Modena and Reggio Emilia. At baseline, we measured serum and cerebrospinal fluid (CSF) concentrations of cadmium, copper, iron, manganese, and zinc using inductively coupled plasma mass spectrometry. With immuno-enzymatic assays, we estimated concentrations of β-amyloid 1-40, β-amyloid 1-42, Total Tau and phosphorylated Tau181 proteins, neurofilament light chain (NfL), and the mini-mental state examination (MMSE) to assess cognitive status. We used spline regression to explore the shape of the association between exposure and each endpoint, adjusted for age at diagnosis, educational attainment, MMSE, and sex. Results: In analyses between the serum and CSF concentrations of trace metals, we found monotonic positive correlations between copper and zinc, while an inverse association was observed for cadmium. Serum cadmium concentrations were inversely associated with amyloid ratio and positively associated with Tau proteins. Serum iron concentrations showed the opposite trend, while copper, manganese, and zinc displayed heterogeneous non-linear associations with amyloid ratio and Tau biomarkers. Regarding CSF exposure biomarkers, only cadmium consistently showed an inverse association with amyloid ratio, while iron was positively associated with Tau. Cadmium concentrations in CSF were not appreciably associated with serum NfL levels, while we observed an inverted U-shaped association with CSF NfL, similar to that observed for copper. In CSF, zinc was the only trace element positively associated with NfL at high concentrations. Conclusions: In this cross-sectional study, high serum cadmium concentrations were associated with selected biomarkers of cognitive impairment. Findings for the other trace elements were difficult to interpret, showing complex and inconsistent associations with the neurodegenerative endpoints examined. Full article