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Abstract Background Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels. Methods We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer’ disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins. Results CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p

Artificial intelligence (AI) has meant a turning point in data analysis, allowing predictions of unseen outcomes with precedented levels of accuracy. In multiple sclerosis (MS), a chronic inflammatory-demyelinating condition of the central nervous system with a complex pathogenesis and potentially devastating consequences, AI-based models have shown promising preliminary results, especially when using neuroimaging data as model input or predictor variables. The application of AI-based methodologies to serum/blood and CSF biomarkers has been less explored, according to the literature, despite its great potential. In this review, we aimed to investigate and summarise the recent advances in AI methods applied to body fluid biomarkers in MS, highlighting the key features of the most representative studies, while illustrating their limitations and future directions.

Abstract Corticobasal syndrome (CBS) is a clinical syndrome determined by various underlying neurodegenerative disorders requiring a pathological assessment for a definitive diagnosis. A literature review was performed following the methodology described in the Cochrane Handbook for Systematic Reviews to investigate the additional value of traditional and cutting-edge cerebrospinal fluid (CSF) and serum/plasma biomarkers in profiling CBS. Four databases were screened applying predefined inclusion criteria: (1) recruiting patients with CBS; (2) analyzing CSF/plasma biomarkers in CBS. The review highlights the potential role of the association of fluid biomarkers in diagnostic workup of CBS, since they may contribute to a more accurate diagnosis and patient selection for future disease-modifying agent; for example, future trial designs should consider baseline CSF Neurofilament Light Chains (NfL) or progranulin dosage to stratify treatment arms according to neuropathological substrates, and serum NfL dosage might be used to monitor the evolution of CBS. In this scenario, prospective cohort studies, starting with neurological examination and neuropsychological tests, should be considered to assess the correlations of clinical profiles and various biomarkers.

Abstract Background Amidst growing concern about the safety of sport-related repetitive subconcussive head impacts (RSHI), biofluid markers may provide sensitive, informative, and practical assessment of the effects of RSHI exposure. Objective This scoping review aimed to systematically examine the extent, nature, and quality of available evidence from studies investigating the effects of RSHI on biofluid markers, to identify gaps and to formulate guidelines to inform future research. Methods PRISMA extension for Scoping Reviews guidelines were adhered to. The protocol was pre-registered through publication. MEDLINE, Scopus, SPORTDiscus, CINAHL, PsycINFO, Cochrane Library, OpenGrey, and two clinical trial registries were searched (until March 30, 2022) using descriptors for subconcussive head impacts, biomarkers, and contact sports. Included studies were assessed for risk of bias and quality. Results Seventy-nine research publications were included in the review. Forty-nine studies assessed the acute effects, 23 semi-acute and 26 long-term effects of RSHI exposure. The most studied sports were American football, boxing, and soccer, and the most investigated markers were (in descending order): S100 calcium-binding protein beta (S100B), tau, neurofilament light (NfL), glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE), brain-derived neurotrophic factor (BDNF), phosphorylated tau (p-tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and hormones. High or moderate bias was found in most studies, and marker-specific conclusions were subject to heterogeneous and limited evidence. Although the evidence is weak, some biofluid markers—such as NfL—appeared to show promise. More markedly, S100B was found to be problematic when evaluating the effects of RSHI in sport. Conclusion Considering the limitations of the evidence base revealed by this first review dedicated to systematically scoping the evidence of biofluid marker levels following RSHI exposure, the field is evidently still in its infancy. As a result, any recommendation and application is premature. Although some markers show promise for the assessment of brain health following RSHI exposure, future large standardized and better-controlled studies are needed to determine biofluid markers’ utility.

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients with ALS and to expedite ALS treatment development. Here, we provide a review of the efforts made towards identifying diagnostic, prognostic, susceptibility/risk, and response fluid biomarkers with the intent to facilitate a more rapid and accurate ALS diagnosis, to better predict prognosis, to improve clinical trial design, and to inform interpretation of clinical trial results. Over the course of 20 + years, several promising fluid biomarker candidates for ALS have emerged. These will be discussed, as will the exciting new strategies being explored for ALS biomarker discovery and development.

Neurodegenerative diseases (NDs) represent an unsolved problem to date with an ever-increasing population incidence. Particularly, Alzheimer’s disease (AD) is the most widespread ND characterized by an accumulation of amyloid aggregates of beta-amyloid (Aβ) and Tau proteins that lead to neuronal death and subsequent cognitive decline. Although neuroimaging techniques are needed to diagnose AD, the investigation of biomarkers within body fluids could provide important information on neurodegeneration. Indeed, as there is no definitive solution for AD, the monitoring of these biomarkers is of strategic importance as they are useful for both diagnosing AD and assessing the progression of the neurodegenerative state. In this context, exercise is known to be an effective non-pharmacological management strategy for AD that can counteract cognitive decline and neurodegeneration. However, investigation of the concentration of fluid biomarkers in AD patients undergoing exercise protocols has led to unclear and often conflicting results, suggesting the need to clarify the role of exercise in modulating fluid biomarkers in AD. Therefore, this critical literature review aims to gather evidence on the main fluid biomarkers of AD and the modulatory effects of exercise to clarify the efficacy and usefulness of this non-pharmacological strategy in counteracting neurodegeneration in AD.

Abstract Background Idiopathic Normal pressure hydrocephalus (iNPH) is a form of adult hydrocephalus that is clinically characterized by progressive gait impairment, cognitive dysfunction, and urinary incontinence. The current standard method of treatment involves surgical installation of a CSF diversion shunt. However, only a fraction of patients shows an alleviation of symptoms from shunt surgery. Thus, the purpose of this prospective explorative proteomic study was to identify prognostic CSF biomarkers to predict shunt responsiveness in iNPH patients. Further, we evaluated the ability of the core Alzheimer’s disease (AD) CSF biomarkers phosphorylated (p)-tau, total (t)-tau, and amyloid-β 1–42 (Aβ1–42) to serve as predictors of shunt response. Methods We conducted a tandem mass tag (TMT) proteomic analysis of lumbar CSF from 68 iNPH patients, sampled pre-shunt surgery. Tryptic digests of CSF samples were labelled with TMTpro reagents. The TMT multiplex samples were fractionated in 24 concatenated fractions by reversed-phase chromatography at basic pH and analysed by liquid chromatography coupled to mass spectrometry (LC–MS) on an Orbitrap Lumos mass spectrometer. The relative abundances of the identified proteins were correlated with (i) iNPH grading scale (iNPHGS) and (ii) gait speed change 1 year after surgery from baseline to identify predictors of shunt responsiveness. Results We identified four CSF biomarker candidates which correlated most strongly with clinical improvement on the iNPHGS and were significantly changed in shunt-responsive compared to shunt-unresponsive iNPH patients 1 year post-surgery: FABP3 (R = − 0.46, log2(fold change (FC)) = − 0.25, p

Cerebral amyloid angiopathy (CAA) is a type of cerebrovascular disorder characterised by the accumulation of amyloid within the leptomeninges and small/medium-sized cerebral blood vessels. Typically, cerebral haemorrhages are one of the first clinical manifestations of CAA, posing a considerable challenge to the timely diagnosis of CAA as the bleedings only occur during the later disease stages. Fluid biomarkers may change prior to imaging biomarkers, and therefore, they could be the future of CAA diagnosis. Additionally, they can be used as primary outcome markers in prospective clinical trials. Among fluid biomarkers, blood-based biomarkers offer a distinct advantage over cerebrospinal fluid biomarkers as they do not require a procedure as invasive as a lumbar puncture. This article aimed to provide an overview of the present clinical data concerning fluid biomarkers associated with CAA and point out the direction of future studies. Among all the biomarkers discussed, amyloid β, neurofilament light chain, matrix metalloproteinases, complement 3, uric acid, and lactadherin demonstrated the most promising evidence. However, the field of fluid biomarkers for CAA is an under-researched area, and in most cases, there are only one or two studies on each of the biomarkers mentioned in this review. Additionally, a small sample size is a common limitation of the discussed studies. Hence, it is hard to reach a solid conclusion on the clinical significance of each biomarker at different stages of the disease or in various subpopulations of CAA. In order to overcome this issue, larger longitudinal and multicentered studies are needed.

Abstract Background Studies have reported higher plasma matrix metalloproteinase-9 (MMP-9) levels in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Despite evidence that MMP-9 activity and its influence on AD pathophysiology may be modulated by sex hormones, sex differences in the association between MMP-9 and AD biomarkers and cognition have not been explored. Methods Our sample included 238 amyloid-β (Aβ)-positive participants with MCI or AD dementia from the Alzheimer’s Disease Neuroimaging Initiative (37.4% women, 74.6 ± 7.3 years). We used linear regression models to examine whether sex modified free and total plasma MMP-9 associations with CSF t-tau, p-tau181, and Aβ42. We used linear mixed effects models to examine whether sex modified total and free plasma MMP-9 associations with cognition, using longitudinal Mini-Mental Status Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) data. Results Total and free MMP-9 levels did not differ by sex, but AD dementia patients had higher total MMP-9 levels than participants with MCI (β = 0.06 [−0.11 to −0.01], p = 0.031). Sex modified the association of CSF t-tau with total (β = 128.68 [55.37 to 201.99], p < 0.001) and free MMP-9 (β = 98.61 [33.61 to 163.62], p = 0.003), whereby higher total and free MMP-9 correlated with higher CSF t-tau in women and lower CSF t-tau in men. Higher free MMP-9 correlated with lower CSF p-tau181 among men (β = −14.98 [−27.37 to −2.58], p = 0.018), but not women. In participants with MCI, higher free MMP-9 levels were associated with higher CSF Aβ42 among men (β = 26.88 [4.03 to 49.73], p = 0.022) but not women. In the overall sample, higher free and total MMP-9 at baseline predicted worsening MMSE scores in women (β = −2.10 [−3.97 to −0.27], p = 0.027 and β = −2.24 [−4.32 to −0.18], p = 0.035) but not men. Higher free MMP-9 correlated with worse ADAS-cog scores (β = 12.34 [3.02 to 21.65], p = 0.011) in women (β = 12.34 [3.02 to 21.65], p = 0.011) but not men with AD dementia cross-sectionally but correlated with worsening ADAS-cog scores longitudinally only in men (β = 8.98 [0.27 to 17.68], p = 0.042). Conclusions MMP-9 may have more detrimental effects on AD-related pathological and cognitive changes in women. If replicated, our findings could help uncover potential mechanisms contributing to women’s elevated susceptibility to AD.

Abstract Fluid biomarkers are currently measured in cerebrospinal fluid and blood for Alzheimer's disease diagnosis and are promising targets for drug development and for patients’ follow‐up in clinical trials. These biomarkers have been grouped in an unbiased research framework, the amyloid (Aβ), tau, and neurodegeneration (AT[N]) biomarker system to aid patients’ early diagnosis and stratification. Metrological approaches relying on mass spectrometry have been used for the development of reference materials and reference measurement procedures. Despite their excellent performances as clinical tools, fluid biomarkers often present an important between‐laboratory variation. Standardization efforts were carried out on the biomarkers currently included in the AT(N) classification system, involving the collaboration of national metrology institutes, clinicians, researchers, and in vitro diagnostic providers. This article provides an overview of current activities towards standardization. These reference methods and reference materials may be used for recalibration of immunoassays and the establishment of standardized cutoff values allowing a better stratification of Alzheimer's disease patients. Highlights The AT(N) biomarker system allows stratifying AD patients on the basis of biomarker profiles. Fluid biomarker measurements often present an important between‐laboratory variation preventing the establishment of standardized cutoff values. Overview on the standardization initiatives involving the fluid biomarkers currently included in the AT(N) framework.

Sport-related concussion (SRC) is a major concern among athletes and clinicians around the world. Research into fluid biomarkers of SRC has made significant progress in understanding the complex underlying pathophysiology of concussion. However, little headway has been made toward clinically validating any biomarkers to improve the clinical management of SRC. A major obstacle toward clinical translation of any fluid biomarker is the heterogeneity of SRC overlapping with multiple physiological systems involved in pathology and recovery. Neuroinflammation post-SRC is one such system that may confound fluid biomarker data on many fronts. Neuroinflammatory processes consist of cell mediators, both within the central nervous system and the periphery, that play vital roles in regulating the response to brain injury. Further, neuroinflammation is influenced by many biopsychosocial variables present in most athletic populations. In this commentary, we propose that future fluid biomarker research should take a systems biology approach in the context of the neuroinflammatory response to SRC. We highlight how biological variables, such as age, sex, immune challenges, and hypothalamic-pituitary-adrenal (HPA)-axis responses to stress, may alter neuroinflammation. Further, we underscore the importance of accounting for health and lifestyle variables, such as diet, exercise, sleep, and pre-morbid medical factors, when measuring inflammatory markers of SRC. To successfully move toward clinical translation, fluid biomarker research should take a more holistic approach in study design and data interpretation, collecting information on hidden variables that may be influencing the neuroinflammatory response to SRC.

Alzheimer’s disease (AD) is a leading cause of dementia, impacting millions worldwide. However, its complex neuropathologic features and heterogeneous pathophysiology present significant challenges for diagnosis and treatment. To address the urgent need for early AD diagnosis, this review focuses on surface-enhanced Raman scattering (SERS)-based biosensors, leveraging the excellent optical properties of nanomaterials to enhance detection performance. These highly sensitive and noninvasive biosensors offer opportunities for biomarker-driven clinical diagnostics and precision medicine. The review highlights various types of SERS-based biosensors targeting AD biomarkers, discussing their potential applications and contributions to AD diagnosis. Specific details about nanomaterials and targeted AD biomarkers are provided. Furthermore, the future research directions and challenges for improving AD marker detection using SERS sensors are outlined.

To date, sport-related concussion diagnosis and management is primarily based on subjective clinical tests in the absence of validated biomarkers. A major obstacle to clinical validation and application is a lack of studies exploring potential biomarkers in non-injured populations. This cross-sectional study examined the associations between saliva telomere length (TL) and multiple confounding variables in a healthy university athlete population. One hundred eighty-three (108 male and 75 female) uninjured varsity athletes were recruited to the study and provided saliva samples at either pre- or mid-season, for TL analysis. Multiple linear regression was used to determine the associations between saliva TL and history of concussion, sport contact type, time in season (pre vs. mid-season collection), age, and sex. Results showed no significant associations between TL and history of concussion, age, or sport contact type. However, TL from samples collected mid-season were longer than those collected pre-season [β = 231.4, 95% CI (61.9, 401.0), p = 0.008], and males had longer TL than females [β = 284.8, 95% CI (111.5, 458.2), p = 0.001] when adjusting for all other variables in the model. These findings population suggest that multiple variables may influence TL. Future studies should consider these confounders when evaluating saliva TL as a plausible fluid biomarker for SRC.

Relevance of blood-based biomarkers is increasing into the neurodegenerative diseases field, but data on Parkinson's disease (PD) remain still scarce. In this study, we used the SiMoA technique to measure serum content of total tau protein and amyloid-β peptides (Aβ-42, Aβ-40) in 22 PD patients and ten control subjects. Serum levels of each biomarker were correlated with the respective CSF levels in both the groups; in PD patients, also the correlations between serum biomarkers and main clinical parameters were tested (motor, non-motor, cognitive scores and levodopa equivalent daily dose). Serum biomarkers did not exhibit quantitative differences between patients and controls; however, only PD patients had inter-fluids (serum-CSF) associations in tau and amyloid-β-42 levels. Moreover, serum content of tau protein was inversely correlated with cognitive performances (MoCA score). These findings, albeit preliminary, indicate that brain-derived peptides may change in parallel in both peripheral blood and CSF of PD patients, eventually even in association with some clinical features. Further studies are now needed to validate the use of blood-based biomarkers in PD.

Abstract Introduction Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open‐label Phase 1b study of sodium selenate as a disease‐modifying treatment for behavioral variant frontotemporal dementia (bvFTD). Methods Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t‐tau), phosphorylated tau (p‐tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. Results Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t‐tau, p‐tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study—one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12‐month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). Conclusion Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized‐controlled trials are warranted to investigate potential efficacy.

The rate of progression from Mild Cognitive Impairment (MCI) to Alzheimer's disease (AD) is estimated at >10% per year, reaching up to 80–90% after 6 years. MCI is considered an indicator of early-stage AD. In this context, the diagnostic screening of MCI is crucial for detecting individuals at high risk of AD before they progress and manifest further severe symptoms. Typically, MCI has been determined using neuropsychological assessment tools such as the Montreal Cognitive Assessment (MoCA) or Mini-Mental Status Examination (MMSE). Unfortunately, other diagnostic methods are not available or are unable to identify MCI in its early stages. Therefore, identifying new biomarkers for MCI diagnosis and prognosis is a significant challenge. In this framework, miRNAs in serum, plasma, and other body fluids have emerged as a promising source of biomarkers for MCI and AD-related cognitive impairments. Interestingly, miRNAs can regulate several signaling pathways via multiple and diverse targets in response to pathophysiological stimuli. This systematic review aims to describe the current state of the art regarding AD-related target genes modulated by differentially expressed miRNAs in peripheral fluids samples in MCI subjects to identify potential miRNA biomarkers in the early stages of AD. We found 30 articles that described five miRNA expression profiles from peripheral fluid in MCI subjects, showing possible candidates for miRNA biomarkers that may be followed up as fluid biomarkers or therapeutic targets of early-stage AD. However, additional research is needed to validate these miRNAs and characterize the precise neuropathological mechanisms.

Alzheimer’s disease (AD) is the leading cause of dementia due to neurodegeneration and is characterized by extracellular senile plaques composed of amyloid β1–42 (Aβ) as well as intracellular neurofibrillary tangles consisting of phosphorylated tau (p-tau). Dementia with Lewy bodies constitutes a continuous spectrum with Parkinson’s disease, collectively termed Lewy body disease (LBD). LBD is characterized by intracellular Lewy bodies containing α-synuclein (α-syn). The core clinical features of AD and LBD spectra are distinct, but the two spectra share common cognitive and behavioral symptoms. The accumulation of pathological proteins, which acquire pathogenicity through conformational changes, has long been investigated on a protein-by-protein basis. However, recent evidence suggests that interactions among these molecules may be critical to pathogenesis. For example, Aβ/tau promotes α-syn pathology, and α-syn modulates p-tau pathology. Furthermore, clinical evidence suggests that these interactions may explain the overlapping pathology between AD and LBD in molecular imaging and post-mortem studies. Additionally, a recent hypothesis points to a common mechanism of prion-like progression of these pathological proteins, via neural circuits, in both AD and LBD. This suggests a need for understanding connectomics and their alterations in AD and LBD from both pathological and functional perspectives. In AD, reduced connectivity in the default mode network is considered a hallmark of the disease. In LBD, previous studies have emphasized abnormalities in the basal ganglia and sensorimotor networks; however, these account for movement disorders only. Knowledge about network abnormalities common to AD and LBD is scarce because few previous neuroimaging studies investigated AD and LBD as a comprehensive cohort. In this paper, we review research on the distribution and interactions of pathological proteins in the brain in AD and LBD, after briefly summarizing their clinical and neuropsychological manifestations. We also describe the brain functional and connectivity changes following abnormal protein accumulation in AD and LBD. Finally, we argue for the necessity of neuroimaging studies that examine AD and LBD cases as a continuous spectrum especially from the proteinopathy and neurocircuitopathy viewpoints. The findings from such a unified AD and Parkinson’s disease (PD) cohort study should provide a new comprehensive perspective and key data for guiding disease modification therapies targeting the pathological proteins in AD and LBD.

Biomarkers are crucial in oncology, from detection and monitoring to guiding management and predicting treatment outcomes. Histological assessment of tissue biopsies is currently the gold standard for oropharyngeal cancers, but is technically demanding, invasive, and expensive. This systematic review aims to review current markers that are detectable in biofluids, which offer promising non-invasive alternatives in oropharyngeal carcinomas (OPCs). A total of 174 clinical trials from the PubMed search engine in the last 5 years were identified and screened by 4 independent reviewers. From these, 38 eligible clinical trials were found and subsequently reviewed. The biomarkers involved, categorized by human papillomavirus (HPV)-status, were further divided according to molecular and cellular levels. Recent trials investigating biomarkers for both HPV-positive and HPV-negative OPCs have approaches from various levels and different biofluids including plasma, oropharyngeal swabs, and oral rinse. Promising candidates have been found to aid in detection, staging, and predicting prognosis, in addition to well-established factors including HPV-status, drinking and smoking status. These studies also emphasize the possibility of enhancing prediction results and increasing statistical significance by multivariate analyses. Liquid biopsies offer promising assistance in enhancing personalized medicine for cancer treatment, from lowering barriers towards early screening, to facilitating de-escalation of treatment. However, further research is needed, and the combination of liquid biopsies with pre-existing methods, including in vivo imaging and invasive techniques such as neck dissections, could also be explored in future trials.

The identification of biomarkers for neurodegenerative disorders such as Huntington’s disease (HD) is crucial for monitoring disease progression and therapeutic trial outcomes, especially in the pre-manifest disease stage (pre-HD). In a previous study, we observed that leukocyte telomere length (LTL) was strongly correlated with the estimated time to clinical onset in pre-HD subjects. To validate this hypothesis, we designed a follow-up study in which we analyzed LTL in 45 pre-HD stage subjects at baseline (T0) and then again after clinical onset at follow-up (T1); the follow-up interval was about 3 years, and the CAG range was 39–51 repeats; 90 peripheral blood mononuclear cell samples (PBMCs) were obtained from the Enroll-HD biorepository. In pre-HD subjects at T0, LTL was significantly reduced by 22% compared to the controls and by 14% from T0 at T1. No relationship was observed between the LTL and CAG numbers in subjects carrying different CAG repeats at T0 and at T1, suggesting that LTL reduction occurs independently of CAG number in pre-HD subjects. ROC curve analysis was used to test the validity of LTL as a potential biomarker of HD progression and showed that LTL measurement is extremely accurate in discriminating pre-HD subjects from the controls and even pre-HD from manifest HD, thus yielding a robust prognostic value in pre-HD subjects.

Plasma small RNAs have been recently explored as biomarkers in Huntington’s disease (HD). We performed an exploratory study on nine HD patients, eight healthy subjects (HS), and five psychiatric patients (PP; to control for iatrogenic confounder effects) through an Affymetrix-Gene-Chip-miRNA-Array. We validated the results in an independent population of 23 HD, 15 pre-HD, 24 PP, 28 Alzheimer’s disease (AD) patients (to control the disease-specificity) and 22 HS through real-time PCR. The microarray results showed higher levels of U13 small nucleolar RNA (SNORD13) in HD patients than controls (fold change 1.54, p = 0.003 HD vs. HS, and 1.44, p = 0.0026 HD vs. PP). In the validation population, a significant increase emerged with respect to both pre-HD and the control groups (p < 0.0001). SNORD13 correlated with the status of the mutant huntingtin carrier (r = 0.73; p < 0.001) and the disease duration (r = 0.59; p = 0.003). The receiver operating characteristic (ROC) curve analysis showed the high accuracy of SNORD13 in discriminating HD patients from other groups (AUC = 0.963). An interactome and pathway analysis on SNORD13 revealed enrichments for factors relevant to HD pathogenesis. We report the unprecedented finding of a potential disease-specific role of SNORD13 in HD. It seems to peripherally report a ‘tipping point’ in the pathogenic cascade at the neuronal level.

Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.

Traumatic brain injury (TBI) accounts for approximately 16% of acute symptomatic seizures which usually occur in the first week after trauma. Children are at higher risk for post-traumatic seizures than adults. Post-traumatic seizures are a risk factor for delayed development of epilepsy. Delayed, chronic post-traumatic epilepsy is preceded by a silent period during which therapeutic interventions may arrest, revert or prevent epileptogenesis. A number of recent review articles summarize the most important features of post-traumatic seizures and epilepsy; this review will instead focus on the link between cerebrovascular permeability, epileptogenesis and ictal events after TBI. The possibility of acting on the blood-brain barrier (BBB) and the neurovascular unit to prevent, disrupt or treat post-traumatic epilepsy is also discussed. Finally, we describe the latest quest for biomarkers of epileptogenesis which may allow for a more targeted intervention.

Traumatic brain injury is a significant public health issue and represents the main contributor to death and disability globally among all trauma-related injuries. Martial arts practitioners, military veterans, athletes, victims of physical abuse, and epileptic patients could be affected by the consequences of repetitive mild head injuries (RMHI) that do not resume only to short-termed traumatic brain injuries (TBI) effects but also to more complex and time-extended outcomes, such as post-concussive syndrome (PCS) and chronic traumatic encephalopathy (CTE). These effects in later life are not yet well understood; however, recent studies suggested that even mild head injuries can lead to an elevated risk of later-life cognitive impairment and neurodegenerative disease. While most of the PCS hallmarks consist in immediate consequences and only in some conditions in long-termed processes undergoing neurodegeneration and impaired brain functions, the neuropathological hallmark of CTE is the deposition of p-tau immunoreactive pre-tangles and thread-like neurites at the depths of cerebral sulci and neurofibrillary tangles in the superficial layers I and II which are also one of the main hallmarks of neurodegeneration. Despite different CTE diagnostic criteria in clinical and research approaches, their specificity and sensitivity remain unclear and CTE could only be diagnosed post-mortem. In CTE, case risk factors include RMHI exposure due to profession (athletes, military personnel), history of trauma (abuse), or pathologies (epilepsy). Numerous studies aimed to identify imaging and fluid biomarkers that could assist diagnosis and probably lead to early intervention, despite their heterogeneous outcomes. Still, the true challenge remains the prediction of neurodegeneration risk following TBI, thus in PCS and CTE. Further studies in high-risk populations are required to establish specific, preferably non-invasive diagnostic biomarkers for CTE, considering the aim of preventive medicine.

Abstract Introduction Several blood‐based biomarkers are associated with neuronal injury, but their utility in interventional clinical trials is unclear. This study retrospectively evaluated the utility of plasma neurofilament light (NfL) and total tau (t‐tau) in an 18‐month trial in mild Alzheimer's disease (AD). Methods Correlation and conditional independence analyses and Gaussian graphical models were used to investigate cross‐sectional and longitudinal relations between NfL, t‐tau, and clinical scales. Results NfL had a stronger association than t‐tau with clinical scales; t‐tau did not hold additional information to that given by NfL (P > 0.05 at all time points). NfL held independent information about shorter‐term (3‐ to 6‐month) progression beyond patient age and clinical scores. However, no meaningful gain in power was found when adjusting a longitudinal analysis of cognitive scores for baseline NfL. Discussion Plasma NfL is superior to t‐tau in mild AD. The ability of NfL to detect changes before clinical manifestations makes it a promising biomarker of drug response in trials of disease‐modifying drugs.

Alzheimer’s Disease (AD) is one of the most common form of dementia occurring in elderly population worldwide. Currently Aβ42, tau and p-tau in the cerebrospinal fluid is estimated for confirmation of AD. CSF which is being used as the potent source for biomarker screening is obtained by invasive lumbar punctures. Thus, there is an urgent need of minimal invasive methods for identification of diagnostic markers for early detection of AD. Blood serum and plasma serves as an appropriate source, due to minimal discomfort to the patients, promoting frequent testing, better follow-up and better consent to clinical trials. Hence, the need of the hour demands discovery of diagnostic and prognostic patient specific signature biomarkers by using emerging technologies of mass spectrometry, microarrays and peptidomics. In this review we summarize the present scenario of AD biomarkers such as circulatory biomarkers, blood based amyloid markers, inflammatory markers and oxidative stress markers being investigated and also some of the potent biomarkers which might be able to predict early onset of Alzheimer’s and delay cognitive impairment.

Alzheimer’s disease is the most common cause of dementia. Over the last three decades, research has advanced dramatically and provided a detailed understanding of the molecular events underlying the pathogenesis of Alzheimer’s disease. In parallel, assays for the detection of biomarkers that reflect the typical Alzheimer’s disease-associated pathology have been developed and validated in myriads of clinical studies. Such biomarkers complement clinical diagnosis and improve diagnostic accuracy. The use of biomarkers will become even more important with the advent of disease-modifying therapies. Such therapies will likely be most beneficial when administered early in the disease course. Here, we summarise the development of the core Alzheimer’s disease cerebrospinal fluid biomarkers: amyloid-β and tau. We provide an overview of their role in cellular physiology and Alzheimer’s disease pathology, and embed their development as cerebrospinal fluid biomarkers into the historical context of Alzheimer’s disease research. Finally, we summarise recommendations for their use in clinical practice, and outline perspectives for novel cerebrospinal fluid candidate biomarkers.