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To assess the variations and diagnostic performance of serum biomarkers of neurodegenerative diseases. In this monocentric prospective study, neurofilament light (NFL), T-tau, p-tau181, p-tau217, Aβ40, and Aβ42 were measured in serum collected from orthopedic patients (control group, n=114) and patients in the neurology department (n=69) previously diagnosed with Alzheimer's disease (AD, n=52), parkinsonian syndromes (n=10), and other etiologies of neurodegeneration (non-AD, n=7). In the control group, serum NFL, T-tau, p-tau181, p-tau217, and Aβ40 significantly increased with age, independently of sex. NFL (p=0.0078), p-tau217 (p<0.001) were significantly increased with neurodegeneration when compared to controls, with only p-tau217 significant in the multivariate analysis (p<0.001). Multivariate regression analysis accounting for age highlighted a significant increase of p-tau217 (p<0.001) in the AD subgroup. NFL was significantly increased in the non-AD patients (p<0.001), and in the parkinsonian syndromes subgroup (p=0.016) when compared to negative controls. Serum p-tau181 and p-tau217 were significantly correlated with CSF p-tau181 (Spearman's coefficients of 0.43 and 0.48 respectively, n=40). Areas under the ROC curves for the identification of patients with neurodegenerative diseases were 0.62 (0.54–0.70) for NFL, 0.62 (0.54–0.71) for T-tau, 0.83 (0.76–0.89) for p-tau217, and 0.66 (0.58–0.74) for Aβ40. Serum biomarkers can help identify patients with neurodegenerative disease and may be a valuable tool for care and orientation. Phosphorylated tau p-tau217 is a promising blood biomarker for AD and NFL for other etiologies. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To investigate the genetic determinants affecting the rate of change in CSF total tau (t-tau). METHODS: This study conducted a genome-wide association study (GWAS) on longitudinal CSF t-tau and genotype data from 319 non-Hispanic Caucasians within the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. The aim was to identify genetic determinants influencing the rate of change in CSF t-tau, a key biomarker in AD. RESULTS: The GWAS identified a significant single nucleotide polymorphism (SNP), rs17149074, within the C9orf171 (CFAP77) gene region that showed significant association with changes in CSF t-tau over time. Additionally, five other SNPs--rs10916844, rs10916846, rs9425869, rs3744474, and rs8078303--were found to potentially influence CSF t-tau variability. CONCLUSIONS: These findings not only enhance our understanding of t-tau's progression in AD but also suggest that these identified SNPs could serve as novel genetic biomarkers, potentially providing novel insights in the prognostic landscape of AD by refining the predictive value of CSF-tau measurements [ABSTRACT FROM AUTHOR]

Idiopathic normal-pressure hydrocephalus (iNPH) is a clinic-radiological neurological syndrome presenting with cognitive deficits, gait disturbances and urinary incontinence. It often coexists with Alzheimer's disease (AD). Due to the reversible nature of iNPH when promptly treated, a lot of studies have focused on possible biomarkers, among which are cerebrospinal fluid (CSF) biomarkers. The aim of the present study was to determine the rate of beta-amyloid pathology and AD co-pathology by measuring AD CSF biomarkers, namely, amyloid beta with 42 and 40 amino acids (Aβ42), the Aβ42/Aβ40 ratio, total Tau protein (t-Tau) and phosphorylated Tau protein at threonine 181 (p-Tau), in a cohort of iNPH patients, as well as to investigate the possible associations among CSF biomarkers and iNPH neuropsychological profiles. Fifty-three patients with iNPH were included in the present study. CSF Aβ42, Aβ40, t-Tau and p-Tau were measured in duplicate with double-sandwich ELISA assays. The neuropsychological evaluation consisted of the Mini-Mental State Examination, Frontal Assessment Battery, Five-Word Test and CLOX drawing tests 1 and 2. After statistical analysis, we found that amyloid pathology and AD co-pathology are rather common in iNPH patients and that higher values of t-Tau and p-Tau CSF levels, as well as the existence of the AD CSF profile, are associated with more severe memory impairment in the study patients. In conclusion, our study has confirmed that amyloid pathology and AD-co-pathology are rather common in iNPH patients and that CSF markers of AD pathology and t-Tau are associated with a worse memory decline in these patients. [ABSTRACT FROM AUTHOR]

Abstract Background An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p

Background: An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence. [ABSTRACT FROM AUTHOR]

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer's Coordinating Center's Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer's disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer's patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. Objectives: The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. Methods: CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Results: Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. Conclusions: The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS. [ABSTRACT FROM AUTHOR]

Several research studies have demonstrated the potential use of cerebrospinal fluid biomarkers such as amyloid beta 1-42, T-tau, and P-tau, in early diagnosis of Alzheimer's disease stages. The levels of these biomarkers in conjunction with the dementia rating scores are used to empirically differentiate the dementia patients from normal controls. In this work, we evaluated the performance of standard machine learning classifiers using cerebrospinal fluid biomarker levels as the features to differentiate dementia patients from normal controls. We employed various types of machine learning models, that includes Discriminant, Logistic Regression, Tree, K-Nearest Neighbor, Support Vector Machine, and Naïve Bayes classifiers. The results demonstrate that these models can distinguish cognitively impaired subjects from normal controls with an accuracy ranging from 64% to 69% and an area under the curve of the receiver operating characteristics between 0.64 and 0.73. In addition, we found that the levels of 2 biomarkers, amyloid beta 1-42 and T-tau, provide a modest improvement in accuracy when distinguishing dementia patients from healthy controls. [ABSTRACT FROM AUTHOR]

Abstract Purpose Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) concentration is increased in cerebrospinal fluid (CSF) in early symptomatic phase of Alzheimer’s disease (AD). This study investigated whether CSF sTREM2 has a relationship with early cognitive dysfunction following surgery in cardiac surgery patients. Methods A total of 82 patients undergoing thoracoabdominal aortic replacement were recruited in this study. Neuropsychological testing battery was conducted before and after surgery. Postoperative cognitive dysfunction (POCD) was defined as a Z-score > 1.96 on at least 2 different tests or Telephone Interviews for Cognitive Status-Modified (TICS-M) score

In clinical pratice, tau protein measurement generally relies on immunoassays (IAs), whose major drawback is the lack of results comparability due to differences in selectivity and/or calibration. This underlines the importance of establishing a traceability chain for total tau (t-tau) measurements. The objective of this work is to develop a higher order candidate reference measurement procedure (RMP) for the absolute quantification of t-tau in cerebrospinal fluid (CSF). To calibrate the candidate RMP and establish metrological traceability to the SI units, a primary calibrator consisting in a highly purified recombinant protein was sourced. Its purity was evaluated by liquid chromatography coupled with high resolution mass spectrometry (LC-HRMS) and the protein mass fraction in solution was certified by amino acid analysis (AAA). An isotopically-labelled homologue was obtained to develop a candidate RMP by isotope dilution mass spectrometry (IDMS) for t-tau absolute quantification in CSF. Calibration blends and quality control (QC) materials were gravimetrically prepared and subjected to the same preparation workflow as CSF samples, followed by LC-HRMS analysis in Parallel Reaction Monitoring (PRM) mode. A primary calibrator has been developed and an IDMS candidate RMP has been validated for CSF t-tau. The candidate RMP was used to certify t-tau concentration in three pools of CSF (low, medium, high). The candidate RMP will pave the road towards global standardization of CSF t-tau measurements. Together with commutable Certified Reference Materials (CRMs), it will allow evaluating and improving the accuracy and comparability of results provided by IAs. [ABSTRACT FROM AUTHOR]

New diagnostic methods have been developed for the early diagnosis of Alzheimer’s disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau181, Aβ1–42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques’ presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ42, t-Tau and p-Tau181 values, with higher accuracy for the t-Tau/Aβ1–42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders.

The levels of several glial and neuronal plasma biomarkers have been found to increase during the acute phase in COVID-19 patients with neurological symptoms. However, replications in patients with minor or non-neurological symptoms are needed to understand their potential as indicators of CNS injury or vulnerability. Plasma levels of glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), and total Tau (T-tau) were determined by Single molecule array (Simoa) immunoassays in 45 samples from COVID-19 patients in the acute phase of infection [moderate (n = 35), or severe (n = 10)] with minor or non-neurological symptoms; in 26 samples from fully recovered patients after ~2 months of clinical follow-up [moderate (n = 23), or severe (n = 3)]; and in 14 non-infected controls. Plasma levels of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), were also determined by Western blot. Patients with COVID-19 without substantial neurological symptoms had significantly higher plasma concentrations of GFAP, a marker of astrocytic activation/injury, and of NfL and T-tau, markers of axonal damage and neuronal degeneration, compared with controls. All these biomarkers were correlated in COVID-19 patients at the acute phase. Plasma GFAP, NfL and T-tau levels were all normalized after recovery. Recovery was also observed in the return to normal values of the quotient between the ACE2 fragment and circulating full-length species, following the change noticed in the acute phase of infection. None of these biomarkers displayed differences in plasma samples at the acute phase or recovery when the COVID-19 subjects were sub-grouped according to occurrence of minor symptoms at re-evaluation 3 months after the acute episode (so called post-COVID or "long COVID"), such as asthenia, myalgia/arthralgia, anosmia/ageusia, vision impairment, headache or memory loss. Our study demonstrated altered plasma GFAP, NfL and T-tau levels in COVID-19 patients without substantial neurological manifestation at the acute phase of the disease, providing a suitable indication of CNS vulnerability; but these biomarkers fail to predict the occurrence of delayed minor neurological symptoms. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's disease cerebrospinal fluid (CSF) biomarkers amyloid-β 1–42 (Aβ42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. Objective: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. Methods: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1–73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aβ42, T-tau, and P-tau181 were analyzed using commercial ELISA assays. Results: Preoperative L-CSF Aβ42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ= 0.34–0.55, p < 0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aβ42: 0.77–0.88, T-tau: 0.91–0.94, P-tau181: 0.94–0.96, p < 0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aβ42: V-CSF = 185+0.34*L-CSF, T-tau: Ln(V-CSF) = 3.11+0.49*Ln(L-CSF), P-tau181: V-CSF = 8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aβ42: V-CSF = 86.7+0.75*L-CSF, T-tau: V-CSF = 86.9+0.62*L-CSF, P-tau181: V-CSF = 2.6+0.74*L-CSF). Conclusion: Aβ42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted. [ABSTRACT FROM AUTHOR]

Purpose: Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) concentration is increased in cerebrospinal fluid (CSF) in early symptomatic phase of Alzheimer's disease (AD). This study investigated whether CSF sTREM2 has a relationship with early cognitive dysfunction following surgery in cardiac surgery patients. Methods: A total of 82 patients undergoing thoracoabdominal aortic replacement were recruited in this study. Neuropsychological testing battery was conducted before and after surgery. Postoperative cognitive dysfunction (POCD) was defined as a Z-score > 1.96 on at least 2 different tests or Telephone Interviews for Cognitive Status-Modified (TICS-M) score < 27. The CSF and serum sTREM2, Aβ42, T-tau and P-tau were collected and measured by ELISA on day before surgery and postoperative day 3. Results: Patients were classified into POCD (n = 34) and non-POCD (n = 48) groups according to Z-score. Compared to non-POCD group, the levels of CSF sTREM2 (p < 0.001) and serum sTREM2 (p = 0.001) were significantly higher in POCD group on postoperative day 3. The levels of Aβ42 (p = 0.005) and Aβ42/T-tau ratio (p = 0.036) were significantly lower in POCD group on postoperative day 3. Multivariate logistic regression analysis revealed that higher value of postoperative CSF sTREM2 (odds ratio: 1.06, 95% confidence interval: 1.02–1.11, p = 0.009), age (OR: 1.15, 95%CI: 1.03–1.28, p = 0.014) and POD duration (OR: 2.47, 95%CI: 1.15–5.29, p = 0.02) were the risk factors of POCD. Conclusion: This study indicates that anesthesia and surgery-induced elevation of CSF sTREM2 is associated with an increased risk of early cognitive dysfunction following surgery. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. Objectives: The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. Methods: CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Results: Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. Conclusions: The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS. [ABSTRACT FROM AUTHOR]

Background and Purpose: To investigate the diagnostic and prognostic value of axonal injury biomarkers in patients with inflammatory polyneuropathies. Methods: Neurofilament light chain (NfL) and total tau (T‐tau) were measured in the cerebrospinal fluid (CSF) and plasma in 41 patients with Guillain–Barré syndrome (GBS), 32 patients with chronic inflammatory demyelinating polyneuropathy (CIDP), 10 with paraproteinemia‐related demyelinating polyneuropathy (PDN), and 8 with multifocal motor neuropathy (MMN), in comparison with 39 disease‐free controls and 59 other controls. Outcome was measured with the GBS‐disability score (GBS‐ds) or Inflammatory Neuropathy Cause and Treatment (INCAT) disability score. Results: Neurofilament light chain levels in CSF and plasma were higher in GBS, CIDP, and PDN vs. disease‐free controls. Patients with MMN had higher NfL levels in plasma vs. disease‐free controls, but lower levels in CSF and plasma vs. patients with amyotrophic lateral sclerosis (ALS). T‐tau levels in plasma were higher in GBS, CIDP, PDN, and MMN vs. all control groups. Neurofilament light chain levels in CSF and plasma in patients with GBS correlated with GBS‐ds, as higher levels were associated with inability to run after 6 and 12 months. NfL levels in CSF and plasma in CIDP did not correlate significantly with outcome. Conclusions: Acute and chronic inflammatory neuropathies are associated with an increase in levels of NfL in CSF and plasma, but NfL is validated as a prognostic biomarker only in GBS. NfL could be used in differentiating patients with MMN from ALS. T‐tau in plasma is a novel biomarker that could be used in a diagnostic assessment of patients with acute and chronic inflammatory polyneuropathies. [ABSTRACT FROM AUTHOR]

BackgroundCerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear.ObjectivesThe aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them.MethodsCSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software.ResultsCompared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment.ConclusionsThe CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS.

Objectives: Exosomal Phospho-Tau-181(P-T181-tau), Total tau (T-tau), and amyloid-β peptide 42 (Aβ42) have been proved the capacity for the amnestic mild cognitive impairment (MCI) and the diagnosis of Alzheimer's disease (AD). This study aimed to explore the cognitive function and the levels of P-T181-tau, T-tau, and Aβ42 in neuronal-derived exosomes (NDEs) extracted from plasma in normal cognitive adults over 45 years old with olfactory dysfunction. Methods: A cross-sectional survey of 29 participants aged over 45 was conducted. Plasma exosomes were isolated, precipitated, and enriched by immuno-absorption with anti- L1 cell adhesion molecule (L1CAM) antibody. NDEs were characterized by CD81, and extracted NDE protein (P-T181-tau, T-tau, and Aβ42) biomarkers were quantified by enzyme-linked immunosorbent assay (ELISAs). Olfactory performance was assessed by Sniffin' Sticks and cognitive performance was assessed by Montreal Cognitive Assessment (MoCA). Results: There was no significant difference between adults with olfactory dysfunction and without olfactory dysfunction regarding the cognitive function as measured by MoCA and all the participants showed normal cognition. Adults with olfactory dysfunction showed a higher concentration of P-T181-tau in plasma NDEs than did adults without olfactory dysfunction (P = 0.034). Both the levels of P-T181-tau (r = − 0.553, P = 0.003) and T-tau (r = − 0.417, P = 0.034) negatively correlated with the odor identification scores. In addition, the level of T-tau negatively correlated with MoCA scores (r = − 0.597, P = 0.002). The levels of P-T181-tau (r = − 0.464, P = 0.022) and T-tau (r = − 0.438, P = 0.032) negatively correlated with the delayed recall scores. Conclusions: This study demonstrated that cognition-related pathogenic proteins including P-T181-tau in plasma NDEs were significantly increased in adults over 45 years old with olfactory dysfunction before the occurrence of cognitive impairment. The impaired odor identification and the delayed recall function were highly associated with the increased levels of P-T181-tau and T-tau in plasma NDEs. [ABSTRACT FROM AUTHOR]

New diagnostic methods have been developed for the early diagnosis of Alzheimer's disease (AD) with the primary purpose of intercepting the transition-phase (mild cognitive impairment, MCI) between normal aging and dementia. We aimed to explore whether the five-word test (FWT) and the mini-mental state examination (MMSE) are predictive for the early diagnosis of MCI due to AD (AD-MCI). We computed ROC analyses to evaluate the sensitivity and specificity of MMSE and FWT in predicting abnormal CSF (t-Tau, p-Tau181, Aβ1–42) and amyloid-PET biomarkers. AD-MCI patients showed lower MMSE and FWT scores (all p < 0.001) than non-AD-MCI. The best predictor of amyloid plaques' presence at amyloid-PET imaging was the encoding sub-score of the FWT (AUC = 0.84). Both FWT and MMSE had low/moderate accuracy for the detection of pathological CSF Aβ42, t-Tau and p-Tau181 values, with higher accuracy for the t-Tau/Aβ1–42 ratio. In conclusion, the FWT, as a single-domain cognitive screening test, seems to be prompt and moderately accurate tool for the identification of an underlying AD neuropathological process in patients with MCI, supporting the importance of associating biomarkers evaluation in the work-up of patients with dementing neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Introduction: Alzheimer's disease (AD) will become a prominent public health issue in the future given its cognitively debilitating nature. As the advent of global ageing society is expected, AD may bring tremendous socioeconomical costs if current diagnosis methods stay put. In this article, we performed a systematic review of a recent (less than 10 years) ultrasensitive technology, the immunomagnetic reduction (IMR), which shows promising potential of early diagnosis of AD. Methods: We searched the Pubmed and Embase databases for studies that included keywords “early-stage Alzheimer's disease” and “immunomagnetic signal reduction.” Results: After full-text review, a total of 7 studies were included for final analysis. Most included studies have reported on Aβ40, Aβ42, t-tau, and levels of these biomarkers in the plasma of early AD patients comparing those in the healthy population. The ranges of the mean Aβ40 levels are as follows: 59.2 to 60.9 for control groups and 36.9 to 39.5 pg/mL for AD. Aβ42 and t-tau concentrations are both markedly lower than Aβ40, Aβ42 at 15.5 to 16.1 for control groups and 17.9 to 19 pg/mL for AD; t-tau levels were 13.5 to 14.3 for control groups and 39.4 to 46.7 pg/mL for AD. There is a significant increasing level of plasma Aβ42 by IMR assays in early AD patients across nearly all the included studies. There is a possible relationship between plasma levels of IMR AD biomarkers and (1) degree of hippocampal atrophy using magnetic resonance imaging, and (2) amount of brain amyloid accumulation using positron emission tomography. Conclusion: IMR assay is an ultrasensitivity technique that is useful for detection of early AD, which can provide benefits on understanding the disease progression of AD and encourage early medical invention for AD patients.

Background: This study explores whether the differences in cognitive performance among individuals with permanent atrial fibrillation (AF) are attributable to the duration of AF and anticoagulant therapy and explores the possible inflammatory mechanism of cognitive dysfunction related to AF. Methods: A total of 260 patients aged 50–75 years without previous cerebrovascular events were enrolled in this study. These 260 patients had been divided into the AF group (140 patients) and sinus rhythm group (120 patients). In the AF group, we divided participants into cognitive impairment (CI) group (90 patients) and cognitive normal (CN) group (50 patients). In the sinus rhythm group, we also divided participants into CI group (61 patients) and CN group (59 patients). The Mini‐Mental State Examination (MMSE) was used to assess the cognitive function of all participants. Neuronal‐derived exosomes were enriched in peripheral blood by immunoprecipitation and were confirmed by a transmission electron microscope, nanoparticle tracking analysis, and western blot. Alzheimer's disease‐pathogenic exosomal proteins and inflammatory cytokines were quantified. The association between AF and cognitive function was estimated by logistic regression analysis. ANOVA or Welch's t‐test compared the difference in protein concentrations between groups. Results: Non‐anticoagulant therapy in patients with AF was significantly associated with CI (OR = 13.99, 95% CI: 2.67–73.36, p <.01). The incidence of dementia in patients with AF > 3 years was significantly higher than in patients with AF ≤ 3 years, but there was no significant difference in total cognitive dysfunction (mild cognitive impairment [MCI] + dementia) (p =.126). The adjusted exosome concentrations of T‐tau and amyloid-β protein 42 (Aβ42) in the CI group were significantly higher than in the CN group (p <.001). The serum concentrations of IL‐6 and matrix metalloproteinase‐9 (MMP‐9) in patients with AF were higher than those in patients with sinus rhythm (p <.001). Conclusion: Aβ42 and T‐tau in peripheral blood neuronal‐derived exosomes maybe be associated with the early diagnosis of CI in patients with permanent AF. However, the value of Aβ42 and T‐tau for CI in patients with permanent AF still needs to be confirmed in future randomized control trials. [ABSTRACT FROM AUTHOR]

Background: Toxic amyloid-β (Aβ) peptides aggregate into higher molecular weight assemblies and accumulate not only in the extracellular space, but also in the walls of blood vessels in the brain, increasing their permeability, and promoting immune cell migration and activation. Given the prominent role of the immune system, phagocytic blood cells may contact pathological brain materials.Objective: To develop a novel method for early Alzheimer's disease (AD) detection, we used blood leukocytes, that could act as "sentinels" after trafficking through the brain microvasculature, to detect pathological amyloid by labelling with a conformationally-sensitive fluorescent amyloid probe and imaging with confocal spectral microscopy.Methods: Formalin-fixed peripheral blood mononuclear cells (PBMCs) from cognitively healthy control (HC) subjects, mild cognitive impairment (MCI) and AD patients were stained with the fluorescent amyloid probe K114, and imaged. Results were validated against cerebrospinal fluid (CSF) biomarkers and clinical diagnosis.Results: K114-labeled leukocytes exhibited distinctive fluorescent spectral signatures in MCI/AD subjects. Comparing subjects with single CSF biomarker-positive AD/MCI to negative controls, our technique yielded modest AUCs, which improved to the 0.90 range when only MCI subjects were included in order to measure performance in an early disease state. Combining CSF Aβ42 and t-Tau metrics further improved the AUC to 0.93.Conclusion: Our method holds promise for sensitive detection of AD-related protein misfolding in circulating leukocytes, particularly in the early stages of disease. [ABSTRACT FROM AUTHOR]

Introduction: Blood‐based Alzheimer's disease (AD) biomarkers show promise, but pre‐analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta [Aβ]42${\rm{A\beta }}]{_{42}}$, Aβ40${\rm{A}}{{{\beta}}_{40}}$, phosphorylatedtau[p−tau181${\rm{phosphorylated\;tau\;[p - ta}}{{\rm{u}}_{181}}$, total tau [t‐tau], neurofilament light chain [NfL], Aβ4240,${\rm{A}}{{{\beta}}_{\frac{{42}}{{40}}}},$ and p−tau181Aβ42$\frac{{{\rm{p - ta}}{{\rm{u}}_{181}}}}{{{\rm{A}}{{{\beta}}_{42}}}}$) in three collection tube types (ethylenediaminetetraacetic acid [EDTA] plasma, heparin plasma, serum). Methods: Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography‐positive and ‐negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis. Results: Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (R2${{\rm{R}}^2}\;$= 0.94), adequate for amyloid (R2${{\rm{R}}^2}\;$= 0.40‐0.69), and weaker for t‐tau (R2${{\rm{R}}^2}\;$= 0.04‐0.42) and p−tau181${\rm{p - ta}}{{\rm{u}}_{181}}$ (R2${{\rm{R}}^2}\;$= 0.22‐0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTau181Aβ42$\frac{{{\rm{pTa}}{{\rm{u}}_{181}}}}{{{\rm{A}}{\beta _{42}}}}$ (d$d\;$= 1.29). Discussion: AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood. [ABSTRACT FROM AUTHOR]

An enriched environment is effective in stimulating learning and memory in animal models as well as in humans. Environmental enrichment increases brain-derived neurotrophic factor (BDNF) in aged rats and reduces levels of Alzheimer-related proteins in the blood, including amyloid-β (Aβ) peptides and misfolded toxic forms of tau. To address whether stimulation of curiosity, which is a form of enrichment, may provide a buffer against Alzheimer’s disease (AD), we measured levels of biomarkers associated with AD at baseline and after a 6-week intervention in older adults (>65 years of age) randomized to one of three different intervention conditions. Specifically, in this pilot study, we tested the effectiveness of a traditional, structured learning environment compared to a self-motivated learning environment designed to stimulate curiosity. There were no significant differences from baseline to post-intervention in any of the groups for Aβ42/Aβ40 ratio or t-tau (total-tau) plasma levels. Serum BDNF levels decreased significantly in the control group. Interestingly, individuals who had the lowest serum BDNF levels at baseline experienced significantly higher increases in BDNF over the course of the 6-week intervention compared to individuals with higher serum BDNF levels at baseline. As expected, older individuals had lower MoCA scores. Years of education correlated negatively with Aβ levels, suggesting a protective effect of education on levels of this toxic protein. ECog scores were negatively correlated with BDNF levels, suggesting that better performance on the ECog questionnaire was associated with higher BDNF levels. Collectively, these findings did not suggest that a 6-week cognitive training intervention focused on curiosity resulted in significant alterations in blood biomarkers but showed interesting correlations between cognitive scores and BDNF levels, further supporting the role of this trophic factor in brain health in older adults.

Purpose: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers—encompassing the 42 amino-acid isoform of amyloid-β (Aβ42), phosphorylated-tau (P-tau), and Total-tau (T-tau)—with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. Methods: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. Results: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aβ42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. Conclusions: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy. [ABSTRACT FROM AUTHOR]

Biomarkers are the only feasible way to detect and monitor presymptomatic Alzheimer's disease (AD). No single biomarker can predict future cognitive decline with an acceptable level of accuracy. In addition to designing powerful multimodal diagnostic platforms, a careful investigation of the major sources of disease heterogeneity and their influence on biomarker changes is needed. Here we investigated the accuracy of a novel multimodal biomarker classifier for differentiating cognitively normal (NC), mild cognitive impairment (MCI) and AD subjects with and without stratification by ApoE4 genotype. 111 NC, 182 MCI and 95 AD ADNI participants provided both structural MRI and CSF data at baseline. We used an automated machine-learning classifier to test the ability of hippocampal volume and CSF Aβ, t-tau and p-tau levels, both separately and in combination, to differentiate NC, MCI and AD subjects, and predict conversion. We hypothesized that the combined hippocampal/CSF biomarker classifier model would achieve the highest accuracy in differentiating between the three diagnostic groups and that ApoE4 genotype will affect both diagnostic accuracy and biomarker selection. The combined hippocampal/CSF classifier performed better than hippocampus-only classifier in differentiating NC from MCI and NC from AD. It also outperformed the CSF-only classifier in differentiating NC vs. AD. Our amyloid marker played a role in discriminating NC from MCI or AD but not for MCI vs. AD. Neurodegenerative markers contributed to accurate discrimination of AD from NC and MCI but not NC from MCI. Classifiers predicting MCI conversion performed well only after ApoE4 stratification. Hippocampal volume and sex achieved AUC = 0.68 for predicting conversion in the ApoE4-positive MCI, while CSF p-tau, education and sex achieved AUC = 0.89 for predicting conversion in ApoE4-negative MCI. These observations support the proposed biomarker trajectory in AD, which postulates that amyloid markers become abnormal early in the disease course while markers of neurodegeneration become abnormal later in the disease course and suggests that ApoE4 could be at least partially responsible for some of the observed disease heterogeneity.

Background: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant.Objective: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-β (Aβ) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared.Methods: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aβ plaques in frontal cortical brain biopsy and 13 iNPH patients without Aβ pathology. CSF Amyloid-β42 (Aβ42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs.Results: All biomarkers but Aβ42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aβ42 instead showed divergent longitudinal decrease between Aβ-positive and -negative patients in L-CSF, and thereafter increase in Aβ-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aβ42 R = 0.87, T-tau R = 0.83, P-tau R = 0.92, NFL R = 0.94, NRGN R = 0.9; all p < 0.0001) but were systematically lower in V-CSF (Aβ42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aβ42 showed higher concentration in non-carriers of allele ɛ4.Conclusion: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aβ pathology, while NFL normalized toward its pre-shunt levels. Aβ42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations. [ABSTRACT FROM AUTHOR]

Chronic pain leads to tau accumulation and hippocampal atrophy in mice. In this study, we provide one of the first assessments in humans, examining the associations of probable chronic pain with hippocampal volume, integrity of the locus coeruleus (LC)-an upstream site of tau deposition-and Alzheimer's Disease-related plasma biomarkers. Participants were mostly cognitively unimpaired men. Probable chronic pain was defined as moderate-to-severe pain in 2+ study waves at average ages 56, 62, and 68. At age 68, 424 participants underwent structural magnestic resonance imaging (MRI) of hippocampal volume and LC-sensitive MRI providing an index of LC integrity (LC contrast-to-noise ratio). Analyses adjusted for confounders including major health conditions, depressive symptoms, and opioid use. Models showed that men with probable chronic pain had smaller hippocampal volume and lower rostral-middle-but not caudal-LC contrast-to-noise ratio compared to men without probable chronic pain. Men with probable chronic pain also had higher levels of plasma total tau, beta-amyloid-42, and beta-amyloid-40 compared to men without probable chronic pain. These findings suggest that probable chronic pain is associated with tau accumulation and reduced structural brain integrity in regions affected early in the development of Alzheimer's Disease. PERSPECTIVE: Probable chronic pain was associated with plasma biomarkers and brain regions that are affected early in Alzheimer's disease (AD). Reducing pain in midlife and elucidating biological mechanisms may help to reduce the risk of AD in older adults., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Abstract Introduction Cerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau (p‐tau) are biomarkers of Alzheimer's disease (AD), yet much is unknown about AD‐associated changes in tau metabolism and tau tangle etiology. Methods We assessed the variation of t‐tau and p‐tau explained by 38 previously identified CSF metabolites using linear regression models in middle‐age controls from the Wisconsin Alzheimer's Disease Research Center, and predicted AD/mild cognitive impairment (MCI) versus an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO). Results The 38 CSF metabolites explained 70.3% and 75.7% of the variance in t‐tau and p‐tau, respectively. Of these, seven LASSO‐selected metabolites improved the prediction ability of AD/MCI versus older controls (area under the curve score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model. Discussion These tau‐correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology.

Sex differences in molecular biomarkers after sports-related concussion (SRC) could steadily advance our understanding of injury heterogeneity and complexity, and help capture phenotypic characteristics, by unveiling sex-dependent pathobiological processes and disease mechanisms. Such knowledge will help improve diagnosis, clinical management, and prognosis. Total-tau (t-tau) has recently emerged as a promising blood marker showing sex-associated differences in neurodegenerative diseases. Nonetheless, to date, little is known about the potential influence of sex on its injury-related concentration and dynamics after SRC. We hypothesized that measurements of circulating levels of t-tau over time would reflect a differential vulnerability signature, providing insights into the sex-related phenotypes and their relationship with clinical outcomes. To test this hypothesis, plasma levels of t-tau were measured using an ultrasensitive immunoassay up to 7 days after injury, in 46 concussed athletes (20 males, 26 females). We used trajectory analysis to generate two distinct temporal profiles of t-tau, which were then compared with gender and return to play (RTP). The majority of subjects (~63%) started with low t-tau concentrations that further declined within the first 48 h; while the remaining (“maximal decliners”) started with concentrations comparable to the baseline levels that also fell over time, but persisting markedly higher compared with the first profile. The maximal decliner group was primarily composed of female subjects (p = 0.007) and was significantly associated with poor outcome (RTP ≥ 10 days after concussion) (p = 0.011). Taken together, our data provide evidence for the existence of sex-related biosignatures following sports-related concussions, possibly indicating a differential effect as a result of distinct brain vulnerability and inherent injury response. Future studies will be required to further elucidate underlying sex-based biological and pathophysiological mechanisms, and determine the value of t-tau signatures for management and therapeutic decision-making in sports-related concussions.

ObjectiveIn this study, we assessed plasma biomarkers to identify cognitive impairment in Parkinson’s disease (PD) patients by applying ultra-sensitive immunomagnetic reduction-based immunoassay (IMR).MethodsThe study enrolled 60 PD patients and 28 age- and sex-matched normal controls. Complete cognitive function assessments were performed on participants using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating. PD patients with an MMSE score of ≦26 were defined as having cognitive impairment. Meanwhile, a 99mTc-TRODAT-1 scan was performed and plasma levels of Aβ-40, Aβ-42, T-tau, and α-synuclein were evaluated using IMR, subsequent correlation analyses were then performed.ResultsCompared with normal adults, PD patients have higher plasma levels of α-synuclein and T-tau, and a lower level of Aβ-40 (p < 0.05). Plasma levels of α-synuclein (r = −0.323, p = 0.002), Aβ-40 (r = 0.276, p = 0.01), and T-tau (r = −0.322, p = 0.002) are significantly correlated with MMSE scores. The TRODAT scan results, including visual inspection and quantification, revealed significant correlations between Aβ-40 and PD. Multiple regression analysis showed that the plasma levels of Aβ-40 (OR = 0.921, 95% CI = 0.879–0.962), α-synuclein (OR = 3.016, 95% CI = 1.703–5.339), and T-tau (OR = 1.069, 95% CI = 1.026–1.115) were independently associated with PD patients with cognitive impairment. The cutoff values for predicting cognitive deficits in PD patients were 45.101 pg/ml of Aβ-40, (Area under curve (AUC) = 0.791), 0.389 pg/ml of α-synuclein, (AUC = 0.790), and 30.555 pg/ml of T-tau (AUC = 0.726).ConclusionPlasma levels of α-synuclein, Aβ-40, and T-tau are potential biomarkers to detect cognitive impairment in PD patients.

Introduction: Obstructive sleep apnea (OSA) is associated with Alzheimer's disease (AD) biomarkers in cognitively normal (CN) and mild cognitive impaired (MCI) participants. However, independent and combined effects of OSA, amyloid beta (Aβ) and tau‐accumulation on AD time‐dependent progression risk is unclear. Methods: Study participants grouped by biomarker profile, as described by the A/T/N scheme, where "A" refers to aggregated Aβ, "T" aggregated tau, and "N" to neurodegeneration, included 258 CN (OSA‐positive [OSA+] [A+TN+ n = 10, A+/TN− n = 6, A−/TN+ n = 10, A−/TN− n = 6 and OSA‐negative [OSA‐] [A+TN+ n = 84, A+/TN− n = 11, A−/TN+ n = 96, A−/TN− n = 36]) and 785 MCI (OSA+ [A+TN+ n = 35, A+/TN− n = 15, A−/TN+ n = 25, A−/TN− n = 16] and OSA− [A+TN+ n = 388, A+/TN− n = 28, A−/TN+ n = 164, A−/TN− n = 114]) older‐adults from the Alzheimer's Disease Neuroimaging Initiative cohort. Cox proportional hazards regression models estimated the relative hazard of progression from CN‐to‐MCI and MCI‐to‐AD, among baseline OSA CN and MCI patients, respectively. Multi‐level logistic mixed‐effects models with random intercept and slope investigated the synergistic associations of self‐reported OSA, Aβ, and tau burden with prospective cognitive decline. Results: Independent of TN‐status (CN and MCI), OSA+/Aβ+ participants were approximately two to four times more likely to progress to MCI/AD (P <.001) and progressed 6 to 18 months earlier (P <.001), compared to other participants combined (ie, OSA+/Aβ−, OSA−/Aβ+, and OSA−/Aβ−). Notably, OSA+/Aβ− versus OSA−/Aβ− (CN and MCI) and OSA+/TN− versus OSA−/TN− (CN) participants showed no difference in the risk and time‐to‐MCI/AD progression. Mixed effects models demonstrated OSA synergism with Aβ (CN and MCI [β = 1.13, 95% confidence interval (CI), 0.74 to 1.52, and β = 1.18, 95%CI, 0.82 to 1.54]) respectively, and with tau (MCI [β = 1.31, 95% CI, 0.87 to 1.47]), P <.001 for all. Discussion: OSA acts in synergism with Aβ and with tau, and all three acting together result in synergistic neurodegenerative mechanisms especially as Aβ and tau accumulation becomes increasingly abnormal, thus leading to shorter progression time to MCI/AD in CN and MCI‐OSA patients, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Cerebrospinal fluid (CSF) total tau (t‐tau) and phosphorylated tau (p‐tau) are biomarkers of Alzheimer's disease (AD), yet much is unknown about AD‐associated changes in tau metabolism and tau tangle etiology. Methods: We assessed the variation of t‐tau and p‐tau explained by 38 previously identified CSF metabolites using linear regression models in middle‐age controls from the Wisconsin Alzheimer's Disease Research Center, and predicted AD/mild cognitive impairment (MCI) versus an independent set of older controls using metabolites selected by the least absolute shrinkage and selection operator (LASSO). Results: The 38 CSF metabolites explained 70.3% and 75.7% of the variance in t‐tau and p‐tau, respectively. Of these, seven LASSO‐selected metabolites improved the prediction ability of AD/MCI versus older controls (area under the curve score increased from 0.92 to 0.97 and 0.78 to 0.93) compared to the base model. Discussion: These tau‐correlated CSF metabolites increase AD/MCI prediction accuracy and may provide insight into tau tangle etiology. [ABSTRACT FROM AUTHOR]

Sex differences in molecular biomarkers after sports-related concussion (SRC) could steadily advance our understanding of injury heterogeneity and complexity, and help capture phenotypic characteristics, by unveiling sex-dependent pathobiological processes and disease mechanisms. Such knowledge will help improve diagnosis, clinical management, and prognosis. Total-tau (t-tau) has recently emerged as a promising blood marker showing sex-associated differences in neurodegenerative diseases. Nonetheless, to date, little is known about the potential influence of sex on its injury-related concentration and dynamics after SRC. We hypothesized that measurements of circulating levels of t-tau over time would reflect a differential vulnerability signature, providing insights into the sex-related phenotypes and their relationship with clinical outcomes. To test this hypothesis, plasma levels of t-tau were measured using an ultrasensitive immunoassay up to 7 days after injury, in 46 concussed athletes (20 males, 26 females). We used trajectory analysis to generate two distinct temporal profiles of t-tau, which were then compared with gender and return to play (RTP). The majority of subjects (~63%) started with low t-tau concentrations that further declined within the first 48 h; while the remaining ("maximal decliners") started with concentrations comparable to the baseline levels that also fell over time, but persisting markedly higher compared with the first profile. The maximal decliner group was primarily composed of female subjects (p = 0.007) and was significantly associated with poor outcome (RTP ≥ 10 days after concussion) (p = 0.011). Taken together, our data provide evidence for the existence of sex-related biosignatures following sports-related concussions, possibly indicating a differential effect as a result of distinct brain vulnerability and inherent injury response. Future studies will be required to further elucidate underlying sex-based biological and pathophysiological mechanisms, and determine the value of t-tau signatures for management and therapeutic decision-making in sports-related concussions. [ABSTRACT FROM AUTHOR]

Objective: In this study, we assessed plasma biomarkers to identify cognitive impairment in Parkinson's disease (PD) patients by applying ultra-sensitive immunomagnetic reduction-based immunoassay (IMR). Methods: The study enrolled 60 PD patients and 28 age- and sex-matched normal controls. Complete cognitive function assessments were performed on participants using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating. PD patients with an MMSE score of ≦26 were defined as having cognitive impairment. Meanwhile, a 99mTc-TRODAT-1 scan was performed and plasma levels of Aβ-40, Aβ-42, T-tau, and α-synuclein were evaluated using IMR, subsequent correlation analyses were then performed. Results: Compared with normal adults, PD patients have higher plasma levels of α-synuclein and T-tau, and a lower level of Aβ-40 (p < 0.05). Plasma levels of α-synuclein (r = −0.323, p = 0.002), Aβ-40 (r = 0.276, p = 0.01), and T-tau (r = −0.322, p = 0.002) are significantly correlated with MMSE scores. The TRODAT scan results, including visual inspection and quantification, revealed significant correlations between Aβ-40 and PD. Multiple regression analysis showed that the plasma levels of Aβ-40 (OR = 0.921, 95% CI = 0.879–0.962), α-synuclein (OR = 3.016, 95% CI = 1.703–5.339), and T-tau (OR = 1.069, 95% CI = 1.026–1.115) were independently associated with PD patients with cognitive impairment. The cutoff values for predicting cognitive deficits in PD patients were 45.101 pg/ml of Aβ-40, (Area under curve (AUC) = 0.791), 0.389 pg/ml of α-synuclein, (AUC = 0.790), and 30.555 pg/ml of T-tau (AUC = 0.726). Conclusion: Plasma levels of α-synuclein, Aβ-40, and T-tau are potential biomarkers to detect cognitive impairment in PD patients. [ABSTRACT FROM AUTHOR]

Background: An elevated neutrophil-lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau 181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally., Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β=-12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ+ (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data., Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau 181 in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence., Competing Interests: Competing Interests HZ has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures in symposia sponsored by Alzecure, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, and Roche, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). KB has served as a consultant and at advisory boards for AC Immune, Acumen, ALZPath, AriBio, BioArctic, Biogen, Eisai, Lilly, Moleac Pte. Ltd, Novartis, Ono Pharma, Prothena, Roche Diagnostics, and Siemens Healthineers; has served at data monitoring committees for Julius Clinical and Novartis; has given lectures, produced educational materials and participated in educational programs for AC Immune, Biogen, Celdara Medical, Eisai and Roche Diagnostics; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program, outside the work presented in this paper. The other authors declare no competing interests.

Background: To alleviate the interpretation of the core Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers, amyloid β1-42 (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau), the Erlangen Score (ES) interpretation algorithm has been proposed.Objective: In this study, we aim to assess the predictive properties of the ES algorithm on cognitive and neuroimaging outcomes in mild cognitive impairment (MCI).Methods: All MCI subjects with an available baseline CSF sample from ADNI-1 were included (n = 193), and assigned an ES between 0 and 4 based on their baseline CSF biomarker profile. Structural magnetic resonance imaging brain scans and MMSE and ADAS-Cog scores were collected at up to 7 times in follow-up examinations.Results: We observed strong and significant correlations between the ES at baseline and neuroimaging and cognitive results with patients with neurochemically probable AD (ES = 4) progressing significantly (p≤0.01) faster than those with a neurochemically improbable AD (ES = 0 or 1), and the subjects with neurochemically possible AD (ES = 2 or 3) in-between these two groups.Conclusion: This study further demonstrates the utility of the ES algorithm as a as a tool in predicting cognitive and imaging progression in MCI patients. [ABSTRACT FROM AUTHOR]

Objectives: To characterise a panel of neuroinjury-related blood biomarkers after sport-related concussion (SRC). We hypothesised significant differences in biomarker profiles between athletes with SRC and healthy controls at both subacute and medical clearance time points.Methods: Thirty-eight interuniversity athletes were recruited over two athletic seasons (n = 19 SRC; n = 19 healthy matched-control). High-sensitivity immunoassay was used to evaluate 11 blood analytes at both the subacute phase after SRC and at medical clearance.Results: Univariate analysis identified elevated circulating peroxiredoxin-6 (PRDX-6) in athletes with SRC compared to healthy controls at the subacute time point. Multivariate analyses yielded similar results in the subacute phase, but identified both PRDX-6 and T-tau as significant contributors to class separation between athletes with SRC and controls at medical clearance.Conclusions: Our results are consistent with the increasing recognition that physiological recovery after SRC extends beyond clinical recovery. Blood biomarkers appear to be useful in elucidating the biology of brain restitution after SRC. However, their implementation requires mindfulness of factors such as academic stress, exercise, and injury heterogeneity. [ABSTRACT FROM AUTHOR]

The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n = 20) compared to patients without neurodegenerative disorders (non-ND, n = 11): 2.80 versus 2.30 (p < 0.005) and 2.83 versus 2.30 ng/mL (p = NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD. [ABSTRACT FROM AUTHOR]

Background: Idiopathic normal pressure hydrocephalus (INPH) has no reliable biomarker to assist in the selection of patients who could benefit from ventriculo-peritoneal (VP) shunt insertion. The neurodegenerative markers T-tau and Aβ1-42 have been found to successfully differentiate between Alzheimer's disease (AD) and INPH and therefore are candidate biomarkers for prognosis and shunt response in INPH. The aim of this study was to test the predictive value of cerebrospinal fluid (CSF) T-tau and Aβ1-42 for shunt responsiveness. In particular, we pay attention to the subset of INPH patients with raised T-tau, who are often expected to be poor surgical candidates. Methods: Single-centre retrospective analysis of probable INPH patients with CSF samples collected from 2006 to 2016. Index test: CSF levels of T-tau and Aβ1-42. Reference standard: postoperative outcome. ROC analysis assessed the predictive value. Results: A total of 144 CSF samples from INPH patients were analysed. Lumbar T-tau was a good predictor of post-operative mobility (AUROC 0.80). The majority of patients with a co-existing neurodegenerative disease responded well, including those with high T-tau levels. Conclusion: INPH patients tended to exhibit low levels of CSF T-tau, and this can be a good predictor outcome. However levels are highly variable between individuals. Raised T-tau and being shunt-responsive are not mutually exclusive, and such patients ought not necessarily be excluded from having a VP shunt. A combined panel of markers may be a more specific method for aiding selection of patients for VP shunt insertion. This is the most comprehensive presentation of CSF samples from INPH patients to date, thus providing further reference values to the current literature. [ABSTRACT FROM AUTHOR]

Background: There is a need to find very early markers for pre-clinical Alzheimer's disease as interventions early in the disease process are thought to be most effective.Objective: The present study aimed to address the potential relation between cerebrospinal fluid (CSF) biomarkers and reduced cognitive function in a relatively young cohort of memory clinic patients with subjective cognitive decline.Methods: 122 patients (mean age 63 years) with subjective cognitive decline were recruited from two university memory clinics and followed for two years.Results: The main finding was that the subgroup with objective memory decline during the study period had significantly higher T-tau at baseline than the group with improved memory. Baseline CSF variables showed a trend toward more pathological values in the patients with memory decline compared to those who improved or remained stable. The baseline memory score of those who declined was significantly better than the baseline score of those who improved over two years. The general trend for the whole group was improved memory and executive test scores. There were no differences in cognitive scores based on CSF quartiles at baseline, nor were there differences in cognitive outcome for patients with early amnestic mild cognitive impairment versus average cognitive function at baseline.Conclusions: The main finding that T-tau rather than amyloid-β was associated with memory decline do not support the prevailing opinion about the chain of events assumed to take place in Alzheimer's disease. In addition, memory decline was not associated with poor baseline memory score. Thus, a memory cut-off indicating low baseline memory would not would have identified the declining group. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau and p-tau have a characteristic pattern in Alzheimer’s Disease (AD). Their roles in HIV-associated neurocognitive disorder (HAND) remains unclear. Methods: Adults with chronic treated HIV disease were recruited (n = 43, aged 56.7 ± 7.9; 32% aged 60+; median HIV duration 20 years, >95% plasma and CSF HIV RNA <50 cp/mL, on cART for a median 24 months). All underwent standard neuropsychological testing (61% had HAND), APOE genotyping (30.9% carried APOE ε4 and 7.1% were ε4 homozygotes) and a lumbar puncture. Concentrations of Aβ1-42, t-tau and p-tau were assessed in the CSF using commercial ELISAs. Current neurocognitive status was defined using the continuous Global Deficit Score, which grades impairment in clinically relevant categories. History of HAND was recorded. Univariate correlations informed multivariate models, which were corrected for nadir CD4-T cell counts and HIV duration. Results: Carriage of APOE ε4 predicted markedly lower levels of CSF Aβ1-42 in univariate (r = -.50; p = .001) and multivariate analyses (R2 = .25; p < .0003). Greater levels of neurocognitive impairment were associated with higher CSF levels of p-tau in univariate analyses (r = .32; p = .03) and multivariate analyses (R2 = .10; p = .03). AD risk prediction cut-offs incorporating all three CSF biomarkers suggested that 12.5% of participants had a high risk for AD. Having a CSF-AD like profile was more frequent in those with current (p = .05) and past HIV-associated dementia (p = .03). Conclusions: Similarly to larger studies, APOE ε4 genotype was not directly associated with HAND, but moderated CSF levels of Aβ1-42 in a minority of participants. In the majority of participants, increased CSF p-tau levels were associated with current neurocognitive impairment. Combined CSF biomarker risk for AD in the current HIV+ sample is more than 10 times greater than in the Australian population of the same age. Larger prospective studies are warranted. [ABSTRACT FROM AUTHOR]