Total Tau Levels Research Articles

Sex-differences in the association of social health and marital status with blood-based immune and neurodegeneration markers in a cohort of community-dwelling older adults

BackgroundThe immune system has been proposed to play a role in the link between social health and all-cause dementia risk. We explored cross-sectional and longitudinal associations between social health, immune system balance and plasma neurodegeneration markers in community-dwelling older adults, and explored whether the balance between innate and adaptive immunity mediates associations between social health and both cognition and total brain volume. MethodsSocial health markers (social support, marital status, loneliness) were measured in the Rotterdam Study between 2002–2008. Immune system cell counts and balance were assessed repeatedly from 2002 to 2016 using white blood-cell-based indices and individual counts (granulocyte-to-lymphocyte ratio (GLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII)). Plasma neurodegeneration biomarkers (amyloid-β40, amyloid-β42, total tau and neurofilament light chain) were measured once from blood samples collected between 2002–2008. Global cognitive function and total brain volume (MRI) were measured at the follow-up visit between 2009–2014. We used linear mixed models to study longitudinal associations and performed causal mediation analyses. ResultsIn 8374 adults (mean age 65.7, 57 % female), never married participants (n = 394) had higher GLR, PLR and SII compared to married peers at baseline and during follow-up, indicating imbalance towards innate immunity. Being never married was associated with higher plasma amyloid-β40, and being widowed or divorced with higher plasma total tau levels at baseline. Widowed or divorced males, but not females, had higher GLR, PLR and SII at baseline. Higher social support was associated with lower PLR in females, but higher PLR in males. Loneliness was not associated with any of the immune system balance ratios. Never married males had higher levels of all plasma neurodegeneration markers at baseline. Immune system balance did not mediate associations between social health and cognition or total brain volume, but does interact with marital status. ConclusionThis study indicates that marital status is associated with blood-based immune system markers toward innate immunity and higher levels of plasma neurodegeneration markers. This is particularly evident for never married or previously married male older adults compared to married or female peers.

Cerebral Amyloidosis in Individuals with Subjective Cognitive Decline: From Genetic Predisposition to Actual Cerebrospinal Fluid Measurements.

The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer's Disease (AD), amyloid-beta 42 (Aβ42) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aβ42 and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aβ42 and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aβ42 were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aβ42 was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings.

The relation of a cerebrospinal fluid profile associated with Alzheimer’s disease with cognitive function and neuropsychiatric symptoms in sporadic cerebral amyloid angiopathy

BackgroundPatients with sporadic cerebral amyloid angiopathy (sCAA) frequently report cognitive or neuropsychiatric symptoms. The aim of this study is to investigate whether in patients with sCAA, cognitive impairment and neuropsychiatric symptoms are associated with a cerebrospinal fluid (CSF) biomarker profile associated with Alzheimer’s disease (AD).MethodsIn this cross-sectional study, we included participants with sCAA and dementia- and stroke-free, age- and sex-matched controls, who underwent a lumbar puncture, brain MRI, cognitive assessments, and self-administered and informant-based-questionnaires on neuropsychiatric symptoms. CSF phosphorylated tau, total tau and Aβ42 levels were used to divide sCAA patients in two groups: CAA with (CAA-AD+) or without a CSF biomarker profile associated with AD (CAA-AD-). Performance on global cognition, specific cognitive domains (episodic memory, working memory, processing speed, verbal fluency, visuoconstruction, and executive functioning), presence and severity of neuropsychiatric symptoms, were compared between groups.ResultssCAA-AD+ (n=31; mean age: 72 ± 6; 42%, 61% female) and sCAA-AD- (n=23; 70 ± 5; 42% female) participants did not differ with respect to global cognition or type of affected cognitive domain(s). The number or severity of neuropsychiatric symptoms also did not differ between sCAA-AD+ and sCAA-AD- participants. These results did not change after exclusion of patients without prior ICH.ConclusionsIn participants with sCAA, a CSF biomarker profile associated with AD does not impact global cognition or specific cognitive domains, or the presence of neuropsychiatric symptoms.

Storage time affects the level and diagnostic efficacy of plasma biomarkers for neurodegenerative diseases.

JOURNAL/nrgr/04.03/01300535-202508000-00027/figure1/v/2024-09-30T120553Z/r/image-tiff Several promising plasma biomarker proteins, such as amyloid-β (Aβ), tau, neurofilament light chain, and glial fibrillary acidic protein, are widely used for the diagnosis of neurodegenerative diseases. However, little is known about the long-term stability of these biomarker proteins in plasma samples stored at -80°C. We aimed to explore how storage time would affect the diagnostic accuracy of these biomarkers using a large cohort. Plasma samples from 229 cognitively unimpaired individuals, encompassing healthy controls and those experiencing subjective cognitive decline, as well as 99 patients with cognitive impairment, comprising those with mild cognitive impairment and dementia, were acquired from the Sino Longitudinal Study on Cognitive Decline project. These samples were stored at -80°C for up to 6 years before being used in this study. Our results showed that plasma levels of Aβ42, Aβ40, neurofilament light chain, and glial fibrillary acidic protein were not significantly correlated with sample storage time. However, the level of total tau showed a negative correlation with sample storage time. Notably, in individuals without cognitive impairment, plasma levels of total protein and tau phosphorylated protein threonine 181 (p-tau181)also showed a negative correlation with sample storage time. This was not observed in individuals with cognitive impairment. Consequently, we speculate that the diagnostic accuracy of plasma p-tau181 and the p-tau181 to total tau ratio may be influenced by sample storage time. Therefore, caution is advised when using these plasma biomarkers for the identification of neurodegenerative diseases, such as Alzheimer's disease. Furthermore, in cohort studies, it is important to consider the impact of storage time on the overall results.

Neurodegeneration Biomarkers in Adult Spinal Muscular Atrophy (SMA) Patients Treated with Nusinersen.

The objective of this study is to evaluate biomarkers for neurodegenerative disorders in adult SMA patients and their potential for monitoring the response to nusinersen. Biomarkers for neurodegenerative disorders were assessed in plasma and CSF samples obtained from a total of 30 healthy older adult controls and 31 patients with adult SMA type 2 and 3. The samples were collected before and during nusinersen treatment at various time points, approximately at 2, 6, 10, and 22 months. Using ELISA technology, the levels of total tau, pNF-H, NF-L, sAPPβ, Aβ40, Aβ42, and YKL-40 were evaluated in CSF samples. Additionally, plasma samples were used to measure NF-L and total tau levels using SIMOA technology. SMA patients showed improvements in clinical outcomes after nusinersen treatment, which were statistically significant only in walkers, in RULM (p = 0.04) and HFMSE (p = 0.05) at 24 months. A reduction in sAPPβ levels was found after nusinersen treatment, but these levels did not correlate with clinical outcomes. Other neurodegeneration biomarkers (NF-L, pNF-H, total tau, YKL-40, Aβ40, and Aβ42) were not found consistently changed with nusinersen treatment. The slow progression rate and mild treatment response of adult SMA types 2 and 3 may not lead to detectable changes in common markers of axonal degradation, inflammation, or neurodegeneration, since it does not involve large pools of damaged neurons as observed in pediatric forms. However, changes in biomarkers associated with the APP processing pathway might be linked to treatment administration. Further studies are warranted to better understand these findings.

A Prospective Study on Neural Biomarkers in Patients with Long-COVID Symptoms.

this prospective observational study aims to assess serum levels of glial fibrillary acidic protein (GFAP), s100b, and total Tau in long-COVID patients, exploring correlations with symptoms, cognitive decline, mental health, and quality of life. Long-COVID patients visiting our outpatient clinic (February 2021-December 2022) were screened alongside age- and sex-matched controls. GFAP, s100b, and total Tau in serum were measured with ELISA. Cognitive function, depression, anxiety, post-traumatic stress disorder, and quality of life were evaluated using MoCA, HADS (depression and anxiety), IES-R, and SF-36, respectively. Sixty-five long-COVID patients and 20 controls were included. GFAP levels were significantly higher in long-COVID patients (p = 0.031), though not correlating with the presence of long-COVID symptoms. S100b and total Tau showed no significant differences between patients and controls. Nervous system-related symptoms were reported in 47% of patients. High rates of cognitive decline (65.9%), depression (32.2%), anxiety (47.5%), and post-traumatic stress disorder (44.1%) were observed. Over 80% of the study population scored below normative cutoffs for SF-36, indicating a significant impact on quality of life. in this long-COVID cohort with substantial psychological and cognitive symptoms, GFAP levels were elevated compared to controls, though not correlating with the presence of long-COVID symptoms.

Effect of outer membrane vesicles of Lactobacillus pentosus on Tau phosphorylation and CDK5-Calpain pathway in mice

Alzheimer's disease (AD) stands as a neurodegenerative disorder causing cognitive decline, posing a significant health concern for the elderly population in China. This study explored the effects of outer membrane vesicles (OMVs) from the gut microbiota of AD patients on learning and memory abilities and Tau protein phosphorylation in mice. In contrast to the OMVs from healthy controls and the PBS treatment group, mice treated with AD-OMVs exhibited notable declines in learning and memory capabilities, as evidenced by results from the Morris water maze, Y-maze, and novel object recognition tests. Immunohistochemistry and Western blot assessments unveiled elevated levels of hyperphosphorylated Tau in the cortex and hippocampus of mice treated with AD-OMVs. However, there were no alterations observed in the total Tau levels. In addition, AD-OMVs treated mice showed increased neuroinflammation indicated by elevated astrocytes and microglia. Molecular mechanism studies demonstrated that AD-OMVs could activate GSK3β, CDK5-Calpain and NF-κB pathways in mice hippocampus. These studies suggest AD patient gut microbiota derived OMVs can promote host Tau phosphorylation and improved neuroinflammation.

BDNF Val66Met moderates episodic memory decline and tau biomarker increases in early sporadic Alzheimer's disease.

Allelic variation in the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism has been shown to moderate rates of cognitive decline in preclinical sporadic Alzheimer's disease (AD; i.e., Aβ + older adults), and pre-symptomatic autosomal dominant Alzheimer's disease (ADAD). In ADAD, Met66 was also associated with greater increases in CSF levels of total-tau (t-tau) and phosphorylated tau (p-tau181). This study sought to determine the extent to which BDNF Val66Met is associated with changes in episodic memory and CSF t-tau and p-tau181 in Aβ + older adults in early-stage sporadic AD. Aβ + Met66 carriers (n = 94) and Val66 homozygotes (n = 192) enrolled in the Alzheimer's Disease Neuroimaging Initiative who did not meet criteria for AD dementia, and with at least one follow-up neuropsychological and CSF assessment, were included. A series of linear mixed models were conducted to investigate changes in each outcome over an average of 2.8years, covarying for CSF Aβ42, APOE ε4 status, sex, age, baseline diagnosis, and years of education. Aβ + Met66 carriers demonstrated significantly faster memory decline (d = 0.33) and significantly greater increases in CSF t-tau (d = 0.30) and p-tau181 (d = 0.29) compared to Val66 homozygotes, despite showing equivalent changes in CSF Aβ42. These findings suggest that reduced neurotrophic support, which is associated with Met66 carriage, may increase vulnerability to Aβ-related tau hyperphosphorylation, neuronal dysfunction, and cognitive decline even prior to the emergence of dementia. Additionally, these findings highlight the need for neuropsychological and clinicopathological models of AD to account for neurotrophic factors and the genes which moderate their expression.

Blood Pressure Variability and Plasma Alzheimer's Disease Biomarkers in the SPRINT Trial.

Recent observational studies suggest higher blood pressure (BP) variability (BPV) is associated with Alzheimer's disease (AD) biomarkers amyloid-beta (Aβ) and tau. Less is known about relationships in interventional cohorts with strictly controlled mean BP levels. Investigate the longitudinal relationship between BPV and change in plasma AD biomarkers under standard versus intensive BP treatment. In this post hoc analysis of the SPRINT trial, 457 participants (n = 206 in standard group, n = 251 in intensive group) underwent repeated BP measurement between baseline and 12-months follow-up, and venipuncture at baseline and median (IQR) 3.5 (3.0-4.0) years later to determine plasma AD biomarkers total tau and Aβ1-42:Aβ1-40 ratio. BPV was calculated as tertiles of variability independent of mean. Linear mixed models investigated the effect of BPV×time on AD biomarker levels. Higher BPV was associated with increased levels of total tau in the standard group (β [95% CI] 1st versus 3rd tertiles of BPV: 0.21 [0.02, 0.41], p = 0.035), but not in the intensive group (β [95% CI] 1st versus 3rd tertiles of BPV: -0.02 [-0.19, 0.16], p = 0.843). BPV was not associated with Aβ 1-42:Aβ 1-40 ratio in either group. Mean BP was not associated with biomarkers. Higher BPV was associated with increased plasma total tau under standard BP treatment. Findings add new evidence to prior observational work linking BPV to AD pathophysiology and suggest that, despite strict control of mean BP, BPV remains a risk for pathophysiological change underlying risk for AD.

Different reactive profiles of calmodulin in the CSF samples of Chinese patients of four types of genetic prion diseases.

Calmodulin (CaM) levels exhibit significant elevation in the brain tissue of rodent and cell line models infected with prion, as well as in the cerebrospinal fluid (CSF) samples from patients diagnosed with sporadic Creutzfeldt-Jakob disease (sCJD). However, the status of CSF CaM in patients with genetic prion diseases (gPrDs) remains unclear. This study aims to assess the characteristics of CSF CaM in Chinese patients presenting four subtypes of gPrDs. A total of 103 CSF samples from patients diagnosed with T188K-gCJD, E200K-gCJD, D178N-FFI, P102L-GSS were included in this study, along with 40 CSF samples from patients with non-prion diseases (non-PrDs). The presence of CSF CaM and 14-3-3 proteins was assessed using Western blots analysis, while levels of CSF 14-3-3 and total tau were measured using enzyme-linked immunosorbent assays (ELISAs). Statistical methods including multivariate logistic regression were employed to evaluate the association between CSF CaM positivity and relevant clinical, laboratory, and genetic factors. The positive rates of CSF CaM were significantly higher in cases of T188K-gCJD (77.1%), E200K-gCJD (86.0%), and P102-GSS (90.9%) compared to non-PrD cases (22.5%). In contrast, CSF CaM positivity was slightly elevated in D178N-FFI (34.3%). CSF CaM positivity was remarkably high in patients who tested positive for CSF 14-3-3 by Western blot and exhibited high levels of total tau (≥1400 pg/ml) as measures by ELISA. Multivariate logistic regression analysis confirmed a significant association between CSF CaM positivity and specific mutations in PRNP, as well as with CSF 14-3-3 positivity. Furthermore, the diagnostic performance of CaM surpassed that of 14-3-3 and tau when analyzing CSF samples from T188K-gCJD and E200K-gCJD patients. Western blot analysis reveals significant variations in the positivity of CSF CaM among the four genotypes of gPrD cases, demonstrating a positive correlation with 14-3-3 positivity and elevated tau levels in CSF.

Probable chronic pain, brain structure, and Alzheimer’s plasma biomarkers in older men

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. PerspectiveProbable 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.

Plasma neurofilament light as a promising biomarker in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder lacking reliable biomarkers. This study investigates plasma protein levels as potential biomarkers of disease severity and progression in NIID. In this study, we enrolled 30 NIID patients and 36 age- and sex-matched controls, following them for 1-2years. Plasma neurofilament light (NfL), glial fibrillary acidic protein (GFAP), ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), and tau were measured using ultrasensitive single molecule array (Simoa) assays. Disease severity was evaluated with the Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Activities of Daily Living (ADL), and CNS symptom counts, in addition to neuroimaging data. Our study revealed that NIID patients has significantly higher plasma NfL (median, 35.2 vs. 8.61pg/mL, p < 0.001) and GFAP (102 vs. 79.0pg/mL, p = 0.010) levels compared to controls, with NfL emerging as a robust diagnostic marker (AUC = 0.956). NfL levels were notably higher in acute-onset NIID (77.5 vs. 28.8pg/mL, p = 0.001). NfL correlated strongly with disease severity, including MMSE (ρ = - 0.687, p < 0.001), MoCA (ρ = - 0.670, p < 0.001), ADL (ρ = 0.587, p = 0.001), CNS symptoms (ρ = 0.369, p = 0.045), and white matter hyperintensity volume (ρ = 0.620, p = 0.004). Higher baseline NfL (≥ 35.2pg/mL) associated with increased ADL scores, CNS symptoms, and white matter hyperintensity at follow-up. UCH-L1 and total tau levels showed no significant differences. Our results suggested the potential of NfL as a promising biomarker of disease severity and progression in NIID.

Palmitic Acid Induces Posttranslational Modifications of Tau Protein in Alzheimer’s Disease–Related Epitopes and Increases Intraneuronal Tau Levels

Metabolic diseases derived from an unhealthy lifestyle have been linked with an increased risk for developing cognitive impairment and even Alzheimer’s disease (AD). Although high consumption of saturated fatty acids such as palmitic acid (PA) has been associated with the development of obesity and type II diabetes, the mechanisms connecting elevated neuronal PA levels and increased AD marker expression remain unclear. Among other effects, PA induces insulin resistance, increases intracellular calcium and reactive oxygen species (ROS) production, and reduces the NAD+/NADH ratio, resulting in decreased activity of the deacetylase Sirtuin1 (SIRT1) in neurons. These mechanisms may affect signaling pathways that impact the posttranslational modifications (PTMs) of the tau protein. To analyze the role played by PA in inducing the phosphorylation and acetylation of tau, we examined PTM changes in human tau in differentiated neurons from human neuroblastoma cells. We found changes in the phosphorylation state of several AD-related sites, namely, S199/202 and S214, that were mediated by a mechanism associated with the dysregulated activity of the kinases GSK3β and mTOR. PA also increased the acetylation of residue K280 and elevated total tau level after long exposure time. These findings provide information about the mechanisms by which saturated fatty acids cause tau PTMs that are similar to those observed in association with AD biochemical changes.Graphical

Blood Markers in Relation to a History of Traumatic Brain Injury Across Stages of Cognitive Impairment in a Diverse Cohort.

Traumatic brain injury (TBI) has been linked to multiple pathophysiological processes that could increase risk for Alzheimer's disease and related dementias (ADRD). However, the impact of prior TBI on blood biomarkers for ADRD remains unknown. Using cross-sectional data, we assessed whether a history of TBI influences serum biomarkers in a diverse cohort (approximately 50% Hispanic) with normal cognition, mild cognitive impairment, or dementia. Levels of glial fibrillary acidic protein (GFAP), neurofilament light (NFL), total tau (T-tau), and ubiquitin carboxy-terminal hydrolase-L1 (UCHL1) were measured for participants across the cognitive spectrum. Participants were categorized based on presence and absence of a history of TBI with loss of consciousness, and study samples were derived through case-control matching. Multivariable general linear models compared concentrations of biomarkers in relation to a history of TBI and smoothing splines modelled biomarkers non-linearly in the cognitively impaired groups as a function of time since symptom onset. Each biomarker was higher across stages of cognitive impairment, characterized by clinical diagnosis and Mini-Mental State Examination performance, but these associations were not influenced by a history of TBI. However, modelling biomarkers in relation to duration of cognitive symptoms for ADRD showed differences by history of TBI, with only GFAP and UCHL1 being elevated. Serum GFAP, NFL, T-tau, and UCHL1 were higher across stages of cognitive impairment in this diverse clinical cohort, regardless of TBI history, though longitudinal investigation of the timing, order, and trajectory of the biomarkers in relation to prior TBI is warranted.

Magnetic Resonance Imaging-Negative Cerebral Amyloid Angiopathy: Cerebrospinal Fluid Amyloid-β42 over Amyloid Positron Emission Tomography.

Cerebral amyloid angiopathy (CAA) pathology is becoming increasingly important in Alzheimer's disease (AD) because of its potential link to amyloid-related imaging abnormalities, a critical side effect observed during AD immunotherapy. Identification of CAA without typical magnetic resonance imaging (MRI) markers (MRI-negative CAA) is challenging, and novel detection biomarkers are needed. We included 69 participants with high neuritic plaques (NP) burden, with and without CAA pathology (NP with CAA vs. NP without CAA) based on autopsy data from the Alzheimer's Disease Neuroimaging Initiative. Two participants with hemorrhagic CAA markers based on MRI were excluded and the final analysis involved 36 NP without CAA and 31 NP with CAA. A logistic regression model was used to compare the cerebrospinal fluid (CSF) amyloid-β42 (Aβ42), phosphorylated tau181, and total tau levels, the amyloid positron emission tomography (PET) standardized uptake ratio (SUVR), and cognitive profiles between NP with and without CAA. Regression models for CSF and PET were adjusted for age at death, sex, and the last assessed clinical dementia rating sum of boxes score. Models for cognitive performances was adjusted for age at death, sex, and education level. NP with CAA had significantly lower CSF Aβ42 levels when compared with those without CAA (110.5 pg/mL vs. 134.5 pg/mL, p-value = 0.002). Logistic regression analysis revealed that low CSF Aβ42 levels were significantly associated with NP with CAA (odds ratio [OR]: 0.957, 95% confidence interval [CI]: 0.928, 0.987, p-value = 0.005). However, amyloid PET SUVR did not differ between NP with CAA and those without CAA (1.39 vs. 1.48, p-value = 0.666). Logistic regression model analysis did not reveal an association between amyloid PET SUVR and NP with CAA (OR: 0.360, 95% CI: 0.007, 1.741, p-value = 0.606). CSF Aβ42 is more sensitive to predict MRI-negative CAA in high NP burden than amyloid PET.

Cardiovascular Risk Scales Association with Cerebrospinal Fluid Alzheimer's Disease Biomarkers in Cardiovascular Low Cardiovascular Risk Regions.

Cardiovascular risk factors are associated with Alzheimer's Disease (AD) development. However, few studies compare the overall cardiovascular risk with AD biomarkers, and when done, they are mainly performed in moderate cardiovascular risk regions. To determine whether cardiovascular risk in older adults is associated with pathological cerebrospinal fluid (CSF) biomarkers of AD in a low cardiovascular risk population. This is a cross-sectional study performed between 2017 and 2020. The present work included patients between 50 and 75 years old who were negative for CSF AD biomarkers and had minimum cognitive alterations (controls) and patients with positive CSF AD biomarkers and in early stages of AD (cases). CSF biomarkers included total tau, phosphorylated tau 181 and amyloid ß42 (Aß42). Analytical variables were obtained. ERICE, SCORE2 and Framingham scales were used to calculate the overall patient's cardiovascular risk. The Aß42/Aß40 ratio and neurofilaments were explored when available. Two hundred and thirty-three patients were included. Nearly 76% of the sample had AD. AD patients had higher cardiovascular risk than controls (p-value < 0.05). ERICE and SCORE2 were associated with AD presence. Framingham was not. A correlation between elevated cardiovascular risk and higher total tau and NfL levels was observed when adjusted by age. Cardiovascular risk assessment may be helpful in neurodegenerative disorders detection, as it is associated with CSF total tau and NfL. ERICE and SCORE2 may be useful scales in low cardiovascular risk regions to improve cardiovascular control and prevent neurodegenerative pathologies.

Tau Accumulation in the Spinal Cord Contributes to Chronic Inflammatory Pain by Upregulation of IL-1β and BDNF

Microtubule-associated protein Tau is responsible for the stabilization of neuronal microtubules under normal physiological conditions. Much attention has been focused on Tau’s contribution to cognition, but little research has explored its role in emotions such as pain, anxiety, and depression. In the current study, we found a significant increase in the levels of p-Tau (Thr231), total Tau, IL-1β, and brain-derived neurotrophic factor (BDNF) on day 7 after complete Freund's adjuvant (CFA) injection; they were present in the vast majority of neurons in the spinal dorsal horn. Microinjection of Mapt-shRNA recombinant adeno-associated virus into the spinal dorsal cord alleviated CFA-induced inflammatory pain and inhibited CFA-induced IL-1β and BDNF upregulation. Importantly, Tau overexpression was sufficient to induce hyperalgesia by increasing the expression of IL-1β and BDNF. Furthermore, the activation of glycogen synthase kinase 3 beta partly contributed to Tau accumulation. These findings suggest that Tau in the dorsal horn could be a promising target for chronic inflammatory pain therapy.

Baseline serum neurofilament light chain levels differentiate aggressive from benign forms of relapsing–remitting multiple sclerosis: a 20-year follow-up cohort

Background and objectivesSerum biomarkers are emerging as useful prognostic tools for multiple sclerosis (MS); however, long-term studies are lacking. We aimed to evaluate the long-term prognostic value of the serum levels of neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and chitinase 3-like-1 (CHI3L1) measured close to the time of MS onset.MethodsIn this retrospective, exploratory, observational, case and controls study, patients with relapsing–remitting MS (RRMS) with available baseline serum samples and prospectively follow-up in our MS unit for a long time were selected based on their clinical evolution to form two groups: (1) a benign RRMS (bRRMS) group, defined as patients with an Expanded Disability Status Scale (EDSS) score of ≤ 3 at ≥ 10 years of follow-up; (2) an aggressive RRMS (aRRMS) group, defined as patients with an EDSS score of ≥ 6 at ≤ 15 years of follow-up. An age-matched healthy control (HC) group was selected. NfL, total tau, and GFAP serum levels were quantified using a single-molecule array (SIMOA), and CHI3L1 was quantified using ELISA.ResultsThirty-one patients with bRRMS, 19 with aRRMS, and 10 HC were included. The median follow-up time from sample collection was 17.74 years (interquartile range, 14.60–20.37). Bivariate and multivariate analyses revealed significantly higher NfL and GFAP levels in the aRRMS group than in the bRRMS group. A receiver operating characteristic curve analysis identified serum NfL level as the most efficient marker for distinguishing aRRMS from bRRMS.DiscussionThis proof-of-concept study comparing benign and aggressive RRMS groups reinforces the potential role of baseline NfL serum levels as a promising long-term disability prognostic marker. In contrast, serum GFAP, total tau, and CHI3L1 levels demonstrated a lower or no ability to differentiate between the long-term outcomes of RRMS.

Development of FKBP5 ASOs to mitigate tau pathology

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of abnormal protein aggregates, including tau tangles, in the brain. FKBP51 (encoded by FKBP5 gene) is a chaperone protein that regulates tau and has been implicated in AD pathology. FKBP51 overexpression in the brains of tau transgenic mice correlates with increased tau oligomers and neuronal toxicity, whereas siRNA mediated knockdown of FKBP5 decreased tau levels in cell culture models. In this study, we developed antisense oligonucleotides (ASOs) to target FKBP5, in an effort to lower tau levels. We hypothesize that ASOs targeting FKBP5 will reduce FKBP51, which will decrease tau levels and improve tau‐associated deficits.MethodWe designed and synthesized vivo‐morpholino ASOs that specifically bind to and target FKBP5 mRNA degradation. We tested three ASOs in vitro using human neuroglioma and mouse hippocampal neuronal cultures but encountered tissue toxicity when using direct injections into the brains of wild‐type mice. To overcome this, we designed and synthesized locked‐nucleic acid (LNA) GapmeR ASOs targeting regions conserved between human and mouse FKBP5. These have been tested in human neuroglioma and mouse hippocampal neuroblastoma cells lines for their ability to decrease dexamethasone induced FKBP5 upregulation and assessed for toxicity.ResultInitial screening of vivo morpholino ASOs resulted in 50% ‐ 80% reduction in dexamethasone induced FKBP51 levels at 10 µM. This was further corroborated in mouse primary cortico‐hippocampal neurons where FKBP51 levels were reduced by 50% ‐ 75%, which correlated with significant reduction in total tau levels. However, in vivo pilot studies showed tissue toxicity for our control construct. LNA GapmeR ASOs reduced FKBP51 levels at much lower concentrations (&lt;10 nM) with no apparent toxicity.Conclusion Fkbp5 ASOs have shown promising results at decreasing FKBP51 and total tau levels. Future studies will include further testing in vivo for efficacy and safety, followed by studies in tau transgenic mice.

Novel Small‐Molecular Ligands for Prolyl Oligopeptidase to Combat Tauopathies

AbstractBackgroundTauopathies that include e.g. frontotemporal dementia and Alzheimer’s disease, are neurodegenerative diseases characterized by accumulation of hyperphosphorylated Tau in the brain. Tau is a tempting drug target for tauopathies but no Tau‐targeting therapies are in clinical use. We have recently shown that small‐molecular inhibitors of prolyl oligopeptidase (PREP) can activate protein phosphatase 2A (PP2A) by regulating PREP‐PP2A interaction. PP2A is the main phosphatase regulating Tau, and therefore, we decided to test the efficacy of a reference PREP inhibitor, KYP‐2047, and novel PREP ligands on cellular and animal models of tauopathies.MethodThe compounds, KYP‐2047 and HUP‐46, 55 and 59 (1, 5 and 10 μM), were first screened in the GFP‐2N4R‐Tau transfected HEK‐293 cells where the Tau aggregation was induced by small‐dose okadaic acid (OA; 10 nM), a PP2A inhibitor. The results were verified by using 2N4R‐Tau transfected HEK‐293 cells with 10 nM OA. After the treatment the cells were fractioned to RIPA soluble and SDS‐fractions, and total Tau and S262 phosphorylated Tau (pS262 Tau) levels were studied by Western blot (WB). Finally, KYP‐2047 and HUP‐46 were tested in PS19 Tau transgenic mouse. PS19 mice were treated with the ligands for 4 weeks (10 mg/kg/day, Alzet minipump i.p.) starting from 5.5 months old when the behavioral deficits were observed. After the treatment, the mice behavior was tested by Barnes Maze and locomotor activity assay, and total Tau, pS262 Tau and PP2A levels were studied.ResultIn the GFP‐Tau aggregation assay, all compounds decreased the GFP signal as an indicative of Tau aggregation with 10 mM concentration but HUP‐46 was the most effective (Fig. 1). WB that showed that PREP ligands had the most significant effect on total Tau and pS262 Tau in the SDS‐fraction. In the PS19 mice, KYP‐2047 restored normal behavior in Barnes maze and locomotor activity assay. HUP‐46 had similar effect but did not reach significance (Fig. 2). However, both compounds reduced significantly total Tau and pS262 Tau levels in mouse hippocampus and cortex, and activated PP2A (Fig. 3).ConclusionSmall‐molecular PREP ligands, such as KYP‐2047 and HUP‐46 have disease‐modifying effects on cellular and animal models of tauopathies.