T-tau Levels Research Articles

Five Creutzfeldt-Jakob Disease Cases Within One Year in Spectrum Health Hospitals in Grand Rapids, Michigan (P10-4.007)

<h3>Objective:</h3> NA <h3>Background:</h3> Creutzfeldt-Jakob disease (CJD) is a rare but fatal neurodegenerative disease. Its prevalence is reportedly one in 1–1.5 million worldwide annually with fewer than 1,000 cases per year in the United States. We presented two CJD cases seen between July and August in 2021 at the 2022 AAN annual meeting. From May to June in 2022, we encountered three additional CJD cases in our two hospitals in West Michigan where a rough 1.6 million people reside. <h3>Design/Methods:</h3> NA <h3>Results:</h3> <h3>Case Summary:</h3> <h3>Case three:</h3> A 77-year-old white man, a retired attorney, was transferred to our hospital on May 3^rd with complaints of dyscognia and visual disturbance which started in mid-March. Case four was a 78-year-old white woman, a housewife, admitted on June 3^rd for rapidly cognitive decline over 3 months with subacute cognitive dysfunction the year prior. Case five was a 64-year-old white woman, a nurse, admitted on June 17^th with rapidly cognitive decline and gait instability with initial symptoms including dyscognia, dizziness and fatigue started in January. All patients’ MRI brain demonstrated characteristic CJD patterns; CSF reported &gt;98% probability of CJD except in patient four who had inconclusive probability of CJD and T-tau level was 19,937 but RT-QuIC was negative due to discolored sample. Only patient 3’s EEG showed characteristic CJD patterns. So far, all five patients have died with two of them confirmed sCJD on autopsy, two patients with pending autopsy results and one patient’s family declined autopsy. <h3>Conclusions:</h3> These additional cases suggest an expanding cluster of CJD. Five cases within one year in one community is alarming. All five patients lived within 90-mile radius from Grand Rapids with two patients even in the same county, it warrants urgent investigation for possible regional outbreak of CJD. <b>Disclosure:</b> Dr. Rong has nothing to disclose. Dr. Lannen has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Genentech. Dr. Lannen has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for TG Therapeutics. Dr. Tank has nothing to disclose. Dr. Feistel has nothing to disclose. Dr. Potluri has nothing to disclose. Dr. DeJesus Brazitis has nothing to disclose. The institution of Dr. Khan has received research support from NINDS. The institution of Dr. Khan has received research support from Genentech. The institution of Dr. Khan has received research support from Spectrum Health-MSU alliance. Dr. Khan has received research support from NIH. Dr. Min has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbott . Dr. Min has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medtronic .

Assessment of Plasma Biomarkers by ImmunoMagnetic Reduction in Parkinson’s Disease Dementia and Dementia with Lewy Bodies (P10-6.008)

<h3>Objective:</h3> To use ImmunoMagnetic Reduction (IMR) assay to assess the diagnostic utility of plasma Aβ42, total Tau (t-Tau), phosphorylated Tau-181 (p-Tau-181) and α-synuclein in identifying and differentiating cases of Parkinson’s Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB). <h3>Background:</h3> PDD and DLB represent pathological subtypes along a continuum of synucleinopathies. Clinical differentiation is ultimately based on arbitrary and subjectively-reported timing of cognitive and motor symptoms. Ancillary tests are invasive, costly, and exhibit suboptimal sensitivity and specificity. Developments in plasma biomarker assays have increased detection thresholds and provide the opportunity to reassess whether core PDD/DLB plasma biomarkers would be useful for diagnosis. <h3>Design/Methods:</h3> Plasma samples from 61 total subjects (37 normal controls (NC), 12 with PDD, 12 with DLB) and were sent for IMR assay to quantify α-synuclein, Aβ42, t-Tau, and p-Tau-181. To determine discrimination between NC, PDD, and DLB, receiver operating characteristic (ROC) curve analysis was used to obtain sensitivity, specificity, and area under curve (AUC). <h3>Results:</h3> Plasma p-tau levels were significantly higher in DLB compared to NC and PD (p&lt;0.05). Plasma α-synuclein levels were significantly higher in PDD compared to DLB and NC. Plasma t-Tau and Aβ42 levels did not differ between NC, PDD and DLB subjects. When plasma biomarkers were combined, Aβ42 x t-Tau revealed no differences between DLB, PDD and NC. For the α-synuclein x p-Tau-181 combination, both PDD and DLB were greater than NC. <h3>Conclusions:</h3> Investigations into the discrimination of DLB vs. PDD are rare. In this pilot study, we show that IMR assays of plasma for α-synuclein, p-Tau-181, and Aβ42 x t-tau are useful in differentiating PDD from DLB, as well as NC. Thus, our data suggest clinical utility of these novel biomarker modalities and panels. Differentiating DLB from PDD could be consequential in clinical characterization. Future studies will aim to replicate our findings on larger group sizes. <b>Disclosure:</b> Dr. Malaty has nothing to disclose. Dr. Lue has nothing to disclose. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amneal Pharmaceuticals. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurocrine Biosciences. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Shill has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbive. Dr. Decourt has received personal compensation for serving as an employee of Cleveland Clinic. Dr. Decourt has received personal compensation in the range of $0-$499 for serving as a Reviewer with NIH. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eisai. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech=Roche. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Novo Nordisk. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Dr. Sabbagh has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Synaptogenix. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Signant Health. Dr. Sabbagh has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for T3D. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for EIP Pharma. Dr. Sabbagh has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Quince-Cortexyme. Dr. Sabbagh has stock in Neurotau. Dr. Sabbagh has stock in Seq Biomarque. Dr. Sabbagh has stock in uMethod Health. Dr. Sabbagh has stock in Athira. Dr. Sabbagh has stock in Lighthouse Pharmaceuticals. Dr. Sabbagh has stock in Alzheom. The institution of Dr. Sabbagh has received research support from NIH. The institution of Dr. Sabbagh has received research support from ADDF. Dr. Sabbagh has received publishing royalties from a publication relating to health care.

Functional gradients of the medial parietal cortex in a healthy cohort with family history of sporadic Alzheimer’s disease

BackgroundThe medial parietal cortex is an early site of pathological protein deposition in Alzheimer’s disease (AD). Previous studies have identified different subregions within this area; however, these subregions are often heterogeneous and disregard individual differences or subtle pathological alterations in the underlying functional architecture. To address this limitation, here we measured the continuous connectivity gradients of the medial parietal cortex and assessed their relationship with cerebrospinal fluid (CSF) biomarkers, ApoE ε4 carriership and memory in asymptomatic individuals at risk to develop AD.MethodsTwo hundred sixty-three cognitively normal participants with a family history of sporadic AD who underwent resting-state and task-based functional MRI using encoding and retrieval tasks were included from the PREVENT-AD cohort. A novel method for characterizing spatially continuous patterns of functional connectivity was applied to estimate functional gradients in the medial parietal cortex during the resting-state and task-based conditions. This resulted in a set of nine parameters that described the appearance of the gradient across different spatial directions. We performed correlation analyses to assess whether these parameters were associated with CSF biomarkers of phosphorylated tau181 (p-tau), total tau (t-tau), and amyloid-ß1-42 (Aß). Then, we compared the spatial parameters between ApoE ε4 carriers and noncarriers, and evaluated the relationship between these parameters and memory.ResultsAlterations involving the superior part of the medial parietal cortex, which was connected to regions of the default mode network, were associated with higher p-tau, t-tau levels as well as lower Aß/p-tau levels during the resting-state condition (p < 0.01). Similar alterations were found in ApoE ε4 carriers compared to non-carriers (p < 0.003). In contrast, lower immediate memory scores were associated with changes in the middle part of the medial parietal cortex, which was connected to inferior temporal and posterior parietal regions, during the encoding task (p = 0.001). No results were found when using conventional connectivity measures.ConclusionsFunctional alterations in the medial parietal gradients are associated with CSF AD biomarkers, ApoE ε4 carriership, and lower memory in an asymptomatic cohort with a family history of sporadic AD, suggesting that functional gradients are sensitive to subtle changes associated with early AD stages.

Associations of Neurodegeneration Biomarkers in Cerebrospinal Fluid with Markers of Alzheimer's Disease and Vascular Pathology.

The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers.

Associations Between Plasma Klotho with Renal Function and Cerebrospinal Fluid Amyloid-β Levels in Alzheimer's Disease: The Chongqing Ageing & Dementia Study.

The kidney-brain crosstalk has been involved in Alzheimer's disease (AD) with the mechanism remaining unclear. The anti-aging factor Klotho was reported to attenuate both kidney injury and AD pathologies. To investigate whether plasma Klotho participated in kidney-brain crosstalk in AD. We enrolled 33 PiB-PET-positive AD patients and 33 amyloid-β (Aβ)-negative age- and sex-matched cognitively normal (CN) controls from the Chongqing Ageing & Dementia Study (CADS). The levels of plasma Klotho, Aβ, and tau in the cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay. We found higher plasma Klotho and lower estimated glomerular filtration rate (eGFR) levels in AD patients compared with CN. The eGFR was positively associated with Aβ42, Aβ40 levels in CSF and negatively associated with CSF T-tau levels. Plasma Klotho levels were both negatively correlated with CSF Aβ42 and eGFR. Mediation analysis showed that plasma Klotho mediated 24.96% of the association between eGFR and CSF Aβ42. Renal function impacts brain Aβ metabolism via the kidney-brain crosstalk, in which the plasma Klotho may be involved as a mediator. Targeting Klotho to regulate the kidney-brain crosstalk provides potential therapeutic approaches for AD.

The relationship between obstructive sleep apnea and circulating tau levels: A meta-analysis.

Alzheimer's disease (AD) is an irreversible, progressive brain disorder that impairs memory, thinking, language, and, eventually, the ability to carry out the simplest of tasks. Tau protein, the major component of neurofibrillary tangles, is considered a key mediator of AD pathogenesis. The association between obstructive sleep apnea (OSA) and circulating tau remains unclear. The aim of the present meta-analysis was to evaluate the relationship between OSA and circulating tau via quantitative analysis. A systematic search of Pubmed, Embase, and Web of Science were performed. The mean values of circulating total tau (T-tau) and phosphorylated tau (P-tau) in OSA and control groups were extracted. Standardized mean difference (SMD) with 95% confidence interval (CI) was calculated by using a random-effect model or fixed-effect model. A total of seven studies comprising 233 controls and 306 OSA patients were included in this study. The meta-analysis showed that the circulating T-tau level was significantly higher in OSA patients than those in the control group (SMD=1.319, 95% CI=0.594 to 2.044, z=3.56, p<.001). OSA patients also had significantly higher circulating P-tau level than control group (SMD=0.343, 95% CI=0.122 to 0.564, z=3.04, p=.002). The present meta-analysis demonstrated that both circulating T-tau and P-tau levels were significantly increased in OSA subjects when compared with non-OSA subjects. Larger sample-size studies on the association between OSA and circulating tau are still required to further validate our results.

White matter hyperintensity mediating gait disorders in iNPH patients via neurofilament light chain.

This study aimed to analyze the differences in regional white matter hyperintensities (WMH) volume and cerebrospinal fluid biomarker levels between idiopathic normal pressure hydrocephalus (iNPH) patients with or without gait disorder. Forty-eight iNPH patients undergoing bypass surgery and 20 normal senile individuals were included. The LST toolkit was used to segment all MRI fluid attenuation inversion images and quantify the WMH volume in each brain region. Cerebrospinal fluid was collected from all individuals and measured for concentrations of Aβ, t-tau, p-tau, and neurofilament light chain (NfL). Patients with iNPH were followed up for 1 year and divided categorized into a gait disorder improvement group and no improvement group according to the 3 m round-trip test time parameter improvement by more than 10%. We found that WMH in all areas of iNPH patients was higher than that in the control group. CSF levels of Aβ, t-tau, and p-tau were lower than those in the control group, while NfL levels were higher than those in the control group. The gait (+) group NfL level was higher than that in gait (-), and there were no statistical differences in Aβ, t-tau, and p-tau levels. The gait (+) group of frontal and parietal lobe WMH volume PVH above the gait (-) group. The mediating effect model analysis showed that PVH might affect the gait disorder of iNPH patients through NfL. A 1-year follow-up of the patients after the bypass surgery found that 24 of the 35 patients in the gait (+) group had improvements, while 11 had no significant improvements. The comparison of CSF marker levels between the two groups showed that the CSF NfL level in the improved group was lower than that in the non-improved group. The WMH volume and PVH in the frontal-parietal lobe of the improved group were lower than those of the non-improved group. iNPH patients have more serious frontoparietal and periventricular white matter lesions, and WMH volume in the frontoparietal may mediate the occurrence of gait disorder in iNPH patients through the increase of NfL level.

Diagnostic Role of Tau Proteins in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Background. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that currently lacks reliable diagnostic biomarkers. The meta-analysis is performed with an aim to evaluate the diagnostic potential of cerebrospinal fluid (CSF) total tau (t-tau), phosphorylated-tau (p-tau), and their ratio in ALS patients. Methods. A comprehensive search for literature published between the 1st of January 2000 and the 15th of May 2022 was performed in databases PubMed, medRxiv, and Google Scholar. The retrieved articles were first screened by title and abstract, and later, full-text screening was performed based on the eligibility criteria. Data on p-tau and t-tau levels and p-tau/t-tau ratio in ALS patients and controls were extracted, and a meta-analysis was performed using random-effects models in Review Manager version 5.4. Results. Data were analyzed from seven studies reporting p-tau and t-tau levels and their ratio among ALS patients and controls. The number of total study participants was 1,100. In ALS patients, the levels of p-tau didn’t differ significantly with controls (standardized mean difference (SMD): 0.14 (95% CI: -0.41 to 0.70); p = 0.61 ). In contrast, there were significantly elevated levels of t-tau and significantly lowered p-tau/t-tau ratio in ALS (SMD: 1.76 (95% CI: 0.53 to 2.98); p = 0.005 and SMD: -3.09 (95% CI: -5.33 to -0.86); p = 0.007 , respectively). Conclusion. Our meta-analysis study supports the role of core CSF biomarkers of neurodegeneration: t-tau and p-tau/t-tau ratio as a diagnostic biomarker of amyotrophic lateral sclerosis. This study found that t-tau is elevated while p-tau/t-tau ratio is lowered in ALS.

Regional White Matter Hyperintensities and Alzheimer's Disease Biomarkers Among Older Adults with Normal Cognition and Mild Cognitive Impairment.

Alzheimer's disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40, Aβ 42, Aβ 42/Aβ 40 ratio, phosphorylated tau-181 [p-tau181], and total tau [t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181, t-tau, and Aβ 40), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42/Aβ 40. In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42/Aβ 40 and p-tau181. These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42/Aβ 40) in parietal WMHs.

Alzheimer Disease Blood Biomarkers in Patients With Out-of-Hospital Cardiac Arrest

Blood phosphorylated tau (p-tau) and amyloid-β peptides (Aβ) are promising peripheral biomarkers of Alzheimer disease (AD) pathology. However, their potential alterations due to alternative mechanisms, such as hypoxia in patients resuscitated from cardiac arrest, are not known. To evaluate whether the levels and trajectories of blood p-tau, Aβ42, and Aβ40 following cardiac arrest, in comparison with neural injury markers neurofilament light (NfL) and total tau (t-tau), can be used for neurological prognostication following cardiac arrest. This prospective clinical biobank study used data from the randomized Target Temperature Management After Out-of-Hospital Cardiac Arrest (TTM) trial. Unconscious patients with cardiac arrest of presumed cardiac origin were included between November 11, 2010, and January 10, 2013, from 29 international sites. Serum analysis for serum NfL and t-tau were performed between August 1 and August 23, 2017. Serum p-tau, Aβ42, and Aβ40 were analyzed between July 1 and July 15, 2021, and between May 13 and May 25, 2022. A total of 717 participants from the TTM cohort were examined: an initial discovery subset (n = 80) and a validation subset. Both subsets were evenly distributed for good and poor neurological outcome after cardiac arrest. Serum p-tau, Aβ42, and Aβ40 concentrations using single molecule array technology. Serum levels of NfL and t-tau were included as comparators. Blood biomarker levels at 24 hours, 48 hours, and 72 hours after cardiac arrest. Poor neurologic outcome at 6-month follow-up, defined according to the cerebral performance category scale as category 3 (severe cerebral disability), 4 (coma), or 5 (brain death). This study included 717 participants (137 [19.1%] female and 580 male [80.9%]; mean [SD] age, 63.9 [13.5] years) who experienced out-of-hospital cardiac arrest. Significantly elevated serum p-tau levels were observed at 24 hours, 48 hours, and 72 hours in cardiac arrest patients with poor neurological outcome. The magnitude and prognostication of the change was greater at 24 hours (area under the receiver operating characteristic curve [AUC], 0.96; 95% CI, 0.95-0.97), which was similar to NfL (AUC, 0.94; 95% CI, 0.92-0.96). However, at later time points, p-tau levels decreased and were weakly associated with neurological outcome. In contrast, NfL and t-tau maintained high diagnostic accuracies, even 72 hours after cardiac arrest. Serum Aβ42 and Aβ40 concentrations increased over time in most patients but were only weakly associated with neurological outcome. In this case-control study, blood biomarkers indicative of AD pathology demonstrated different dynamics of change after cardiac arrest. The increase of p-tau at 24 hours after cardiac arrest suggests a rapid secretion from the interstitial fluid following hypoxic-ischemic brain injury rather than ongoing neuronal injury like NfL or t-tau. In contrast, delayed increases of Aβ peptides after cardiac arrest indicate activation of amyloidogenic processing in response to ischemia.

Plasma biomarkers for diagnosis of Alzheimer's disease and prediction of cognitive decline in individuals with mild cognitive impairment.

The last few years have seen major advances in blood biomarkers for Alzheimer's Disease (AD) with the development of ultrasensitive immunoassays, promising to transform how we diagnose, prognose, and track progression of neurodegenerative dementias. We evaluated a panel of four novel ultrasensitive electrochemiluminescence (ECL) immunoassays against presumed CNS derived proteins of interest in AD in plasma [phosphorylated-Tau181 (pTau181), total Tau (tTau), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP)]. Two sets of banked plasma samples from the Massachusetts Alzheimer's Disease Research Center's longitudinal cohort study were examined: A longitudinal prognostic sample (n = 85) consisting of individuals with mild cognitive impairment (MCI) and 4 years of follow-up and a cross-sectional sample (n = 238) consisting of individuals with AD, other neurodegenerative diseases (OND), and normal cognition (CN). Participants with MCI who progressed to dementia due to probable AD during follow-up had higher baseline plasma concentrations of pTau181, NfL, and GFAP compared to non-progressors. The best prognostic discrimination was observed with pTau181 (AUC = 0.83, 1.7-fold increase) and GFAP (AUC = 0.83, 1.6-fold increase). Participants with autopsy- and/or biomarker verified AD had higher plasma levels of pTau181, tTau and GFAP compared to CN and OND, while NfL was elevated in AD and further increased in OND. The best diagnostic discrimination was observed with pTau181 (AD vs CN: AUC = 0.90, 2-fold increase; AD vs. OND: AUC = 0.84, 1.5-fold increase) but tTau, NfL, and GFAP also showed good discrimination between AD and CN (AUC = 0.81-0.85; 1.5-2.2 fold increase). These new ultrasensitive ECL plasma assays for pTau181, tTau, NfL, and GFAP demonstrated diagnostic utility for detection of AD. Moreover, the absolute baseline plasma levels of pTau181 and GFAP reflect cognitive decline over the next 4 years, providing prognostic information that may have utility in both clinical practice and clinical trial populations.

Continuous Positive Airway Pressure Reduces Plasma Neurochemical Levels in Patients with OSA: A Pilot Study

Obstructive sleep apnea (OSA) is a risk factor for neurodegenerative diseases. This study determined whether continuous positive airway pressure (CPAP), which can alleviate OSA symptoms, can reduce neurochemical biomarker levels. Thirty patients with OSA and normal cognitive function were recruited and divided into the control (n = 10) and CPAP (n = 20) groups. Next, we examined their in-lab sleep data (polysomnography and CPAP titration), sleep-related questionnaire outcomes, and neurochemical biomarker levels at baseline and the 3-month follow-up. The paired t-test and Wilcoxon signed-rank test were used to examine changes. Analysis of covariance (ANCOVA) was performed to increase the robustness of outcomes. The Epworth Sleepiness Scale and Pittsburgh Sleep Quality Index scores were significantly decreased in the CPAP group. The mean levels of total tau (T-Tau), amyloid-beta-42 (Aβ42), and the product of the two (Aβ42 × T-Tau) increased considerably in the control group (ΔT-Tau: 2.31 pg/mL; ΔAβ42: 0.58 pg/mL; ΔAβ42 × T-Tau: 48.73 pg2/mL2), whereas the mean levels of T-Tau and the product of T-Tau and Aβ42 decreased considerably in the CPAP group (ΔT-Tau: -2.22 pg/mL; ΔAβ42 × T-Tau: -44.35 pg2/mL2). The results of ANCOVA with adjustment for age, sex, body mass index, baseline measurements, and apnea-hypopnea index demonstrated significant differences in neurochemical biomarker levels between the CPAP and control groups. The findings indicate that CPAP may reduce neurochemical biomarker levels by alleviating OSA symptoms.

Correlation of blood-brain barrier leakage with cerebral small vessel disease including cerebral microbleeds in Alzheimer's disease.

Blood-brain barrier (BBB) damage is considered an important part of Alzheimer's disease (AD) progression, and cerebral small-vessel disease (CSVD) is commonly associated with AD. However, the relationship between BBB damage, small cerebrovascular lesions, especially cerebral microbleeds (CMBs), and amyloid and tau biomarkers remains controversial. Therefore, our study aimed to further investigate their association in our cohort of patients with AD. A total of 139 individuals were divided into probable AD (18F-florbetapir PET positive, n = 101) and control group (cognitively normal, n = 38). The levels of cerebrospinal fluid (CSF) and plasma t-tau, p-tau181, Aβ40, Aβ42, and albumin were measured using corresponding commercial assay kits, and the CSF/plasma albumin ratio (Qalb), an indicator of BBB dysfunction, was calculated. CSVD burden and the number of CMBs were defined using magnetic resonance imaging. Patients with AD had higher Qalb (p = 0.0024), higher numbers of CMBs (p = 0.03), and greater CSVD burden (p < 0.0001). In the AD group, CMBs and CSVD correlated with a higher Qalb (p = 0.03), and the numbers of CMBs negatively correlated with CSF Aβ42 (p = 0.02). Blood-brain barrier damage was accompanied by a more severe burden of CSVD, including CMB, in patients with AD.

Transient Changes in the Plasma of Astrocytic and Neuronal Injury Biomarkers in COVID-19 Patients without Neurological Syndromes.

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.

Plasma tau and neurofilament light chain as biomarkers of Alzheimer's disease and their relation to cognitive functions.

Alzheimer's disease (AD) dementia is the most frequent cause of neurodegenerative dementia. The cognitive and behavioral symptoms associated with this disorder often have overlapping characteristics, potentially resulting in delayed diagnosis or misdiagnosis. This study aimed to assess the level of peripheral blood neurofilament light chain (NfL) and total tau (t-tau) protein in AD patients and investigate their relationship with cognitive impairment. The study included 80 participants of both sexes between the ages of 60 to 85 years. The participants were divided into two groups, consisting of 40 individuals in the control group (mean age 75±6.6 years) who had no cognitive or functional impairments and 40 AD patients (mean age 74.98±5.03 years). This study utilized the DSM-5 diagnostic criteria for major or mild neurocognitive disorder attributed to Alzheimer's disease (AD). The clinical and biochemical features of all participants were documented, and the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-cog) scores were evaluated. Sandwich ELISA was employed to determine serum NfL and t-tau protein levels. The median serum NfL and t-tau protein levels in AD patients were significantly higher than those of the controls (47.84 pg/ml versus 17.66 pg/ml and 12.05 pg/ml versus 11.13 pg/ml, respectively). Age was positively correlated with NfL, t-tau levels, and ADAS-cog. Although elevated NfL and t-tau protein levels may play a role in disease progression, their diagnostic value for AD was limited.

Longitudinal study of Alzheimer's disease biomarkers, allostatic load, and cognition among memory clinic patients

BackgroundAllostatic load (AL) is defined as the cumulative dysregulation of neuroendocrine, immunological, metabolic, and cardiovascular systems that increases the susceptibility to stress-related health problems. Several dementia and Alzheimer's disease (AD) risk factors have been identified, yet little is known about the role of AL and its associations with AD biomarkers (e.g., beta-amyloid (Aβ) or tau) and cognitive function among memory clinic patients. Hence, this study aims to assess the association between AL and AD biomarkers, cognitive performance, and cognitive decline after 3-years of follow-up. MethodsData from 188 memory clinic patients were derived from the Cortisol and Stress in AD (Co-STAR) study in Sweden. Participants underwent baseline assessments including blood tests for AL measures (including cortisol, thyroid stimulating hormone, cobalamin, homocysteine, leukocytes, glycated hemoglobin, albumin, high-density and low-density lipoprotein cholesterol, triglycerides, and creatinine), cerebrospinal fluid (CSF) sampling for AD biomarkers and neuropsychological tests including five cognitive domains. Linear regressions were conducted, adjusting for age, sex, and education. ResultsHigher AL was associated with lower CSF Aβ1-42 levels (β = −0.175, p = 0.025), reflecting higher brain levels of Aβ1-42. Stratified analyses suggested a significant association among women but not men, although the AL-sex interaction was not statistically significant. AL was not significantly associated with T-tau level (β = −0.030, p = 0.682) and P-tau level (β = 0.091, p = 0.980). There were no significant associations between AL and cognition or cognitive decline after 3 years. ConclusionThis study showed that higher AL was associated with increased brain amyloid accumulation. This suggests that AL may play a role in AD/dementia pathophysiology. Potential sex-related differences should be assessed in further larger studies.

Serum assessment of traumatic axonal injury: the correlation of GFAP, t-Tau, UCH-L1, and NfL levels with diffusion tensor imaging metrics and its prognosis utility.

Diagnosis of traumatic axonal injury (TAI) is challenging because of its underestimation by conventional MRI and the technical requirements associated with the processing of diffusion tensor imaging (DTI). Serum biomarkers seem to be able to identify patients with abnormal CT scanning findings, but their potential role to assess TAI has seldomly been explored. Patients with all severities of traumatic brain injury (TBI) were prospectively included in this study between 2016 and 2021. They underwent blood extraction within 24 hours after injury and imaging assessment, including DTI. Serum concentrations of glial fibrillary acidic protein, total microtubule-associated protein (t-Tau), ubiquitin C-terminal hydrolase L1 (UCH-L1), and neurofilament light chain (NfL) were measured using an ultrasensitive Simoa multiplex assay panel, a digital form of enzyme-linked immunosorbent assay. The Glasgow Outcome Scale-Extended score was determined at 6 months after TBI. The relationships between biomarker concentrations, volumetric analysis of corpus callosum (CC) lesions, and fractional anisotropy (FA) were analyzed by nonparametric tests. The prognostic utility of the biomarker was determined by calculating the C-statistic and an ordinal regression analysis. A total of 87 patients were included. Concentrations of all biomarkers were significantly higher for patients compared with controls. Although the concentration of the biomarkers was affected by the presence of mass lesions, FA of the CC was an independent factor influencing levels of UCH-L1 and NfL, which positioned these two biomarkers as better surrogates of TAI. Biomarkers also performed well in determining patients who would have had unfavorable outcome. NfL and the FA of the CC are independent complementary factors related to outcome. UCH-L1 and NfL seem to be the biomarkers more specific to detect TAI. The concentration of NfL combined with the FA of the CC might help predict long-term outcome.

Lower semantic fluency scores and a phonemic-over-semantic advantage predict abnormal CSF P-tau181 levels in Aβ + patients within the Alzheimer's disease clinical spectrum.

The present study aimed to determine whether patients with mild cognitive impairment (MCI) and dementia due to Alzheimer's disease (AD), semantic verbal fluency (SVF), and the semantic-phonemic discrepancy (SPD) could predict abnormal cerebrospinal fluid (CSF) phosphorylated tau (P-tau181) and total tau (T-tau) levels. Phonemic verbal fluency (PVF) and SVF scores of N = 116 Aβ-positive patients with either MCI due to AD (N = 39) or probable AD dementia (ADD; N = 77) were retrospectively collected. The SPD was computed by subtracting PVF scores from SVF ones (positive and negative values corresponding to a semantic and phonemic advantage, respectively). Patients were cognitively phenotyped via a thorough test battery and profiled according to the amyloidosis/tauopathy/neurodegeneration (ATN) framework via CSF analyses. Two separate sets of logistic regressions were run to predict normal vs. abnormal P-tau181 and T-tau levels by encompassing as predictors SVF + PVF and SPD and covarying for demographic, disease-related features, and cognitive profile. Lower SVF, but not PVF, scores, as well as a greater phonemic advantage (i.e., negative SPD values), predicted abnormal CSF P-tau181 levels (p ≤ .01). Moreover, lower SVF scores were selectively predictive of abnormal CSF T-tau levels too (p = .016), while the SPD was not. SVF and the SPD are able to predict tauopathy across the AD spectrum, thus supporting their status of valid, and sufficiently specific, cognitive markers of AD.

Alzheimer's disease biomarkers in patients with obstructive sleep apnea hypopnea syndrome and effects of surgery: A prospective cohort study.

Obstructive sleep apnea hypopnea syndrome (OSAHS) may cause Alzheimer's disease (AD), t-tau, p-tau, Aβ42, and Aβ40 are important elements in the process of AD, and changes in the levels of these biomarkers may affect the cognitive functioning of patients. Our objective was to investigate whether uvulopalatopharyngoplasty could reduce the plasma levels of AD biomarkers in OSAHS patients and the potential correlations of AD biomarkers with cognitive impairment and sleepiness, and explore the independent influencing factors of cognitive function. Alzheimer's disease biomarkers were measured in the plasma of 35 patients with severe OSAHS requiring surgical treatment and 16 healthy controls without OSAHS. The cognitive function and sleepiness of OSAHS patients was also evaluated. The case group was given uvulopalatopharyngoplasty and followed at the postoperative sixth month, the follow-up cases were 27, and plasma AD biomarker levels, cognitive function, and sleepiness were re-evaluated. The preoperative and postoperative AD biomarker levels OSAHS patients were compared with each other and those of the control group. Linear stepwise regression and lasso regression were used to explore the relationships of AD biomarkers with cognitive impairment and sleepiness. Significantly higher Aβ40, t-tau, p-tau in plasma were observed preoperatively in OSAHS patients comparing to controls (29.24 ± 32.52 vs. 13.18 ± 10.78, p = 0.049; 11.88 ± 7.05 vs. 7.64 ± 4.17, p = 0.037; 26.31 ± 14.41 vs. 17.34 ± 9.12, p = 0.027). The sixth month of postoperation, the plasma AD biomarkers (Aβ42, Aβ40, t-tau, p-tau) in plasma levels decreased significantly (0.23 ± 0.17 vs. 0.20 ± 0.16, p = 0.0001; 29.24 ± 32.52 vs. 23.52 ± 24.46, p = 0.0046; 11.88 ± 7.05 vs. 8.88 ± 6.21, p = 0.0001;26.31 ± 14.41 vs. 20.43 ± 10.50, p = 0.0001). A comparison of MMSE and ESS scores from before to after surgery revealed obvious differences (27.14 ± 1.65 vs. 29.07 ± 1.78, p = 0.0001; 11.91 ± 4.84 vs. 5.89 ± 2.83, p = 0.0001). Changes in cognitive function and sleepiness scores from before to after uvulopalatopharyngoplasty were significantly correlated with AD biomarkers. Body mass index and t-tau were potential influencing factors cognitive function. Obstructive sleep apnea hypopnea syndrome can increase plasma AD biomarkers levels. Uvulopalatopharyngoplasty can improve patients' cognition and sleepiness, and the mechanism may be related to changes in plasma AD biomarkers. Higher AHI and higher t-tau level were identified as independent risk factors for cognitive decline.

Plasma biomarker profiles in autosomal dominant Alzheimer's disease.

Emerging plasma biomarkers of Alzheimer's disease might be non-invasive tools to trace early Alzheimer's disease-related abnormalities such as the accumulation of amyloid-beta peptides, neurofibrillary tau tangles, glial activation and neurodegeneration. It is, however, unclear which pathological processes in the CNS can be adequately detected by peripheral measurements and whether plasma biomarkers are equally applicable in both clinical and preclinical phases. Here we aimed to explore the timing and performance of plasma biomarkers in mutation carriers compared to non-carriers in autosomal dominant Alzheimer's disease. Samples (n = 164) from mutation carriers (n = 33) and non-carriers (n = 42) in a Swedish cohort of autosomal dominant Alzheimer's disease (APP p.KM670/671NL, APP p.E693G and PSEN1 p.H163Y) were included in explorative longitudinal analyses. Plasma phosphorylated tau (P-tau181), total tau (T-tau), neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) concentrations were measured with a single-molecule array method as previously described. Plasma biomarkers were additionally correlated to Alzheimer's disease core biomarkers in the CSF. Results from the longitudinal analyses confirmed that plasma P-tau181, NfL and GFAP concentrations were higher in mutation carriers compared to non-carriers. This change was observed in the presymptomatic phase and detectable first as an increase in GFAP approximately 10 years before estimated symptom onset, followed by increased levels of P-tau181 and NfL closer to expected onset. Plasma P-tau181 levels were correlated to levels of P-tau181 and T-tau in the CSF. Altogether, plasma P-tau181, GFAP and NfL seem to be feasible biomarkers to detect different Alzheimer's disease-related pathologies already in presymptomatic individuals. Interestingly, changes in plasma GFAP concentrations were detected prior to P-tau181 and NfL. Our results suggest that plasma GFAP might reflect Alzheimer's disease pathology upstream to accumulation of tangles and neurodegeneration. The implications of these findings need additional validation, in particular because of the limited sample size.