Cerebrospinal Fluid Tau Levels Research Articles

Gait Disturbances are Associated with Increased Cognitive Impairment and Cerebrospinal Fluid Tau Levels in a Memory Clinic Cohort.

Background:Gait analysis with accelerometers is a relatively inexpensive and easy to use method to potentially support clinical diagnoses of Alzheimer’s disease and other dementias. It is not clear, however, which gait features are most informative and how these measures relate to Alzheimer’s disease pathology.Objective:In this study, we tested if calculated features of gait 1) differ between cognitively normal subjects (CN), mild cognitive impairment (MCI) patients, and dementia patients, 2) are correlated with cerebrospinal fluid (CSF) biomarkers related to Alzheimer’s disease, and 3) predict cognitive decline.Methods:Gait was measured using tri-axial accelerometers attached to the fifth lumbar vertebra (L5) in 58 CN, 58 MCI, and 26 dementia participants, while performing a walk and dual task. Ten gait features were calculated from the vertical L5 accelerations, following principal component analysis clustered in four domains, namely pace, rhythm, time variability, and length variability. Cognitive decline over time was measured using MMSE, and CSF biomarkers were available in a sub-group.Results:Linear mixed models showed that dementia patients had lower pace scores than MCI patients and CN subjects (p < 0.05). In addition, we found associations between the rhythm domain and CSF-tau, especially in the dual task. Gait was not associated with CSF Aβ42 levels and cognitive decline over time as measured with the MMSE.Conclusion:These findings suggest that gait — particularly measures related to pace and rhythm — are altered in dementia and have a direct link with measures of neurodegeneration.

MicroRNA-195 rescues ApoE4-induced cognitive deficits and lysosomal defects in Alzheimer\u2019s disease pathogenesis

Our recent findings link the apolipoprotein E4 (ApoE4)-specific changes in brain phosphoinositol biphosphate (PIP2) homeostasis to the susceptibility of developing Alzheimer’s Disease (AD). In the present study, we have identified miR-195 as a top micro-RNA candidate involved in the ApoE/PIP2 pathway using miRNA profiles in human ROSMAP datasets and mouse microarray studies. Further validation studies have demonstrated that levels of miR-195 are significantly lower in human brain tissue of ApoE4+/− patients with clinical diagnosis of mild cognitive impairment (MCI) or early AD when compared to ApoE4−/− subjects. In addition, brain miR-195 levels are reduced along with disease progression from normal aging to early AD, and cerebrospinal fluid (CSF) miR-195 levels of MCI subjects are positively correlated with cognitive performances as measured by mini-mental status examination (MMSE) and negatively correlated with CSF tau levels, suggesting the involvement of miR-195 in early development of AD with a potential impact on cognition. Similar differences in miR-195 levels are seen in ApoE4+/+ mouse hippocampal brain tissue and cultured neurons when compared to ApoE3+/+ counterparts. Over-expressing miR-195 reduces expression levels of its top predicted target synaptojanin 1 (synj1), a brain PIP2-degrading enzyme. Furthermore, elevating miR-195 ameliorates cognitive deficits, amyloid plaque burden, and tau hyper-phosphorylation in ApoE4+/+ mice. In addition, elevating miR-195 rescues AD-related lysosomal defects in inducible pluripotent stem cells (iPSCs)-derived brain cells of ApoE4+/+ AD subjects while inhibiting miR-195 exacerbates these phenotypes. Together, our data uncover a novel regulatory mechanism of miR-195 targeted at ApoE4-associated brain PIP2 dyshomeostasis, cognitive deficits, and AD pathology.

18F]THK5317 imaging as a tool for predicting prospective cognitive decline in Alzheimer\u2019s disease

Cross-sectional studies have indicated potential for positron emission tomography (PET) in imaging tau pathology in Alzheimer’s disease (AD); however, its prognostic utility remains unproven. In a longitudinal, multi-modal, prognostic study of cognitive decline, 20 patients with a clinical biomarker-based diagnosis in the AD spectrum (mild cognitive impairment or dementia and a positive amyloid-beta PET scan) were recruited from the Cognitive Clinic at Karolinska University Hospital. The participants underwent baseline neuropsychological assessment, PET imaging with [18F]THK5317, [11C]PIB and [18F]FDG, magnetic resonance imaging, and in a subgroup cerebrospinal fluid (CSF) sampling, with clinical follow-up after a median 48 months (interquartile range = 32:56). In total, 11 patients declined cognitively over time, while 9 remained cognitively stable. The accuracy of baseline [18F]THK5317 binding in temporal areas was excellent at predicting future cognitive decline (area under the receiver operating curve 0.84–1.00) and the biomarker levels were strongly associated with the rate of cognitive decline (β estimate −33.67 to −31.02, p < 0.05). The predictive accuracy of the other baseline biomarkers was poor (area under the receiver operating curve 0.58–0.77) and their levels were not associated with the rate of cognitive decline (β estimate −4.64 to 15.78, p > 0.05). Baseline [18F]THK5317 binding and CSF tau levels were more strongly associated with the MMSE score at follow-up than at baseline (p < 0.05). These findings support a temporal dissociation between tau deposition and cognitive impairment, and suggest that [18F]THK5317 predicts future cognitive decline better than other biomarkers. The use of imaging markers for tau pathology could prove useful for clinical prognostic assessment and screening before inclusion in relevant clinical trials.

Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease

Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF). Alzheimer's disease (AD) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that accompany AD. Here, we present a highly reproducible mass spectrometry (MS)‐based proteomics workflow for the in‐depth analysis of CSF from minimal sample amounts. From three independent studies (197 individuals), we characterize differences in proteins by AD status (> 1,000 proteins, CV < 20%). Proteins with previous links to neurodegeneration such as tau, SOD1, and PARK7 differed most strongly by AD status, providing strong positive controls for our approach. CSF proteome changes in Alzheimer's disease prove to be widespread and often correlated with tau concentrations. Our unbiased screen also reveals a consistent glycolytic signature across our cohorts and a recent study. Machine learning suggests clinical utility of this proteomic signature.

Identification of novel candidate autoantibodies in Alzheimer's disease.

Accumulated failures in Alzheimer's disease (AD) clinical trials have highlighted an urgent need to identify additional biomarkers involved in AD. Recently, mounting evidence reported that autoantibodies are ubiquitous in human sera. However, it is unknown whether autoantibodies are upregulated in amyloid-tau biomarker-confirmed AD. A total of 40 subjects with mild dementia (Clinical Dementia Rating=1) were stratified into AD (n=16) and non-AD (n=24) groups according to their cerebrospinal fluid levels of tau and Aβ42 . Their sera were collected and analyzed using a microarray containing>1600 potential human autoantigens. Autoantibodies that were present exclusively in the AD group were identified and selected using the penetrance-based fold change method with the following criteria: penetrance fold change(AD) ≥2, frequency(AD) ≥15% and frequency(non-AD) =0%. All controls and samples passed the quality control criteria and were further used for biomarker analysis. Six autoantibodies with elevated responses to the following autoantigens were found exclusively in the AD group: nucleosome assembly protein 1-like 3 (31.3%, 5/16 subjects) and microtubule-associated protein 4, pantothenic acid kinase 3, phosphoinositide-3-kinase regulatory subunit 1, protein tyrosine phosphatase type IVA member 1 and SRY (sex-determining region Y)-box 15 (all 18.8%, 3/16 subjects). Although some identified autoantigens are linked to AD and cognitive dysfunction, the increased autoantibody levels have not been reported in AD. Autoantibodies may provide deeper insights into the pathogenesis of AD and serve as diagnostic biomarkers; their corresponding antigens can be further studied to assess their potential as therapeutic targets.

Cerebrospinal fluid levels of alpha-synuclein, amyloid β, tau, phosphorylated tau, and neuron-specific enolase in patients with Parkinson’s disease, dementia with Lewy bodies or other neurological disorders: Their relationships with cognition and nuclear medicine imaging findings

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders, but no established biochemical markers for these diseases have been identified. We enrolled 78 subjects (27 patients with PD/DLB, 34 patients with non-PD/DLB neurodegenerative disorders [non-PD/DLB], and 17 controls). Cerebrospinal fluid (CSF) was collected via the standard lumbar puncture technique. The CSF levels of alpha-synuclein, amyloid β40, amyloid β42, tau, phosphorylated tau (p-tau), neuron-specific enolase (NSE), and hemoglobin were measured with enzyme-linked immunosorbent assays. Dopamine transporter imaging with 123I-ioflupane was also performed. The PD/DLB patients exhibited significantly lower CSF alpha-synuclein levels than non-PD/DLB group. Significantly elevated CSF levels of tau, p-tau, and NSE were detected in the non-PD/DLB group. Multivariate analysis revealed that the mini-mental state examination score was correlated with the CSF amyloid β42 level. The specific binding ratio on 123I-ioflupane imaging was decreased in the PD/DLB group, but it was not correlated with the CSF alpha-synuclein level. These results indicate that (1) the CSF alpha-synuclein level is a useful biomarker of PD/DLB; (2) the CSF levels of tau, p-tau, and NSE can be used to discriminate PD/DLB from non-PD/DLB; and (3) the CSF amyloid β42 level is an independent predictor of cognitive decline in neurological disorders.

White matter hypointensities and hyperintensities have equivalent correlations with age and CSF β-amyloid in the nondemented elderly.

IntroductionT1‐ and T2‐weighted sequences from MRI often provide useful complementary information about tissue properties. Leukoaraiosis results in signal abnormalities on T1‐weighted images, which are automatically quantified by FreeSurfer, but this marker is poorly characterized and is rarely used. We evaluated associations between white matter hyperintensity (WM‐hyper) volume from FLAIR and white matter hypointensity (WM‐hypo) volume from T1‐weighted images and compared their associations with age and cerebrospinal fluid (CSF) β‐amyloid and tau.MethodsA total of 56 nondemented participants (68–94 years) were recruited and gave informed consent. All participants went through MR imaging on a GE 1.5T scanner and of these 47 underwent lumbar puncture for CSF analysis. WM‐hypo was calculated using FreeSurfer analysis of T1 FSPGR 3D, and WM‐hyper was calculated with the Lesion Segmentation Toolbox in the SPM software package using T2‐FLAIR.ResultsWM‐hyper and WM‐hypo were strongly correlated (r = .81; parameter estimate (p.e.): 1.53 ± 0.15; p < .0001). Age was significantly associated with both WM‐hyper (r = .31, p.e. 0.078 ± 0.030, p = .013) and WM‐hypo (r = .42, p.e. 0.055 ± 0.015, p < .001). CSF β‐amyloid levels were predicted by WM‐hyper (r = .33, p.e. −0.11 ± 0.044, p = .013) and WM‐hypo (r = .42, p.e. −0.24 ± 0.073, p = .002). CSF tau levels were not correlated with either WM‐hyper (p = .9) or WM‐hypo (p = .99).ConclusionsStrong correlations between WM‐hyper and WM‐hypo, and similar associations with age, abnormal β‐amyloid, and tau suggest a general equivalence between these two imaging markers. Our work supports the equivalence of white matter hypointensity volumes derived from FreeSurfer for evaluating leukoaraiosis. This may have particular utility when T2‐FLAIR is low in quality or absent, enabling analysis of older imaging data sets.

Clinical analysis of adult-onset neuronal intranuclear inclusion disease

Neuronal intranuclear inclusion disease (NIID) is characterized by eosinophilic nuclear inclusions (NI) in the nervous systems and the visceral organs. Ante-mortem diagnoses have been made by NI identification in skin biopsy samples based on characteristic corticomedullary junction (CMJ) high intensity in brain diffusion-weighted imaging (DWI). However, the clinical symptoms of NIID are variable. We analyzed 14 (10 sporadic, 4 familial) adult-onset NIID patients with clinical examination, electrophysiological study, brain MRI, cerebrospinal fluid (CSF) biomarker, and skin biopsy. The mean onset-age was 63.8 years. Initial symptoms were consciousness disturbance, memory impairment, gait disturbance, etc. The mean scores of MMSE, Japanese version of Montreal Cognitive Assessment and Frontal Assessment Battery were 20.7/30, 14.2/30 and 9.2/18, respectively. Neurological examination demonstrated hypo-areflexia, miosis and urinary dysfunction. All patients showed abnormal nerve conduction. Thirteen of 14 patients revealed high intensities of CMJ in DWI and leukoencephalopathy with ventricular dilatation and brain atrophy in MRI FLAIR images. In one patient with leukoencephalopathy, DWI high intensity was not detected. The levels of total Tau in CSF were increased in accordance with the grade of DWI high intensity. Skin biopsies from all patients demonstrated that NI immunostained with anti-ubiquitin and anti-p62 antibodies in the sweat gland cells, adipocytes and fibroblasts, were composed of filamentous structure without limiting membrane by electron microscopy. In patients with miosis and hyporeflexia with leukoencephalopathy, NIID should be considered for differential diagnosis even when DWI high intensity is negative. Total Tau in CSF will be a biomarker for progression of NIID.

Plasma lipocalin-2 levels in the preclinical stage of Alzheimer's disease

IntroductionLipocalin-2 is an acute-phase protein with pleotropic functions that has been implicated in several diseases including Alzheimer's disease (AD). However, it is unknown if circulating lipocalin-2 levels are altered in the preclinical stage of AD, where AD pathology has accumulated but cognition remains relatively intact. MethodsIn this cross-sectional study, we used an immunoassay to measure plasma lipocalin-2 levels in cognitively normal (Clinical Dementia Rating 0) elderly individuals. 38 of 156 subjects were classified as preclinical AD by cerebrospinal fluid criteria. ResultsPlasma lipocalin-2 levels were higher in preclinical AD compared with control subjects and associated with cerebrospinal fluid amyloid-beta42 levels but not cerebrospinal fluid tau or phosphorylated-tau181 levels. Exploratory analyses revealed that plasma lipocalin-2 was associated with executive function but not episodic memory. DiscussionCollectively, these results raise the possibility that circulating lipocalin-2 is involved early in AD pathogenesis and may represent an early blood biomarker of amyloid-beta pathology.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study.

BackgroundProprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer’s disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge.Methods and findingsTo test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 “at-risk” subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals.ConclusionsPCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.

Cerebrospinal fluid amyloid levels are associated with delayed memory retention in cognitively normal biomarker-negative older adults

Alzheimer's disease is defined by abnormal levels of amyloid and tau biomarkers. Even cognitively normal older adults with clinically relevant amyloid and tau levels perform worse on memory tests. However, it is unclear if the relationship between biomarker level and memory extends below clinical thresholds. We hypothesized that even subclinical biomarker levels are associated with memory when measured with neuropsychological tests designed to detect dysfunction in preclinical disease states. In a group of cognitively normal, “biomarker-negative” older men and women, we investigated the relationship between cerebrospinal fluid biomarker levels and memory measured with the ModRey, a list-learning task designed to assess memory in preclinical and cognitively normal adults. Cerebrospinal amyloid levels were associated with ModRey memory retention, the proportion of information retained after a delay period. When older adults with mild impairment were included, cerebrospinal fluid tau levels were also associated with ModRey retention. The association of amyloid and tau levels with memory was independent of each other. These results suggest cognitive changes associated with Alzheimer's disease pathology might occur earlier than currently thought.

Cerebrospinal Fluid Markers of Synaptic Injury and Functional Connectivity in Alzheimer Disease: Protocol for a Cross-Sectional Study.

BackgroundSynaptic loss is the best surrogate for cognitive decline in Alzheimer disease (AD) and is more closely associated with cognitive function than amyloid or tau pathologies. Neurogranin (Ng) and synaptosome–associated protein-25 (SNAP-25) have demonstrated utility as cerebrospinal fluid (CSF) markers of synaptic injury in presymptomatic and symptomatic AD. While these synaptic markers have been shown to correlate with cognitive impairment and whole brain or regional atrophy in previous studies of AD, to our knowledge, the relationship between fluid markers of synaptic injury and functional brain imaging has not been previously investigated.ObjectiveThe main objective of this study is to examine the relationship between CSF markers of synaptic injury (Ng and SNAP-25) and functional connectivity (FC) in the default mode and semantic memory networks in individuals with mild cognitive impairment (MCI) and mild dementia due to AD (Clinical Dementia Rating [CDR] 0.5-1) and cognitively normal controls (CDR 0), adjusting for age, gender, and the apolipoprotein E4 (APOE4) genotype. Secondary objectives include investigating the associations between CSF markers of amyloid and tau pathology (CSF tau, p-tau181, and Aβ42) and FC in the default mode and semantic memory networks in AD (CDR 0.5-1) and controls (CDR 0), adjusting for age, gender, and the APOE4 genotype.MethodsThis is a cross-sectional study of individuals with MCI or mild dementia due to AD (CDR 0.5-1; n=20), and cognitively normal controls (CDR 0; n=20). Participants will undergo detailed clinical and neuropsychological assessments, CSF biomarker assessments (CSF Ng, SNAP-25, tau, p-tau181, and Aβ42 levels) and functional magnetic resonance imaging assessments, using a Siemens 3.0 Tesla Prisma scanner, during resting state and during the performance of a semantic memory task. All study procedures will be completed within 4 months of enrollment. Partial correlation analyses will examine associations of CSF biomarker measures with FC in the default mode and semantic memory networks in AD and controls.ResultsThis study was funded by the Chronic Brain Injury Discovery Themes of the Ohio State University College of Medicine. Study enrollment began in April 2018. Study procedures and data analysis are currently underway. Results are expected by December 2019.ConclusionsFindings from this study will further support the utility of CSF Ng and SNAP-25 as markers of synaptic injury by examining their associations with functional alterations in cortical networks affected by early AD pathology.International Registered Report Identifier (IRRID)DERR1-10.2196/14302

Lipid Metabolism in Late-Onset Alzheimer's Disease Differs from Patients Presenting with Other Dementia Phenotypes.

Abnormal cerebrospinal fluid (CSF) levels of β-amyloid peptides (Aβ42) and Tau and cognitive decline are typical characteristics of Alzheimer’s disease (AD). Since dysregulation in lipid metabolism accompanies abnormal amyloid formation, we quantified glycerophospholipids (GP) and sphingolipids (SP) in CSF fractions from participants with late-onset AD (LOAD, n = 29) or with Other Dementia (OD, n = 10) to determine if alterations in lipid metabolism account for pathological differences. Aβ42 and total Tau levels were determined using a sandwich ELISA. Liposomal-based fluorescent assays were used to measure phospholipase A2 (PLA2) and acid or neutral sphingomyelinase (aSMase, nSMase) activities. Supernatant fluid (SF) and nanoparticle (NP) lipids were quantified using LC-MS/MS. Although CSF Aβ42 and Tau levels are similar, phosphatidylserine (PS) in SF and ceramide (CM) levels in NP are significantly higher in OD compared with LOAD. The aSMase but not the nSMase activity is higher in OD. PLA2 activity in CSF from OD subjects positively correlates with several GP classes in SF and NP fractions but not in LOAD fractions. Our data indicate differences in CSF lipid metabolism between dementia variants. Higher levels of inflammatory and apoptotic lipids may induce faster neuronal death, resulting in the earlier cognitive decline in patients with OD phenotypes.

Age-related hearing loss accelerates cerebrospinal fluid tau levels and brain atrophy: a longitudinal study.

Age-related hearing loss (ARHL) has been considered as a promising modifiable risk factor for cognitive impairment and dementia. Nonetheless, it is still unclear whether age-related hearing loss associates with neurodegenerative biomarkers of Alzheimer’s disease (AD). Participants with ARHL were selected from the established Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. In multivariable models, the cross-sectional and longitudinal associations of ARHL with CSF β-amyloid (Aβ) and tau measurements, brain Aβ load, and cortical structural measures were explored. ARHL was associated with higher CSF levels of tau (p < 0.001) or ptau181 (p < 0.05) at baseline as well as faster elevation rates of these two types of biomarkers (p < 0.05). Although the baseline volume/thickness of hippocampus (p < 0.05) and entorhinal cortex (p < 0.0005) were higher in individuals with ARHL, these two regions (p < 0.01 for hippocampus, p < 0.05 for entorhinal cortex) displayed significantly accelerated atrophy in individuals with ARHL. No association of ARHL with CSF or brain Aβ levels was found. Subgroup analyses indicated that the above effects of ARHL were more significant in non-demented stage. Age-related hearing loss was associated with elevated cerebrospinal fluid tau levels and atrophy of entorhinal cortex.

Comparative study of methods for the determination of free light chains (FLC) in 24-hour urine

Cerebrospinal fluid (CSF) biomarkers are valuable tools for the diagnosis of neurological diseases. We aimed to investigate within a retrospective multicentric study the final diagnosis associated with very high CSF Tau levels and to identify patterns of biomarkers that would differentiate them in clinical practice, to help clinical biologists into physicians' counseling.Within the national multicentric network ePLM, we included 1743 patients from January 1, 2008, to December 31, 2013, with CSF biomarkers assayed by the same Innotest assays (protein Tau, phospho-Tau [pTau], and Aβ 1-42). We identified 205 patients with protein Tau concentration higher than 1200 pg/mL and final diagnosis.Among those patients, 105 (51.2%) were suffering from Alzheimer's disease, 37 (18%) from sporadic Creuztfeldt-Jakob disease, and 63 (30.7%) from other neurological diseases including paraneoplastic/ central nervous system tumor, frontotemporal dementia, other diagnoses, amyloid angiopathy, Lewy body dementia, and infections of the central nervous system. Phospho-Tau, Aβ1-42 and Aβ1-42/pTau values differed significantly between the three groups of patients (p < .001). An Aβ1-42/pTau ratio between 4.7 and 9.7 was suggestive of other neurological diseases (threshold in AD: 8.3). CSF 14-3-3 was useful to discriminate Alzheimer's disease from Creuztfeldt-Jakob disease in case of Aβ1-42 concentrations <550 pg/mL or pTau>60 pg/mL.This work emphasizes the interest of a well-thought-out interpretation of CSF biomarkers in neurological diseases, particularly in the case of high Tau protein concentrations in the CSF.

Mass Spectrometry-Based Quantification of Tau in Human Cerebrospinal Fluid Using a Complementary Tryptic Peptide Standard.

Here, we report a method for the generation of complementary tryptic (CompTryp) isotope-labeled peptide standards for the relative and absolute quantification of proteins by mass spectrometry (MS). These standards can be digested in parallel with either trypsin (Tryp-C) or trypsin-N (Tryp-N), to generate peptides that significantly overlap in primary sequence having C- and N-terminal arginine and lysine residues, respectively. As a proof of concept, an isotope-labeled CompTryp standard was synthesized for Tau, a well-established biomarker in Alzheimer's disease (AD), which included both N- and C-terminal heavy isotope-labeled (15N and 13C) arginine residues and flanking amino acid sequences to monitor proteolytic digestion. Despite having the exact same mass, the N- and C-terminal heavy Tau peptides are distinguishable by retention time and MS/MS fragmentation profiles. The isotope-labeled Tau CompTryp standard was added to human cerebrospinal fluid (CSF) followed by parallel digestion with Tryp-N and Tryp-C. The native and isotope-labeled peptide pairs were quantified by parallel reaction monitoring (PRM) in a single assay. Notably, both tryptic peptides were effective at quantifying Tau in human CSF, and both showed a significant difference in CSF Tau levels between AD and controls. Treating these CompTryp Tau peptide measurements as independent replicates also improved the coefficient of variation and correlation with Tau immunoassays. More broadly, we propose that CompTryp standards can be generated for any protein of interest, providing an efficient method to improve the robustness and reproducibility for MS analysis of clinical and research samples.

Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer's disease

Amyloid β (Aβ) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aβ and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aβ1–42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aβ−), mild cognitively impaired (Aβ−), preclinical AD (Aβ+), and prodromal AD (Aβ+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = −0.434; p < 0.001) and p-tau181P (r = −0.389; p < 0.001). When classified by Aβ status, this correlation to t-tau was applicable only in Aβ+ participants (n = 139; r = −0.451, p < 0.001) but not Aβ− participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aβ1–42 with tau (p = 0.006) affected RBANS, but not Aβ1–42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aβ dependent.

Association of IL1RAP-related genetic variation with cerebrospinal fluid concentration of Alzheimer-associated tau protein

A possible involvement of the gene IL1RAP (interleukin-1 receptor-associated protein) in the pathogenesis of Alzheimer’s disease (AD) has been suggested in GWASs of cerebrospinal fluid (CSF) tau levels and longitudinal change in brain amyloid burden. The aim of this study was to examine previously implicated genetic markers in and near IL1RAP in relation to AD risk, CSF tau and Aβ biomarkers, as well as cognitive decline, in a case (AD)-control study and an age homogenous population-based cohort. Genotyping of IL1RAP-related single nucleotide polymorphisms (SNPs), selected based on previous GWAS results, was performed. 3446 individuals (1154 AD cases and 2292 controls) were included in the analyses of AD risk, 1400 individuals (cognitively normal = 747, AD = 653) in the CSF biomarker analyses, and 861 individuals in the analyses of cognitive decline. We found no relation between IL1RAP-related SNPs and AD risk. However, CSF total-tau and phospho-tau were associated with the SNP rs9877502 (p = 6 × 10−3 and p = 5 × 10−4). Further, nominal associations (p = 0.03–0.05) were found between three other SNPs and CSF biomarker levels, or levels of cognitive performance and decline in a sub-sample from the general population. These results support previous studies suggesting an association of IL1RAP with disease intensity of AD.

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults

Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07). Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Cerebrospinal Fluid and Plasma Tau as aBiomarker for Brain Tauopathy.

Cerebrospinal fluid (CSF) tau and phosphorylated tau (ptau) are definite biomarkers of Alzheimer's disease (AD). After discovery of presence and increased levels tau in CSF from AD patients using specific ELISA, numerous reports revealed that CSF levels of tau are increased in AD and brain injury, phosphorylated tau are specifically increased in AD. Many large cohort studies also confirmed that natural course of CSF tau and ptau levels initiated from cognitively unimpaired AD stage after longstanding progress of brain Aß amyloidosis. Close correlation with neuroimaging findings of Tau PET and with deterioration of cognitive function domains have been elucidated. CSF tau also increase in neurodegeneration and acute brain injury. Global standardization, assay technology inventions, and research of tau kinetics from brain synthesis and clearance into CSF are developing. Trace amount of plasma p-tau assay are also validated. Development of these studies provide that CSF tau is the biomarker of CNS neurodegeneration and CSF ptau is the specific biomarker of CNS tauopathy. Assays of CSF and plasma tau and ptau are essential tools not only for prediction and diagnosis of AD and but for newly developing disease modified therapies of AD.