High Tau Research Articles

Variability of Reaction Time as a Marker of Executive Function Impairments in Fibromyalgia.

In addition to chronic widespread pain and depression and anxiety symptoms, patients with fibromyalgia frequently experience cognitive problems. This study investigated executive functions in fibromyalgia via a Go/No-Go task. To obtain comprehensive information about performance, traditional and ex-Gaussian parameters of reaction time (RT) variability were used, in addition to speed and accuracy indices. Ex-Gaussian parameters show an excellent fit to empirical RT distributions. Fifty-two female fibromyalgia patients and twenty-eight healthy controls participated. The task included 60 visual stimuli, which participants had to respond to (Go stimuli) or withhold the response to (No-Go stimuli). After 30 trials, the task rule changed, such that previous No-Go stimuli had to be responded to. Performance was indexed by the hit rate, false alarm rate, and mean (M) and intraindividual standard deviation (SD) of RT and the ex-Gaussian parameters mu, sigma, and tau. Mu and sigma indicate the M and SD of the Gaussian distribution; tau reflects the M and SD of the exponential function. Patients exhibited a lower hit rate, higher M RT, and higher tau than controls. Moreover, patients showed greater decrease of the hit rate after the change of task rule. In the entire sample, SD, sigma, and tau were inversely associated with the hit rate and positively associated with the false alarm rate. While the greater decline in hit rate after the change in task rule indicates deficient cognitive flexibility, the lack of any difference in false alarm rate suggests intact response inhibition. Higher M RT reflects reduced cognitive or motor speed. Increased tau in fibromyalgia indicates greater fluctuations in executive control and more frequent temporary lapses of attention. For the first time, this study demonstrated that indices of RT variability, in particular those derived from the ex-Gaussian function, may complement speed and accuracy parameters in the assessment of executive function impairments in fibromyalgia. Optimized assessment may facilitate the personalization of therapies aimed at improving the cognitive function of those with the disorder.

Relationship between Phenolic Compounds, Antioxidant Activity and Color Parameters of Red Table Grape Skins Using Linear Ordering Analysis

Color, being one of the most important sensory characteristics, could be associated to the phenolic compound content and/or the antioxidant activity of fruits and vegetables. In this study, linear ordering was used to build quality rankings of red table grapes based on color parameters or phenolic compounds. First, the principle component analysis (PCA) was used to show the association between color of red grape skins (evaluated in CIE L*a*b* and L*C*h systems) and their individual phenolic compounds (investigated by the HPLC), total polyphenol content (TPC), total anthocyanins (ACNs), as well as the antioxidant activity (DPPH) of five table grape varieties. It could be observed that the lightness (L*) and hue angle (h) are the color coordinates strongly related to some phenolic compounds and ACN, whereas a* was related to DPPH and TPC. Five distinct clusters could be observed from PCA analysis with dark-colored grape varieties showing high levels of ACN (3.48–5.83 mg/g), low lightness (47.8–53.0), and high h values (353.7–359.8°). L*, a*, and h color coordinates were used to build table grape ranking. The second ranking was built based on phenolic compound content. Results of the two rankings were correlated. High Tau Kendall correlation coefficient (0.51, p = 0.000) indicated that linear ordering analysis, based on the simple color measurements, could be a useful tool for rapid screening of the quality of grapes. This could be valuable information for producers and consumers of the fruit making decision on the market.

The PUMAS library

The PUMAS library is a transport engine for muon and tau leptons in matter. It can operate with a configurable level of details, from a fast deterministic CSDA mode to a detailed Monte Carlo simulation. A peculiarity of PUMAS is that it is revertible, i.e. it can run in forward or in backward mode. Thus, the PUMAS library is particularly well suited for muography applications. In the present document, we provide a detailed description of PUMAS, of its physics and of its implementation. Program summaryProgram Title: The PUMAS libraryCPC Library link to program files:https://doi.org/10.17632/dnry8jwkd7.1Developer's repository link:https://niess.github.io/pumas-pagesCode Ocean capsule:https://codeocean.com/capsule/4593807Licensing provisions: LGPL-3.0Programming language: C99Nature of problem: Transport of high energy muon or tau leptons in matter.Solution method: Transport engine with a configurable level of details, from a fast deterministic CSDA mode to a detailed Monte Carlo simulation. The transport engine can operate in both forward and backward modes.

CPKCγ Deficiency Exacerbates Autophagy Impairment and Hyperphosphorylated Tau Buildup through the AMPK/mTOR Pathway in Mice with Type 1 Diabetes Mellitus.

Type 1 diabetes mellitus (T1DM)-induced cognitive dysfunction is common, but its underlying mechanisms are still poorly understood. In this study, we found that knockout of conventional protein kinase C (cPKC)γ significantly increased the phosphorylation of Tau at Ser214 and neurofibrillary tangles, but did not affect the activities of GSK-3β and PP2A in the hippocampal neurons of T1DM mice. cPKCγ deficiency significantly decreased the level of autophagy in the hippocampal neurons of T1DM mice. Activation of autophagy greatly alleviated the cognitive impairment induced by cPKCγ deficiency in T1DM mice. Moreover, cPKCγ deficiency reduced the AMPK phosphorylation levels and increased the phosphorylation levels of mTOR in vivo and in vitro. The high glucose-induced Tau phosphorylation at Ser214 was further increased by the autophagy inhibitor and was significantly decreased by an mTOR inhibitor. In conclusion, these results indicated that cPKCγ promotes autophagy through the AMPK/mTOR signaling pathway, thus reducing the level of phosphorylated Tau at Ser214 and neurofibrillary tangles.

Mesial temporal tau in amyloid-\u03b2-negative cognitively normal older persons

BackgroundTau deposition in the mesial temporal lobe (MTL) in the absence of amyloid-β (Aβ−) occurs with aging. The tau PET tracer 18F-MK6240 has low non-specific background binding so is well suited to exploration of early-stage tau deposition. The aim of this study was to investigate the associations between MTL tau, age, hippocampal volume (HV), cognition, and neocortical tau in Aβ− cognitively unimpaired (CU) individuals.MethodsOne hundred and ninety-nine Aβ− participants (Centiloid < 25) who were CU underwent 18F-MK6240 PET at age 75 ± 5.2 years. Tau standardized uptake value ratio (SUVR) was estimated in mesial temporal (Me), temporoparietal (Te), and rest of the neocortex (R) regions and four Me sub-regions. Tau SUVR were analyzed as continuous variables and compared between high and low MTL SUVR groups.ResultsIn this cohort with a stable clinical classification of CU for a mean of 5.3 years prior to and at the time of tau PET, MTL tau was visually observed in 9% of the participants and was limited to Braak stages I–II. MTL tau was correlated with age (r = 0.24, p < 0.001). Age contributed to the variance in cognitive scores but MTL tau did not. MTL tau was not greater with subjective memory complaint, nor was there a correlation between MTL tau and Aβ Centiloid value, but high tau was associated with smaller HV. Participants with MTL tau had higher tau SUVR in the neocortex but this was driven by the cerebellar reference region and was not present when using white matter normalization.ConclusionsIn an Aβ− CU cohort, tau tracer binding in the mesial temporal lobe was age-related and associated with smaller hippocampi, but not with subjective or objective cognitive impairment.

Alzheimer's Disease: An Update and Insights Into Pathophysiology.

Alzheimer’s disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important “omics” tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual’s metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in “omics”-based biomarkers in AD.

Characterizing Amyloid-Positive Individuals With Normal Tau PET Levels After 5 Years: An ADNI Study.

Individuals with biomarker evidence of β-amyloid (Aβ) deposition are increasingly being enrolled in clinical treatment trials but there is a need to identify markers to predict which of these individuals will also develop tau deposition. We aimed to determine whether Aβ-positive individuals can remain tau-negative for at least 5 years and identify characteristics that could distinguish between these individuals and those who develop high tau within this period. Tau PET positivity was defined using a Gaussian mixture model with log-transformed standard uptake value ratio values from 7 temporal and medial parietal regions using all participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI) with flortaucipir PET. Tau PET scans were classified as normal if the posterior probability of elevated tau was less than 1%. Aβ PET positivity was defined based on ADNI cutpoints. We identified all Aβ-positive individuals from ADNI who had normal tau PET more than 5 years after their first abnormal Aβ PET (amyloid with low tau [ALT] group) and all Aβ-positive individuals with abnormal tau PET within 5 years (biomarker AD). In a case-control design, logistic regression was used to model the odds of biomarker AD vs ALT accounting for sex, age, APOE ε4 carriership, Aβ Centiloid, and hippocampal volume. We identified 45 individuals meeting criteria for ALT and 157 meeting criteria for biomarker AD. The ALT group had a lower proportion of APOE ε4 carriers, lower Aβ Centiloid, larger hippocampal volumes, and more preserved cognition, and were less likely to develop dementia, than the biomarker AD group. APOE ε4, higher Aβ Centiloid, and hippocampal atrophy were independently associated with increased odds of abnormal tau within 5 years. A Centiloid value of 50 effectively discriminated biomarker AD and ALT with 80% sensitivity and specificity. The majority of the ALT participants did not develop dementia throughout the 5-year interval. Aβ-positive individuals can remain tau-negative for at least 5 years. Baseline characteristics can help identify these ALT individuals who are less likely to develop dementia. Conservative Aβ cutpoints should be utilized for clinical trials to better capture individuals with high risk of developing biomarker AD.

Cerebral biomarkers in neurologic complications of preeclampsia

There is no tool to accurately predict who is at risk of developing neurologic complications of preeclampsia, and there is no objective method to determine disease severity. We assessed whether plasma concentrations of the cerebral biomarkers neurofilament light, tau, and glial fibrillary acidic protein could reflect disease severity in several phenotypes of preeclampsia. Furthermore, we compared the cerebral biomarkers with the angiogenic biomarkers soluble fms-like tyrosine kinase 1, placental growth factor, and soluble endoglin. In this observational study, we included women from the South African Preeclampsia Obstetric Adverse Events biobank. Plasma samples taken at diagnosis (preeclampsia cases) or admission for delivery (normotensive controls) were analyzed for concentrations of neurofilament light, tau, glial fibrillary acidic protein, placental growth factor, soluble fms-like tyrosine kinase 1, and soluble endoglin. The cerebrospinal fluid concentrations of inflammatory markers and albumin were analyzed in a subgroup of 15 women. Analyses were adjusted for gestational age, time from seizures and delivery to sampling, maternal age, and parity. Compared with 28 women with normotensive pregnancies, 146 women with preeclampsia demonstrated 2.18-fold higher plasma concentrations of neurofilament light (95% confidence interval, 1.64-2.88), 2.17-fold higher tau (95% confidence interval, 1.49-3.16), and 2.77-fold higher glial fibrillary acidic protein (95% confidence interval, 2.06-3.72). Overall, 72 women with neurologic complications (eclampsia, cortical blindness, and stroke) demonstrated increased plasma concentrations of tau (2.99-fold higher; 95% confidence interval, 1.92-4.65) and glial fibrillary acidic protein (3.22-fold higher; 95% confidence interval, 2.06-5.02) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications (n=31). Moreover, angiogenic markers were higher, but to a lesser extent. Women with hemolysis, elevated liver enzymes, and low platelet count (n=20) demonstrated increased plasma concentrations of neurofilament light (1.64-fold higher; 95% confidence interval, 1.06-2.55), tau (4.44-fold higher; 95% confidence interval, 1.85-10.66), and glial fibrillary acidic protein (1.82-fold higher; 95% confidence interval, 1.32-2.50) compared with women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications. There was no difference shown in the angiogenic biomarkers. There was no difference between 23 women with preeclampsia complicated by pulmonary edema and women with preeclampsia without pulmonary edema; hemolysis, elevated liver enzymes, and low platelet count; or neurologic complications for any of the biomarkers. Plasma concentrations of tau and glial fibrillary acidic protein were increased in women with several neurologic complications compared with women with eclampsia only. Plasma neurofilament light, glial fibrillary acidic, and tau were candidate biomarkers for the diagnosis and possibly prediction of cerebral complications of preeclampsia.

Role of tau deposition in early cognitive decline in Down syndrome.

IntroductionDrawing on the amyloid/tau/neurodegeneration (AT[N]) model, the study examined whether the tau positron emission tomography (PET) biomarker [18F]AV‐1451 was associated with episodic memory problems beyond what was predicted by the amyloid beta (Aβ) PET in Down syndrome (DS).MethodsData from 123 non‐demented adults with DS (M = 47 years, standard deviation = 6.34) were analyzed. The Cued Recall Test assessed episodic memory. Tau PET standardized update value ratio (SUVR) was assessed across Braak regions as continuous and binary (high tau [TH] vs. low tau [TL]) variable. Global PET Aβ SUVR was assessed as binary variable (Aβ– vs. Aβ+).ResultsIn models adjusting for controls, tau SUVR was negatively associated with episodic memory performance in the Aβ+ but not Aβ– group. The Aβ+/TH group evidenced significantly worse episodic memory than the Aβ+/TL group.DiscussionSimilar to late‐onset and autosomal dominant Alzheimer's disease (AD), high tau was an indicator of early prodromal AD in DS.

Discordant low amyloid‐β PET and high neocortical tau PET retention

AbstractBackgroundExtracellular amyloid‐β (Aβ) plaques and intracellular tau neurofibrillary tangles characterize Alzheimer’s disease (AD). Combined use of Aβ and tau PET biomarkers demonstrates that high neocortical tau is rarely observed in the absence of high Aβ. We describe the prevalence of participants with high neocortical tau PET retention (visually and quantitatively) with a correspondingly low Aβ PET result and characterize these participants.MethodAIBL participants who had both an Aβ and tau PET scan were included. Centiloid &lt;25 defined a low (negative) Aβ result. Tau PET SUVR (standardized uptake value ratio) was estimated in three composite regions of interest (ROI): mesial temporal (Me), temporoparietal (Te) and rest of neocortex (R). The 99%ile of the Aβ‐ve cognitively unimpaired participants determined the threshold for each ROI.ResultFour hundred and sixty‐six participants were included. Of all Aβ‐ participants (n=287), 12 were above the threshold in Te and R ROIs. Four participants (1.4% of all Aβ‐) had high neocortical tau tracer retention, quantitatively and visually, in a pattern consistent with AD (Braak stage V‐VI) (Figure 1). Despite the low Aβ PET, one participant had high plasma Aβ, while another had low CSF Aβ1‐42, high CSF pTau and tTau and an 18F‐FDG PET pattern consistent with AD. High plasma pTau‐217‐plus was observed for three of these four participants (result unavailable for one participant).ConclusionWe have identified four participants with low Aβ PET and high neocortical tau PET retention. The alternative biomarker results in these cases are suggestive of a diagnosis of AD, despite the low Aβ PET result. We propose that in these instances, the Aβ PET ligand may not be detecting Aβ, maybe due to a different conformation of the aggregates. While infrequent, this finding has been reported using 11C‐PiB. Overall, the prevalence of this discordance was &lt;2% in the sampled cohort, suggesting it is an uncommon occurrence. However, this study is limited by the lack of alternative Aβ biomarker results. Studies in larger cohorts are necessary to validate these findings, while genetic testing and postmortem correlation will enhance our understanding of the potential explanation for this finding.

Correspondence between cortical tau and atrophy in aged non‐demented adults with Down syndrome

AbstractBackgroundIndividuals with Down syndrome (DS) have a higher likelihood of developing early‐onset Alzheimer’s disease which has been associated with abnormal tau proteins and atrophy in the brain [1]. Prior research has shown a spatial relationship between tau and atrophy in neurotypicals with dementia [2]. Although tau and atrophy certainly contribute independently to dementia, the synergistic relationship in a non‐demented population with DS is not well understood. This study aims to identify cortical regions with high tau and atrophy in aged, non‐demented participants with DS.MethodAnalysis included 28 non‐demented participants (49.8 +/‐ 6.4 years; 17 males) with DS from the Alzheimer’s Disease in Down Syndrome (ADDS) study. Tau PET (18F‐AV1451) and MRI scans were acquired within the same timeframe (1.8 months +/‐1.5). Gray‐matter cortical ribbons were extracted from T1 MRI segmentations with Freesurfer (RRID: SCR_001847). The cortical ribbons were used to mask the coregistered PET scan data and converted to standard uptake value ratio (SUVR) units using the cerebellar cortex reference region. The tau and gray‐matter images were converted to z‐score images using the group mean and standard deviation. We defined high tau as voxels with z‐scores &gt;=2.0 and high atrophy as voxels with gray matter z‐scores &lt;= ‐2.0. The z‐score images were spatially normalized into MNI space with ANTs (RRID: SCR_004757) and a voxel‐based correspondence analysis was performed. Voxels surviving the high tau and high atrophy thresholds were evaluated to determine anatomical localization using the Desikan/Killiany atlas [3].ResultWe found high correspondence between tau and atrophy in the following regions (figure 1): entorhinal cortex, insula, fusiform, pars orbitalis, paracentral, precentral, superior temporal, medial orbitofrontal, lateral orbitofrontal, temporal pole, rostral middle frontal, superior frontal, pars triangularis, lingual, and the amygdala.ConclusionOur study demonstrated a correspondence between atrophy and tau in deep cortical structures, as well as frontotemporal regions in aged, non‐demented adults with DS. Many of these regions are consistent with findings in neurotypical populations and shown in our prior work to be regions associated with increased amyloid (18F‐AV‐45) as a function of disease severity in DS [4].

Concordance between [18F] GTP1 PET and fluid tau biomarkers in the Tauriel phase II Study

AbstractBackgroundThe Tauriel Study (NCT03289143) was a Phase 2 randomized, double‐blind, placebo‐controlled, parallel‐group clinical trial that assessed the safety and efficacy of semorinemab in patients with prodromal‐to‐mild Alzheimer’s disease. We examined the concordance of fluid tau biomarkers with Tau PET for the identification of patients with high tau burden at enrollment.MethodTau at baseline was assessed by [18F]GTP1 PET imaging and assays for multiple CSF and plasma tau indices, including pTau181 and mid‐domain tTau (Elecsys assays), tau peptides 2‐24 and 93‐105 (anti‐peptide capture mass‐spec assay), and phosphotau/unphosphorylated tau217 ratio (mass‐spec assay). The association between imaging and fluid tau levels were assessed with Spearman correlations. AUC, sensitivity and specificity are reported in the context of predicting tau burden with a single fluid biomarker, where ‘high tau’ is defined as GTP1 temporal meta‐ROI SUVR ≥1.3. Cutoffs were derived using Youden’s index.Result354 participants had both PET and plasma samples; 68 subjects had paired PET and CSF data. GTP1 significantly correlated with each fluid marker, highly with pT217 (r = 0.78), moderately with other CSF assays (r = 0.44 ‐ 0.56) and weakly with plasma tTau (r = 0.19) (Table 1). Discrimination was highest for CSF pTau217 ( AUC = 0.909). Specificity was 0.862 and 0.84 for pTau181 and pTau217 respectively, while sensitivity was 0.564 and 0.868 (Figure 1). Empirically defined cutoffs were 36.88 pg/mL for pTau181 and 0.052 for pT217.ConclusionBaseline Tau PET is shown to be prognostic for future cognitive decline and thus could be included in enrollment criteria for future clinical studies in AD. Alternative approaches include the use of fluid biomarkers for tau. While pTau181 and n‐terminal tau indices can only be optimized for either high specificity or high sensitivity, both can be concurrently optimized using pTau217, thus positioning it as a potential alternative marker for Tau pathology. Additional CSF and plasma tau indices are pending similar analyses.

Serum immunoglobulins and biomarkers of dementia: A population‐based study

AbstractBackgroundDementia is a complex syndrome with multiple interacting pathways leading to brain damage and ultimately the clinical manifestation. In recent years, studies have identified the immune response as a novel contributing process to the aetiology of dementia, but it remains unclear how this links to established biomarkers of dementia, for instance those measured in plasma or on neuroimaging. We studied the association of serum immunoglobulins, markers of the adaptive immune response, with biomarkers of dementia.MethodBetween 1997 and 2009, serum immunoglobulins (IgA, IgG and IgM) were measured in 8,768 participants of the population‐based Rotterdam Study (median age 62.2 years, 57.0% women). Plasma biomarkers of dementia (total tau, neurofilament light chain (NfL), amyloid‐β40 (Aβ‐40), amyloid‐β42 (Aβ‐42)) were measured in a random sample of 3,455 participants. Neuroimaging was performed for 3,139 participants to quantify brain volume, white matter structural integrity and markers of cerebral small vessel disease. We used linear regression models to determine cross‐sectional associations of IgA, IgG, IgM and biomarkers of dementia in plasma and on neuroimaging, while adjusting for age, sex, cohort, education, cardiovascular risk factors and stratifying for APOE‐ε4 carriership. Plasma biomarkers were log2 transformed and neuroimaging markers were standardized to facilitate comparison.ResultHigher levels of IgA corresponded to higher log2 plasma levels of NfL (β=0.019, p=0.031), and a lower or higher tau and Aβ burden, depending on carriership of the APOE‐ε4 allele. Higher IgM was consistent with lower levels of all plasma biomarkers, particularly among no carriers of the APOE‐ε4 allele. No significant associations were found between IgG levels and plasma biomarkers, although associations were moderately driven by APOE‐ε4 allele carriership. Subsequently, higher serum immunoglobulin levels and in particular IgA, generally amounted to more brain atrophy (total brain volume (β=‐0.013, p=0.032), gray matter volume (β=‐0.026, p=0.009), decreased white matter integrity and increase of cerebral small vessel disease markers (white matter hyperintensities (β=0.041, p=0.008)).ConclusionThe associations between serum immunoglobulins and biomarkers of dementia in plasma partly depend on APOE‐ε4 carriership. Higher serum immunoglobulins generally correspond to more brain atrophy, diminished white matter integrity and more cerebral small vessel disease.

Inflammatory, degeneration and neuritic growth biomarkers predict cognitive decline and dementia in Parkinson’s disease

AbstractBackgroundCognitive decline is common in Parkinson’s disease (PD) and has been associated with cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers such as Aβ1‐42, total tau and phosphorylated tau in addition to inflammatory proteins. VGF, a nerve growth factor, is a promising marker that has recently been implicated in cognitive decline in dementia with Lewy bodies and could potentially play a role in PD. The aim of this study is to assess a wide panel of CSF biomarkers reflecting different neuropathological processes to determine which best predict cognitive decline and conversion to dementia in PD.MethodWe included 174 PD patients from the Swedish BioFINDER study, who were followed for up to 10 years. At baseline, 47 CSF biomarkers were measured, including Aβ1‐42, Aβ42/40, total tau, phosphorylated tau, α‐synuclein as well as markers of neurodegeneration, vascular, inflammatory, synaptic and lysosomal dysfunction. Cox regression analyses were applied to identify biomarkers predicting dementia, adjusting for age, sex, education and disease duration. We then used linear mixed effects models to assess whether the significant biomarkers predicted longitudinal cognitive decline in MMSE, memory and semantic fluency, controlling for age, sex, education and disease duration.ResultOf the PD patients, 29% converted to dementia during follow‐up (4.9 ± 2.2 years). At baseline, converters were older (p&lt;0.001) and had worse memory and semantic fluency tests (&lt;0.008) compared with non‐converters. Levels of CSF Aβ1‐42, Aβ42/40, tau, Neurofilament light, Serum Amyloid A (SAA), Interleukin 7, Interferon‐gamma‐inducible Protein‐10 (IP‐10) and VGF (p&lt;0.037) significantly predicted conversion to dementia in univariate models. When these biomarkers were included in a multivariable regression model, only higher tau (p&lt;0.001), lower VFG (p&lt;0.001) and higher SAA (p=0.028) independently predicted dementia. Further, CSF tau predicted cognitive decline in MMSE and semantic fluency (p&lt;0.005), lower VGF predicted decline in memory (0.012) and SAA predicted decline in MMSE (p=0.011).ConclusionThese findings suggest that CSF tau, SAA and VGF are useful markers to predict conversion to dementia and cognitive decline in PD. VGF is emerging as an additional prognostic biomarker for cognitive decline in PD.

Tau‐PET is associated with knowledge of COVID‐19, COVID‐19‐related distress, and change in sleep quality during the pandemic

BackgroundWhile the global COVID‐19 pandemic has hindered many human research operations, it has allowed for the investigation of novel scientific questions. Particularly, the effects of the pandemic and its resulting social isolation on elderly individuals and their association with Alzheimer’s disease biomarkers remains a broad and open question. Here, we sought to investigate whether knowledge of COVID‐19, pandemic‐related distress, and changes in sleep quality were associated with in vivo tau deposition in an AD‐enriched cohort.MethodsCOVID‐19 telephone assessments were conducted in N=292 individuals (29 young/174 CN/52 MCI/19 AD/18 other) of the TRIAD cohort in April‐July 2020. Assessment consisted of clinical and neuropsychiatric, instruments, including scales assessing the individual’s experience of the pandemic. Structural MRI and [18F]MK6240 tau‐PET were acquired before the pandemic. [18F]MK6240 standardized uptake value ratio (SUVR) were calculated 90‐110 minutes post‐injection using cerebellar grey matter as the reference region. Voxel‐based regression analyses were conducted to examine the associations between baseline [18F]MK6240 SUVR and knowledge of COVID‐19, distress related to COVID‐19, and change in sleep quality since the pandemic.ResultsHigher tau‐PET SUVR was associated with less knowledge of COVID‐19 in N=210 individuals in the cuneus, cingulate and superior temporal regions. Tau‐PET was similarly associated with lower levels of COVID‐19‐related distress in the isthmus and rostral anterior cingulate (N=201 individuals). Furthermore, tau‐PET tracer uptake was significantly associated with increases in sleep quality as assessed by rate of change in Pittsburgh Sleep Quality Index before and during the pandemic (N=176 individuals). All results survived correction for multiple comparisons using random field theory with a cluster threshold of p < 0.001.ConclusionOur results suggest that those with increased tau deposition may have a weaker understanding of symptoms and prevention of COVID‐19 and lower levels of distress related to the pandemic than individuals with less brain tau. Individuals with higher tau may also experience improved sleep quality during the pandemic. While these observations appear to be favourable effects of tau, the first may suggest that public health information about COVID‐19 is less accessible to the aging population. The interactions and mediation of these effects remain to be properly elucidated.

Locus coeruleus integrity as a proxy of initial tau burden: in vivo versus ex vivo observations

AbstractBackgroundAutopsy studies reported the locus coeruleus (LC) as one of the initial regions in the brain harboring hyperphosphorylated tau pathology. MR signal intensity in the LC has been proposed as a measure of LC integrity, but the contribution of tau pathology, commonly found in LC, to this signal intensity is not currently measurable in vivo. We related in‐vivo LC MR signal intensity to Alzheimer’s disease (AD) phenotype and PET measures and used ROSMAP autopsy data to guide interpretation of the MR LC measure as tau‐related or cellular integrity‐related.MethodOne‐hundred seventy‐two participants from the Harvard Aging Brain Study (HABS) underwent 3T LC‐MRI imaging, FTP and PiB‐PET imaging (median age: 75 years, 58% female, n=22 with CDR=0.5/1). In 160 individuals from ROSMAP, LC tangle density and neuronal density were quantified at autopsy (median age at death: 89 years, 67% female, 66 control, 53 mild cognitively impaired, 41 AD patients; Figure 1). Groups were compared using ANCOVA. LC measures were related to Mini‐Mental State Examination (MMSE) scores using Spearman correlations (age‐adjusted). In HABS, LC integrity was vertex‐wise regressed on tau‐PET. In ROSMAP, Spearman correlations related LC tangle or neuronal density to cortical tangle density or Braak staging.ResultLC measures correlated with measures of disease progression: in HABS, LC integrity was lower in impaired individuals compared to controls, and correlated positively with MMSE score. In ROSMAP, LC tangle density was higher in MCI/AD patients compared to controls; and correlated negatively with MMSE scores. No associations were found for LC neuronal density (Figure 2). Furthermore, lower LC integrity correlated with higher tau in medial‐lateral temporal regions in HABS, mirroring the consecutive Braak‐staging. Similarly, In ROSMAP, higher LC tangle density, but not LC neuronal density, correlated positively with cortical tangle burden and Braak staging (Figure 3).ConclusionThe comparable associations of MRI‐LC integrity or LC tangle density with disease progression and tau suggest that MRI‐measures of LC integrity may be a proxy for tau pathology, rather than neuronal density. Future verification using head‐to‐head comparison is warranted, but our results indicate that LC integrity holds promise as marker for detection of initial AD‐related processes.

Clinical value of CSF tau, p‐tau181, neurogranin and neurofilaments in familial frontotemporal lobar degeneration

AbstractBackgroundBlood neurofilament light chain (NfL) is a robust predictor of phenoconversion in familial frontotemporal lobar degeneration (fFTLD). The comparative value of CSF NfL and other CSF markers of degeneration in fFTLD remains unexplored.MethodFLTD‐causing mutation carriers were recruited through ALLFTD (n = 113, 56.6% female, mean age 48.1 ± 13 years; 29 C9orf72, 16 GRN, 34 MAPT, 34 mutation non‐carriers) and prospectively evaluated for 3 years. Baseline CSF was analyzed for NfL, phosphorylated neurofilament heavy chain (p‐NfH), tau, phosphorylated tau181 (p‐tau) and neurogranin using fit‐for‐purpose immunoassays. Mixed effect linear models, with random slopes, corrected for age, sex, genotype and total intracranial volume related CSF biomarkers to longitudinal clinical variables.ResultNfL (β = 0.64, p &lt; 0.001), p‐NfH (β = 0.68, p &lt; 0.001) and tau (β = 0.46, p &lt; 0.001) correlated with age. There were no differences in biomarker concentrations by phenotype or severity, except for higher NfL and p‐NfH in full phenotype, compared to prodromal disease and asymptomatic carriers. Low neurogranin (β = ‐0.39, p &lt; 0.001), low p‐tau (β = ‐0.33, p &lt; 0.001) and high NfL (β = 0.42, p &lt; 0.001) correlated with worse baseline disease severity measured by the CDR® Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module sum of boxes (CDR®+NACC‐FTLDsb), and with other measures of global cognition, instrumental and daily function, and frontal and temporal brain volumes. Regardless of genotype, the predicted annualized rate of CDR®+NACC‐FTLDsb score worsenings per higher baseline CSF biomarker Log pg/mL were tau: 3.0 ± 0.2, NfL: 2.8 ± 0.2 and p‐NfH: 2.8 ± 0.2. High tau, NfL and p‐NfH also predicted worsening in other measures of global cognition and instrumental and daily function. Neurogranin and p‐tau did not predict clinical decline.ConclusionCSF tau, p‐tau, neurogranin, NfL and p‐NfH reflect important aspects of disease severity in fFTLD. In contrast to Alzheimer’s disease, low p‐tau and neurogranin are inversely related to clinical severity, which suggests a distinctive pathophysiological process and has implications for therapeutic development. CSF NfL, p‐NfH and tau have strong prognostic value in fFTLD.

Tracing individual trajectory of longitudinal tau spreading in deep latent space

AbstractBackgroundAlzheimer’s disease (AD) usually appears in mid‐60s (Late‐Onset AD, LOAD), but also rarely appears in patients younger than 65 (Early‐Onset AD, EOAD), while showing distinct features. Tau shows high correlation with AD prognosis and can be detected through positron emission tomography (PET) scan. Tau data mapped into a low dimensional latent space will help detect longitudinal change pattern along AD spectrum. Furthermore, fitting tensors using individual line segments will enable us to track individual tau trajectory in the latent space.MethodWe recruited 74 healthy controls, 75 mild cognitive impairment patients, and 38 AD patients with two PET scans ([18F]Flortaucipir for tau and [18F]Florbetaben for Aβ) with two‐year follow‐up. We used standardized uptake value ratios (SUVRs) for tau PET data. All patients’ tau data went through autoencoder and principal component analysis, pretrained using baseline (BL) tau data. Using only amyloid positive AD patients’ BL – follow‐up (FU) line segments, we fit tensors and tracked individual trajectories in the latent space using a tensor tracing algorithm.ResultIn the 2‐dimensional latent space the points dispersed toward the upper‐ and right‐side as the disease deteriorated. Reconstructed SUVR maps showed tau accumulation pattern of EOAD through x‐axis, such as tau spreading in temporal, prefrontal, and parietal lobes. Reconstructed map of 1st quartile group in y‐axis showed tau spreading dominance in parietal lobe and 4th quartile group showed dominance in prefrontal, temporal lobe. Each patient’s trajectory, predicted based on the latent space, showed reconstructed map following individual tau accumulation pattern. In addition, EOAD tau spreading trajectory tend to precede LOAD tau spreading trajectory.ConclusionWe decomposed high dimensional tau accumulation pattern into 2 independent components through deep‐learning methods. X‐axis showed EOAD tau accumulation pattern and y‐axis was divided into LOAD tau accumulation pattern and non‐prefrontal dominant pattern. In addition, tensor fitting of the longitudinal vector field enables us to find individual tau spreading trajectories which can be used to predict future and past spreading. Even though this study was done using only one factor, tau, it has the potential to be expanded to other factors such as amyloid or neurodegeneration data.

Contribution of cerebrospinal fluid Alzheimer biomarkers to the diagnosis of Creutzfeldt‐Jakob disease

AbstractBackgroundThe definite diagnosis of Creutzfeldt‐Jakob disease (CJD) requires a neuropathological examination revealing the presence of the pathogenic prion protein. As a reliable in vivo diagnosis is required for clinical care, without pathological confirmation, diagnostic criteria for CJD have been proposed including neuroimaging, electrophysiology and 14.3.3 protein positivity in cerebrospinal fluid (CSF) but their accuracy remains suboptimal. Tau protein in cerebrospinal fluid was found to be extremely elevated in CJD and the phosphorylated‐Tau to Tau ratio (P‐Tau/Tau) was reported to be decreased for some CJD patients.MethodWe first aimed to evaluate the efficiency of the P‐Tau/Tau ratio to distinguish CJD from other neurodegenerative disorders in a cohort of patients with a rapidly progressive cognitive disorder and high CSF Tau level above 1000 pg/ml. Then, retrospectively gathering 49 CJD patients from 7 French University Hospital, the Alzheimer CSF biomarkers and the P‐Tau/Tau ratio sensitivity were compared to current CJD diagnosis criteria. A P‐Tau/Tau ratio value below 0.075 was considered as indicative of CJD.ResultThe diagnoses in the first cohort of 24 patients were: CJD (n = 11), Alzheimer disease (n = 11), Frontotemporal dementia (n = 1) and a Gayet‐Wernicke’s encephalopathy (GWE) (n = 1). Using the threshold of 0.075, the ratio P‐Tau/Tau correctly categorized all CJD patients and only one patient, with GWE, was wrongly classified (fig. 1). The area under the curve of the P‐Tau/Tau ratio was 95% (IC 95% 0.85‐1.0). In the 49 CJD series, the ratio was abnormal in 100% of the patients, while the clinical criteria were met in 81.6% and 91.7% for neuroimaging, 50% for helectroencephalogram and 55.1% for protein 14‐3‐3.ConclusionAlzheimer CSF biomarkers with Tau level and P‐Tau/Tau ratio may increase diagnosis accuracy for positive and differential diagnosis of CJD with a complementary value to current validated diagnosis criteria. They could be particularly helpful in clinical practice for patients with rapid cognitive decline and Tau &gt; 1000 pg/ml or in atypical cases with unmet diagnosis criteria.

Longitudinal associations between amyloid and tau‐PET: Impact for prevention trials

AbstractBackgroundIn Alzheimer’s disease, cognitive decline is associated with a rapid increase in tau pathology, making tau‐PET a potentially useful outcome in prevention trials. To identify individuals most at‐risk of tau accumulation, we investigated the longitudinal associations between amyloid and tau in clinically normal (CN) and impaired (MCI/AD) participants from the Harvard Aging Brain Study.MethodSerial Flortaucipir tau‐PET measures (2‐4 observations over a median 2.2years [0.8 to 6.0]) were obtained from 128CN and 11MCI/AD participants (Table 1). PiB (amyloid‐PET) data were expressed as Centiloid (CL) values. Flortaucipir data were expressed as PVC‐SUVr in inferior temporal neocortex scaled to subcortical white matter. We obtained tau slopes per subject from linear mixed‐effect models with random intercept and slopes. We tested in the entire sample, and in CN only, the association between Tau slope and baseline PiB and Tau‐PET. Linear, quadratic, and cubic relationships were tested. Age and sex were used as covariates. We computed power curves simulating therapeutic trials.ResultIn the entire sample (n=139), both baseline Tau (R2=0.34, Fig. 1 red‐line) and PiB (R2=0.30, Fig. 2 red‐line) were linearly associated with subsequent tau slope. In CN (n=128), these associations were lower than in MCI/AD, but significant (Tau: R2=0.16, PiB: R2=0.15, p≤0.00001). Importantly, a cubic fit best matched the PiB data (Fig. 2 blue‐line): A positive association between baseline PiB and Tau changes was only observed between PiB CL=‐2 and CL=66, with a maximal association at CL=32. In CN, the greatest tau changes were observed at CL=66. There was evidence of slowing in tau accumulation rate in the small number of CN with higher PiB CL. As a result, trials simulations demonstrated that increasing the Centiloid threshold to enroll CN participants did not increase power (Fig. 3 blue‐lines); in contrast, power was increased when excluding CN with CL&gt;66 (Fig. 3 red‐line) or when enrolling CN with high baseline tau (Fig. 4 red‐lines). Enrolling MCI patients in therapeutic trials had a similar effect than enrolling high‐amyloid CN participants with baseline Tau SUVr&gt;1.30 (Fig. 4 blue‐line).ConclusionA combination of amyloid and tau thresholds proved more effective to increase the power of Tau‐PET outcomes in prevention trials than using only amyloid.