Plasma Tau Levels Research Articles

Sleep-wake body temperature regulates tau secretion in mice and correlates with CSF and plasma tau in humans.

The sleep-wake cycle regulates interstitial fluid and cerebrospinal fluid (CSF) tau levels in both mouse and human by mechanisms that remain unestablished. Here, we reveal a novel pathway by which wakefulness increases extracellular tau levels in mouse and humans. In mice, higher body temperature (BT) associated with wakefulness and sleep deprivation increased CSF tau. In vitro, wakefulness temperatures upregulated tau secretion via a temperature-dependent increase in activity and expression of unconventional protein secretion pathway-1 components, namely caspase-3-mediated C-terminal cleavage of tau (TauC3), and membrane expression of PIP2 and syndecan-3. In humans, the increase in both CSF and plasma tau levels observed post-wakefulness correlated with BT increase during wakefulness. Our findings suggest sleep-wake variation in BT may contribute to regulating extracellular tau levels, highlighting the importance of thermoregulation in pathways linking sleep disturbance to neurodegeneration, and the potential for thermal intervention to prevent or delay tau-mediated neurodegeneration.

Associations of Alzheimer’s disease Plasma Biomarkers' and slow wave sleep within Black and White Cognitively Normal Older‐Adults

AbstractBackgroundWe studied whether plasma levels of Aβ40, Aβ42, Aβ42/Aβ40, Tau, tau/Aβ42 and NfL are associated with slow wave sleep, and if this association varied within non‐Hispanic Whites and Blacks/African‐Americans.MethodThis was a cross‐sectional analysis of baseline data from 171 cognitively normal older‐adults, volunteering in active NYU studies on memory and sleep. Plasma Aβ40, Aβ42, Tau and NfL were measured using single molecule array (SIMOA). Non‐rapid eye movement sleep (NREM) slow wave sleep (SWS) duration was assessed from 2 nights of in‐lab NPSGs. Associations of NREM SWS duration and plasma AD biomarker levels were examined by applying adjusted generalized linear models and Pearson correlation analysis after data normalization. Analyses were adjusted for age, sex, BMI, race, and education.ResultOf the 171 subjects (128 Whites and 43 Blacks), 112 (65.5%) were females, and mean (SD) age was 68.6 (6.6) years, BMI was 27.6 (6.1) kg/m**2, and education was 16.9 (2.1). There were no racial differences in age, sex, and BMI, SWS and AHI4%. In comparison to whites, blacks had significantly lower years of education (14.2 vs. 17.2, p <.01). Black/African‐American subjects had significantly lower plasma Aβ40 (248.3 vs. 262.5 pg/ml) and NfL levels (11.4 vs. 15.2 pg/ml). p<.05 for both. There were no significant racial differences in levels of plasma Aβ42, Aβ42/Aβ40, Tau, Tau/Aβ40 and Tau/Aβ42. NREM SWS duration was not associated with plasma Aβ42, Aβ40 or tau in the overall sample. However, in Whites, SWS negatively correlated with plasma Aβ42 (r = ‐0.28, p< = 0.05). In Black/African‐Americans, SWS positively correlated with plasma Aβ42 (r = 0.48, p = 0.05). In Whites, SWS negatively correlated with plasma Aβ40 (r = ‐0.087, p = 0.72), though not significant. In Black/African‐Americans, SWS positively correlated with plasma Aβ40 levels (r = 0.32, p = 0.04). In Whites, SWS negatively correlated with plasma Tau (r = ‐0.153, p = 0.27), though not significant. In Black/African‐Americans, SWS positively correlated with plasma Tau levels (r = 0.52, p = 0.04). NREM SWS was not associated with plasma tau/Aβ42, plasma tau/Aβ40 or plasma NfL in the overall sample and across racial‐subgroups.ConclusionRace‐specific relationships between NREM SWS and plasma Aβ42, Aβ40 & Tau might propose differences in SDOH mechanisms that may affect sleep and AD‐risk in older‐adults.

Plasma-derived biomarkers of Alzheimer's disease and neuropsychiatric symptoms: A community-based study.

We examined associations between plasma-derived biomarkers of Alzheimer's disease (AD) and neuropsychiatric symptoms (NPS) in community-dwelling older adults. Cross-sectional study involving 1005 persons ≥50 years of age (mean 74 years, 564 male, 118 cognitively impaired), who completed plasma-derived biomarker (amyloid beta 42 [Aβ42]/Aβ40, phosphorylated tau 181 [p-tau181], p-tau217, total tau [t-tau], neurofilament light [NfL]), and NPS assessment. P-tau181 (odds ratio [OR] 2.06, 95% confidence interval [CI] 1.41-3.00, p<0.001), p-tau217 (OR 1.70, 95% CI 1.10-2.61, p=0.016), and t-tau (OR 1.44, 95% CI 1.08-1.92, p=0.012) were associated with appetite change. We also found that p-tau181 and p-tau217 were associated with increased symptoms of agitation (OR 1.93, 95% CI 1.20-3.11, p=0.007 and OR 2.04, 95% CI 1.21-3.42, p=0.007, respectively), and disinhibition (OR 2.39, 95% CI 1.45-3.93, p=0.001 and OR 2.30, 95% CI 1.33-3.98, p=0.003, respectively). Aβ42/Aβ40 and NfL were not associated with NPS. Higher plasma-derived p-tau181 and p-tau217 levels are associated with increased symptoms of appetite change, agitation, and disinhibition. These findings may support the validity of plasma tau biomarkers for predicting behavioral symptoms that often accompany cognitive impairment. We studied 1005 community-dwelling persons aged ≥ 50 yearsHigher plasma tau levels are associated with increased neuropsychiatric symptomsAβ42/Aβ40 and NfL are not associated with neuropsychiatric symptomsClinicians should treat neuropsychiatric symptoms in persons with high plasma-derived tau.

Associations of Blood and Cerebrospinal Fluid Aβ and tau Levels with Renal Function.

Amyloid β (Aβ) and tau play pivotal roles in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that brain-derived Aβ and tau can be cleared through transport into the periphery, and the kidneys may be vital organs involved in the clearance of Aβ and tau. However, the effects of deficiency in the clearance of Aβ and tau by the kidneys on brain AD-type pathologies in humans remain largely unknown. In this study, we first recruited 41 patients with chronic kidney disease (CKD) and 40 age- and sex-matched controls with normal renal function to analyze the associations of the estimated glomerular filtration rate (eGFR) with plasma Aβ and tau levels. To analyze the associations of eGFR with cerebrospinal fluid (CSF) AD biomarkers, we recruited 42 cognitively normal CKD patients and 150 cognitively normal controls with CSF samples. Compared with controls with normal renal function, CKD patients had higher plasma levels of Aβ40, Aβ42 and total tau (T-tau), lower CSF levels of Aβ40 and Aβ42 and higher levels of CSF T-tau/Aβ42 and phosphorylated tau (P-tau)/Aβ42. Plasma Aβ40, Aβ42, and T-tau levels were negatively correlated with eGFR. In addition, eGFR was negatively correlated with CSF levels of T-tau, T-tau/Aβ42, and P-tau/Aβ42 but positively correlated with Mini-Mental State Examination (MMSE) scores. Thus, this study showed that the decline in renal function was correlated with abnormal AD biomarkers and cognitive decline, which provides human evidence that renal function may be involved in the pathogenesis of AD.

Effectiveness and Safety of Bu Shen Kai Qiao Fang in the Treatment of Alzheimer's Disease: Study Protocol for a Multicenter, Prospective, Real-World Clinical Trial.

Alzheimer's disease (AD) is a common degenerative disease of the nervous system with serious impact on quality of life of patients and their families. With an aging population, AD has become a major public health problem in China and worldwide. However, the physiological and pathological mechanisms of AD have not been fully elucidated, and there is a lack of effective prevention and clinical treatment methods. Many studies have found that traditional Chinese medicine (TCM) has a good therapeutic effect on cognitive function in AD patients. Bu Shen Kai Qiao Fang (BSKQF) is one such Chinese herbal preparation used in the treatment of AD. We designed a protocol for a real-world clinical study of BSKQF combined with Donepezil hydrochloride (DH) to evaluate the efficacy and safety of this approach in the treatment of AD patients. This is a protocol for a real-world, multicenter, prospective, observational cohort study. The study will recruit 860 AD patients from four hospitals across China. Equal numbers of patients will be treated with BSKQF and DH or with DH only. The criteria for grouping are based primarily on patient preference. Outcome measures include scores on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment Scale (MOCA) and will be recorded at baseline, and at one, two and three months after enrollment. The plasma Aβ42 and plasma Tau levels of participating patients will also be measured by ELISA at baseline and after 3 months of treatment. Safety metrics and adverse events (AEs) of participating patients will be monitored and recorded. This study will evaluate the clinical efficacy and safety of BSKQF in the treatment of AD. The results will provide reliable evidence for the clinical application of BSKQF in the treatment of AD. Trial registration: Chinese Clinical Trial Registry, NO. ChiCTR2000039670, Registered 5 November 2020 https://www.chictr.org.cn/showprojEN.html?proj=63800.

0887 Divergent Slow wave sleep and Alzheimer's disease Plasma Biomarkers’ Associations in Black and White Cognitive Normal Older-Adults

Abstract Introduction We determined whether slow wave sleep is associated with plasma levels of Aβ40, Aβ42, Aβ42/Aβ40, Tau, tau/Aβ42 and NfL and whether this relationship differed between Blacks/African-Americans and non-Hispanic Whites. Methods This was a cross-sectional analysis of baseline data from 171 community-dwelling cognitively normal older-adults, participating in ongoing NYU studies on memory, sleep and aging. Non-rapid eye movement sleep (NREM) slow wave sleep (SWS) duration was calculated from 2 nights of in-lab NPSGs. Plasma Aβ40, Aβ42, Tau and NfL were determined using single molecule array (SIMOA). Associations of NREM SWS duration and plasma AD biomarker levels were assessed using adjusted generalized linear models and Pearson correlation analysis after data normalization. Analyses were adjusted for age, sex, BMI, race, and education. Results Of the 171 subjects (128 non-Hispanic Whites and 43 Blacks/African-Americans), 112 (65.5%) were females, and mean (SD) age was 68.6 (6.6) years, BMI was 27.6 (6.1) kg/m**2, and education was 16.9 (2.1). There were no racial differences in age, sex, BMI, NREM SWS and AHI4%. Compared to non-Hispanic Whites, Blacks/African-Americans had significantly lower years of education (14.2 vs. 17.2, p &amp;lt;.01), plasma Aβ40 (248.3 vs. 262.5 pg/ml) and NfL levels (11.4 vs. 15.2 pg/ml) p&amp;lt;.05 for both. There were no significant racial differences in levels of plasma Aβ42, Aβ42/Aβ40, Tau, Tau/Aβ40 and Tau/Aβ42 (p&amp;gt;.05 for all). NREM SWS duration was not associated with plasma Aβ42, Aβ40 or tau in the overall sample (p&amp;gt;.05 for all). However, in non-Hispanic Whites, NREM SWS negatively correlated with plasma Aβ42 (r=-0.28, p&amp;lt;=0.05), plasma Aβ40 (r=-0.087, p=0.72), though not significant, and plasma Tau (r=-0.153, p=0.27), though not significant. In Black/African-Americans, NREM SWS positively correlated with plasma Aβ42 (r=0.48, p=0.05), plasma Aβ40 levels (r=0.32, p=0.04), and plasma Tau levels (r=0.52, p=0.04). NREM SWS was not associated with plasma tau/Aβ42, plasma tau/Aβ40 or plasma NfL in the overall sample and across racial subgroups. Conclusion Race-specific divergent associations between NREM SWS and plasma Aβ42, Aβ40 &amp; Tau may suggest differences in SDOH factors and mechanisms that could influence sleep and AD-risk in older-adults. Support (if any) AASMBTS#231-BS-20, NIAK23AG068534A, AARG-D- 21-848397, BFFA2022033S

Modulating heart rate oscillation affects plasma amyloid beta and tau levels in younger and older adults

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αβ40, Αβ42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc−). They practiced 20–40 min daily. Four weeks of practicing the Osc+ and Osc− conditions produced large effect size differences in change in plasma Aβ40 and Aβ42 levels. The Osc+ condition decreased plasma Αβ while the Osc− condition increased Αβ. Decreases in Αβ were associated with decreases in gene transcription indicators of β-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc− interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.

Abstract TP219: Rns60 Brain Protection In Mouse Ischemic Stroke Mitigates Plasma Tau And Cortical Microvascular Perfusion

Introduction: RNS60 is 0.9% saline solution hypothesized to contain oxygen nanobubbles. Recently, we showed that 13 days of RNS60 treatment after transient middle cerebral artery occlusion (tMCAo) preserves recovery of memory and reduces brain infarction, neuronal cell death, microglial activation, amyloid pathology, and white matter damage. Previously, we also demonstrated the relationship between white matter demyelination and circulating tau in tMCAo. Here we report that RNS60 decreases plasma tau and increases cortical microvascular perfusion (MVP). Methods: Male C57BL/6J mice, 3-4 months old, were randomly divided into sham surgery or unilateral 60-minute tMCAo. Each group was subdivided into three treatment arms, receiving daily intraperitoneal administration of 0.2 mL of RNS60, pressurized normal saline (PNS60), or normal saline (NS) starting 2 hours after surgery for 13 days. Treatment assignments were blinded throughout the study. To assess circulating tau, plasma was collected before surgery and on day 14 post-surgery (after MVP measurements). Animals were then euthanized to assess infarct volume using TTC staining. Results: RNS60 treatment significantly (p&lt;0.05) reduced brain infarction by 90% compared to controls, reduced plasma tau by 74% of controls, and significantly (p&lt;0.05) increased MVP in motor cortex by 38% and by 39% in the parietal cortex. Conclusion: RNS60-treated mice exhibit significant brain protection after ischemic stroke and display decreased plasma tau levels and a significant increase in microvascular perfusion. Ongoing studies are investigating whether increased MVP is due to activation of angiogenesis. These data further support the evaluation of RNS60 in clinical stroke trials.

Phone-Based Memory Test Predicts In-Clinic Memory, MCI Diagnosis, and Alzheimer’s Neuroimaging &amp; Plasma Biomarkers

Background: Early detection of dementia has become important for interventions that are developed to slow disease progression. Due to technological advancements, healthcare is trending toward using more telehealth screenings due to the convenience it provides patients. In our research, we evaluate the accuracy of a phone-based memory screen at diagnosing mild cognitive impairment.&#x0D; Methods: 181 participants from the Indiana Alzheimer’s Disease Research Center (IADRC)were screened using the Memory and Aging Telephone Screen (MATS) and diagnosed as cognitively normal (CN), subjective cognitive decline (SCD), or mild cognitive impairment (MCI). 177 underwent Rey Auditory Verbal Learning Testing (RAVLT); 103 received Aβ PET scans([18F]florbetapir or [18F]florbetaben); 91 had plasma tau levels measured; and 140 received MRI scans (Freesurfer v6). ANCOVAs were used to evaluate differences between diagnostic groups covarying for age, sex, and education. ROC analysis and logistic regressions were used to predict MCI and Aβ positivity. Partial correlations covarying for sex and age (and education for RAVLT) were conducted to evaluate relationships between MATS scores with RAVLT, brain atrophy, pTau level, and amyloid deposition. &#x0D; Results: MCI patients showed significantly lower MATS scores for immediate (p&lt;0.001) and delayed recall (p&lt;0.001) compared to controls. Scores on the MATS correlated well with clinical based testing (MATS learning vs RAVLT learning: r2= 0.318, p&lt;0.001). MATS scores showed strong associations for Alzheimer biomarkers: amyloid and tau deposition, hippocampus atrophy, and temporal atrophy. The accuracy of MATS to predict MCI was found to be about 75% with cutoffs of ≤16 for learning and ≤4 for delayed recall.&#x0D; Conclusion and Potential Impact: The findings support that the phone memory screen can be used to detect dementia early in disease progression. By establishing cutoffs for this screening tool, physicians can easily and quickly detect signs of early Alzheimer’s disease, thus allowing for early intervention to slow disease progression.

Traumatic encephalopathy syndrome: application of new criteria to a cohort exposed to repetitive head impacts

ObjectiveTo examine the characteristics of those who fulfil the recent National Institute of Neurological Disease and Stroke (NINDS) Consensus Diagnostic Criteria for Traumatic Encephalopathy Syndrome (TES) and test whether they...

The Correlation of Tau Levels with Blood Monocyte Count in Patients with Alzheimer's Disease.

Recent studies have shown that monocytes can phagocytize the tau protein, which may ameliorate tau-type pathology in Alzheimer's disease (AD). However, there are few clinical studies on the relationship between monocytes and tau-type pathology in AD patients. We aimed to explore changes in peripheral monocytes and their association with tau protein in AD patients. A total of 127 clinically diagnosed AD patients and 100 age- and sex-matched cognitively normal controls were recruited for analysis of the correlation of plasma tau levels with the blood monocyte count. Cerebrospinal fluid (CSF) samples from 46 AD patients and 88 controls were further collected to analyze the correlation of CSF tau and amyloid-β (Aβ) levels with the blood monocyte count. 105 clinically diagnosed mild cognitive impairment (MCI) patients and 149 age- and sex-matched cognitively normal controls were recruited from another cohort for verification. Compared to normal controls, AD patients showed a significant reduction in the blood monocyte count. In addition, the monocyte count of AD patients was negatively correlated with CSF t-tau and p-tau levels but not with plasma tau levels. In normal people, monocyte count lack correlation with tau levels both in plasma and CSF. Monocyte count were not correlated with CSF Aβ levels in either group but were negatively correlated with CSF tau/Aβ42 levels in the AD group. We had further verified the correlations of monocyte count with CSF tau levels in another cohort. This study suggests that monocytes may play an important role in the clearance of tau protein in the brain.

Association of Plasma Tau With Mortality and Long-term Neurocognitive Impairment in Survivors of Pediatric Cerebral Malaria and Severe Malarial Anemia

Cerebral malaria (CM) and severe malarial anemia (SMA) are associated with persistent neurocognitive impairment (NCI) among children in Africa. Identifying blood biomarkers of acute brain injury that are associated with future NCI could allow early interventions to prevent or reduce NCI in survivors of severe malaria. To investigate whether acutely elevated tau levels are associated with future NCI in children after CM or SMA. This prospective cohort study was conducted at Mulago National Referral Hospital in Kampala, Uganda, from March 2008 to October 2015. Children aged 1.5 to 12 years with CM (n = 182) or SMA (n = 162) as well as community children (CC; n = 123) were enrolled in the study. Data analysis was conducted from January 2020 to May 2021. CM or SMA. Enrollment plasma tau levels were measured using single-molecule array detection technology. Overall cognition (primary) and attention and memory (secondary) z scores were measured at 1 week and 6, 12, and 24 months after discharge using tools validated in Ugandan children younger than 5 years or 5 years and older. A total of 467 children were enrolled. In the CM group, 75 (41%) were girls, and the mean (SD) age was 4.02 (1.92) years. In the SMA group, 59 (36%) were girls, and the mean (SD) age was 3.45 (1.60) years. In the CC group, 65 (53%) were girls, and the mean (SD) age was 3.94 (1.92) years. Elevated plasma tau levels (>95th percentile in CC group; >6.43 pg/mL) were observed in 100 children (55%) with CM and 69 children (43%) with SMA (P < .001). In children with CM who were younger than 5 years, elevated plasma tau levels were associated with increased mortality (odds ratio [OR], 3.06; 95% CI, 1.01-9.26; P = .048). In children with CM who were younger than 5 years at both CM episode and follow-up neurocognitive testing, plasma tau levels (log10 transformed) were associated with worse overall cognition scores over 24-month follow-up (β = -0.80; 95% CI, -1.32 to -0.27; P = .003). In children with CM who were younger than 5 years at CM episode and 5 years or older at follow-up neurocognitive testing, plasma tau was associated with worse scores in attention (β = -1.08; 95% CI, -1.79 to -0.38; P = .003) and working memory (β = -1.39; 95% CI, -2.18 to -0.60; P = .001). In this study, plasma tau, a marker of injury to neuronal axons, was elevated in children with CM or SMA and was associated with mortality and persistent NCI in children with CM younger than 5 years.

Stability of blood‐based biomarkers of cognitive impairment

AbstractBackgroundWidespread investigation of these biomarkers in large population studies has been hampered as several blood biomarkers of cognitive impairment need the blood to be processed immediately into plasma/serum. We evaluated the stability of these biomarkers to delayed blood processing using an ultra‐sensitive assay.MethodWe processed blood collected from 20 volunteers immediately (0 hours), and after a delay of 24 hours and 48 hours to obtain serum. In addition, we also processed blood from five volunteers immediately (0 hours) and after a delay of 24 hours, 48 hours and 72 hours to obtain plasma. All serum and plasma samples were analyzed in duplicate for Aβ42, Aβ40, tau and neurofilament light (NfL) on the Quanterix platform using commercially available assays.ResultThe decrease in plasma Aβ42 and Aβ40 values were relatively modest in blood processed after a delay of 24 hours (6% and 11% respectively), 48 hours (20% and 21% respectively) and 72 hours (30% and 32% respectively) as compared to samples processed immediately. Furthermore, the plasma Aβ42/ Aβ40 ratio showed only a 9% decrease in plasma processed after a delay of 72 hours. Plasma tau levels decreased by 20% at 48 hours as compared to a 9% decrease in serum. Plasma levels of Aβ42, Aβ40 and tau were substantially higher than serum levels. However, even at 48 hours, plasma tau levels were higher as compared to serum levels. NfL levels were comparable in serum and plasma and NfL levels decreased 10% and 6% in plasma and serum at 48 hours.ConclusionDespite a decrease in plasma levels of Aβ42 and Aβ40 was substantial after 48 hours the Aβ42/ Aβ40 was stable in plasma processed up to 72 hours after blood collection. Plasma and serum levels of NfL appear to be stable even when blood was processed for up to 48 hours after blood collection while plasma tau levels showed only modest reduction in values over 48 hours. These results suggest that blood‐based biomarkers of cognitive impairment can be reliably measured in plasma samples that were processed even after a delay of up to 48 hours after blood collection.

A phase 1b open label study of sodium selenate as a disease‐modifying treatment for behavioural variant fronto‐temporal dementia

AbstractBackgroundHyperphosphorylated tau is a pathological hallmark of ∼45% of behavioural variant frontotemporal dementia (bvFTD). For this reason, hyperphosphorylated tau represents a promising treatment target for this population. Sodium selenate stimulates the PP2A enzyme, which directly dephosphorylates hyperphosphorylated tau. This Phase 1b, open‐labelled, study investigated sodium selenate as a disease‐modifying treatment for patients with bvFTD.MethodTwelve patients with bvFTD were treated with sodium selenate (15mg tds) for twelve months. Participants underwent a cognitive and behavioural battery, MRI, lumbar puncture and safety assessments at screening, baseline, and at regular intervals following treatment commencement. Adverse events were monitored via diary cards between clinic visits.ResultAll 12 patients completed the study. Safety analysis found that sodium selenate was safe and well tolerated, with no study withdrawals. Commonly reported mild‐moderate adverse events were nail changes (n=6), muscles aches (n=4), headache, fatigue, hair loss and fall (n=3). Five patients reduced their dose to 10mg tds due to adverse events. No treatment‐related serious adverse events occurred. Analyses of efficacy data are ongoing. A mixed‐effects analysis showed an overall small but significant decline on cognition and behaviour, including total NUCOG score (b=‐0.18, 95% CI=‐0.28–0.08) Cambridge Behavioural Index (b=0.32, 95% CI=0.18‐0.46) and Carer Burden Scale score (b=0.1, 95% CI = 0.02‐0.18). Percentage change in whole‐brain volume from baseline to week 52 ranged from ‐0.26% to ‐6.51% (n=7 &gt;‐1.8%, n=4 &lt;‐1.8%). Plasma tau levels (n=6) did not change from baseline (3.73±0.26pg/mL) to week 52 (4.66±0.24pg/mL). CSF tau also showed no change from baseline (167.8±11.2pg/mL) to week 52 (156.1±2.49pg/mL). Although not significant, the directional changes are in line with the proposed mechanism of sodium selenate.Exploratory analyses of “responders” (brain volume change &gt;‐1.8%, n=7) found no change in NUCOG total score (b=‐0.03, 95% CI ‐0.14‐0.07) or CBS score (b=‐0.05, 95% CI ‐0.04‐0.13) over time.ConclusionSodium selenate is safe and well tolerated in patients with bvFTD. Exploratory analyses indicate it may reduce atrophy and halt cognitive decline in a subset of bvFTD patients. Sodium selenate should be further investigated as a potential treatment for bvFTD, and biomarkers to identify the subset of “responder” patients explored.

Pre‐analytical and clinical validation on the highway to implementation of novel dementia blood tests

AbstractBackgroundBlood based biomarkers for Alzheimer’s disease and other dementias are now a reality. Results in large well‐defined research cohorts suggest high potential for implementation for diagnosis (pTau, amyloid isoforms, GFAP), prognosis (pTau, GFAP, NfL) or monitoring (pTau, NfL) in clinical practice and treatment development. Implementation of novel blood based biomarkers requires several aspects to be addressed, among which pre‐analytical sample handling, patient heterogeneity and the development of cut‐offs and computer‐assisted tools for interpretation.MethodTo mimic pre‐analytical variations occurring in current practice, systematic experiments were performed and effects on plasma Amyloid beta(42/40), (p)Tau, NfL and GFAP levels were measured using different technologies. To understand patient heterogeneity, these markers are measured in several cohorts of normal aging elderly using Simoa technology. To develop cut‐offs and tools for interpretation, these markers are measured in a retrospective cohort of patients with various dementias. Lastly, prospective analysis of these markers in the memory clinic setting has been started.ResultThe generated knowledge on the most important pre‐analytical factors affecting Amyloidbeta(42/40), (p)Tau, NfL and GFAP levels resulted in the construction of a standardized operating procedure for use in clinical practise and research (Figure). Results in the normal aging population followed longitudinally show that these biomarkers are higher in patients that are proven to be amyloid positive 10 year later. Detailed results of patient biomarker heterogeneity will be presented as well as a decision tool for use in clinical practice. Lastly, pilot data on experience with these novel blood based biomarkers and the decision tools for dementia diagnosis in the memory clinic setting will be presented.ConclusionTogether, the addressed are important steps towards smooth and widespread implementation of blood based biomarkers in clinical practise.

Subacute plasma neurofilament light predicts neurodegeneration after moderate‐severe traumatic brain injury

AbstractBackgroundTBI is an environmental risk factor for the development of dementia. Axonal injury is thought be a significant determinant of clinical outcomes post‐injury, which can now be assessed using novel techniques such as fluid biomarkers including plasma neurofilament light and advanced MRI assessment.MethodBIO‐AX‐TBI (Developing and Validating Blood and Imaging BIOmarkers of AXonal Injury Following Traumatic Brain Injury, NCT03534154) is a multi‐centre cohort study of patients after acute moderate‐severe TBI. Patients admitted to major trauma units underwent baseline clinical assessment, serial blood biomarker and MRI over one year, with detailed outcome ascertainment. Blood concentrations of neurofilament light (NFL), total‐tau, S100‐B, ubiquitin carboxy‐terminal hydrolase L1 (UCHL1) and glial fibrillary acidic protein (GFAP) were quantified.Result197 patients after TBI had acute blood biomarker assessment with clinical outcomes ascertained at 6 and 12 months. 95 healthy participants with imaging and blood biomarker workup were assessed, alongside 28 healthy controls with longitudinal neuroimaging and 24 trauma patients with extracranial injuries (non‐TBI trauma, ‘NTT’). TBI patients had significant elevations of blood biomarkers including NfL and tau compared with controls and NTTs. Diffusion tensor imaging (DTI) showed reduced fractional anisotropy in TBI patients, which remained abnormal into the chronic phase and correlated with subacute NFL. Grey matter atrophy rates were elevated in the first 6 months post injury and correlated with peak plasma tau levels, which additionally predicted cognitive performance. Abnormal chronic (6‐12) month white matter atrophy, particularly of the right internal capsule/posterior thalamic radiation, was predicted by subacute plasma NFL, which furthermore predicted functional outcome.ConclusionIn this longitudinal investigation, subacute plasma NFL was highly sensitive to axonal injury after TBI, predicted functional outcome at 6 and 12 months and predicted accelerated white matter atrophy in the chronic phase. Early plasma tau predicted grey matter atrophy post‐injury and 12 month cognitive function. Plasma NFL and tau appear to be a valuable non‐invasive means to diagnose significant injuries and identify those patients at high risk of chronic neurodegeneration, which may inform recruitment into clinical trials of anti‐neurodegenerative therapies in future.

Whole Blood Expression Pattern of Inflammation and Redox Genes in Mild Alzheimer's Disease.

BackgroundAlthough Alzheimer’s disease (AD) is associated with alterations of the central nervous system, this disease has an echo in blood that might represent a valuable source of biomarkers for improved diagnosis, prognosis and for monitoring drug response.MethodsWe performed a targeted transcriptomics study on 38 mild Alzheimer’s disease (AD) patients and 38 matched controls for evaluating the expression levels of 136 inflammation and 84 redox genes in whole blood. Patients were diagnosed as mild AD based on altered levels of total TAU, phospho-TAU and Abeta(1–42) in cerebrospinal fluid, and Abeta(1–40), Abeta(1–42) and total TAU levels in plasma. Whenever possible, blood and brain comparisons were made using public datasets.ResultsWe found 48 inflammation and 34 redox genes differentially expressed in the blood of AD patients vs controls (FC >1.5, p < 0.01), out of which 22 pro-inflammatory and 12 redox genes exhibited FC >2 and p < 0.001. Receiver operating characteristic (ROC) analysis identified nine inflammation and seven redox genes that discriminated between AD patients and controls (area under the curve >0.9). Correlations of the dysregulated inflammation and redox transcripts indicated that RELA may regulate several redox genes including DUOX1 and GSR. Based on the gene expression profile, we have found that the master regulators of inflammation and redox homeostasis, NFκB and NRF2, were significantly disturbed in the blood of AD patients, as well as several zinc finger and helix-loop-helix transcription factors.ConclusionThe selected inflammation and redox genes might be useful biomarkers for monitoring anti-inflammatory therapy in mild AD.

ELISA Evaluation of Tau Accumulation in the Brains of Patients with Alzheimer Disease.

Despite the routine use of sandwich enzyme-linked immunosorbent assays (ELISAs) for quantifying tau levels in CSF and plasma, tau accumulations in the brains of patients with Alzheimer disease (AD) have rarely been evaluated by this method. Thus, by introducing several tau ELISAs that target different epitopes, we evaluated accumulated tau levels in postmortem brains depending on disease stage, brain areas, and other AD-related changes. Notably, tau levels in insoluble fraction determined by each ELISAs differ depending on the epitopes of antibodies: non-AD control samples yield relatively high signals when an antibody against the N-terminal region of tau is used. On the other hand, ELISAs combining antibodies against the later-middle to C-terminal regions of tau produced substantially increased signals from AD samples, compared to those from non-AD controls. Such ELISAs better distinguish AD and non-AD controls, and the results are more closely associated with Braak neurofibrillary tangles stage, Aβ accumulation, and glial markers. Moreover, these ELISAs can reflect the pattern of tau spread across brain regions. In conclusion, Tau ELISAs that combine antibodies against the later-middle to C-terminal regions of tau can better reflect neuropathological tau accumulation, which would enable to evaluate tau accumulation in the brain at a biochemical level.

Integrated 18F-T807 Tau PET, Structural MRI, and Plasma Tau in Tauopathy Neurodegenerative Disorders.

Background and Objective: Tau-specific positron emission topography (PET) imaging enables in vivo assessment of Alzheimer's disease (AD). We aimed to investigate its performance in combination with plasma tau levels in patients with non-AD tauopathy.Methods: A total of 47 participants were enrolled, including 10 healthy controls, 16 with tauopathy parkinsonism syndromes (9 with corticobasal syndrome [CBS], 7 with progressive supranuclear palsy [PSP]), 9 with frontotemporal dementia (FTD), 4 with AD, and 8 with Parkinson's disease (PD). All participants underwent clinical assessments, 18F-T807 tau PET, brain MRI, and plasma tau assay.Results: The global cortical standard uptake value ratio (SUVR) of 18F-T807 PET was comparable between PD and control (p = 0.088). The cortical SUVR was significantly higher in AD group (p = 0.002) but was modestly increased in PSP group compared to the PD group (p = 0.044), especially in parietal and pallidal regions. Asymmetric 18F-T807 uptake at the pallidum was noted in patients with CBS and FTD. Cortical tau tracer uptake was associated with increased plasma total tau level (p = 0.016), especially in frontal and parietal regions. Regional tracer uptake was correlated with cortical thinning in patients with CBS and PSP (CBS: r = −0.092, p = 0.025; PSP: r = −0.114, p = 0.015).Conclusions: The 18F-T807 tau tracer uptake was only modestly increased in patients with PSP. Although the cortical tau tracer uptake correlated with regional cortical atrophy and plasma tau levels, a four-repeated tau-specific tracer is needed for future classifying tauopathy parkinsonism syndromes.

The Correlations Between Plasma Fibrinogen With Amyloid-Beta and Tau Levels in Patients With Alzheimer's Disease.

Recent studies show that fibrinogen plays a role in the pathogenesis of Alzheimer’s disease (AD), which may be crucial to neurovascular damage and cognitive impairment. However, there are few clinical studies on the relationship between fibrinogen and AD. 59 11C-PiB-PET diagnosed AD patients and 76 age- and gender-matched cognitively normal controls were included to analyze the correlation between plasma β-amyloid (Aβ) and tau levels with fibrinogen levels. 35 AD patients and 76 controls with cerebrospinal fluid (CSF) samples were included to further analyze the correlation between CSF Aβ and tau levels with fibrinogen levels. In AD patients, plasma fibrinogen levels were positively correlated with plasma Aβ40 and Aβ42 levels, and negatively correlated with CSF Aβ42 levels. Besides, fibrinogen levels were positively correlated with CSF total tau (t-tau), and phosphorylated tau-181 (p-tau) levels and positively correlated with the indicators of Aβ deposition in the brain, such as t-tau/Aβ42, p-tau/Aβ42 levels. In normal people, fibrinogen levels lack correlation with Aβ and tau levels in plasma and CSF. This study suggests that plasma fibrinogen levels are positively correlated with Aβ levels in the plasma and brain in AD patients. Fibrinogen may be involved in the pathogenesis of AD.