Cerebrospinal Fluid Phosphorylated-tau Research Articles

STREM2 Mediates the Correlation Between BIN1 Gene Polymorphism and Tau Pathology in Alzheimer's Disease.

Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). To explore the association of BIN1 loci with neuroinflammation and AD pathology. Alzheimer's Disease Neuroimaging Initiative (ADNI, N = 495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, N = 619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pc = 0.017; 0.010, respectively) and total-tau (T-tau) (pc = 0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pc = 0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528 : 20.8%; Proportion of rs744373 : 24.8%) and T-tau (Proportion of rs7561528 : 36.5%; Proportion of rs744373 : 43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson's Disease.

In early-stage Parkinson′s disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-β42, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-β42, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1–2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sβ = 0.40). Higher CSF neurofilament light was associated with worse memory (sβ = −0.59), attentional (sβ = −0.32), and executive functioning (sβ = −0.35). Reduced CSF amyloid-β42 levels were associated with poorer attentional functioning (sβ = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sβ = −0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment.

Amyloid PETs are commonly negative in suspected Alzheimer's disease with an increase in CSF phosphorylated-tau protein concentration but an Aβ42 concentration in the very high range: a prospective study.

Atypical cerebrospinal fluid (CSF) patterns, involving an increase in the concentration of phosphorylated-tau (P-tau) proteins but normal amyloid-β concentration, are not uncommon in patients with mild neurocognitive disorders and suspected Alzheimer's disease (AD). In these conditions, however, AD diagnosis may be ruled out in the absence of any amyloid deposition at positron-emission tomography (PET). This pilot cross-sectional study was aimed to determine whether this negativity of amyloid PET can be predicted by CSF profiles in such patients. Twenty-five patients (73 [68-80]years, 10 women) with mild neurocognitive disorders, suspected AD and an increase in the CSF concentration of P-tau proteins but normal Aβ42 concentration and Aβ42/Aβ40 ratio were prospectively included and referred to a 18F-florbetaben PET. The latter was considered as definitively negative with the conjunction of both visual (brain amyloid plaque load score) and quantified (standard uptake value ratios) criteria. Predictors of a negative PET were searched among current CSF biomarkers (Aß42, Aß40, T-tau, P-tau, Aß42/Aß40, Aß42/p-tau). Amyloid PET was negative in 15 patients (60%) with a CSF Aß42 concentration being the sole independent predictor of this negativity. The criterion of an Aß42 concentration in the very high range (> 843pg/mL), observed in 60% (15/25) of the study patients, was associated with a negative amyloid PET in 93% (14/15) of cases. In mild neurocognitive disorders patients with suspected AD and showing an increase in CSF P-tau protein level, amyloid PETs are commonly negative, when Aß42 concentration is in the very high range. In such case, AD diagnosis based on biomarkers can be ruled out with reasonable certainty, without the need for additional CSF second-line assays or results from amyloid PET.

The structural MRI markers and cognitive decline in prodromal Alzheimer's disease: a 2-year longitudinal study.

Being clinically diagnosed with a mild cognitive impairment (MCI) due to Alzheimer's disease (AD) is widely studied. Yet, the clinical and structural neuroimaging characteristics for prodromal AD, which are defined as A+T+MCI based on the AT (N) system are still highly desirable. This study evaluates the differences of the cognitive assessments and structural magnetic resonance imaging (MRI) between the early MCI (EMCI) and late MCI (LMCI) participants based on the AT (N) system. The potential clinical value of the structural MRI as a predictor of cognitive decline during follow-up in prodromal AD is further investigated. A total of 406 MCI participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database were chosen and dichotomized into EMCI and LMCI groups according to the Second Edition (Logical Memory II) Wechsler Memory Scale. Multiple markers' data was collected, including age, sex, years of education, ApoE4 status, cerebrospinal fluid (CSF) biomarkers, standardized uptake values ratios (SUVR) means of florbetapir-PET-AV45, cognitive measures, and structural MRI. We chose 197 A+T+MCI participants (prodromal AD) with positive biomarkers of Aβ plaques (labeled "A") and fibrillar tau (labeled "T"). We diagnosed Aβ plaques positive by the SUVR means of florbetapir-PET-AV45 (cut-off >1.1) and fibrillar tau positive by CSF phosphorylated-tau at threonine 181 (p-tau) (cut-off >23 pg/mL). The differences of cognitive assessments and regions of interest (ROIs) defined on the MRI template between EMCI and LMCI were compared. Furthermore, the potential clinical utility of the MRI as the predictor of cognitive decline in prodromal AD was evaluated by investigating the relationship between baseline MRI markers and cognition decline at the follow-up period, through a linear regression model. The LMCI participants had a significantly more amyloid burden and CSF levels of total t-tau than the EMCI participants. The LMCI participants scored a lower result than the EMCI group in the global cognition scales and subscales which included tests for memory, delayed recall memory, executive function, language, attention and visuospatial skills. The cognition levels declined faster in the LMCI participants during the 12- and 24-month follow-up. There were significant differences in ROIs on the structural MRI between the two groups, including a bilateral entorhinal, a bilateral hippocampus, a bilateral amygdala, a bilateral lateral ventricle and cingulate, a corpus callosum, and a left temporal. The thickness average of the left entorhinal, the left middle temporal, the left superior temporal, and the right isthmus cingulate was a main contributor to the decreased global cognition levels. The thickness average of the left superior temporal and bilateral entorhinal played a key role in the memory domain decline. The thickness average of the left middle temporal, and the right isthmus cingulate was significantly associated with an executive function decline. Based on the AT (N) system, surely, both the EMCI and LMCI diagnoses presented significant differences in multiple cognition domains. Signature ROIs from the structural MRI tests had correlated a cognitive decline, and could act as one potential predictive marker.

Ante mortem cerebrospinal fluid tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration.

To test the hypotheses that (1) antemortem cerebrospinal fluid (CSF) tau levels correlate with postmortem tau pathology in frontotemporal lobar degeneration (FTLD) and (2) tauopathy patients have higher phosphorylated-tau levels compared to transactivation response element DNA-binding protein 43 (TDP-43) proteinopathy patients while accounting for Alzheimer's disease (AD) copathology. Patients had autopsy-confirmed FTLD with tauopathy (n = 31), TDP-43 proteinopathy (n = 49), or AD (n = 26) with antemortem CSF. CSF tau levels were compared between groups and correlated with digital histology measurement of postmortem tau pathology averaged from three cerebral regions (angular gyrus, mid-frontal cortex, and anterior cingulate gyrus). Multivariate linear regression tested the association of ante mortem CSF tau levels with postmortem tau pathology adjusting for demographics. Multivariate regression found an independent association of ante mortem CSF phosphorylated tau levels with postmortem cerebral tau pathology in FTLD (Beta = 1.3; 95% confidence interval = 0.2-2.4; p < 0.02). After excluding patients with coincident AD-associated tau pathology accompanying sporadic FTLD, we found lower CSF phosphorylated tau levels in the TDP-43 group (median = 7.4pg/ml; interquartile range [IQR] = 6.0, 12.3; n = 26) compared to the tauopathy group (median = 12.5pg/ml; IQR = 10.7, 15.0; n = 23; Z = 2.6; p < 0.01). CSF phosphorylated-tau levels are positively associated with cerebral tau burden in FTLD. In vivo detection of AD copathology in sporadic FTLD patients may help stratify clinical cohorts with pure neuropathology in which low CSF phosphorylated-tau levels may have diagnostic utility to distinguish TDP-43 proteinopathy from tauopathy. Autopsy-confirmed samples are critical for FTLD biomarker development and validation. Ann Neurol 2017;82:247-258.

Cerebrospinal fluid markers detect Alzheimer's disease in nonamnestic dementia

IntroductionThe accuracy of cerebrospinal fluid (CSF) biomarkers for detecting Alzheimer's disease (AD) pathology has not been fully validated in autopsied nonamnestic dementias. MethodsWe retrospectively evaluated CSF amyloid β 1–42, phosphorylated-tau, and amyloid-tau index as predictors of Alzheimer pathology in patients with primary progressive aphasia, frontotemporal dementia, and progressive supranuclear palsy. ResultsNineteen nonamnestic autopsied cases with relevant CSF values were included. At autopsy, nine had AD and 10 had non-AD pathologies. All six patients whose combined CSF phosphorylated-tau and amyloid β levels were “consistent with AD” had postmortem Alzheimer pathology. The two patients whose biomarker values were “not consistent with AD” had non-AD pathologies. The CSF values of the remaining eight non-AD cases were in conflicting or borderline ranges. DiscussionCSF biomarkers reliably identified Alzheimer pathology in nonamnestic dementias and may be useful as a screening measure for inclusion of nonamnestic cases into Alzheimer's trials.

Orexin-A is Associated with Increases in Cerebrospinal Fluid Phosphorylated-Tau in Cognitively Normal Elderly Subjects.

To evaluate the role of orexin-A with respect to cerebrospinal fluid (CSF) Alzheimer disease (AD) biomarkers, and explore its relationship to cognition and sleep characteristics in a group of cognitively normal elderly individuals. Subjects were recruited from multiple community sources for National Institutes of Health supported studies on normal aging, sleep and CSF biomarkers. Sixty-three participants underwent home monitoring for sleep-disordered breathing, clinical, sleep and cognitive evaluations, as well as a lumbar puncture to obtain CSF. Individuals with medical history or with magnetic resonance imaging evidence of disorders that may affect brain structure or function were excluded. Correlation and linear regression analyses were used to assess the relationship between orexin-A and CSF AD-biomarkers controlling for potential sociodemographic and sleep confounders. Levels of orexin-A, amyloid beta 42 (Aβ42), phosphorylated-tau (P-Tau), total-tau (T-Tau), Apolipoprotein E4 status, age, years of education, reported total sleep time, number of awakenings, apnea-hypopnea indices (AHI), excessive daytime sleepiness, and a cognitive battery were analyzed. Subjects were 69.59 ± 8.55 years of age, 57.1% were female, and 30.2% were apolipoprotein E4+. Orexin-A was positively correlated with Aβ42, P-Tau, and T-Tau. The associations between orexin-A and the AD-biomarkers were driven mainly by the relationship between orexin-A and P-Tau and were not influenced by other clinical or sleep characteristics that were available. Orexin-A is associated with increased P-Tau in normal elderly individuals. Increases in orexin-A and P-Tau might be a consequence of the reduction in the proportion of the deeper, more restorative slow wave sleep and rapid eye movement sleep reported with aging. Clinicaltrials.gov registration number NCT01962779.

Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.

P4‐118: Tau phosphorylation pathway genes and cerebrospinal fluid tau levels in Alzheimer's disease

Alzheimer's disease (AD) is characterized by the presence in the brain of amyloid plaque, consisting primarily of A β, and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. The hypothesis of this investigation was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5' and 3' regions of kinase and phosphatase genes and two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. The rs7768046 and rs913275 SNPs were both associated with CSF p-tau and t-tau levels in AD. The rs7768043 SNP and rs913275 were also differentially associated with either CSF t-tau or CSF p-tau relative to t-tau levels in AD compared to controls, respectively. These results suggest that the rs7668046 of the FYN kinase gene and the rs913275 of the PPP2R4 phosphatase gene influence CSF tau levels in an AD specific manner.