Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson\'s disease (PD) is challenging due to overlapping phenotypes and the late onset of specific atypical signs. Therefore, easily assessable diagnostic biomarkers are highly needed. Since PD is a synucleopathy while PSP is a tauopathy, here, we investigated the clinical usefulness of serum oligomeric-α-synuclein (o-α-synuclein) and 181Thr-phosphorylated tau (p-tau181), which are considered as the most important pathological protein forms in distinguishing between these two parkinsonisms. We assessed serum o-α-synuclein and p-tau181 by ELISA and SIMOA, respectively, in 27 PSP patients, 43 PD patients, and 39 healthy controls (HC). Moreover, we evaluated the correlation between serum biomarkers and biological and clinical features of these subjects. We did not find any difference in serum concentrations of p-tau181 and o-α-synuclein nor in the o-α-synuclein/p-tau181 ratio between groups. However, we observed that serum p-tau181 positively correlated with age in HC and PD, while serum o-α-synuclein correlated positively with disease severity in PD and negatively with age in PSP. Finally, the o-α-synuclein/p-tau181 ratio showed a negative correlation with age in PD.

We aimed to assess diagnostic accuracy of plasma p-tau181 and NfL separately and in combination in discriminating Subjective Cognitive Decline (SCD) and Mild Cognitive Impairment (MCI) patients carrying Alzheimer\'s Disease (AD) pathology from non-carriers; to propose a flowchart for the interpretation of the results of plasma p-tau181 and NfL. We included 43 SCD, 41 MCI and 21 AD-demented (AD-d) patients, who underwent plasma p-tau181 and NfL analysis. Twenty-eight SCD, 41 MCI and 21 AD-d patients underwent CSF biomarkers analysis (Aβ1-42, Aβ1-42/1-40, p-tau, t-tau) and were classified as carriers of AD pathology (AP+) it they were A+/T+ , or non-carriers (AP-) when they were A-, A+/T-/N-, or A+/T-/N+ according to the A/T(N) system. Plasma p-tau181 and NfL separately showed a good accuracy (AUC = 0.88), while the combined model (NfL + p-tau181) showed an excellent accuracy (AUC = 0.92) in discriminating AP+ from AP- patients. Plasma p-tau181 and NfL results were moderately concordant (Coehn\'s k = 0.50, p < 0.001). Based on a logistic regression model, we estimated the risk of AD pathology considering the two biomarkers: 10.91% if both p-tau181 and NfL were negative; 41.10 and 76.49% if only one biomarker was positive (respectively p-tau18 and NfL); 94.88% if both p-tau181 and NfL were positive. Considering the moderate concordance and the risk of presenting an underlying AD pathology according to the positivity of plasma p-tau181 and NfL, we proposed a flow chart to guide the combined use of plasma p-tau181 and NfL and the interpretation of biomarker results to detect AD pathology.

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer\'s Coordinating Center\'s Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer\'s disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer\'s patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.

There is a need for blood biomarkers to detect individuals at different Alzheimer\'s disease (AD) stages because obtaining cerebrospinal fluid-based biomarkers is invasive and costly. Plasma phosphorylated tau proteins (p-tau) have shown potential as such biomarkers. This systematic review was conducted according to the PRISMA guidelines and aimed to determine whether quantification of plasma tau phosphorylated at threonine 181 (p-tau181), threonine 217 (p-tau217) and threonine 231 (p-tau231) is informative in the diagnosis of AD. All p-tau isoforms increase as a function of Aβ-accumulation and discriminate healthy individuals from those at preclinical AD stages with high accuracy. P-tau231 increases earliest, followed by p-tau181 and p-tau217. In advanced stages, all p-tau isoforms are associated with the clinical classification of AD and increase with disease severity, with the greatest increase seen for p-tau217. This is also reflected by a better correlation of p-tau217 with Aβ scans, whereas both, p-tau217 and p-tau181 correlated equally with tau scans. However, at the very advanced stages, p-tau181 begins to plateau, which may mirror the trajectory of the Aβ pathology and indicate an association with a more intermediate risk of AD. Across the AD continuum, the incremental increase in all biomarkers is associated with structural changes in widespread brain regions and underlying cognitive decline. Furthermore, all isoforms differentiate AD from non-AD neurodegenerative disorders, making them specific for AD. Incorporating p-tau181, p-tau217 and p-tau231 in clinical use requires further studies to examine ideal cut-points and harmonize assays.

Elevated tau phosphorylation has been linked to the Apolipoprotein E (APOE) ɛ4 allele, which is considered one of the most significant genes related to Alzheimer\'s disease (AD). However, it is uncertain whether the impact of increased plasma tau phosphorylated at threonine 181 (p-tau181) on memory and executive function decline would be greater among APOEɛ4 carriers.
To investigate the effects of plasma p-tau181 and APOEɛ4 on memory and executive function.
The longitudinal analysis included 608 older adults without dementia (aged 72±7 years; 47% female; follow-up period of 1.59±1.47 years) from the ADNI dataset, including 180 individuals with normal cognition and 429 individuals with mild cognitive impairment. Linear mixed-effects models were utilized to assess the contributions of APOEɛ4 status and plasma p-tau181 to longitudinal changes in memory composite score and executive function composite score.
At baseline, the APOEɛ4+/Tau+ group exhibited poorer performance in memory composite score and executive function composite score, and an elevated load of cerebrospinal fluid Aβ and tau pathologies. To further understand longitudinal changes, we compared groups directly based on plasma p-tau181 and APOEɛ4 status (four groups: APOEɛ4-/Tau-, APOEɛ4-/Tau+, APOEɛ4+/Tau-, APOEɛ4+/Tau+). Both the memory composite score and executive function composite score showed a significantly greater decline in the APOEɛ4+/Tau+ group than in all other groups.
Our findings indicate that there is an interaction between plasma p-tau181 levels and APOEɛ4 status, which contributes to the longitudinal changes of memory and executive function in older adults without dementia.

Alzheimer\'s disease studies often lack ethnic diversity.
We evaluated associations between plasma biomarkers commonly studied in Alzheimer\'s (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aβ-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry.
Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aβ-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aβ-PET[+] and Aβ-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006).
Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer\'s contributions to memory loss.
Alzheimer\'s biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

UNASSIGNED: The aim of this study was to investigate phosphorylated tau (p-tau181) protein in plasma in a cohort of mild traumatic brain injury (mTBI) patients and a cohort of concussed athletes.
UNASSIGNED: This pilot study comprised two independent cohorts. The first cohort-part of a Traumatic Head Injury Neuroimaging Classification (THINC) study-with a mean age of 46 years was composed of uninjured controls (UIC, n = 30) and mTBI patients (n = 288) recruited from the emergency department with clinical computed tomography (CT) and research magnetic resonance imaging (MRI) findings. The second cohort-with a mean age of 19 years-comprised 133 collegiate athletes with (n = 112) and without (n = 21) concussions. The participants enrolled in the second cohort were a part of a multicenter, prospective, case-control study conducted by the NCAA-DoD Concussion Assessment, Research and Education (CARE) Consortium at six CARE Advanced Research Core (ARC) sites between 2015 and 2019. Blood was collected within 48 h of injury for both cohorts. Plasma concentration (pg/ml) of p-tau181 was measured using the Single Molecule Array ultrasensitive assay.
UNASSIGNED: Concentrations of plasma p-tau181 in both cohorts were significantly elevated compared to controls within 48 h of injury, with the highest concentrations of p-tau181 within 18 h of injury, with an area under the curve (AUC) of 0.690-0.748, respectively, in distinguishing mTBI patients and concussed athletes from controls. Among the mTBI patients, the levels of plasma p-tau181 were significantly higher in patients with positive neuroimaging (either CT+/MRI+, n = 74 or CT-/MRI+, n = 89) compared to mTBI patients with negative neuroimaging (CT-/MRI-, n = 111) findings and UIC (P-values < 0.05).
UNASSIGNED: These findings indicate that plasma p-tau181 concentrations likely relate to brain injury, with the highest levels in patients with neuroimaging evidence of injury. Future research is needed to replicate and validate this protein assay\'s performance as a possible early diagnostic biomarker for mTBI/concussions.

Plasma phosphorylated-tau threonine 181 (p-tau181) is a promising biomarker for predicting Alzheimer\'s disease (AD) and mild cognitive impairment (MCI), which is the symptomatic pre-dementia stage of AD. To date, there are limitations in the current diagnosis and classification of the two stages of MCI and AD in clinical practice remain a dilemma. In this study, we aimed to discriminate and diagnose patients with MCI, AD, and healthy participants based on the accurate, label-free, and ultrasensitive detection of p-tau181 levels in human clinical plasma samples using our developed electrochemical impedance-based biosensor, which allows to detect p-tau181 at a very low concentration of 0.92 fg mL-1. Human plasma samples were collected from 20 patients with AD, 20 patients with MCI, and 20 individuals with healthy control. The change in charge-transfer resistance of the developed impedance-based biosensor caused by capturing p-tau181 in plasma samples was recorded to evaluate the determination of plasma p-tau181 levels in human clinical samples for discrimination and diagnosis of AD, MCI, and healthy control individuals, respectively. Receiver operating characteristic (ROC) curve, a standard analysis to judge the clinically diagnostic capability of our biosensor platform based on the estimated levels of plasma p-tau181, resulted a sensitivity of 95%, a specificity of 85%, the area under the ROC curve (AUC) value of 0.94 of the accuracy for discriminating AD patients from healthy controls; a sensitivity of 70%, a specificity of 70%, the AUC of 0.75 to discriminate MCI patients from healthy controls. Statistical analysis (one-way analysis of variance (ANOVA)) was used to compare the estimated plasma p-tau181 levels in clinical samples, indicated significantly higher for AD patients with healthy controls (***p ≤ 0.001), AD with MCI patients (***p ≤ 0.001), and MCI patients with healthy controls (*p ≤ 0.05), respectively. In addition, we compared our sensor to the global cognitive function scales and discovered that it performed noticeably improvement in diagnosing the stages of AD. These results demonstrated the good application of our developed electrochemical impedance-based biosensor in the identification of clinical disease stages. Moreover, in this study, a small dissociation constant (KD) of 0.533 pM was first determined to evaluate the high binding affinity between the p-tau181 biomarker and its antibody, providing a reference parameter for future studies of the p-tau181 biomarker and AD.

Plasma phosphorylated tau (p-tau) and glial fibrillary acidic protein (GFAP) both reflect early changes in Alzheimer\'s disease (AD) pathology. Here, we compared the biomarker levels and their association with regional β-amyloid (Aβ) pathology and cognitive performance head-to-head in clinically unimpaired elderly (n = 88) at three levels of APOE4-related genetic risk for sporadic AD (APOE4/4 n = 19, APOE3/4 n = 32 or non-carriers n = 37). Concentrations of plasma p-tau181, p-tau231 and GFAP were measured using Single molecule array (Simoa), regional Aβ deposition with 11C-PiB positron emission tomography (PET), and cognitive performance with a preclinical composite. Significant differences in plasma p-tau181 and p-tau231, but not plasma GFAP concentrations were present between the APOE4 gene doses, explained solely by brain Aβ load. All plasma biomarkers correlated positively with Aβ PET in the total study population. This correlation was driven by APOE3/3 carriers for plasma p-tau markers and APOE4/4 carriers for plasma GFAP. Voxel-wise associations with amyloid-PET revealed different spatial patterns for plasma p-tau markers and plasma GFAP. Only higher plasma GFAP correlated with lower cognitive scores. Our observations suggest that plasma p-tau and plasma GFAP are both early AD markers reflecting different Aβ-related processes.

We examined whether plasma p-tau181 and p-tau217 are specific biomarkers of pathologically confirmed Alzheimer\'s disease (AD). In particular, we investigated the utility of plasma p-tau for differentiating AD from primary age-related tauopathy (PART), as well as AD with mixed pathologies. Data came from 269 older adults who participated in the Religious Orders Study or the Rush Memory and Aging Project. Blood samples were collected during annual clinical evaluations. Participants died and underwent brain autopsy. P-tau181 and p-tau217 were quantified in the plasma samples proximate to death (average interval before death: 1.4 years) using Lilly-developed MSD immunoassays. Uniform neuropathologic evaluations assessed AD, PART, and other common degenerative and cerebrovascular conditions. Plasma p-tau217 was more strongly correlated with brain β-amyloid and paired helical filament tau (PHFtau) tangles than p-tau181. Both p-tau markers were associated with greater odds of AD, but p-tau217 had higher accuracy (area under the ROC curve (AUC): 0.83) than p-tau181 (AUC: 0.76). Plasma p-tau markers were almost exclusively associated with AD pathologic indices with the exception of cerebral amyloid angiopathy. Compared to p-tau181, p-tau217 showed a higher AUC (0.82 versus 0.74) in differentiating AD from PART. For either p-tau, we did not observe a level difference between individuals with AD alone and those with mixed AD pathologies. In summary, plasma p-tau181and p-tau217 were specifically associated with AD pathological changes. Further, our data provide initial evidence that p-tau217 may be able to differentiate between AD and PART in individuals with comparable burdens of tau tangle pathology. These results demonstrate the specificity of p-tau217 for AD, supporting its use to identify patients suitable for anti-AD therapies including β-amyloid immunotherapies.