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In Alzheimer's disease (AD), Aβ triggers p-tau secretion, which drives tau aggregation. Therefore, it is critical to characterize modulators of Aβ-related p-tau increases which may alter AD trajectories. Here, we assessed whether factors known to alter tau levels in AD modulate the association between fibrillar Aβ and secreted p-tau181 determined in the cerebrospinal fluid (CSF). To assess potentially modulating effects of female sex, younger age, and ApoE4, we included 322 ADNI participants with cross-sectional/longitudinal p-tau181. To determine effects of microglial activation on p-tau181, we included 454 subjects with cross-sectional CSF sTREM2. Running ANCOVAs for nominal and linear regressions for metric variables, we found that women had higher Aβ-related p-tau181 levels. Higher sTREM2 was associated with elevated p-tau181, with stronger associations in women. Similarly, ApoE4 was related to higher p-tau181 levels and faster p-tau181 increases, with stronger effects in female ApoE4 carriers. Our results show that sex alone modulates the Aβ to p-tau axis, where women show higher Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation and stronger effects of ApoE4 carriership in women. Synopsis: This study examined whether sex, age, microglial activation or ApoE4 modulates the Aβ to p-tau axis, a critical event in the amyloid cascade that triggers the progression of Alzheimer's disease (AD) from amyloidosis towards tauopathy. Only sex but not age, sTREM2-related microglial activation or ApoE4 modulated the Aβ to p-tau axis. Higher sTREM2-related microglial activation and ApoE4 positivity were linked to elevated p-tau levels, with stronger associations in women than in men. Female sex is associated with a stronger Aβ-dependent p-tau secretion, potentially driven by elevated sTREM2-related microglial activation. This study examined whether sex, age, microglial activation or ApoE4 modulates the Aβ to p-tau axis, a critical event in the amyloid cascade that triggers the progression of Alzheimer's disease (AD) from amyloidosis towards tauopathy. [ABSTRACT FROM AUTHOR]

Background: Phosphorylated Tau (p-Tau), an early biomarker of neuronal damage, has emerged as a promising candidate for predicting neurological outcomes in cardiac arrest (CA) survivors. Despite its potential, the correlation of p-Tau with other clinical indicators remains underexplored. This study assesses the predictive capability of p-Tau and its effectiveness when used in conjunction with other predictors. Methods: In this single-center retrospective study, 230 CA survivors had plasma and brain computed tomography scans collected within 24 h after the return of spontaneous circulation (ROSC) from January 2016 to June 2023. The patients with prearrest Cerebral Performance Category scores ≥ 3 were excluded (n = 33). The neurological outcomes at discharge with Cerebral Performance Category scores 1–2 indicated favorable outcomes. Plasma p-Tau levels were measured using an enzyme-linked immunosorbent assay, diastolic blood pressure (DBP) was recorded after ROSC, and the gray-to-white matter ratio (GWR) was calculated from brain computed tomography scans within 24 h after ROSC. Results: Of 197 patients enrolled in the study, 54 (27.4%) had favorable outcomes. Regression analysis showed that higher p-Tau levels correlated with unfavorable neurological outcomes. The levels of p-Tau were significantly correlated with DBP and GWR. For p-Tau to differentiate between neurological outcomes, an optimal cutoff of 456 pg/mL yielded an area under the receiver operating characteristic curve of 0.71. Combining p-Tau, GWR, and DBP improved predictive accuracy (area under the receiver operating characteristic curve = 0.80 vs. 0.71, p = 0.008). Conclusions: Plasma p-Tau levels measured within 24 h following ROSC, particularly when combined with GWR and DBP, may serve as a promising biomarker of neurological outcomes in CA survivors, with higher levels predicting unfavorable outcomes. [ABSTRACT FROM AUTHOR]

Blood-based biomarkers are minimally invasive tools to detect the pathological changes of Alzheimer's Disease (AD). This meta-analysis aims to investigate the use of blood-derived p-tau isoforms (181, 217, 231) to predict conversion from mild cognitive impairment (MCI) to AD dementia (ADD). Studies involving MCI patients with data on blood p-tau isoforms at baseline and clinical diagnosis at follow-up (≥1 year) were included. Twelve studies on p-tau 181 (4340 MCI, conversion rate 20.6%), four on p-tau 217 (913 MCI, conversion rate 33.4%), and one on p-tau 231 (135 MCI, conversion rate 33%) were included. For p-tau 181, the pooled area under the receiver operating characteristic curve (AUC) was 0.73 (95% CI = 0.68–0.78), and for p-tau 217 was 0.85 (95% CI = 0.75–0.91). Plasma levels of p-tau 181 had good discriminatory power to identify MCI patients who will convert to ADD. Although only four studies on p-tau 217 have been included in the meta-analysis, in the last year the predictive power of p-tau 217 is emerging as superior to that of other isoforms. However, given the high heterogeneity detected in the p-tau 217 studies included in this meta-analysis, additional supportive evidence is needed. Insufficient results were available for p-tau 231. These findings support the prognostic utility of p-tau 181 and p-tau 217 measured in blood to predict progression to ADD in MCI and encourage its future implementation in clinical practice. [ABSTRACT FROM AUTHOR]

This narrative review explores the current landscape of blood biomarkers in Frontotemporal dementia (FTD). Neurofilament light chain (NfL) may be useful in the differentiation of behavioral variant FTD from primary psychiatric disorders (PPDs) or dementia with Lewy bodies (DLB). In prodromal FTD and presymptomatic mutation carriers (GRN, MAPT, C9orf72), elevated NfL may herald pheno-conversion to full-blown dementia. Baseline NfL correlates with steeper neuroanatomical changes and cognitive, behavioral and functional decline, making NfL promising in monitoring disease progression. Phosphorylated neurofilament heavy chain (pNfH) levels have a potential limited role in the demarcation of the conversion stage to full-blown FTD. Combined NfL and pNfH measurements may allow a wider stage stratification. Total tau levels lack applicability in the framework of FTD. p-tau, on the other hand, is of potential value in the discrimination of FTD from Alzheimer's dementia. Progranulin concentrations could serve the identification of GRN mutation carriers. Glial fibrillary acidic protein (GFAP) may assist in the differentiation of PPDs from behavioral variant FTD and the detection of GRN mutation carriers (additional research is warranted). Finally, TAR DNA-binding protein-43 (TDP-43) appears to be a promising diagnostic biomarker for FTD. Its potential in distinguishing TDP-43 pathology from other FTD-related pathologies requires further research. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Blood tests have the potential to improve the accuracy of Alzheimer's disease (AD) clinical diagnosis, which will enable greater access to AD‐specific treatments. This study compared leading commercial blood tests for amyloid pathology and other AD‐related outcomes. METHODS: Plasma samples from the Alzheimer's Disease Neuroimaging Initiative were assayed with AD blood tests from C2N Diagnostics, Fujirebio Diagnostics, ALZPath, Janssen, Roche Diagnostics, and Quanterix. Outcomes measures were amyloid positron emission tomography (PET), tau PET, cortical thickness, and dementia severity. Logistic regression models assessed the classification accuracies of individual or combined plasma biomarkers for binarized outcomes, and Spearman correlations evaluated continuous relationships between individual plasma biomarkers and continuous outcomes. RESULTS: Measures of plasma p‐tau217, either individually or in combination with other plasma biomarkers, had the strongest relationships with all AD outcomes. DISCUSSION: This study identified the plasma biomarker analytes and assays that most accurately classified amyloid pathology and other AD‐related outcomes. Highlights: Plasma p‐tau217 measures most accurately classified amyloid and tau status.Plasma Aβ42/Aβ40 had relatively low accuracy in classification of amyloid status.Plasma p‐tau217 measures had higher correlations with cortical thickness than NfL.Correlations of plasma biomarkers with dementia symptoms were relatively low. [ABSTRACT FROM AUTHOR]

Our previous study showed that dimethyl fumarate (DMF) treatment performed within three weeks after intracerebroventricular (ICV) injection of streptozotocin (STZ) attenuated spatial memory impairment, hippocampal neurodegeneration, and neuroinflammation in rats. The present study is aimed at verifying the hypothesis that DMF alleviates late effects of STZ (6 months after ICV injection) which reflects advanced stage of the Alzheimer's disease (AD) in human patients. Spatial memory was assessed with Morris water maze (MWM), general brain level of amyloid β (Aβ) and p-tau was measured by western blot, immunofluorescent labelling of active microglia (IBA1), Aβ and p-tau and histological assay of neurodegeneration (Fluoro-Jade C) were performed in hippocampus and cortex. Two-week oral therapy with DMF normalized spatial memory disrupted by STZ but had no influence on general brain level of Aβ and p-tau. However, immunofluorescence showed local reduction of Aβ aggregates number in parietal cortex and p-tau+ cells in CA2 hippocampal area. Microgliosis was alleviated by DMF in CA1 area and parietal cortex. DMF-treated STZ injected rats showed higher number of Aβ containing microglia than untreated group in CA2 and frontal cortex, which may be the result of increased phagocytic activity in these areas after DMF treatment. STZ-induced neurodegeneration was alleviated by DMF in dentate gyrus and frontal cortex. In conclusion DMF treatment exerts beneficial effect on spatial memory in the rat model of late stage of AD, but weakly influences neuropathological features, as only local reduction in number of Aβ aggregates, p-tau containing cells, neurodegeneration, and microgliosis was found. [ABSTRACT FROM AUTHOR]

Urgency: Effect of Centella asiatica (CA) and aerobic exercise on Amyloid beta-42 (Aβ42) and phosphorylated tau (p-tau) as biomarkers of dementia is not yet known. Objectives: This study aimed to analyze the effect of CA, aerobic exercise, and their combination on Aβ42 and p-tau in older women with dementia. Design: It was a 24-week randomized, double-blind controlled trial. Partisipant: Subjects were divided into four groups: the Centella asiatica group (CA, 1x500 mg/day, n = 16), the aerobic exercise group (AE, 3x60 minutes/week, n = 16), the CA-AE combination group (1x500 mg/day and exercise, n = 15), and the placebo group (n = 15). Instruments: The dementia screening test used the Mini Mental State Examination (Intraclass correlation coefficients : ranging from 0.60 to 0.93, sensitivity of 88.3%) and Clinical Dementia Rating questionnaires (sensitivity 93.6% and specificity 100%). The Wilcoxon, Kruskal-Wallis, and Mann-Whitney tests were used to analyze the data. Results: Plasma amyloid beta-42 showed an increase in all groups: CA (p<0.001), AE (p=0.001), CA-AE combination (p<0.001), and placebo (p<0.001). Meanwhile, plasma p-tau also decreased in CA (p<0.001), AE (p<0.001), and CA-AE combination (p=0.001). The Mann-Whitney test showed that Centella asiatica caused the highest increase in Aβ42 (∆=233.5; p<0.001). Conclusion: This study indicate that Centella asiatica, aerobic exercise, and the CA-AE combination were effective in improving plasma Aβ42 and decreasing p-tau in older women with dementia. Contributions: This study can be an alternative therapy for the prevention and treatment of cognitive decline. Research with a larger sample size is recommended. [ABSTRACT FROM AUTHOR]

Abstract Background Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels. Methods We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer’ disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins. Results CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p

Alzheimer's disease (AD) is characterized by the accumulation of amyloid β and phosphorylated τ protein aggregates in the brain, which leads to the loss of neurons. Under the microscope, the function of mitochondria is uniquely primed to play a pivotal role in neuronal cell survival, energy metabolism, and cell death. Research studies indicate that mitochondrial dysfunction, excessive oxidative damage, and defective mitophagy in neurons are early indicators of AD. This review article summarizes the latest development of mitochondria in AD: 1) disease mechanism pathways, 2) the importance of mitochondria in neuronal functions, 3) metabolic pathways and functions, 4) the link between mitochondrial dysfunction and mitophagy mechanisms in AD, and 5) the development of potential mitochondrial-targeted therapeutics and interventions to treat patients with AD. [ABSTRACT FROM AUTHOR]

Background: Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. Objective: We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Methods: Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. Results: The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. Conclusions: NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Cerebral blood flow (CBF) is reduced in cognitively impaired (CI) Alzheimer's disease (AD) patients. We checked the sensitivity of time‐encoded arterial spin labeling (te‐ASL) in measuring CBF alterations in individuals with positive AD biomarkers and associations with relevant biomarkers in cognitively unimpaired (CU) individuals. METHODS: We compared te‐ASL with single‐postlabel delay (PLD) ASL in measuring CBF in 59 adults across the AD continuum, classified as CU amyloid beta (Aβ) negative (−), CU Aβ positive (+), and CI Aβ+. We sought associations of CBF with biomarkers of AD, cerebrovascular disease, synaptic dysfunction, neurodegeneration, and cognition in CU participants. RESULTS: te‐ASL was more sensitive at detecting CBF reduction in the CU Aβ+ and CI Aβ+ groups. In CU participants, lower CBF was associated with altered biomarkers of Aβ, tau, synaptic dysfunction, and neurodegeneration. DISCUSSION: CBF reduction occurs early in the AD continuum. te‐ASL is more sensitive than single‐PLD ASL at detecting CBF changes in AD. Highlights: Lower CBF can be detected in CU subjects in the early AD continuum.te‐ASL is more sensitive than single‐PLD ASL at detecting CBF alterations in AD.CBF is linked to biomarkers of AD, synaptic dysfunction, and neurodegeneration. [ABSTRACT FROM AUTHOR]

Idiopathic normal-pressure hydrocephalus (iNPH) is a clinic-radiological neurological syndrome presenting with cognitive deficits, gait disturbances and urinary incontinence. It often coexists with Alzheimer's disease (AD). Due to the reversible nature of iNPH when promptly treated, a lot of studies have focused on possible biomarkers, among which are cerebrospinal fluid (CSF) biomarkers. The aim of the present study was to determine the rate of beta-amyloid pathology and AD co-pathology by measuring AD CSF biomarkers, namely, amyloid beta with 42 and 40 amino acids (Aβ42), the Aβ42/Aβ40 ratio, total Tau protein (t-Tau) and phosphorylated Tau protein at threonine 181 (p-Tau), in a cohort of iNPH patients, as well as to investigate the possible associations among CSF biomarkers and iNPH neuropsychological profiles. Fifty-three patients with iNPH were included in the present study. CSF Aβ42, Aβ40, t-Tau and p-Tau were measured in duplicate with double-sandwich ELISA assays. The neuropsychological evaluation consisted of the Mini-Mental State Examination, Frontal Assessment Battery, Five-Word Test and CLOX drawing tests 1 and 2. After statistical analysis, we found that amyloid pathology and AD co-pathology are rather common in iNPH patients and that higher values of t-Tau and p-Tau CSF levels, as well as the existence of the AD CSF profile, are associated with more severe memory impairment in the study patients. In conclusion, our study has confirmed that amyloid pathology and AD-co-pathology are rather common in iNPH patients and that CSF markers of AD pathology and t-Tau are associated with a worse memory decline in these patients. [ABSTRACT FROM AUTHOR]

Background: Studies suggest that cerebrospinal fluid (CSF) levels of amyloid-β (Aβ)42 and Aβ40 present a circadian rhythm. However sustained sampling of large volumes of CSF with indwelling intrathecal catheters used in most of these studies might have affected CSF dynamics and thereby confounded the observed fluctuations in the biomarker levels. Methods: We included 38 individuals with either normal (N = 20) or abnormal (N = 18) CSF Aβ42/Aβ40 levels at baseline. CSF and plasma were collected at two visits separated by an average of 53 days with lumbar punctures and venipunctures performed either in the morning or evening. At the first visit, sample collection was performed in the morning for 17 participants and the order was reversed for the remaining 21 participants. CSF and plasma samples were analyzed for Alzheimer' disease (AD) biomarkers, including Aβ42, Aβ40, GFAP, NfL p-tau181, p-tau217, p-tau231 and t-tau. CSF samples were also tested using mass spectrometry for 22 synaptic and endo-lysosomal proteins. Results: CSF Aβ42 (mean difference [MD], 0.21 ng/mL; p = 0.038), CSF Aβ40 (MD, 1.85 ng/mL; p < 0.001), plasma Aβ42 (MD, 1.65 pg/mL; p = 0.002) and plasma Aβ40 (MD, 0.01 ng/mL, p = 0.002) were increased by 4.2-17.0% in evening compared with morning samples. Further, CSF levels of 14 synaptic and endo-lysosomal proteins, including neurogranin and neuronal pentraxin-1, were increased by 4.5-13.3% in the evening samples (MDrange, 0.02-0.56 fmol/µl; p < 0.042). However, no significant differences were found between morning and evening levels for the Aβ42/Aβ40 ratio, different p-tau variants, GFAP and NfL. There were no significant interaction between sampling time and Aβ status for any of the biomarkers, except that CSF t-tau was increased (by 5.74%) in the evening samples compared to the morning samples in Aβ-positive (MD, 16.46 ng/ml; p = 0.009) but not Aβ-negative participants (MD, 1.89 ng/ml; p = 0.47). There were no significant interactions between sampling time and order in which samples were obtained. Discussion: Our findings provide evidence for diurnal fluctuations in Aβ peptide levels, both in CSF and plasma, while CSF and plasma p-tau, GFAP and NfL were unaffected. Importantly, Aβ42/Aβ40 ratio remained unaltered, suggesting that it is more suitable for implementation in clinical workup than individual Aβ peptides. Additionally, we show that CSF levels of many synaptic and endo-lysosomal proteins presented a diurnal rhythm, implying a build-up of neuronal activity markers during the day. These results will guide the development of unified sample collection procedures to avoid effects of diurnal variation for future implementation of AD biomarkers in clinical practice and drug trials. [ABSTRACT FROM AUTHOR]

Abstract Background An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p

Background: K48-linked ubiquitin chain (Ub-K48) is a crucial ubiquitin chain implicated in protein degradation within the ubiquitin-proteasome system. However, the precise function and molecular mechanism underlying the role of Ub-K48 in the pathogenesis of Alzheimer’s disease (AD) and neuronal cell abnormalities remain unclear. The objective of this study was to examine the function of K48 ubiquitination in the etiology of AD, and its associated mechanism of neuronal apoptosis. Methods: A mouse model of AD was constructed, and behavioral phenotypic changes were detected using an open field test (OFT). The expression of glial fibrillary acidic protein (GFAP), an early marker of AD, was detected by western blotting (WB). Neuronal apoptosis in the hippocampal region was assessed by hematoxylin and eosin (HE) and Nissl staining. Immunohistochemistry and immunofluorescence were performed to observe the changes in Phosphorylated tubulin associated unit (p-Tau) and Ub-K48 colocalization in neurons of the hippocampal region of AD mice. WB was further applied to detect the degree of ubiquitylation of K48 and the expression of Tau, p-Tau, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) proteins in neuronal cells of the hippocampus and cortical regions of mice. Results: Mice with AD exhibited significantly longer resting times (p < 0.05) and shorter average speeds (p < 0.01), total distances travelled (p < 0.01), and distances travelled (p < 0.01) in the central region than those in the control group. This indicated cognitive impairment, which occurred concurrent with an increased expression of the AD marker GFAP protein (p < 0.001). The hippocampal region of AD mice showed abnormalities with sparsely and irregularly arranged cells, large gaps between cells, lighter staining, unclear boundaries of the cell membranes and nuclei, and agglutinated and condensed nuclei (p < 0.01). The neuronal cells of AD mice exhibited significantly elevated levels of p-Tau (p < 0.01) and Ub-K48 (p < 0.01), as well as a notable degree of co-localization within the cells. The intracellular pro-inflammatory protein Bax was significantly upregulated (p < 0.05), while the Bcl-2/Bax ratio was significantly lower than that in the control group (p < 0.05), thus inducing apoptosis in AD neuronal cells. Conclusion: Ub-K48 is strongly linked to the development of AD. p-Tau aggregate in neuronal cells in the hippocampal region of the AD brain and colocalize with Ub-K48, which in turn leads to cellular inflammation and the induction of apoptosis in neuronal cells.

Background: An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer's disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results: A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p < 0.001), had a higher proportion of males (49.5% vs. 36.8%, p = 0.042), higher BMIs (27.94 vs. 25.79, p < 0.001), higher prevalence of hypertensive history (47.7% vs. 16.3%, p < 0.001), and a greater percentage of Aβ-positivity (34.2% vs. 20.0%, p = 0.009). In the ADNI cohort, we found cross-sectional associations between the NLR and CSF Aβ42 (β = -12.193, p = 0.021), but not t-tau or p-tau. In the NYU cohort, we found cross-sectional associations between the NLR and CSF t-tau (β = 26.812, p = 0.019) and p-tau (β = 3.441, p = 0.015), but not Aβ42. In the NYU cohort alone, subjects classified as Aβ + (n = 38) displayed a stronger association between the NLR and t-tau (β = 100.476, p = 0.037) compared to Aβ- subjects or the non-stratified cohort. In both cohorts, the same associations observed in the cross-sectional analyses were observed after incorporating longitudinal CSF data. Conclusions: We report associations between the NLR and Aβ42 in the older ADNI cohort, and between the NLR and t-tau and p-tau in the younger NYU cohort. Associations persisted after adjusting for comorbidities, suggesting a direct link between the NLR and AD. However, changes in associations between the NLR and specific AD biomarkers may occur as part of immunosenescence. [ABSTRACT FROM AUTHOR]

Various murine models have been utilized to study TBI, including closed head injury (CHI) and controlled cortical impact (CCI), without direct comparison. The aim of our study was to evaluate these models to determine differences in neurological and behavioral outcomes postinjury. Male C57B/6 mice (9-10 wk) were separated into six groups including: untouched, sham craniotomy (4 mm), CCI 0.9 mm depth of impact, CCI 1.6 mm, CCI 2.2 mm, and CHI. CCI was performed using a 3 mm impact tip at a velocity of 5 m/s, dwell time of 250 ms, and depth as noted above. CHI was completed with a centered 400 g weight drop from 1 cm height. Mice were survived to 14-d (n = 5 per group) and 30-d (n = 5 per group) respectively for histological analysis of p-tau within the hippocampus. These mice underwent Morris Water Maze memory testing and Rotarod motor testing. Serum was collected from a separate cohort of mice (n = 5 per group) including untouched, isoflurane only, CCI 1.6 mm, CHI at 1, 4, 6, and 24 h for analysis of neuron specific enolase and glial fibrillary acidic protein (GFAP) via ELISA. Laser speckle contrast imaging was analyzed prior to and after impact in the CHI and CCI 1.6 mm groups. There were no significant differences in Morris Water Maze or Rotarod testing times between groups at 14- or 30-d. P-tau was significantly elevated in all groups except CCI 1.6 mm contralateral and CCI 2.2 mm ipsilateral compared to untouched mice at 30-d. P-tau was also significantly elevated in the CHI group at 30 d compared to CCI 1.6 mm contralateral and CCI 2.2 mm on both sides. GFAP was significantly increased in mice undergoing CHI (9959 ± 91 pg/mL) compared to CCI (2299 ± 1288 pg/mL), isoflurane only (133 ± 75 pg/mL), and sham (86 ± 58 pg/mL) at 1-h post TBI (P < 0.0001). There were no differences in serum neuron specific enolase levels between groups. Laser doppler imaging demonstrated similar decreases in cerebral blood flow between CHI and CCI; however, CCI mice had a reduction in blood flow with craniotomy only that did not significantly decrease further with impact. Based on our findings, CHI leads to increased serum GFAP levels and increased p-tau within the hippocampus at 30-d postinjury. While CCI allows the comparison of one cerebral hemisphere to the other, CHI may be a better model of TBI as it requires less technical expertise and has similar neurological outcomes in these murine models. [ABSTRACT FROM AUTHOR]

Background and objective: Phosphorylated tau (p-tau) 217 has recently received attention because it seems more reliable than other p-tau variants for identifying Alzheimer's disease (AD) pathology. Thus, we aimed to compare the diagnostic accuracy of plasma and CSF p-tau217 with p-tau181 and p-tau231 in a memory clinic cohort. Methods: The study included 114 participants (CU = 33; MCI = 67; Dementia = 14). The p-tau variants were correlated versus continuous measures of amyloid (A) and tau (T)-PET. The p-tau phospho-epitopes were assessed through: (i) effect sizes (δ) between diagnostic and A ± and T ± groups; (ii) receiver operating characteristic (ROC) analyses in A-PET and T-PET. Results: The correlations between both plasma and CSF p-tau217 with A-PET and T-PET (r range 0.64–0.83) were stronger than those of p-tau181 (r range 0.44–0.79) and p-tau231 (r range 0.46–0.76). Plasma p-tau217 showed significantly higher diagnostic accuracy than p-tau181 and p-tau231 in (i) differences between diagnostic and biomarker groups (δrange: p-tau217 = 0.55–0.96; p-tau181 = 0.51–0.67; p-tau231 = 0.53–0.71); (ii) ROC curves to identify A-PET and T-PET positivity (AUCaverage: p-tau217 = 0.96; p-tau181 = 0.76; p-tau231 = 0.79). On the other hand, CSF p-tau217 (AUCaverage = 0.95) did not reveal significant differences in A-PET and T-PET AUC than p-tau181 (AUCaverage = 0.88) and p-tau231 (AUCaverage = 0.89). Discussion: Plasma p-tau217 demonstrated better performance in the identification of AD pathology and clinical phenotypes in comparison with other variants of p-tau in a memory clinic cohort. Furthermore, p-tau217 had comparable performance in plasma and CSF. Our findings suggest the potential of plasma p-tau217 in the diagnosis and screening for AD, which could allow for a decreased use of invasive biomarkers in the future. [ABSTRACT FROM AUTHOR]

INTRODUCTION: For routine clinical implementation of Alzheimer's disease (AD) plasma biomarkers, fully automated random‐access platforms are crucial to ensure reproducible measurements. We aimed to perform an analytical validation and to establish cutoffs for AD plasma biomarkers measured with Lumipulse. METHODS: Two cohorts were included. UNIPG: n = 450 paired cerebrospinal fluid (CSF)/plasma samples from subjects along the AD‐continuum, subjects affected by other neurodegenerative diseases, and controls with known CSF profile; AMS: n = 40 plasma samples from AD and n = 40 controls. Plasma amyloid β (Aβ)42, Aβ40, and p‐tau181 were measured with Lumipulse. We evaluated analytical and diagnostic performance. RESULTS: Lumipulse assays showed high analytical performance. Plasma p‐tau181 levels accurately reflected CSF A+/T+ profile in AD‐dementia and mild cognitive impairment (MCI)‐AD, but not in asymptomatic‐AD. Plasma and CSF Aβ42/40 values were concordant across clinical AD stages. Cutoffs and probability‐based models performed satisfactorily in both cohorts. DISCUSSION: The identified cutoffs and probability‐based models represent a significant step toward plasma AD molecular diagnosis. [ABSTRACT FROM AUTHOR]

The escalating prevalence of Alzheimer's disease (AD) highlights the urgent need to develop reliable biomarkers for early diagnosis and intervention. AD is characterized by the pathological accumulation of amyloid-beta plaques and tau neurofibrillary tangles. Phosphorylated tau (p-tau) proteins, particularly p-tau217 and p-tau231, have been identified as promising biomarker candidates to differentiate the disease progression from preclinical stages. This narrative review is devoted to a critical evaluation of the diagnostic accuracy, sensitivity, and specificity of p-tau217 and p-tau231 levels in the detection of AD, measured in plasma, serum, and cerebrospinal fluid, compared to established biomarkers. Additionally, the efficacy of these markers in distinguishing AD from other neurodegenerative disorders is examined. The significant advances offered by p-tau217 and p-tau231 in AD diagnostics are highlighted, demonstrating their unique utility in early detection and differential diagnosis. This comprehensive analysis not only confirms the excellent diagnostic capabilities of these markers, but also deepens the understanding of the molecular dynamics of AD, contributing to the broader scientific discourse on neurodegenerative diseases. This review is aimed to provide key information for researchers and clinicians across disciplines, filling interdisciplinary gaps and highlighting the role of p-tau proteins in revolutionizing AD research and clinical practice. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) and serum tau (t-tau, p-tau) are potential biomarkers for neurodegeneration in Alzheimer disease (AD), but their role in amyotrophic lateral sclerosis (ALS) is unclear. Objectives: The aim of our study was to evaluate CSF and serum p-tau and t-tau in patients with ALS and to analyze the correlation and clinical parameters between them. Methods: CSF and serum samples were obtained from 90 patients with ALS, 48 other neurological disease (OND), and 20 with AM (ALS mimic, AM) diseases. The levels of p-tau and t-tau in the CSF and serum were assessed with an enzyme-linked immunosorbent assay, and disease progression parameters, including the duration, the ALSFRS-R score, disease progression rate (DPR), the upper motor neuron (UMN) score, the Mini-mental State Examination (MMSE) score, the Montreal Cognitive Assessment (MoCA) score, and the Edinburgh Cognitive and Behavioral ALS Screen (ECAS) results, were analyzed by registered neurologists. Statistical analyses were performed using Prism software. Results: Compared with controls, patients with ALS displayed significantly lower levels of CSF p-tau and p-tau:t-tau ratio. The CSF p-tau level in patients with ALS and cognition impairment was higher than that in patients with ALS who did not have cognition impairment. CSF p-tau level was negatively correlated with MMSE, MoCA, and ECAS total score and the specific score of ECAS in patients with ALS and cognition impairment. Conclusions: The CSF p-tau level and p-tau:t-tau ratio were lower in patients with ALS than patients with OND and AM. Results suggest that CSF p-tau may be used as an index of cognition impairment in patients with ALS. [ABSTRACT FROM AUTHOR]

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer's dementia (AD) and Parkinson's disease (PD), damage to the locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented and hypothesized to foster the onset and progression of neurodegeneration within target regions. Specifically, the present experiments were designed to assess whether selective damage to LC-NE axons may alter key proteins involved in neurodegeneration within specific limbic regions, such as the hippocampus and piriform cortex, compared with the dorsal striatum. To achieve this, a loss of LC-NE axons was induced by the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in C57 Black mice, as assessed by a loss of NE and dopamine-beta-hydroxylase within target regions. In these experimental conditions, the amount of alpha-synuclein (alpha-syn) protein levels were increased along with alpha-syn expressing neurons within the hippocampus and piriform cortex. Similar findings were obtained concerning phospho-Tau immunoblotting. In contrast, a decrease in inducible HSP70-expressing neurons and a loss of sequestosome (p62)-expressing cells, along with a loss of these proteins at immunoblotting, were reported. The present data provide further evidence to understand why a loss of LC-NE axons may foster limbic neurodegeneration in AD and limbic engagement during PD. [ABSTRACT FROM AUTHOR]

Rationale: The plasma ceramide levels in Alzheimer's disease (AD) patients are found abnormally elevated, which is related to cognitive decline. Objectives: This research was aimed to investigate the mechanisms of aberrant elevated ceramides in the pathogenesis of AD. Results: The ICR mice intracerebroventricularly injected with Aβ1-42 and APP/PS1 transgenic mice were employed as AD mice. The cognitive deficiency, impaired episodic and spatial memory were observed without altered spontaneous ability. The serum levels of p-tau and ceramide were evidently elevated. The modified expressions and activities of glycogen synthase kinase-3β (GSK-3β) and protein phosphatase 2A (PP2A) influenced the serum content of p-tau. The levels of ceramide synthesis-related genes including sptlc1, sptlc2, cers2, and cers6 in the liver of AD mice were increased, while the ceramide degradation-related gene asah2 did not significantly change. The regulations of these genes were conducted by activated nuclear factor kappa-B (NF-κB) signaling. NF-κB, promoted by free fatty acid (FFA), also increased the hepatic concentrations of proinflammatory cytokines. The FFA amount was modulated by fatty acid synthesis-related genes acc1 and srebp-1c. Besides, the decreased levels of pre-proopiomelanocortin (pomc) mRNA and increased agouti-related protein (agrp) mRNA were found in the hypothalamus without significant alteration of melanocortin receptor 4 (MC4R) mRNA. The bioinformatic analyses proved the results using GEO datasets and AlzData. Conclusions: Ceramide was positively related to the increased p-tau and impaired cognitive function. The increased generation of ceramide and endoplasmic reticulum stress in the hypothalamus was positively related to fatty acid synthesis and NF-κB signaling via brain–liver axis. [ABSTRACT FROM AUTHOR]

Several research studies have demonstrated the potential use of cerebrospinal fluid biomarkers such as amyloid beta 1-42, T-tau, and P-tau, in early diagnosis of Alzheimer's disease stages. The levels of these biomarkers in conjunction with the dementia rating scores are used to empirically differentiate the dementia patients from normal controls. In this work, we evaluated the performance of standard machine learning classifiers using cerebrospinal fluid biomarker levels as the features to differentiate dementia patients from normal controls. We employed various types of machine learning models, that includes Discriminant, Logistic Regression, Tree, K-Nearest Neighbor, Support Vector Machine, and Naïve Bayes classifiers. The results demonstrate that these models can distinguish cognitively impaired subjects from normal controls with an accuracy ranging from 64% to 69% and an area under the curve of the receiver operating characteristics between 0.64 and 0.73. In addition, we found that the levels of 2 biomarkers, amyloid beta 1-42 and T-tau, provide a modest improvement in accuracy when distinguishing dementia patients from healthy controls. [ABSTRACT FROM AUTHOR]

Chronic consequences of mild traumatic brain injury (mTBI) are heterogeneous, but may be treatable with targeted medical and rehabilitation interventions. A biological signature for the likelihood of response to therapy (i.e., ?predictive? biomarkers) would empower personalized medicine post-mTBI. The purpose of this study was to correlate pre-intervention blood biomarker levels and the likelihood of response to targeted interventions for patients with chronic issues attributable to mTBI. Patients with chronic symptoms and/or disorders secondary to mTBI >3 months previous (104 days to 15 years; n?=?74) were enrolled. Participants completed pre-intervention assessments of symptom burden, comprehensive clinical evaluation, and blood-based biomarker measurements. Multi-domain targeted interventions for specific symptoms and impairments across a 6-month treatment period were prescribed. Participants completed a follow-up testing after the treatment period. An all-possible model's backward logistic regression was built to identify predictors of improvement in relation to blood biomarker levels before intervention. The minimum clinically important difference (MCID) of the change score (post-intervention subtracted from pre-intervention) for the Post-Concussion Symptom Scale (PCSS) to identify treatment responders from non-responders was the primary outcome. The MCID for total PCSS score was 10. The model to predict change in PCSS score over the 6-month intervention was significant (R2?=?0.09; p?=?0.01) and identified ubiquitin C-terminal hydrolase L1 (odds ratio [OR]?=?2.53; 95% confidence interval [CI], 1.18?5.46; p?=?0.02) and hyperphosphorylated tau (p-tau; OR?=?0.70; 95% CI, 0.51?0.96; p?=?0.03) as significant predictors of symptom improvement beyond the PCSS MCID. In this cohort of chronic TBI subjects, blood biomarkers before rehabilitation intervention predicted the likelihood of response to targeted therapy for chronic disorders post-TBI.

INTRODUCTION: Plasma biomarkers are promising tools for Alzheimer's disease (AD) diagnosis, but comparisons with more established biomarkers are needed. METHODS: We assessed the diagnostic performance of p‐tau181, p‐tau217, and p‐tau231 in plasma and CSF in 174 individuals evaluated by dementia specialists and assessed with amyloid‐PET and tau‐PET. Receiver operating characteristic (ROC) analyses assessed the performance of plasma and CSF biomarkers to identify amyloid‐PET and tau‐PET positivity. RESULTS: Plasma p‐tau biomarkers had lower dynamic ranges and effect sizes compared to CSF p‐tau. Plasma p‐tau181 (AUC = 76%) and p‐tau231 (AUC = 82%) assessments performed inferior to CSF p‐tau181 (AUC = 87%) and p‐tau231 (AUC = 95%) for amyloid‐PET positivity. However, plasma p‐tau217 (AUC = 91%) had diagnostic performance indistinguishable from CSF (AUC = 94%) for amyloid‐PET positivity. DISCUSSION: Plasma and CSF p‐tau217 had equivalent diagnostic performance for biomarker‐defined AD. Our results suggest that plasma p‐tau217 may help reduce the need for invasive lumbar punctures without compromising accuracy in the identification of AD. Highlights: p‐tau217 in plasma performed equivalent to p‐tau217 in CSF for the diagnosis of AD, suggesting the increased accessibility of plasma p‐tau217 is not offset by lower accuracy.p‐tau biomarkers in plasma had lower mean fold‐changes between amyloid‐PET negative and positive groups than p‐tau biomarkers in CSF.CSF p‐tau biomarkers had greater effect sizes than plasma p‐tau biomarkers when differentiating between amyloid‐PET positive and negative groups.Plasma p‐tau181 and plasma p‐tau231 performed worse than p‐tau181 and p‐tau231 in CSF for AD diagnosis. [ABSTRACT FROM AUTHOR]

Uncaria rhynchophylla (Gouteng in Chinese, GT) is the main medicine in many traditional recipes in China. It is commonly used to alleviate central nervous system (CNS) disorders, although its mechanism in Alzheimer's disease is still unknown. This study was designed to predict and validate the underlying mechanism in AD treatment, thus illustrating the biological mechanisms of GT in treating AD. In this study, a PPI network was constructed, KEGG analysis and GO analysis were performed, and an "active ingredient-target-pathway" network for the treatment of Alzheimer's disease was constructed. The active ingredients of GT were screened out, and the key targets were performed by molecular docking. UHPLC-Q-Exactive Orbitrap MS was used to screen the main active ingredients and was compared with the network pharmacology results, which verified that GT did contain the above ingredients. A total of targets were found to be significantly bound up with tau, Aβ, or Aβ and tau through the network pharmacology study. Three SH-SY5Y cell models induced by okadaic acid (OA), Na2S2O4, and H2O2 were established for in vitro validation. We first found that GT can reverse the increase in the hyperphosphorylation of tau induced by OA to some extent, protecting against ROS damage. Moreover, the results also indicated that GT has significant neuroprotective effects. This study provides a basis for studying the potential mechanisms of GT in the treatment of AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Phosphorylated tau (p‐tau) biomarkers have been recently proposed to represent brain amyloid‐β (Aβ) pathology. Here, we evaluated the plasma biomarkers' contribution beyond the information provided by demographics (age and sex) to identify Aβ and tau pathologies in individuals segregated as cognitively unimpaired (CU) and impaired (CI). METHODS: We assessed 138 CU and 87 CI with available plasma p‐tau231, 217+, and 181, Aβ42/40, GFAP and Aβ‐ and tau‐PET. RESULTS: In CU, only plasma p‐tau231 and p‐tau217+ significantly improved the performance of the demographics in detecting Aβ‐PET positivity, while no plasma biomarker provided additional information to identify tau‐PET positivity. In CI, p‐tau217+ and GFAP significantly contributed to demographics to identify both Aβ‐PET and tau‐PET positivity, while p‐tau231 only provided additional information to identify tau‐PET positivity. DISCUSSION: Our results support plasma p‐tau231 and p‐tau217+ as state markers of early Aβ deposition, but in later disease stages they inform on tau tangle accumulation. Highlights: It is still unclear how much plasma biomarkers contribute to identification of AD pathology across the AD spectrum beyond the information already provided by demographics (age + sex).Plasma p‐tau231 and p‐tau217+ contribute to demographic information to identify brain Aβ pathology in preclinical AD.In CI individuals, plasma p‐tau231 contributes to age and sex to inform on the accumulation of tau tangles, while p‐tau217+ and GFAP inform on both Aβ deposition and tau pathology. [ABSTRACT FROM AUTHOR]

BACKGROUND: A combination of plasma phospho‐tau (p‐tau), amyloid beta (Aβ)‐positron emission tomography (PET), brain magnetic resonance imaging, cognitive function tests, and other biomarkers might predict future cognitive decline. This study aimed to investigate the efficacy of combining these biomarkers in predicting future cognitive stage transitions within 3 years. METHODS: Among the participants in the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer's Disease (KBASE‐V) study, 49 mild cognitive impairment (MCI) and 113 cognitively unimpaired (CU) participants with Aβ‐PET and brain imaging data were analyzed. RESULTS: Older age, increased plasma p‐tau181, Aβ‐PET positivity, and decreased semantic fluency were independently associated with cognitive stage transitions. Combining age, p‐tau181, the Centiloid scale, semantic fluency, and hippocampal volume produced high predictive value in predicting future cognitive stage transition (area under the curve = 0.879). CONCLUSIONS: Plasma p‐tau181 and Centiloid scale alone or in combination with other biomarkers, might predict future cognitive stage transition in non‐dementia patients. Highlights: ‐Plasma p‐tau181 and Centiloid scale might predict future cognitive stage transition.‐Combining them or adding other biomarkers increased the predictive value.‐Factors that independently associated with cognitive stage transition were demonstrated. [ABSTRACT FROM AUTHOR]

Abstract Background Diabetic encephalopathy (DE) is a complication of type 2 diabetes mellitus (T2DM) that features Alzheimer's disease (AD)-like pathology, which can be degraded by the autophagy-lysosome pathway (ALP). Since transcription factor EB (TFEB) is a master regulator of ALP, TFEB-mediated ALP activation might have a therapeutic effect on DE, but this has yet to be investigated. Methods We established T2DM mouse models and cultured HT22 cells under high-glucose (HG) conditions to confirm the role of ALP in DE. To further investigate this, both mice and HT22 cells were treated with 3-methyladenine (3-MA). We also analyzed the content of TFEB in the nucleus and cytoplasm to evaluate its role in ALP. To confirm the effect of TFEB activation at the post-translational level in DE, we used rapamycin to inhibit the mechanistic target of rapamycin (mTOR). We transduced both mice and cells with TFEB vector to evaluate the therapeutic effect of TFEB overexpression on DE. Conversely, we conducted TFEB knockdown to verify its role in DE in another direction. Results We found that T2DM mice experienced compromised cognitive function, while HG-cultured HT22 cells exhibited increased cell apoptosis. Additionally, both T2DM mice and HG-cultured HT22 cells showed impaired ALP and heavier AD-like pathology. This pathology worsened after treatment with 3-MA. We also observed decreased TFEB nuclear translocation in both T2DM mice and HG-cultured HT22 cells. However, inhibiting mTOR with rapamycin or overexpressing TFEB increased TFEB nuclear translocation, enhancing the clearance of ALP-targeted AD-like pathology. This contributed to protection against neuronal apoptosis and alleviation of cognitive impairment. Conversely, TFEB knockdown lessened ALP-targeted AD-like pathology clearance and had a negative impact on DE. Conclusion Our findings suggest that impaired ALP is responsible for the aggravation of AD-like pathology in T2DM. We propose that mTOR-dependent TFEB activation and TFEB overexpression are promising therapeutic strategies for DE, as they enhance the clearance of ALP-targeted AD-like pathology and alleviate neuronal apoptosis. Our study provides insight into the underlying mechanisms of DE and offers potential avenues for the development of new treatments for this debilitating complication of T2DM. Graphic Abstract Video abstract

Abstract Alzheimer’s disease (AD) is characterized by genetic and multifactorial risk factors. Many studies correlate AD to sleep disorders. In this study, we performed and validated a mouse model of AD and sleep fragmentation, which properly mimics a real condition of intermittent awakening. We noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to aquaporin-4 (AQP4) modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects aquaporin-4 channel (AQP4) expression according to the stage of the disease, with an up-regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4. Nevertheless, an in-depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms.

Abstract Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta‐amyloid (CSF Aβ1‐42) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau181, and FDG‐PET. To determine disease stage, we stratified participants into early Aβ‐accumulators (Aβ CSF+/PET−; n = 70) or late Aβ‐accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ‐accumulators, higher centiloid was associated with cross‐sectional/longitudinal sTREM2 and p‐tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau181 increases and higher sTREM2 was associated with FDG‐PET hypermetabolism. In late Aβ‐accumulators, we found no association between centiloid and sTREM2 but a cross‐sectional association between higher sTREM2, higher p‐tau181 and glucose hypometabolism. Our findings suggest that a TREM2‐related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p‐tau181 increases in earliest AD.

Abstract Purpose Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) concentration is increased in cerebrospinal fluid (CSF) in early symptomatic phase of Alzheimer’s disease (AD). This study investigated whether CSF sTREM2 has a relationship with early cognitive dysfunction following surgery in cardiac surgery patients. Methods A total of 82 patients undergoing thoracoabdominal aortic replacement were recruited in this study. Neuropsychological testing battery was conducted before and after surgery. Postoperative cognitive dysfunction (POCD) was defined as a Z-score > 1.96 on at least 2 different tests or Telephone Interviews for Cognitive Status-Modified (TICS-M) score

Background: Diabetic encephalopathy (DE) is a complication of type 2 diabetes mellitus (T2DM) that features Alzheimer's disease (AD)-like pathology, which can be degraded by the autophagy-lysosome pathway (ALP). Since transcription factor EB (TFEB) is a master regulator of ALP, TFEB-mediated ALP activation might have a therapeutic effect on DE, but this has yet to be investigated. Methods: We established T2DM mouse models and cultured HT22 cells under high-glucose (HG) conditions to confirm the role of ALP in DE. To further investigate this, both mice and HT22 cells were treated with 3-methyladenine (3-MA). We also analyzed the content of TFEB in the nucleus and cytoplasm to evaluate its role in ALP. To confirm the effect of TFEB activation at the post-translational level in DE, we used rapamycin to inhibit the mechanistic target of rapamycin (mTOR). We transduced both mice and cells with TFEB vector to evaluate the therapeutic effect of TFEB overexpression on DE. Conversely, we conducted TFEB knockdown to verify its role in DE in another direction. Results: We found that T2DM mice experienced compromised cognitive function, while HG-cultured HT22 cells exhibited increased cell apoptosis. Additionally, both T2DM mice and HG-cultured HT22 cells showed impaired ALP and heavier AD-like pathology. This pathology worsened after treatment with 3-MA. We also observed decreased TFEB nuclear translocation in both T2DM mice and HG-cultured HT22 cells. However, inhibiting mTOR with rapamycin or overexpressing TFEB increased TFEB nuclear translocation, enhancing the clearance of ALP-targeted AD-like pathology. This contributed to protection against neuronal apoptosis and alleviation of cognitive impairment. Conversely, TFEB knockdown lessened ALP-targeted AD-like pathology clearance and had a negative impact on DE. Conclusion: Our findings suggest that impaired ALP is responsible for the aggravation of AD-like pathology in T2DM. We propose that mTOR-dependent TFEB activation and TFEB overexpression are promising therapeutic strategies for DE, as they enhance the clearance of ALP-targeted AD-like pathology and alleviate neuronal apoptosis. Our study provides insight into the underlying mechanisms of DE and offers potential avenues for the development of new treatments for this debilitating complication of T2DM. 5ufRcBtb1e2MDbQrLwAyEP Video abstract [ABSTRACT FROM AUTHOR]

Introduction: Plasma biomarkers will likely revolutionize the diagnostic work‐up of Alzheimer's disease (AD) globally. Before widespread use, we need to determine if confounding factors affect the levels of these biomarkers, and their clinical utility. Methods: Participants with plasma and CSF biomarkers, creatinine, body mass index (BMI), and medical history data were included (BioFINDER‐1: n = 748, BioFINDER‐2: n = 421). We measured beta‐amyloid (Aβ42, Aβ40), phosphorylated tau (p‐tau217, p‐tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP). Results: In both cohorts, creatinine and BMI were the main factors associated with NfL, GFAP, and to a lesser extent with p‐tau. However, adjustment for BMI and creatinine had only minor effects in models predicting either the corresponding levels in CSF or subsequent development of dementia. Discussion: Creatinine and BMI are related to certain plasma biomarkers levels, but they do not have clinically relevant confounding effects for the vast majority of individuals. Highlights: Creatinine and body mass index (BMI) are related to certain plasma biomarker levels.Adjusting for creatinine and BMI has minor influence on plasma‐cerebrospinal fluid (CSF) associations.Adjusting for creatinine and BMI has minor influence on prediction of dementia using plasma biomarkers. [ABSTRACT FROM AUTHOR]

Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age- and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid β (Aβ), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas Aβ deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the leading cause of dementia throughout the world. It is characterized by major amyloid plaques and neurofibrillary tangles (NFTs), which are composed of amyloid-β (Aβ) peptide and hyperphosphorylated Tau (p-Tau), respectively. Exosomes, which are secreted by cells, are single-membrane lipid bilayer vesicles found in bodily fluids and they have a diameter of 30–150 nm. Recently, they have been considered as critical carriers and biomarkers in AD, as they facilitate communication between cells and tissues by delivering proteins, lipids, and nucleic acids. This review demonstrates that exosomes are natural nanocontainers that carry APP as well as Tau cleavage products secreted by neuronal cells and that their formation is associated with the endosomal–lysosomal pathway. Moreover, these exosomes can transfer AD pathological molecules and participate in the pathophysiological process of AD; therefore, they have potential diagnostic and therapeutic value for AD and might also provide novel insights for screening and prevention of the disease. [ABSTRACT FROM AUTHOR]

Abstract Background We previously identified four Alzheimer’s disease (AD) subgroups with increasingly higher cerebrospinal fluid (CSF) levels of tau phosphorylated at threonine 181 (p-tau). These subgroups included individuals across the cognitive spectrum, suggesting p-tau subgroups could reflect distinct biological changes in AD, rather than disease severity. Therefore, in the current study, we further investigated which potential processes may be related with p-tau subgroups, by comparing individuals on CSF markers for presynaptic structure [vesicle-associated membrane protein 2 (VAMP2)], postsynaptic structure [neurogranin (NRGN)], axonal damage [neurofilament light (NfL)], and amyloid production [beta-secretase 1 (BACE1) and amyloid-beta 1–40 (Aβ40)]. Methods We selected 348 amyloid-positive (A+) individuals (53 preclinical, 102 prodromal, 193 AD dementia) and 112 amyloid-negative (A−) cognitively normal (CN) individuals from the Amsterdam Dementia Cohort (ADC). Individuals were labeled according to their p-tau subgroup (subgroup 1: p-tau ≤ 56 pg/ml; subgroup 2: 57–96 pg/ml; subgroup 3: 97–159 pg/ml; subgroup 4: > 159 pg/ml). CSF protein levels were measured with ELISA (NRGN, BACE1, Aβ40, NfL) or single-molecule array (Simoa) (VAMP2). We tested whether protein levels differed between the p-tau subgroups within A+ individuals with linear models corrected for age and sex and whether disease stage influenced these relationships. Results Among A+ individuals, higher p-tau subgroups showed a higher percentage of AD dementia [subgroup 1: n = 41/94 (44%); subgroup 2: n = 81/147 (55%); subgroup 3: n = 59/89 (66%); subgroup 4: n = 7/11 (64%)]. Relative to controls, subgroup 1 showed reduced CSF levels of BACE1, Aβ40, and VAMP2 and higher levels of NfL. Subgroups 2 to 4 showed gradually increased CSF levels of all measured proteins, either across the first three (NfL and Aβ40) or across all subgroups (VAMP2, NRGN, BACE1). The associations did not depend on the clinical stage (interaction p-values ranging between 0.19 and 0.87). Conclusions The results suggest that biological heterogeneity in p-tau levels in AD is related to amyloid metabolism and synaptic integrity independent of clinical stage. Biomarkers reflecting amyloid metabolism and synaptic integrity may be useful outcome measures in clinical trials targeting tau pathology.

Abstract Background Recent advances in disease-modifying treatments highlight the need for accurately identifying individuals in early Alzheimer’s disease (AD) stages and for monitoring of treatment effects. Plasma measurements of phosphorylated tau (p-tau) are a promising biomarker for AD, but different assays show varying diagnostic and prognostic accuracies. The objective of this study was to determine the clinical performance of a novel plasma p-tau217 (p-tau217) assay, p-tau217+Janssen, and perform a head-to-head comparison to an established assay, plasma p-tau217Lilly, within two independent cohorts. Methods The study consisted of two cohorts, cohort 1 (27 controls and 25 individuals with mild-cognitive impairment [MCI]) and cohort 2 including 147 individuals with MCI at baseline who were followed for an average of 4.92 (SD 2.09) years. Receiver operating characteristic analyses were used to assess the performance of both assays to detect amyloid-β status (+/−) in CSF, distinguish MCI from controls, and identify subjects who will convert from MCI to AD dementia. General linear and linear mixed-effects analyses were used to assess the associations between p-tau and baseline, and annual change in Mini-Mental State Examination (MMSE) scores. Spearman correlations were used to assess the associations between the two plasma measures, and Bland-Altmann plots were examined to assess the agreement between the assays. Results Both assays showed similar performance in detecting amyloid-β status in CSF (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.89), distinguishing MCI from controls (plasma p-tau217+Janssen AUC = 0.91 vs plasma p-tau217Lilly AUC = 0.91), and predicting future conversion from MCI to AD dementia (plasma p-tau217+Janssen AUC = 0.88 vs p-tau217Lilly AUC = 0.89). Both assays were similarly related to baseline (plasma p-tau217+Janssen rho = −0.39 vs p-tau217Lilly rho = −0.35), and annual change in MMSE scores (plasma p-tau217+Janssen r = −0.45 vs p-tau217Lilly r = −0.41). Correlations between the two plasma measures were rho = 0.69, p < 0.001 in cohort 1 and rho = 0.70, p < 0.001 in cohort 2. Bland-Altmann plots revealed good agreement between plasma p-tau217+Janssen and plasma p-tau217Lilly in both cohorts (cohort 1, 51/52 [98%] within 95%CI; cohort 2, 139/147 [95%] within 95%CI). Conclusions Taken together, our results indicate good diagnostic and prognostic performance of the plasma p-tau217+Janssen assay, similar to the p-tau217Lilly assay.

Abstract Background Up to now, there are no clinically available minimally invasive biomarkers to accurately identify mild cognitive impairment (MCI) patients who are at greater risk to progress to Alzheimer’s disease (AD) dementia. The recent advent of blood-based markers opens the door for more accessible biomarkers. We aimed to identify which combinations of AD related plasma biomarkers and other easily accessible assessments best predict progression to AD dementia in patients with mild cognitive impairment (MCI). Methods We included patients with amnestic MCI (n = 110) followed prospectively over 3 years to assess clinical status. Baseline plasma biomarkers (amyloid-β 42/40, phosphorylated tau217 [p-tau217], neurofilament light and glial fibrillary acidic protein), hippocampal volume, APOE genotype, and cognitive tests were available. Logistic regressions with conversion to amyloid-positive AD dementia within 3 years as outcome was used to evaluate the performance of different biomarkers measured at baseline, used alone or in combination. The first analyses included only the plasma biomarkers to determine the ones most related to AD dementia conversion. Second, hippocampal volume, APOE genotype and a brief cognitive composite score (mPACC) were combined with the best plasma biomarker. Results Of all plasma biomarker combinations, p-tau217 alone had the best performance for discriminating progression to AD dementia vs all other combinations (AUC 0.84, 95% CI 0.75–0.93). Next, combining p-tau217 with hippocampal volume, cognition, and APOE genotype provided the best discrimination between MCI progressors vs. non-progressors (AUC 0.89, 0.82–0.95). Across the few best models combining different markers, p-tau217 and cognition were consistently the main contributors. The most parsimonious model including p-tau217 and cognition had a similar model fit, but a slightly lower AUC (0.87, 0.79–0.95, p = 0.07). Conclusion We identified that combining plasma p-tau217 and a brief cognitive composite score was strongly related to greater risk of progression to AD dementia in MCI patients, suggesting that these measures could be key components of future prognostic algorithms for early AD. Trial registration NCT01028053 , registered December 9, 2009.

Microglial activation occurs early in Alzheimer's disease (AD) and previous studies reported both detrimental and protective effects of microglia on AD progression. Here, we used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. We included 402 patients with measures of earliest beta‐amyloid (CSF Aβ1‐42) and late‐stage fibrillary Aβ pathology (amyloid‐PET centiloid), as well as sTREM2, p‐tau181, and FDG‐PET. To determine disease stage, we stratified participants into early Aβ‐accumulators (Aβ CSF+/PET−; n = 70) or late Aβ‐accumulators (Aβ CSF+/PET+; n = 201) plus 131 controls. In early Aβ‐accumulators, higher centiloid was associated with cross‐sectional/longitudinal sTREM2 and p‐tau181 increases. Further, higher sTREM2 mediated the association between centiloid and cross‐sectional/longitudinal p‐tau181 increases and higher sTREM2 was associated with FDG‐PET hypermetabolism. In late Aβ‐accumulators, we found no association between centiloid and sTREM2 but a cross‐sectional association between higher sTREM2, higher p‐tau181 and glucose hypometabolism. Our findings suggest that a TREM2‐related microglial response follows earliest Aβ fibrillization, manifests in inflammatory glucose hypermetabolism and may facilitate subsequent p‐tau181 increases in earliest AD. Synopsis: In Alzheimer's disease (AD), microglial activation has been linked to both detrimental and protective effects on disease progression. This study used CSF sTREM2 to investigate disease stage‐dependent drivers of microglial activation and to determine downstream consequences on AD progression. In participants with early beta‐amyloid (Aβ) accumulation, higher amyloid‐PET was associated with higher cross sectional/longitudinal CSF sTREM2 and CSF p‐tau181 levels.In participants with early Aβ accumulation, sTREM2 mediated the association between amyloid‐PET and CSF p‐tau181 increases.Higher CSF sTREM2 levels were associated with FDG‐PET glucose hypermetabolism in early Aβ accumulation but with glucose hypometabolism in late Aβ accumulation. [ABSTRACT FROM AUTHOR]