Total Tau Levels Research Articles

TYK2 regulates tau levels, phosphorylation and aggregation in a tauopathy mouse model

Abstract Alzheimer’s disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.

Blood-Based Biomarkers in Frontotemporal Dementia: A Narrative Review

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.

Linking human cerebral and ocular waste clearance: Insights from tear fluid and ultra-high field MRI

Impaired cerebral waste clearance (i.e., glymphatics) is evident in aging and neurodegenerative disorders, such as Alzheimer's disease, where an impaired waste clearance system could be related to the accumulation of pathological proteins (e.g., tau). One marker of impaired cerebral clearance is the abundance of enlarged perivascular spaces (PVS). Preclinical studies propose a similar clearance system in the eye, driven by intraocular pressure (IOP). This cross-sectional pilot study explores the link between ocular and the cerebral waste clearance by examining the association between MRI-visible PVS, tear total-tau, and IOP.Thirty cognitively healthy participants, all aged over 55 years, underwent 7 T MRI, with PVS visually rated in the centrum semiovale (CSO) and basal ganglia. Tear fluid was collected using paper Schirmer's strips and analyzed for total-tau using enzyme-linked immunosorbent assay. IOP was measured using non-contact tonometry. Partial Spearman's correlation coefficients of eye and brain markers were calculated, adjusted for age, sex, tear-wetting length, and hemispheric region of interest volume.Higher CSO PVS scores in the left and right hemisphere were associated with higher levels of tear total-tau. Higher CSO PVS scores in both hemispheres were related to lower ipsilateral IOP. The exploratory results suggest that higher tear total-tau and a reduced driving force of ocular waste clearance are connected to impaired cerebral waste clearance in cognitive healthy individuals. This study connects the potential ocular glymphatic system to cerebral waste clearance. Clarifying waste clearance biology and validating eye biomarkers for cerebral waste clearance could provide treatment targets and diagnostic opportunities for neurological diseases.

Neurosteroids Alter p-ERK Levels and Tau Distribution, Restraining the Effects of High Extracellular Calcium

Neurosteroids are undeniably regarded as neuroprotective mediators, regulating brain function by rapid non-genomic actions involving interference with microtubules. Conversely, hyperphosphorylated Tau is considered responsible for the onset of a plethora of neurodegenerative diseases, as it dissociates from microtubules, leading to their destabilization, thus impairing synaptic vesicle transport and neurotransmission. Consequently, we aimed to investigate the effects of neurosteroids, specifically allopregnanolone (Allo) and dehydroepiandrosterone (DHEA), on the levels of total and phosphorylated at Serine 404 Tau (p-Tau) in C57BL/6 mice brain slices. In total tissue extracts, we found that neurosteroids elevated both total and p-Tau levels without significantly altering the p-Tau/Tau ratio. In addition, the levels of several enzymes implicated in Tau phosphorylation did not display significant differences between conditions, suggesting that neurosteroids influence Tau distribution rather than its phosphorylation. Hence, we subsequently examined the mitochondria-enriched subcellular fraction where, again, both p-Tau and total Tau levels were increased in the presence of neurosteroids. These effects seem actin-dependent, as disrupting actin polymerization by cytochalasin B preserved Tau levels. Furthermore, co-incubation with high [Ca2+] and neurosteroids mitigated the effects of Ca2+ overload, pointing to cytoskeletal remodeling as a potential mechanism underlying neurosteroid-induced neuroprotection.

CSF and Plasma Biomarkers in Patients With Iatrogenic Cerebral Amyloid Angiopathy.

Recently, a subset of patients affected by cerebral amyloid angiopathy (CAA) distinguished by atypical juvenile onset and a hypothesized iatrogenic origin (iatrogenic CAA, iCAA) has emerged. β-Amyloid (Aβ) accumulation evidenced by amyloid PET positivity or CSF Aβ decrease was included in the iCAA diagnostic criteria. Conversely, diagnostic criteria for sporadic CAA (sCAA) do not involve biomarker analysis. The aim of this study was to assess CSF and plasma levels of Aβ and tau in iCAA and sCAA cohorts. Patients affected by probable or possible CAA according to established criteria (Boston 2.0) were prospectively recruited at Fondazione IRCCS Carlo Besta and San Gerardo dei Tintori from May 2021 to January 2024. Patients with probable and possible iCAA or sCAA with available plasma and/or CSF samples were included. Clinical and neurologic data were collected, and levels of Aβ40, Aβ42, total tau, and phospho-tau (p-tau) were assessed in CSF and plasma by SiMoA and Lumipulse. 21 patients with iCAA (72% male, mean age at symptom onset 50 years [36-74]) and 32 patients with sCAA (44% male, mean age at symptom onset 68 years [52-80]) were identified. Cognitive impairment and cardiovascular risk factors in the sCAA cohort were more common compared with the iCAA cohort. Patients with sCAA and iCAA showed similar CSF levels for Aβ40 (p = 0.5 [sCAA, 95% CI 2,604-4,228; iCAA, 95% CI 1,958-3,736]), Aβ42 (p = 0.7 [sCAA, 95% CI 88-157; iCAA, 95% CI 83-155]), and total tau (p = 0.08 [sCAA, 95% CI 80-134; iCAA, 95% CI 37-99]). Plasma levels of Aβ40 (p = 0.08, 95% CI 181-222), Aβ42 (p = 0.3, 95% CI 6-8), and total tau (p = 0.4, 95% CI 3-6) were not statistically different in patients with sCAA compared with iCAA ones (Aβ40, 95% CI 153-193; Aβ42, 95% CI 6-7 and total tau, 95% CI 2-4). Despite presenting with a younger age at onset, fewer cardiovascular risk factors, and lower cognitive impairment, patients with iCAA demonstrated Aβ and tau levels comparable with elderly patients with sCAA, supporting a common molecular paradigm between the 2 CAA forms.

Correlations between Cerebrospinal Fluid Biomarkers and Gray Matter Atrophy in Alzheimer's and Behavioural Variant Frontotemporal Dementia.

Distinguishing between frontotemporal dementia (FTD) and Alzheimer's disease (AD) in their early stages remains a significant clinical challenge. Cerebrospinal fluid (CSF) biomarkers (total Tau, phosphorylated Tau, and beta-amyloid) are promising candidates for identifying early differences between these conditions. This study investigates the relationship between grey matter density and CSF markers in the behavioural variant of frontotemporal dementia (bvFTD) and Alzheimer's disease (AD). CSF and 3D T1-weighted magnetic resonance (MR) images were acquired from 14 bvFTD patients, 15 AD patients, and 13 cognitively normal (CN) matched subjects. The CSF markers and their relative ratios (total Tau/beta-amyloid, phosphorylated Tau/beta-amyloid) were compared across the three groups. Voxel-based morphometry (VBM) was performed to characterize the anatomical changes in bvFTD and AD patients compared to CN subjects. Grey matter density maps were obtained by automatic segmentation of 3.0 Tesla 3D T1-Weighted MR Images, and their correlation with CSF markers and relative ratios was investigated. Results demonstrated that, as compared to CN subjects, AD patients are characterised by higher CSF total Tau levels and lower beta-amyloid levels; however, beta-amyloid and relative ratios discriminated AD from bvFTD. In addition, AD and bvFTD patients showed different patterns of atrophy, with AD exhibiting more central (temporal areas) and bvFTD more anterior (frontal areas) atrophy. A correlation was found between grey matter density maps and CSF marker concentrations in the AD group, with total Tau and phosphorylated Tau levels showing a high association with low grey matter density in the left superior temporal gyrus. The study concludes that while bvFTD lacks a CSF marker profile, CSF beta-amyloid levels are useful for differentiating AD from bvFTD. Furthermore, MR structural imaging can contribute significantly to distinguishing between the two pathologies.

CSF and blood levels of Neurofilaments, T-Tau, P-Tau, and Abeta-42 in amyotrophic lateral sclerosis: a systematic review and meta-analysis.

Recent literature suggests that markers of neuroaxonal damage, such as neurofilaments and tau protein, might serve as potential biomarkers for ALS. We conducted this systematic review and meta-analysis study to compare cerebrospinal fluid (CSF) and blood levels of total tau (t-tau), phosphorylated tau (p-tau), amyloid beta peptide 42 (Abeta-42), and neurofilaments in ALS patients and controls. A systematic search of Cochrane Library, PubMed, Embase, and ISI Web of Science was conducted on March 18, 2022, and updated on January 26, 2023. Observational studies that compared the concentrations of neurofilament light chain (NfL), neurofilament heavy chain (NFH), t-tau, p-tau, or Abeta-42 in CSF or peripheral blood of ALS patients and controls were included. Data from relevant studies were independently extracted and screened for quality using a standard tool, by at least two authors. Meta-analysis was conducted when a minimum of 3 studies reported the same biomarker within the same biofluid. A total of 100 studies were eligible for at least one meta-analysis. CSF and blood levels of NfL (standardized mean difference (SMD) [95% CI]; CSF: 1.46 [1.25-1.68]; blood: 1.35 [1.09-1.60]) and NFH (CSF: 1.32 [1.13-1.50], blood: 0.90 [0.58-1.22]) were significantly higher in ALS patients compared with controls. The pooled differences between ALS patients and controls were not significant for CSF t-tau, blood t-tau, and CSF Abeta-42, but CSF p-tau was lower in ALS patients (-0.27 [-0.47- -0.07]). Significantly decreased p-tau/t-tau ratios were found in ALS patients compared with controls (-0.84 [-1.16- -0.53]). Heterogeneity was considerable in most of our meta-analyses. CSF and blood neurofilament levels, as well as the CSF p-tau/t-tau ratio, might be potential candidates for improving ALS diagnosis. Further research is warranted to better understand the underlying mechanisms and the clinical implications of these biomarker alterations.

Predictive value of neuronal markers for pituitary dysfunction following traumatic brain injury: A preliminary study

Purpose: Traumatic brain injury (TBI), a well-known risk factor for pituitary dysfunction, is associated with increased serum neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and total tau (t-tau) levels. We aimed to assess the predictive value of these markers and pituitary dysfunction following TBI in a prospective manner.Methods: Adult patients following TBI were included. Serum levels of NFL, GFAP, t-tau and pituitary and target hormones were analyzed prospectively during first week and one year after TBI.Results: Twenty-two patients (17 males, 5 females; mean age 40±15 years) were included in the study. Basal NFL levels correlated positively with length of hospital stay and basal cortisol (r=0.643, p=0.001 and r=0.558, p=0.007, respectively) and negatively with Glasgow Coma Scale (GCS) score and basal IGF-1 levels (r=-0.429, p=0.046 and r=-0.481, p=0.023, respectively), while there was no significant correlation between GFAP, t-tau and hormone levels. NFL, GFAP, and t-tau levels significantly decreased, and none of the patients developed hormone deficiencies one year after TBI. No correlations were detected between basal markers and first year pituitary hormone levels.Conclusion: Serum NFL levels were correlated with hormonal changes during acute phase of TBI reflecting the physiological response to trauma. Larger studies are needed to analyze the associations during chronic phase.

Mediating role of obstructive sleep apnea in altering slow-wave activity and elevating Alzheimer’s disease risk: Pilot study from a northern Taiwan cohort

ObjectivesObstructive sleep apnea is associated with alterations in slow-wave activity during sleep, potentially increasing the risk of Alzheimer’s disease. This study investigated the associations between obstructive sleep apnea manifestations such as respiratory events, hypoxia, arousal, slow-wave patterns, and neurochemical biomarker levels. MethodsIndividuals with suspected obstructive sleep apnea underwent polysomnography. Sleep disorder indices, oxygen metrics, and slow-wave activity data were obtained from the polysomnography, and blood samples were taken the following morning to determine the plasma levels of total tau (T-Tau) and amyloid beta-peptide 42 (Aβ42) by using an ultrasensitive immunomagnetic reduction assay. Subsequently, the participants were categorized into groups with low and high Alzheimer’s disease risk on the basis of their computed product Aβ42 × T-Tau. Intergroup differences and the associations and mediation effects between sleep-related parameters and neurochemical biomarkers were analyzed. ResultsForty-two participants were enrolled, with 21 assigned to each of the low- and high-risk groups. High-risk individuals had a higher apnea–hypopnea index, oxygen desaturation index (≥3%, ODI-3%), fraction of total sleep time with oxygen desaturation (SpO2-90% TST), and arousal index and greater peak-to-peak amplitude and slope in slow-wave activity, with a correspondingly shorter duration, than did low-risk individuals. Furthermore, indices such as the apnea–hypopnea index, ODI-3% and SpO2-90% TST were found to indirectly affect slow-wave activity, thereby raising the Aβ42 × T-Tau level. ConclusionsObstructive sleep apnea manifestations, such as respiratory events and hypoxia, may influence slow-wave sleep activity (functioning as intermediaries) and may be linked to elevated neurochemical biomarker levels. However, a longitudinal study is necessary to determine causal relationships among these factors. Statement of significanceThis research aims to bridge gaps in understanding how obstructive sleep apnea is associated with an elevated risk of Alzheimer’s disease, providing valuable knowledge for sleep and cognitive health.

Biomarker Profiles in Serum and CSF for Early Diagnosis of Selected Neurodegenerative Diseases

Biomarker research and justification for neurodegenerative illnesses have seen enormous efforts over the last ten years. Bio-fluid-based biomarkers have been believed to provide a better and easier approach to detecting biomarkers for diagnosing nervous system pathologies. Objectives: To evaluate the diagnostic potential of certain biomarkers in serum and cerebrospinal fluid to diagnose Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease at an initial stage. Methods: 280 participants were taken and distributed into four groups, comprising, 70 patients with early-stage Alzheimer’s disease, 70 with early-stage Parkinson’s disease, 70 with early-stage Huntington’s disease, and 70 age-matched healthy controls. Blood and cerebrospinal fluid samples were drawn and medical history was taken from the patients. Serum and cerebrospinal fluid levels of amyloid-beta (Aβ42), total tau (t-tau), phosphorylated tau (p-tau), alpha-synuclein, huntingtin protein, and neuro-filament light chain were evaluated using enzyme-linked immunosorbent assays. Results: Alzheimer’s disease patients showed reduced serum Aβ42 (80.4 ± 15.6 pg/mL) and elevated t-tau (140.5 ± 18.2 pg/mL). Parkinson’s disease patients had raised serum alpha-synuclein (12.5 ± 2.3 ng/mL) and neuro-filament light chain. Huntington’s disease patients showed significant increases in serum huntingtin protein (8.2 ± 2.0 ng/mL). These profiles indicate efficacy in early diagnosis. Conclusions: It was concluded that Aβ42 and tau effectively detect Alzheimer’s disease, while Parkinson’s disease patients can be effectively diagnosed with Serum and cerebrospinal fluid levels of the neuro-filament light chain. Similarly, huntingtin protein and neuro-filament light chain are sensitive enough to detect Huntington’s disease at its early stages.

A tau dephosphorylation-targeting chimera selectively recruits protein phosphatase-1 to ameliorate Alzheimer’s disease and tauopathies

Abnormal accumulation of hyperphosphorylated tau (pTau) is a major cause of neurodegeneration in Alzheimer's disease (AD) and related tauopathies. Therefore, reducing pTau holds therapeutic promise for these diseases. Here, we developed a chimeric peptide, named D20, for selective facilitation of tau dephosphorylation by recruiting protein phosphatase 1 (PP1) to tau. PP1 is one of the active phosphatases that dephosphorylates tau. In both cultured primary hippocampal neurons and mouse models for AD or related tauopathies, we demonstrated that single-dose D20 treatment significantly reduced pTau by dephosphorylation at multiple AD-related sites and total tau (tTau) levels were also decreased. Multiple-dose administration of D20 through tail vein injection in 3xTg AD mice effectively ameliorated tau-associated pathologies with improved cognitive functions. Importantly, at therapeutic doses, D20 did not cause detectable toxicity in cultured neurons, neural cells, or peripheral organs in mice. These results suggest that D20 is a promising drug candidate for AD and related tauopathies.

High-dimensional proteomic analysis for pathophysiological classification of traumatic brain injury.

Pathophysiology and outcomes after Traumatic Brain Injury (TBI) are complex and heterogenous. Current classifications are uninformative about pathophysiology. Proteomic approaches with fluid-based biomarkers are ideal for exploring complex disease mechanisms, as they enable sensitive assessment of an expansive range of processes potentially relevant to TBI pathophysiology. We used novel high-dimensional, multiplex proteomic assays to assess altered plasma protein expression in acute TBI. We analysed samples from 88 participants from the BIO-AX-TBI cohort (n=38 moderate-severe TBI [Mayo Criteria], n=22 non-TBI trauma, n=28 non-injured controls) on two platforms: Alamar NULISA™ CNS Diseases and OLINK® Target 96 Inflammation. Patient participants were enrolled after hospital admission, and samples taken at a single timepoint up to 10 days post-injury. Participants also had neurofilament light, GFAP, total tau, UCH-L1 (all Simoa®) and S100B (Millipore) data. The Alamar panel assesses 120 proteins, most of which were previously unexplored in TBI, plus proteins with known TBI-specificity, such as GFAP. A subset (n=29 TBI, n=24 non-injured controls) also had subacute (10 days to 6 weeks post-injury) 3T MRI measures of lesion volume and white matter injury (fractional anisotropy). Differential Expression analysis identified 16 proteins with TBI-specific significantly different plasma expression. These were neuronal markers (calbindin2, UCH-L1, visinin-like protein1), astroglial markers (S100B, GFAP), neurodegenerative disease proteins (total tau, pTau231, PSEN1, amyloid-beta-42, 14-3-3γ), inflammatory cytokines (IL16, CCL2, ficolin2), cell signalling (SFRP1), cell metabolism (MDH1) and autophagy related (sequestome1) proteins. Acute plasma levels of UCH-L1, PSEN1, total tau and pTau231 correlated with subacute lesion volume. Sequestome1 was positively correlated, whilst CLL2 was inversely correlated, with white matter fractional anisotropy. Neuronal, astroglial, tau and neurodegenerative proteins correlated with each other, IL16, MDH1 and sequestome1. Exploratory clustering (k means) by acute protein expression identified 3 TBI subgroups that differed in injury patterns, but not age or outcome. One TBI cluster had significantly lower white matter fractional anisotropy than control-predominant clusters, but had significantly lower lesion subacute lesions volumes than another TBI cluster. Proteins that overlapped on two platforms had excellent (r>0.8) correlations between values. We identified TBI-specific changes in acute plasma levels of proteins involved in neurodegenerative disease, inflammatory and cellular processes. These changes were related to patterns of injury, thus demonstrating that processes previously only studied in animal models are also relevant in human TBI pathophysiology. Our study highlights how proteomic approaches might improve classification and understanding of TBI pathophysiology, with implications for prognostication and treatment development.

An Enteric Bacterial Infection Triggers Neuroinflammation and Neurobehavioral Impairment in 3xTg-AD Transgenic Mice.

Klebsiella pneumoniae is infamous for hospital-acquired infections and sepsis, which have also been linked to Alzheimer disease (AD)-related neuroinflammatory and neurodegenerative impairment. However, its causative and mechanistic role in AD pathology remains unstudied. A preclinical model of K. pneumoniae enteric infection and colonization is developed in an AD model (3xTg-AD mice) to investigate whether and how K. pneumoniae pathogenesis exacerbates neuropathogenesis via the gut-blood-brain axis. K. pneumoniae, particularly under antibiotic-induced dysbiosis, was able to translocate from the gut to the bloodstream by penetrating the gut epithelial barrier. Subsequently, K. pneumoniae infiltrated the brain by breaching the blood-brain barrier. Significant neuroinflammatory phenotype was observed in mice with K. pneumoniae brain infection. K. pneumoniae-infected mice also exhibited impaired neurobehavioral function and elevated total tau levels in the brain. Metagenomic analyses revealed an inverse correlation of K. pneumoniae with gut biome diversity and commensal bacteria, highlighting how antibiotic-induced dysbiosis triggers an enteroseptic "pathobiome" signature implicated in gut-brain perturbations. The findings demonstrate how infectious agents following hospital-acquired infections and consequent antibiotic regimen may induce gut dysbiosis and pathobiome and increase the risk of sepsis, thereby increasing the predisposition to neuroinflammatory and neurobehavioral impairments via breaching the gut-blood-brain barrier.

Genome-wide association study meta-analysis of neurofilament light (NfL) levels in blood reveals novel loci related to neurodegeneration

Neurofilament light chain (NfL) levels in circulation have been established as a sensitive biomarker of neuro-axonal damage across a range of neurodegenerative disorders. Elucidation of the genetic architecture of blood NfL levels could provide new insights into molecular mechanisms underlying neurodegenerative disorders. In this meta-analysis of genome-wide association studies (GWAS) of blood NfL levels from eleven cohorts of European ancestry, we identify two genome-wide significant loci at 16p12 (UMOD) and 17q24 (SLC39A11). We observe association of three loci at 1q43 (FMN2), 12q14, and 12q21 with blood NfL levels in the meta-analysis of African-American ancestry. In the trans-ethnic meta-analysis, we identify three additional genome-wide significant loci at 1p32 (FGGY), 6q14 (TBX18), and 4q21. In the post-GWAS analyses, we observe the association of higher NfL polygenic risk score with increased plasma levels of total-tau, Aβ-40, Aβ-42, and higher incidence of Alzheimer’s disease in the Rotterdam Study. Furthermore, Mendelian randomization analysis results suggest that a lower kidney function could cause higher blood NfL levels. This study uncovers multiple genetic loci of blood NfL levels, highlighting the genes related to molecular mechanism of neurodegeneration.

Clinical correlates of obstructive sleep apnoea in idiopathic normal pressure hydrocephalus.

The pathogenesis of idiopathic normal pressure hydrocephalus (iNPH) remains controversial. Limited studies have indicated a high prevalence of obstructive sleep apnoea (OSA) amongst iNPH patients. The aim was to investigate the clinical correlates of OSA in iNPH patients. In this cross-sectional observational study, consecutive iNPH patients were prospectively enrolled. Evaluations included the iNPH Rating Scale, the Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the time and number of steps to walk 10 m, the Epworth Sleepiness Scale, the Pittsburgh Sleep Quality Index, a complete neuropsychological evaluation, 3-T brain MRI, full-night video-polysomnography, tap test and cerebrospinal fluid (CSF) neurodegeneration biomarkers. Fifty-one patients were screened, of whom 38 met the inclusion criteria. Amongst the recruited patients, 19/38 (50%) exhibited OSA, with 12/19 (63.2%) presenting moderate to severe disorder. OSA+ iNPH patients required more time (p = 0.02) and more steps (p = 0.04) to complete the 10-m walking test, had lower scores on the gait subitem of the iNPH Rating Scale (p = 0.04) and demonstrated poorer performance on specific neuropsychological tests (Rey Auditory Verbal Learning Test immediate recall, p = 0.03, and Rey-Osterrieth Complex Figure, p = 0.01). Additionally, OSA+ iNPH patients had higher levels of total tau (p = 0.02) and phospho-tau (p = 0.03) in their CSF but no statistically significant differences in beta-amyloid (1-42) levels compared to OSA- iNPH patients. Obstructive sleep apnoea is highly prevalent in iNPH patients, particularly at moderate to severe levels. OSA is associated with worse motor and cognitive performance in iNPH. The CSF neurodegeneration biomarker profile observed in OSA+ iNPH patients may reflect OSA-induced impairment of cerebral fluid dynamics.

Synergistic effects of GFAP and Aβ42: Implications for white matter integrity and verbal memory across the cognitive spectrum

BackgroundPlasma glial fibrillary acidic protein (GFAP), an astrocytic biomarker, has previously been linked with Alzheimer's disease (AD) status, amyloid levels, and memory performance in older adults. The neuroanatomical pathways by which astrogliosis/astrocyte reactivity might impact cognitive outcomes remains unclear. We evaluated whether plasma GFAP and amyloid levels had a synergistic effect on fornix structure, which is critically involved in AD-associated cholinergic pathways. We also examined whether fornix structure mediates associations between GFAP and verbal memory. MethodsIn a cohort of both asymptomatic and symptomatic older adults (total n = 99), we assessed plasma GFAP, amyloid-β42 (Aβ42), other AD-related proteins, and vascular markers, and we conducted comprehensive memory testing. Tractography-based methods were used to assess fornix structure with whole brain diffusion metrics to control for diffuse alterations in brain white matter. ResultsIn individuals in the low plasma amyloid-β42 (Aβ42) group, higher plasma GFAP was associated with lower fractional anisotropy (FA; p = 0.007), higher mean diffusivity (MD; p < 0.001), higher radial diffusivity (RD; p < 0.001), and higher axial diffusivity (DA; p = 0.001) in the left fornix. These associations were independent of APOE gene status, plasma levels of total tau and neurofilament light, plasma vascular biomarkers, and whole brain diffusion metrics. In a sub-analysis of participants in the low plasma Aβ42 group (n = 33), fornix structure mediated the association between higher plasma GFAP levels and lower verbal memory performance. DiscussionHigher plasma GFAP was associated with altered fornix microstructure in the setting of greater amyloid deposition. We also expanded on our prior GFAP-verbal memory findings by demonstrating that in the low plasma Aβ42 group, left fornix integrity may be a primary white matter conduit for the negative associations between GFAP and verbal memory performance. Overall, these findings suggest that astrogliosis/astrocyte reactivity may play an early, pivotal role in AD pathogenesis, and further demonstrate that high GFAP and low Aβ42 in plasma may reflect a particularly detrimental synergistic role in forniceal-memory pathways.

There Is No Direct Causal Relationship Between Coronary Artery Disease and Alzheimer Disease: A Bidirectional Mendelian Randomization Study.

The association between poor cardiovascular health and cognitive decline as well as dementia progression has been inconsistent across studies. This study used Mendelian randomization (MR) to investigate the causal relationship between Alzheimer disease (AD), circulating levels of total-tau, and coronary artery disease (CAD). This study used MR to investigate the causal relationship between AD or circulating levels of total-tau and CAD, including ischemic heart disease, myocardial infarction, coronary heart disease, coronary atherosclerosis, and heart failure. The primary analysis used the inverse-variance weighted method, with pleiotropy and heterogeneity assessed using MR-Egger regression and the Q statistic. The overall results of the MR analysis indicated that AD did not exhibit a causal effect on heart failure (odds ratio [OR], 0.969 [95% CI, 0.921-1.018]; P=0.209), myocardial infarction (OR, 0.972 [95% CI, 0.915-1.033]; P=0.359), ischemic heart disease (OR, 1.013 [95% CI, 0.949-1.082]; P=0.700), coronary heart disease (OR, 1.005 [95% CI, 0.937-1.078]; P=0.881), or coronary atherosclerosis (OR, 0.987 [95% CI, 0.926-1.052]; P=0.690). No significant causal effect of CAD was observed on AD in the reverse MR analysis. Additionally, our findings revealed that CAD did not influence circulating levels of total-tau, nor did circulating levels of total-tau increase the risk of CAD. Sensitivity analysis and assessment of horizontal pleiotropy suggested that these factors did not distort the causal estimates. The findings of this study indicate the absence of a direct causal relationship between AD and CAD from a genetic perspective. Therefore, managing the 2 diseases should be more independent and targeted. Concurrently, investigating the mechanism underlying their comorbidity may not yield meaningful insights for advancing treatment strategies.

Association of oxidative stress and inflammatory metabolites with Alzheimer’s disease cerebrospinal fluid biomarkers in mild cognitive impairment

BackgroundIsoprostanes and prostaglandins are biomarkers for oxidative stress and inflammation. Their role in Alzheimer's disease (AD) pathophysiology is yet unknown. In the current study, we aim to identify the association of isoprostanes and prostaglandins with the Amyloid, Tau, Neurodegeneration (ATN) biomarkers (Aβ-42, p-tau, and t-tau) of AD pathophysiology in mild cognitive impairment (MCI) subjects.MethodsTargeted metabolomics profiling was performed using liquid chromatography-mass spectrometry (LCMS) in 147 paired plasma-CSF samples from the Ace Alzheimer Center Barcelona and 58 CSF samples of MCI patients from the Mannheim/Heidelberg cohort. Linear regression was used to evaluate the association of metabolites with CSF levels of ATN biomarkers in the overall sample and stratified by Aβ-42 pathology and APOE genotype. We further evaluated the role of metabolites in MCI to AD dementia progression.ResultsIncreased CSF levels of PGF2α, 8,12-iso-iPF2α VI, and 5-iPF2α VI were significantly associated (False discovery rate (FDR) < 0.05) with higher p-tau levels. Additionally, 8,12-iso-iPF2α VI was associated with increased total tau levels in CSF. In MCI due to AD, PGF2α was associated with both p-tau and total tau, whereases 8,12-iso-iPF2α VI was specifically associated with p-tau levels. In APOE stratified analysis, association of PGF2α with p-tau and t-tau was observed in only APOE ε4 carriers while 5-iPF2α VI showed association with both p-tau and t-tau in APOE ε33 carriers. CSF levels of 8,12- iso-iPF2α VI showed association with p-tau and t-tau in APOE ε33/APOE ε4 carriers and with t-tau in APOE ε3 carriers. None of the metabolites showed evidence of association with MCI to AD progression.ConclusionsOxidative stress (8,12-iso-iPF2α VI) and inflammatory (PGF2α) biomarkers are correlated with biomarkers of AD pathology during the prodromal stage of AD and relation of PGF2α with tau pathology markers may be influenced by APOE genotype.

Association of liver function markers and apolipoprotein E ε4 with pathogenesis and cognitive decline in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder influenced by various factors, including liver function, which may impact the clearance of amyloid-β (Aβ) in the brain. This study aimed to explore how the apolipoprotein E (APOE) ε4 allele affects the relationship of liver function markers with AD pathology and cognition. We analyzed data from two independent cohorts, including 732 participants from the Hallym University Medical Center and 483 from the Alzheimer's Disease Neuroimaging Initiative, each group consisting of individuals with and without the APOE ε4 allele. Cross-sectional analyses evaluated the associations of liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, total bilirubin, and albumin) with AD diagnosis, amyloid positron emission tomography (PET) burden, and cerebrospinal fluid biomarkers for AD (Aβ42, total tau, and phosphorylated tau181) at baseline. Longitudinally, we investigated the associations between these liver enzymes and changes in cognitive performance over the course of a year. Logistic and linear regression models were used to analyze these associations and mediation analyses were conducted to assess whether age and amyloid PET burden mediated these associations. Only in the APOE ε4 carrier group, a high AST to ALT ratio and low ALT levels were significantly associated with AD diagnosis, increased amyloid PET burden, and faster longitudinal decline in cognitive function in both cohorts. In particular, the AST to ALT ratio was associated with cerebrospinal fluid Aβ42 levels exclusively in the APOE ε4 carrier group in the Alzheimer's Disease Neuroimaging Initiative cohort but not with phosphorylated tau181 or total tau levels. Moreover, mediation analyses from both cohorts revealed that in the APOE ε4 carriers group, age did not mediate the associations between liver enzymes and AD diagnosis or amyloid PET burden. However, amyloid PET burden partially mediated the association between liver enzymes and AD diagnosis exclusively in the APOE ε4 carriers group. This study provides valuable insights into the significant association of the APOE ε4 allele with liver enzymes and their potential role in Aβ-related pathogenesis and cognition in AD. Further research is required to elucidate the underlying mechanisms and potential therapeutic implications of these findings.

CSF dynamics of orexin and β-amyloid42 levels in narcolepsy and Alzheimer’s disease patients: a controlled study

β-amyloid42 (Aβ42) in Alzheimer’s disease (AD) and orexin in narcolepsy are considered crucial biomarkers for diagnosis and therapeutic targets. Recently, orexin and Aβ cerebral dynamics have been studied in both pathologies, but how they interact with each other remains further to be known. In this study, we investigated the reliability of using the correlation between orexin-A and Aβ42 CSF levels as a candidate marker to explain the chain of events leading to narcolepsy or AD pathology. In order to test the correlation between these biomarkers, patients diagnosed with AD (n = 76), narcolepsy type 1 (NT1, n = 17), narcolepsy type 2 (NT2, n = 23) and healthy subjects (n = 91) were examined. Patients and healthy subjects underwent lumbar puncture between 8:00 and 10:00 am at the Neurology Unit of the University Hospital of Rome “Tor Vergata”. CSF levels of Aβ42, total-tau, phosphorylated-tau, and orexin-A were assessed. The results showed that CSF levels of Aβ42 were significantly lower (p < 0.001) in AD (332.28 ± 237.36 pg/mL) compared to NT1 (569.88 ± 187.00 pg/mL), NT2 (691.00 ± 292.63 pg/mL) and healthy subjects (943.68 ± 198.12 pg/mL). CSF orexin-A levels were statistically different (p < 0.001) between AD (148.01 ± 29.49 pg/mL), NT1 (45.94 ± 13.63 pg/mL), NT2 (104.92 ± 25.55 pg/mL) and healthy subjects (145.18 ± 27.01 pg/mL). Moderate-severe AD patients (mini mental state examination < 21) showed the highest CSF orexin-A levels, whereas NT1 patients showed the lowest CSF orexin-A levels. Correlation between CSF levels of Aβ42 and orexin-A was found only in healthy subjects (r = 0.26; p = 0.01), and not in narcolepsy or AD patients. This lack of correlation in both diseases may be explained by the pathology itself since the correlation between these two biomarkers is evident only in the healthy subjects. This study adds to the present literature by further documenting the interplay between orexinergic neurotransmission and cerebral Aβ dynamics, possibly sustained by sleep.