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Whilst cerebrospinal fluid (CSF) and positron emission tomography (PET) biomarkers for amyloid-β (Aβ) and tau pathologies are accurate for the diagnosis of Alzheimer’s disease (AD), their broad implementation in clinical and trial settings are restricted by high cost and limited accessibility. Plasma phosphorylated-tau181 (p-tau181) is a promising blood-based biomarker that is specific for AD, correlates with cerebral Aβ and tau pathology, and predicts future cognitive decline. In this study, we report the performance of p-tau181 in >1000 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), including cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD dementia patients characterized by Aβ PET. We confirmed that plasma p-tau181 is increased at the preclinical stage of Alzheimer and further increases in MCI and AD dementia. Individuals clinically classified as AD dementia but having negative Aβ PET scans show little increase but plasma p-tau181 is increased if CSF Aβ has already changed prior to Aβ PET changes. Despite being a multicenter study, plasma p-tau181 demonstrated high diagnostic accuracy to identify AD dementia (AUC = 85.3%; 95% CI, 81.4–89.2%), as well as to distinguish between Aβ− and Aβ+ individuals along the Alzheimer’s continuum (AUC = 76.9%; 95% CI, 74.0–79.8%). Higher baseline concentrations of plasma p-tau181 accurately predicted future dementia and performed comparably to the baseline prediction of CSF p-tau181. Longitudinal measurements of plasma p-tau181 revealed low intra-individual variability, which could be of potential benefit in disease-modifying trials seeking a measurable response to a therapeutic target. This study adds significant weight to the growing body of evidence in the use of plasma p-tau181 as a non-invasive diagnostic and prognostic tool for AD, regardless of clinical stage, which would be of great benefit in clinical practice and a large cost-saving in clinical trial recruitment.

Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer’s disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme-linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson’s disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid β (Aβ), t-tau, and p-tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Aβ neuritic plaque (Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, α-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with β-amyloid plaque pathology.

Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts ( n  = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology. A range of blood-based biomarkers have shown high specificity for Alzheimer’s disease (AD) pathophysiology with phosphorylated-tau (p-tau) being the most promising test. Here, the authors show the utility of plasma p-tau212 in autopsy-confirmed AD and memory clinic patient cohorts.

Introduction Neuroinflammation and synaptic degeneration are major neuropathological hallmarks in Alzheimer’s disease (AD). Neurogranin and YKL-40 in cerebrospinal fluid (CSF) are newly discovered markers indicating synaptic damage and microglial activation, respectively. Methods CSF samples from 95 individuals including 39 patients with AD dementia (AD-D), 13 with mild cognitive impairment (MCI) due to AD (MCI-AD), 29 with MCI not due to AD (MCI-o) and 14 patients with non-AD dementias (non-AD-D) were analyzed for neurogranin and YKL-40. Results Patients with dementia or MCI due to AD showed elevated levels of CSF neurogranin ( p  < 0.001 for AD-D and p  < 0.05 for MCI-AD) and YKL-40 ( p  < 0.05 for AD-D and p  = 0.15 for MCI-AD) compared to mildly cognitively impaired subjects not diagnosed with AD. CSF levels of neurogranin and YKL-40 did not differ between MCI not due to AD and non-AD dementias. In AD subjects no correlation between YKL-40 and neurogranin was found. The CSF neurogranin levels correlated moderately with tau and p-tau but not with Aβ 42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aβ 42 , t-tau and p-tau were found in AD subjects. Conclusions Neurogranin and YKL-40 are promising AD biomarkers, independent of and complementary to the established core AD biomarkers, reflecting additional pathological changes in the course of AD.

Background The Gas6/TAM (Tyro3, Axl, and Mer) receptor system has been implicated in demyelination and delayed remyelination in experimental animal models, but data in humans are scarce. We aimed to investigate the role of Gas6/TAM in neurodegenerative processes in multiple sclerosis (MS). Methods From a prospective 5-year follow-up study, soluble Gas6/TAM biomarkers were analyzed in cerebrospinal fluid (CSF) by enzyme-linked immunosorbent assay (ELISA) at baseline in patients with relapsing–remitting MS (RRMS) (n = 40), progressive MS (PMS) (n = 20), and healthy controls (HC) (n = 25). Brain volumes, including myelin content (MyC) and white matter (WM) were measured by synthetic magnetic resonance imaging at baseline, 12 months, and 60-month follow-up. Associations with brain volume changes were investigated in multivariable linear regression models. Gas6/TAM concentrations were also determined at 12 months follow-up in RRMS to assess treatment response. Results Baseline concentrations of Tyro3, Axl, and Gas6 were significantly higher in PMS vs. RRMS and HC. Mer was higher in PMS vs. HC. Tyro3 and Gas6 were associated with reduced WM (β = 25.5, 95% confidence interval [CI] [6.11–44.96, p = 0.012; β = 11.4, 95% CI [0.42–22.4], p = 0.042, respectively) and MyC (β = 7.95, 95%CI [1.84–14.07], p = 0.012; β = 4.4, 95%CI [1.04–7.75], p = 0.012 respectively) at 60 months. Patients with evidence of remyelination at last follow-up had lower baseline soluble Tyro3 (p = 0.033) and Gas6 (p = 0.014). Except Mer, Gas6/TAM concentrations did not change with treatment in RRMS. Discussion Our data indicate a potential role for the Gas6/TAM receptor system in neurodegenerative processes influencing demyelination and ineffective remyelination.

Introduction Synaptic dysfunction and degeneration are central events in Alzheimer’s disease (AD) pathophysiology that are thought to occur early in disease progression. Synaptic pathology may be studied by examining protein biomarkers specific for different synaptic elements. We recently showed that the dendritic protein neurogranin (Ng), including the endogenous Ng peptide 48 to 76 (Ng 48–76 ), is markedly increased in cerebrospinal fluid (CSF) in AD and that Ng 48–76 is the dominant peptide in human brain tissue. The aim of this study was to characterize Ng in plasma and CSF using mass spectrometry and to investigate the performance of plasma Ng as an AD biomarker. Methods Paired plasma and CSF samples from patients with AD (n = 25) and healthy controls (n = 20) were analyzed in parallel using an immunoassay developed in-house on the Meso Scale Discovery platform and hybrid immunoaffinity-mass spectrometry (HI-MS). A second plasma material from patients with AD (n = 13) and healthy controls (n = 17) was also analyzed with HI-MS. High-resolution mass spectrometry was used for identification of endogenous plasma Ng peptides. Results Ng in human plasma is present as several endogenous peptides. Of the 16 endogenous Ng peptides identified, seven were unique for plasma and not detectable in CSF. However, Ng 48–76 was not present in plasma. CSF Ng was significantly increased in AD compared with controls ( P  < 0.0001), whereas the plasma Ng levels were similar between the groups in both studies. Plasma and CSF Ng levels showed no correlation. CSF Ng was stable during storage at −20°C for up to 2 days, and no de novo generation of peptides were detected. Conclusions For the first time, to our knowledge, we have identified several endogenous Ng peptides in human plasma. In agreement with previous studies, we show that CSF Ng is significantly increased in AD as compared with healthy controls. The origin of Ng in plasma and its possible use as a biomarker need to be further investigated. The results suggest that CSF Ng, in particular Ng 48–76 , might reflect the neurodegenerative processes within the brain, indicating a role for Ng as a potential novel clinical biomarker for synaptic function in AD.

Amyloid precursor protein (APP) and its cleavage product amyloid β (Aβ) have been thoroughly studied in Alzheimer’s disease. However, APP also appears to be important for neuronal development. Differentiation of induced pluripotent stem cells (iPSCs) towards cortical neurons enables in vitro mechanistic studies on human neuronal development. Here, we investigated expression and proteolytic processing of APP during differentiation of human iPSCs towards cortical neurons over a 100-day period. APP expression remained stable during neuronal differentiation, whereas APP processing changed. α-Cleaved soluble APP (sAPPα) was secreted early during differentiation, from neuronal progenitors, while β-cleaved soluble APP (sAPPβ) was first secreted after deep-layer neurons had formed. Short Aβ peptides, including Aβ1-15/16, peaked during the progenitor stage, while processing shifted towards longer peptides, such as Aβ1-40/42, when post-mitotic neurons appeared. This indicates that APP processing is regulated throughout differentiation of cortical neurons and that amyloidogenic APP processing, as reflected by Aβ1-40/42, is associated with mature neuronal phenotypes.

Introduction Cerebrospinal fluid (CSF) tau biomarkers are reliable diagnostic markers for Alzheimer’s disease (AD). However, their strong association with amyloid pathology may limit their reliability as specific markers of tau neurofibrillary tangles. A recent study showed evidence that a ratio of CSF C-terminally truncated tau (tau368, a tangle-enriched tau species), especially in ratio with total tau (t-tau), correlates strongly with tau PET tracer uptake. In this study, we set to evaluate the performance of the tau368/t-tau ratio in capturing tangle pathology, as indexed by a high-affinity tau PET tracer, as well as its association with severity of clinical symptoms. Methods In total, 125 participants were evaluated cross-sectionally from the Translational Biomarkers of Aging and Dementia (TRIAD) cohort (21 young, 60 cognitively unimpaired [CU] elderly [15 Aβ+], 10 Aβ+ with mild cognitive impairment [MCI], 14 AD dementia patients, and 20 Aβ− individuals with non-AD cognitive disorders). All participants underwent amyloid and tau PET scanning, with [ 18 F]-AZD4694 and [ 18 F]-MK6240, respectively, and had CSF measurements of p-tau181, p-tau217, and t-tau. CSF concentrations of tau368 were quantified in all individuals with an in-house single molecule array assay. Results CSF tau368 concentration was not significantly different across the diagnostic groups, although a modest increase was observed in all groups as compared with healthy young individuals (all P < 0.01). In contrast, the CSF tau368/t-tau ratio was the lowest in AD dementia, being significantly lower than in CU individuals (Aβ−, P < 0.001; Aβ+, P < 0.01), as well as compared to those with non-AD cognitive disorders ( P < 0.001). Notably, in individuals with symptomatic AD, tau368/t-tau correlated more strongly with [ 18 F]-MK6240 PET SUVR as compared to the other CSF tau biomarkers, with increasing associations being seen in brain regions associated with more advanced disease (isocortical regions > limbic regions > transentorhinal regions). Importantly, linear regression models indicated that these associations were not confounded by Aβ PET SUVr. CSF tau368/t-tau also tended to continue to become more abnormal with higher tau burden, whereas the other biomarkers plateaued after the limbic stage. Finally, the tau368/t-tau ratio correlated more strongly with cognitive performance in individuals with symptomatic AD as compared to t-tau, p-tau217 and p-tau181. Conclusion The tau368/t-tau ratio captures novel aspects of AD pathophysiology and disease severity in comparison to established CSF tau biomarkers, as it is more closely related to tau PET SUVR and cognitive performance in the symptomatic phase of the disease.

Background The underlying disease mechanism of neuropsychiatric symptoms (NPS) in dementia remains unclear. Cerebrospinal fluid (CSF) biomarkers for synaptic and axonal degeneration may provide novel neuropathological information for their occurrence. The aim was to investigate the relationship between NPS and CSF biomarkers for synaptic (neurogranin [Ng], growth-associated protein 43 [GAP-43]) and axonal (neurofilament light [NFL]) injury in patients with dementia. Methods A total of 151 patients (mean age ± SD, 73.5 ± 11.0, females n  = 92 [61%]) were included, of which 64 had Alzheimer’s disease (AD) (34 with high NPS, i.e., Neuropsychiatric Inventory (NPI) score > 10 and 30 with low levels of NPS) and 18 were diagnosed with vascular dementia (VaD), 27 with mixed dementia (MIX), 12 with mild cognitive impairment (MCI), and 30 with subjective cognitive impairment (SCI). NPS were primarily assessed using the NPI. CSF samples were analyzed using enzyme-linked immunosorbent assays (ELISAs) for T-tau, P-tau, Aβ1–42, Ng, NFL, and GAP-43. Results No significant differences were seen in the CSF levels of Ng, GAP-43, and NFL between AD patients with high vs low levels of NPS (but almost significantly decreased for Ng in AD patients < 70 years with high NPS, p  = 0.06). No significant associations between NPS and CSF biomarkers were seen in AD patients. In VaD ( n  = 17), negative correlations were found between GAP-43, Ng, NFL, and NPS. Conclusion Our results could suggest that low levels of Ng may be associated with higher severity of NPS early in the AD continuum (age < 70). Furthermore, our data may indicate a potential relationship between the presence of NPS and synaptic as well as axonal degeneration in the setting of VaD pathology.

Background Neurogranin (Ng) is a small 7.6 kDa postsynaptic protein that has been detected at elevated concentrations in cerebrospinal fluid (CSF) of patients with Alzheimer’s disease (AD), both as a full-length molecule and as fragments from its C-terminal half. Ng is involved in postsynaptic calcium (Ca) signal transduction and memory formation via binding to calmodulin in a Ca-dependent manner. The mechanism of Ng secretion from neurons to CSF is currently unknown, but enzymatic cleavage of Ng may be of relevance. Therefore, the aim of the study was to identify the enzymes responsible for the cleavage of Ng, yielding the Ng fragment pattern of C-terminal fragments detectable and increased in CSF of AD patients. Methods Fluorigenic quenched FRET probes containing sequences of Ng were utilized to identify Ng cleaving activities among enzymes known to have increased activity in AD and in chromatographically fractionated mouse brain extracts. Results Human Calpain-1 and prolyl endopeptidase were identified as the candidate enzymes involved in the formation of endogenous Ng peptides present in CSF, cleaving mainly in the central region of Ng, and between amino acids 75_76 in the Ng sequence, respectively. The cleavage by Calpain-1 affects the IQ domain of Ng, which may deactivate or change the function of Ng in Ca 2+ /calmodulin -dependent signaling for synaptic plasticity. While shorter Ng fragments were readily cleaved in vitro by prolyl endopeptidase, the efficiency of cleavage on larger Ng fragments was much lower. Conclusions Calpain-1 and prolyl endopeptidase cleave Ng in the IQ domain and near the C-terminus, respectively, yielding specific fragments of Ng in CSF. These fragments may give clues to the roles of increased activities of these enzymes in the pathophysiology of AD, and provide possible targets for pharmacologic intervention.