Plasma phosphorylated tau181 and neurodegeneration in Alzheimer's disease

We examined if plasma phosphorylated tau is associated with neurodegeneration in Alzheimer’s disease. We investigated 372 cognitively unimpaired participants, 554 mild cognitive impairment patients, and 141 Alzheimer’s disease dementia patients. Tau phosphorylated at threonine 181, regional cortical thickness (using magnetic resonance imaging) and hypometabolism (using fluorodeoxyglucose positron emission tomography) were measured longitudinally. High plasma tau was associated with hypometabolism and cortical atrophy at baseline and over time, and longitudinally increased tau was associated with accelerated atrophy, but these associations were only observed in Aβ‐positive participants. Plasma phosphorylated tau may identify and track processes linked to neurodegeneration in Alzheimer’s disease

Cerebrospinal Fluid YKL-40 and Neurogranin in Familial Alzheimer's Disease: A Pilot Study

BACKGROUND: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms. OBJECTIVE: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD. METHODS: YKL-40 and neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up. RESULTS: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC. CONCLUSION: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin

Neurofilament light protein levels in cerebrospinal fluid predict long-term disability of Guillain-Barre syndrome: A pilot study

Objectives: Although the recovery from Guillain‐Barré syndrome (GBS) is good in most patients, some develop permanent severe disability or even die. Early predictors would increase the likelihood to identify patients at risk for poor outcome at the acute stage, allowing them intensified therapeutic intervention. Materials and Method: Eighteen patients with a history of GBS 9‐17 years ago were reassessed with scoring of neurological disability and quality of life assessment (QoL). Their previous diagnostic work‐up included clinical examination with scoring of disability, neurophysiological investigation, a battery of serology tests for infections, and cerebrospinal fluid (CSF) examination. Aliquots of CSF were frozen, stored for 20‐28 years, and analyzed by ELISA for determination of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP). Results: Patients with poor outcome (n = 3) had significantly higher NFL and GFAP levels at GBS nadir than those with good outcome (n = 15, P < .01 and P < .05, respectively). High NFL correlated with more prominent disability and worse QoL at long‐term follow‐up (r = .694, P < .001, and SF 36 dimension physical component summary (PCS) (r =−.65, P < .05), respectively, whereas GFAP did not correlate with clinical outcome or QoL. Conclusion: High NFL in CSF at the acute stage of GBS seems to predict long‐term outcome and might, together with neurophysiological and clinical measures, be useful in treatment decisions and clinical care of GBS

Vortex Waves and Channel Capacity: Hopes and Reality

Several recent contributions have envisioned the possibility of increasing currently exploitable maximum channel capacity of a free space link, both at optical and radio frequencies, by using vortex waves, i.e. carrying Orbital Angular Momentum (OAM). Our objective is to disprove these claims by showing that they are in contradiction with very fundamental properties of Maxwellian fields. We demonstrate that the Degrees of Freedom (DoF) of the field cannot be increased by the helical phase structure of electromagnetic vortex waves beyond what can be done without invoking this property. We also show that the often-advocated over-quadratic power decay of OAM beams with distance does not play any fundamental role in the determination of the channel DoF.Comment: 8 pages, 7 figure

Plasma glial fibrillary acidic protein detects Alzheimer pathology and predicts future conversion to Alzheimer dementia in patients with mild cognitive impairment.

INTRODUCTION: Plasma glial fibrillary acidic protein (GFAP) is a marker of astroglial activation and astrocytosis. We assessed the ability of plasma GFAP to detect Alzheimer's disease (AD) pathology in the form of AD-related amyloid-β (Aβ) pathology and conversion to AD dementia in a mild cognitive impairment (MCI) cohort. METHOD: One hundred sixty MCI patients were followed for 4.7 years (average). AD pathology was defined using cerebrospinal fluid (CSF) Aβ42/40 and Aβ42/total tau (T-tau). Plasma GFAP was measured at baseline and follow-up using Simoa technology. RESULTS: Baseline plasma GFAP could detect abnormal CSF Aβ42/40 and CSF Aβ42/T-tau with an AUC of 0.79 (95% CI 0.72-0.86) and 0.80 (95% CI 0.72-0.86), respectively. When also including APOE ε4 status as a predictor, the accuracy of the model to detect abnormal CSF Aβ42/40 status improved (AUC = 0.86, p = 0.02). Plasma GFAP predicted subsequent conversion to AD dementia with an AUC of 0.84 (95% CI 0.77-0.91), which was not significantly improved when adding APOE ε4 or age as predictors to the model. Longitudinal GFAP slopes for Aβ-positive and MCI who progressed to dementia (AD or other) were significantly steeper than those for Aβ-negative (p = 0.007) and stable MCI (p < 0.0001), respectively. CONCLUSION: Plasma GFAP can detect AD pathology in patients with MCI and predict conversion to AD dementia

The effects of different familial Alzheimer's disease mutations on APP processing in vivo

BACKGROUND: Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective. METHODS:In the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families. RESULTS: We observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations. CONCLUSIONS: These findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology

Cerebral Aβ deposition precedes reduced cerebrospinal fluid and serum Aβ42/Aβ40 ratios in the AppNL−F/NL−F knock-in mouse model of Alzheimer’s disease

Background: Aβ42/Aβ40 ratios in cerebrospinal fluid (CSF) and blood are reduced in preclinical Alzheimer’s disease (AD), but their temporal and correlative relationship with cerebral Aβ pathology at this early disease stage is not well understood. In the present study, we aim to investigate such relationships using App knock-in mouse models of preclinical AD. / Methods: CSF, serum, and brain tissue were collected from 3- to 18-month-old AppNL−F/NL−F knock-in mice (n = 48) and 2–18-month-old AppNL/NL knock-in mice (n = 35). The concentrations of Aβ42 and Aβ40 in CSF and serum were measured using Single molecule array (Simoa) immunoassays. Cerebral Aβ plaque burden was assessed in brain tissue sections by immunohistochemistry and thioflavin S staining. Furthermore, the concentrations of Aβ42 in soluble and insoluble fractions prepared from cortical tissue homogenates were measured using an electrochemiluminescence immunoassay. / Results: In AppNL−F/NL−F knock-in mice, Aβ42/Aβ40 ratios in CSF and serum were significantly reduced from 12 and 16 months of age, respectively. The initial reduction of these biomarkers coincided with cerebral Aβ pathology, in which a more widespread Aβ plaque burden and increased levels of Aβ42 in the brain were observed from approximately 12 months of age. Accordingly, in the whole study population, Aβ42/Aβ40 ratios in CSF and serum showed a negative hyperbolic association with cerebral Aβ plaque burden as well as the levels of both soluble and insoluble Aβ42 in the brain. These associations tended to be stronger for the measures in CSF compared with serum. In contrast, no alterations in the investigated fluid biomarkers or apparent cerebral Aβ plaque pathology were found in AppNL/NL knock-in mice during the observation time. / Conclusions: Our findings suggest a temporal sequence of events in AppNL−F/NL−F knock-in mice, in which initial deposition of Aβ aggregates in the brain is followed by a decline of the Aβ42/Aβ40 ratio in CSF and serum once the cerebral Aβ pathology becomes significant. Our results also indicate that the investigated biomarkers were somewhat more strongly associated with measures of cerebral Aβ pathology when assessed in CSF compared with serum

A Western-style dietary pattern is associated with cerebrospinal fluid biomarker levels for preclinical Alzheimer's disease-A population-based cross-sectional study among 70-year-olds

Background: Diet may be a modifiable factor for reducing the risk of Alzheimer's disease (AD). Western-style dietary patterns are considered to increase the risk, whereas Mediterranean-style dietary patterns are considered to reduce the risk. An association between diet and AD-related biomarkers have been suggested, but studies are limited. Aim: To investigate potential relations between dietary patterns and cerebrospinal fluid (CSF) biomarkers for AD among dementia-free older adults. Methods: Data were derived from the population-based Gothenburg H70 Birth Cohort Studies, Sweden. A total of 269 dementia-free 70-year-olds with dietary and cerebrospinal fluid (CSF) amyloid beta (Aβ42 and Aβ40), total tau (t-tau), and phosphorylated tau (p-tau) data were investigated. Dietary intake was determined by the diet history method, and four dietary patterns were derived by principal component analysis. A Western dietary pattern, a Mediterranean/prudent dietary pattern, a high-protein and alcohol pattern, and a high-total and saturated fat pattern. Logistic regression models, with CSF biomarker pathology (yes/no) as dependent variables, and linear regression models with continuous CSF biomarker levels as dependent variables were performed. The analyses were adjusted for sex, energy intake, body mass index (BMI), educational level, and physical activity level. Results: The odds ratio for having total tau pathology (odds ratio [OR] 1.43; 95% confidence interval [CI] 1.02 to 2.01) and preclinical AD (Aβ42 and tau pathology; OR 1.79; 95% CI 1.03 to 3.10) was higher among those with a higher adherence to a Western dietary pattern. There were no other associations between the dietary patterns and CSF biomarkers that remained significant in both unadjusted and adjusted models. Discussion: Our findings suggest that higher adherence to a Western dietary pattern may be associated with pathological levels of AD biomarkers in the preclinical phase of AD. These findings can be added to the increasing amount of evidence linking diet with AD and may be useful for future intervention studies investigating dietary intake in relation to AD

Neuroligin-1 in brain and CSF of neurodegenerative disorders: investigation for synaptic biomarkers

Synaptic pathology is a central event in Alzheimer’s disease (AD) and other neurodegenerative conditions, and investigation of synaptic proteins can provide valuable tools to follow synaptic dysfunction and loss in these diseases. Neuroligin-1 (Nlgn1) is a postsynaptic cell adhesion protein, important for synapse stabilization and formation. Nlgn1 has been connected to cognitive disorders, and specifically to AD, as target of the synaptotoxic effect of amyloid-β (Aβ) oligomers and Aβ fibrils. To address changes in Nlgn1 expression in human brain, brain regions in different neurological disorders were examined by Western blot and mass spectrometry. Brain specimens from AD (n = 23), progressive supranuclear palsy (PSP, n = 11), corticobasal degeneration (CBD, n = 10), and Pick’s disease (PiD, n = 9) were included. Additionally, cerebrospinal fluid (CSF) samples of AD patients (n = 43) and non-demented controls (n = 42) were analysed. We found decreased levels of Nlgn1 in temporal and parietal cortex (~ 50–60% reductions) in AD brains compared with controls. In frontal grey matter the reduction was not seen for AD patients; however, in the same region, marked reduction was found for PiD (~ 77%), CBD (~ 66%) and to a lesser extent for PSP (~ 43%), which could clearly separate these tauopathies from controls. The Nlgn1 level was reduced in CSF from AD patients compared to controls, but with considerable overlap. The dramatic reduction of Nlgn1 seen in the brain extracts of tauopathies warrants further investigation regarding the potential use of Nlgn1 as a biomarker for these neurodegenerative diseases

Increased neurogranin concentrations in cerebrospinal fluid of Alzheimer's disease and in mild cognitive impairment due to AD

Synaptic dysfunction is linked to both major depressive disorder (MDD) and Alzheimer’s disease (AD). Synapse protein concentrations in cerebrospinal fluid (CSF) may be useful biomarkers to monitor synaptic dysfunction and degeneration that lead to depressive symptoms and AD, respectively. CSF neurogranin (Ng), a post-synaptic protein, has emerged as a promising tool to measure synaptic dysfunction and/or loss in AD. The aim of this study was to test the specific hypothesis that CSF neurogranin (Ng) is able to differentiate AD from MDD and cognitively normal controls. CSF samples from 44 healthy control individuals (CTRL), 86 patients with mild cognitive impairment (MCI), 36 of whom had prodromal AD as defined by a positive CSF AD biomarker signature, 25 AD dementia and 6 patients with MDD were analysed using an in house enzyme-linked immunosorbent assay for Ng. CSF Ng levels were significantly higher in AD patients and in prodromal AD (MCI patients with an “AD-like” CSF tau and Aβ42 profile) compared with CTRL individuals (p < 0.0001 for both groups) and MDD patients (p < 0.001 and p < 0.01, respectively). Significantly higher CSF Ng concentration was also seen in prodromal AD patients as compared to MCI patients without biomarker evidence of underlying AD pathology (p < 0.0001). CSF Ng correlated positively with the classical axonal injury markers CSF T-tau and P-tau (p < 0.0001), whereas correlation to plaque pathology as reflected by CSF Aβ42 was less clear. Negative correlations of CSF Ng with cognitive evaluation scores (MMSE and CAMCOG) were observed. This study strengthens the clinical utility of CSF Ng as a CSF biomarker for AD. AD patients in both MCI and dementia stages of the disease had increased CSF Ng concentrations compared with cognitively normal control individuals, patients with non-AD MCI and patients with MDD. The lowest CSF Ng concentrations were seen in patients with MDD, a finding that warrants validation in further studies