Digit Ratio (2D:4D) Is Not Associated with Alzheimer's Disease in the Elderly.

The development of Alzheimer's disease (AD) is influenced by sex hormones-estrogens and androgens in particular. However, the impact of prenatal sex hormone exposure is less clear; very few investigations have examined the relationship between the second-to-fourth digit length ratio (2D:4D), a putative proxy for the ratio of prenatal estrogens to androgens, and AD, with inconsistent results among the few that have. Therefore, we aimed to investigate this relationship using methodologically robust metrics. In a 2 (sex) × 4 (group) MANOVA incorporating 108 participants (30 AD patients, 19 patients with tauopathy but no amyloidopathy, 31 clinical and 28 healthy age- and education-matched controls), the effects of sex and group on the dependent variables right and left 2D:4D were examined. We also explored the association between 2D:4D and the severity of AD symptoms assessed via neuropsychological examination. We did not find any significant differences in the right- and left-hand 2D:4D between patients with AD and the other groups; no significant associations between 2D:4D and neuropsychological task performances were found in the dementia groups. The 2D:4D of healthy women was significantly lower than that of depressed women without AD, i.e., clinical controls, but not significantly different from depressed female patients with AD. This investigation does not support the role of 2D:4D in the development or severity of AD in general, but suggests a potential role of 2D:4D for depression in women. Future studies are warranted to clarify whether 2D:4D can distinguish between early- and late-onset depression in women.

Reconceptualization of the Erlangen Score for the Assessment of Dementia Risk: The ERlangen Score.

BACKGROUND: The established Erlangen Score (ES) for the interpretation of cerebrospinal fluid (CSF) biomarkers in the diagnostics of Alzheimer's disease (AD) uses markers of amyloidopathy and tauopathy, equally weighted to form an easy-interpretable ordinal scale. However, these biomarkers are not equally predictive for AD. OBJECTIVE: The higher weighting of the Aß42/Aß40 ratio, as a reconceptualized ERlangen Score (ERS), was tested for advantages in diagnostic performance. METHODS: Non-demented subjects (N = 154) with a mean follow up of 5 years were assigned to a group ranging from 0 to 4 in ES or ERS. Psychometric trajectories and dementia risk were assessed. RESULTS: The distribution of subjects between ES and ERS among the groups differed considerably, as grouping allocated 32 subjects to ES group 2, but only 2 to ERS group 2. The discriminative accuracy between the ES (AUC 73.2%, 95% CI [64.2, 82.2]) and ERS (AUC 72.0%, 95% CI [63.1, 81.0]) for dementia risk showed no significant difference. Without consideration of the Aß42/Aß40 ratio in ES grouping, the optimal cut-off of the ES shifted to ≥2. CONCLUSIONS: The ERS showed advantages over the ES in test interpretation with comparable overall test performance, as fewer cases were allocated to the intermediate risk group. The established cut-off of ≥2 can be maintained for the ERS, whereas it must be adjusted for the ES when determining the Aß42/Aß40 ratio.

Cerebrospinal fluid biomarkers for cerebral amyloid angiopathy.

Integrating cerebrospinal fluid-biomarkers into diagnostic workup of patients with sporadic cerebral amyloid angiopathy may support early and correct identification. We aimed to identify and validate clinical- and cerebrospinal fluid-biomarkers for in vivo diagnosis of cerebral amyloid angiopathy. This observational cohort study screened 2795 consecutive patients admitted for cognitive complaints to the academic departments of neurology and psychiatry over a 10-year period (2009-2018). We included 372 patients with available hemosiderin-sensitive MR imaging and cerebrospinal fluid-based neurochemical dementia diagnostics, i.e. Aß40, Aß42, t-tau, p-tau. We investigated the association of clinical- and cerebrospinal fluid-biomarkers with the MRI-based diagnosis of cerebral amyloid angiopathy, applying confounder-adjusted modelling, receiver operating characteristic and unsupervised cluster analyses. We identified 67 patients with cerebral amyloid angiopathy, 76 patients with Alzheimer's disease, 75 patients with mild cognitive impairment due to Alzheimer's disease, 76 patients with mild cognitive impairment with unlikely Alzheimer's disease and 78 healthy controls. Patients with cerebral amyloid angiopathy showed a specific cerebrospinal fluid pattern: average concentration of Aß40 [13 792 pg/ml (10 081-18 063)] was decreased compared to all controls (P < 0.05); Aß42 [634 pg/ml (492-834)] was comparable to Alzheimer's disease and mild cognitive impairment due to Alzheimer's disease (P = 0.10, P = 0.93) but decreased compared to mild cognitive impairment and healthy controls (both P < 0.001); p-tau [67.3 pg/ml (42.9-91.9)] and t-tau [468 pg/ml (275-698)] were decreased compared to Alzheimer's disease (P < 0.001, P = 0.001) and mild cognitive impairment due to Alzheimer's disease (P = 0.001, P = 0.07), but elevated compared to mild cognitive impairment and healthy controls (both P < 0.001). Multivariate modelling validated independent clinical association of cerebral amyloid angiopathy with older age [odds-ratio: 1.06, 95% confidence interval (1.02-1.10), P < 0.01], prior lobar intracerebral haemorrhage [14.00 (2.64-74.19), P < 0.01], prior ischaemic stroke [3.36 (1.58-7.11), P < 0.01], transient focal neurologic episodes (TFNEs) [4.19 (1.06-16.64), P = 0.04] and gait disturbance [2.82 (1.11-7.15), P = 0.03]. For cerebrospinal fluid-biomarkers per 1 pg/ml, both lower Aß40 [0.9999 (0.9998-1.0000), P < 0.01] and lower Aß42 levels [0.9989 (0.9980-0.9998), P = 0.01] provided an independent association with cerebral amyloid angiopathy controlled for all aforementioned clinical confounders. Both amyloid biomarkers showed good discrimination for diagnosis of cerebral amyloid angiopathy among adjusted receiver operating characteristic analyses (area under the receiver operating characteristic curves, Aß40: 0.80 (0.73-0.86), P < 0.001; Aß42: 0.81 (0.75-0.88), P < 0.001). Unsupervised Euclidian clustering of all cerebrospinal fluid-biomarker-profiles resulted in distinct segregation of cerebral amyloid angiopathy patients from all controls. Together, we demonstrate that a distinctive set of cerebrospinal fluid-biomarkers effectively differentiate cerebral amyloid angiopathy patients from patients with Alzheimer's disease, mild cognitive impairment with or without underlying Alzheimer's disease, and healthy controls. Integrating our findings into a multiparametric approach may facilitate diagnosing cerebral amyloid angiopathy, and may aid clinical decision-making, but warrants future prospective validation.

PASSED: Brain atrophy in non-demented individuals in a long-term longitudinal study from two independent cohorts.

Introduction: Alzheimer's disease (AD) is indicated by a decrease in amyloid beta 42 (Aß42) level or the Aß42/Aß40 ratio, and by increased levels of Tau with phosphorylated threonine at position 181 (pTau181) in cerebrospinal fluid (CSF) years before the onset of clinical symptoms. However, once only pTau181 is increased, cognitive decline in individuals with subjective or mild cognitive impairment is slowed compared to individuals with AD. Instead of a decrease in Aß42 levels, an increase in Aß42 was observed in these individuals, leading to the proposal to refer to them as nondemented subjects with increased pTau-levels and Aß surge with subtle cognitive deterioration (PASSED). In this study, we determined the longitudinal atrophy rates of AD, PASSED, and Biomarker-negative nondemented individuals of two independent cohorts to determine whether these groups can be distinguished by their longitudinal atrophy patterns or rates. Methods: Depending on their CSF-levels of pTau 181 (T), total Tau (tTau, N), Aß42 or ratio of Aß42/Aß40 (A), 185 non-demented subjects from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and 62 non-demented subjects from Erlangen AD cohort were assigned to an ATN group (A-T-N-, A-T+N±, A+T-N±and A+T+N±) and underwent T1-weighted structural magnetic resonance imaging (sMRI). Longitudinal grey matter (GM) atrophy patterns were assessed with voxel-based morphometry (VBM) using the cat12 toolbox on spm12 (statistical parametric mapping) of MRI scans from individuals in the ADNI cohort with a mean follow-up of 2 and 5 years, respectively. The annualized atrophy rate for individuals in the Erlangen cohort was determined using region of interest analysis (ROI) in terms of a confirmatory analysis. Results: In the A-T+N± group, VBM did not identify any brain region that showed greater longitudinal atrophy than the A+T+N±, A+T+N± or biomarker negative control group. In contrast, marked longitudinal atrophy in the temporal lobe was evident in the A+T-N± group compared with A+T-N± and biomarker-negative subjects. The ROI in the angular gyrus identified by VBM analysis of the ADNI cohort did not discriminate better than the hippocampal volume and atrophy rate between AD and PASSED in the confirmatory analysis. Discussion: In this study, nondemented subjects with PASSED did not show a unique longitudinal atrophy pattern in comparison to nondemented subjects with AD. The nonsignificant atrophy rate compared with controls suggests that increased pTau181-levels without concomitant amyloidopathy did not indicate a neurodegenerative disorder.

Amyloid-ß levels and cognitive trajectories in non-demented pTau181-positive subjects without amyloidopathy.

Phosphorylated Tau181 (pTau181) in CSF and recently in plasma has been associated with Alzheimer's disease. In the absence of amyloidopathy, individuals with increased total Tau levels and/or temporal lobe atrophy experience no or only mild cognitive decline compared with biomarker-negative controls, leading to the proposal to categorize this constellation as suspected non-Alzheimer's disease pathophysiology (SNAP). We investigated whether the characteristics of SNAP also applied to individuals with increased CSF-pTau181 without amyloidopathy. In this long-term observational study, 285 non-demented individuals, including 76 individuals with subjective cognitive impairment and 209 individuals with mild cognitive impairment, were classified based on their CSF levels of pTau181 (T), total Tau (N), amyloid-ß42 (Aß42) and Aß42/Aß40 ratio (A) into A+T+N±, A+T-N±, A-T+N±, and A-T-N-. The longitudinal analysis included 154 subjects with a follow-up of more than 12 months who were followed to a median of 4.6 years (interquartile range = 4.3 years). We employed linear mixed models on psychometric tests and region of interest analysis of structural MRI data. Cognitive decline and hippocampal atrophy rate were significantly higher in A+T+N± compared to A-T+N±, whereas there was no difference between A-T+N± and A-T-N-. Furthermore, there was no significant difference between A-T+N± and controls in dementia risk [hazard ratio 0.3, 95% confidence interval (0.1, 1.9)]. However, A-T+N± and A-T-N- could be distinguished based on their Aß42 and Aß40 levels. Both Aß40 and Aß42 levels were significantly increased in A-T+N± compared to controls. Long term follow-up of A-T+N± individuals revealed no evidence that this biomarker constellation was associated with dementia or more severe hippocampal atrophy rates compared to controls. However, because of the positive association of pTau181 with Aß in the A-T+N± group, a link to the pathophysiology of Alzheimer's disease cannot be excluded in this case. We propose to refer to these individuals in the SNAP group as 'pTau and Aß surge with subtle deterioration' (PASSED). The investigation of the circumstances of simultaneous elevation of pTau and Aß might provide a deeper insight into the process under which Aß becomes pathological.

Cerebrospinal Fluid of Patients With Alzheimer's Disease Contains Increased Percentages of Synaptophysin-Bearing Microvesicles.

INTRODUCTION: In Alzheimer's disease, the severity of symptoms is linked to a loss of synaptic density and the spread of pathologically hyperphosphorylated tau. The established cerebrospinal fluid markers Aß, tau and phospho-tau reflect the histopathological hallmarks of Alzheimer's disease but do not indicate disease progression. Such markers are of special interest, especially for trials of disease modifying drugs. Microvesicles are produced by stressed cells and reflect part of the metabolism of their cells of origin. Therefore, we investigated microvesicles of neuronal origin in cerebrospinal fluid. MATERIALS AND METHODS: We used flow cytometry to analyze microvesicles carrying tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, synaptophysin, and SNAP-25 in the cerebrospinal fluid of 19 patients with Alzheimer's disease and 15 non-inflammatory neurological disease controls. RESULTS: The percentages of synaptophysin-bearing microvesicles were significantly higher in the cerebrospinal fluid of patients with Alzheimer's disease than in the CSF of non-inflammatory neurological disease controls. Tau, phospho-tau-Thr181, phospho-tau-Ser202Thr205, and SNAP-25 did not differ between the groups. The percentages of synaptophysin-bearing vesicles distinguished patients with Alzheimer's disease from the controls (AUC = 0.81). CONCLUSION: The loss of synapses in Alzheimer's disease may be reflected by synaptophysin-bearing microvesicles in the cerebrospinal fluid. Future studies are needed to investigate the possibility of using these MVs as a marker to determine the activity of Alzheimer's disease.

Pharmacological Inhibition of Amyloidogenic APP Processing and Knock-Down of APP in Primary Human Macrophages Impairs the Secretion of Cytokines.

It has been previously shown that the amyloid precursor protein (APP) support the innate immune defense as an immune receptor. Amyloid ß (Aß) peptides seem to have properties of an antimicrobial peptide and can act as opsonines. In APP-deficient mouse models, a reduced secretion of cytokines has been observed. Still, it is unclear whether this can be attributed to the lack of APP or to the missing secretion of Aß peptides. We inhibited the secretion of Aß peptides in primary human monocyte derived macrophages with the γ-secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine-t-butyl-ester (DAPT) or the ß-secretase inhibitor GL-189. Alternatively, we knocked down APP by transfection with siRNA. We measured tumor necrosis factor α (TNFα), interleukin 6 (IL-6) and interleukin (IL-10) by enzyme linked immunosorbent assay (ELISA) and evaluated the phagocytotic activity by flow cytometry. We observed reduced concentrations of TNFα and IL-6 in the media of APPk/d macrophages and after inhibition of the ß-, or γ-secretase, especially after additional immunological activation with lipopolysaccharide (LPS). Secretion of IL-10 was increased after pharmacological inhibition of APP processing when the macrophages were not immunologically activated but was decreased during LPS-induced inflammation in APPk/d macrophages. No changes of the phagocytotic activity were observed. We conclude that macrophage APP and Aß peptides support the initiation of an immune response and are involved in the regulation of TNFα, IL-6, and IL-10 secretion by human monocyte-derived macrophages.

DSC Brain Perfusion Using Advanced Deconvolution Models in the Diagnostic Work-up of Dementia and Mild Cognitive Impairment: A Semiquantitative Comparison with HMPAO-SPECT-Brain Perfusion.

BACKGROUND: SPECT (single-photon emission-computed tomography) is used for the detection of hypoperfusion in cognitive impairment and dementia but is not widely available and related to radiation dose exposure. We compared the performance of DSC (dynamic susceptibility contrast) perfusion using semi- and fully adaptive deconvolution models to HMPAO-SPECT (99mTc-hexamethylpropyleneamine oxime-SPECT). MATERIAL AND METHODS: Twenty-seven patients with dementia of different subtypes including frontotemporal dementia (FTD) and mild cognitive impairment (MCI) received a multimodal diagnostic work-up including DSC perfusion at a clinical 3T high-field scanner and HMPAO-SPECT. Nineteen healthy control individuals received DSC perfusion. For calculation of the hemodynamic parameter maps, oscillation-index standard truncated singular value decomposition (oSVD, semi-adaptive) as well as Bayesian parameter estimation (BAY, fully adaptive) were performed. RESULTS: Patients showed decreased cortical perfusion in the left frontal lobe compared to controls (relative cerebral blood volume corrected, rBVc: 0.37 vs 0.27, p = 0.048, adjusted for age and sex). Performance of rBVc (corrected for T1 effects) was highest compared to SPECT for detection of frontal hypoperfusion (sensitivity 83%, specificity 80% for oSVD and BAY, area under curve (AUC) = 0.833 respectively, p < 0.05) in FTD and MCI. For nonleakage-corrected rBV and for rBF (relative cerebral blood flow), sensitivity of frontal hypoperfusion was above 80% for oSVD and for BAY (rBV: sensitivity 83%, specificity 75%, AUC = 0.908 for oSVD and 0.917 for BAY, p < 0.05 respectively; rBF: sensitivity 83%, specificity 65%, AUC = 0.825, p < 0.05 for oSVD). CONCLUSION: Advanced deconvolution DSC can reliably detect pathological perfusion alterations in FTD and MCI. Hence, this widely accessible technique has the potential to improve the diagnosis of dementia and MCI as part of an interdisciplinary multimodal imaging work-up. Advances in knowledge: Advanced DSC perfusion has a high potential in the work-up of suspected dementia and correlates with SPECT brain perfusion results in dementia and MCI.

The Role of Cathepsin B in the Degradation of Aß and in the Production of Aß Peptides Starting With Ala2 in Cultured Astrocytes.

Astrocytes may not only be involved in the clearance of Amyloid beta peptides (Aß) in Alzheimer's disease (AD), but appear to produce N-terminally truncated Aß (Aßn-x) independently of BACE1, which generates the N-Terminus of Aß starting with Asp1 (Aß1-x). A candidate protease for the generation of Aßn-x is cathepsin B (CatB), especially since CatB has also been reported to degrade Aß, which could explain the opposite roles of astrocytes in AD. In this study, we investigated the influence of CatB inhibitors and the deletion of the gene encoding CatB (CTSB) using CRISPR/Cas9 technology on Aß2-x and Aß1-x levels in cell culture supernatants by one- and two-dimensional Urea-SDS-PAGE followed by immunoblot. While the cell-permeant inhibitors E64d and CA-074 Me did not significantly affect the Aß1-x levels in supernatants of cultured chicken and human astrocytes, they did reduce the Aß2-x levels. In the glioma-derived cell line H4, the Aß2-x levels were likewise decreased in supernatants by treatment with the more specific, but cell-impermeant CatB-inhibitor CA-074, by CA-074 Me treatment, and by CTSB gene deletion. Additionally, a more than 2-fold increase in secreted Aß1-x was observed under the latter two conditions. The CA-074 Me-mediated increase of Aß1-x, but not the decrease of Aß2-x, was influenced by concomitant treatment with the vacuolar H+-ATPase inhibitor Bafilomycin A1. This indicated that non-lysosomal CatB mediated the production of Aß2-x in astrocytes, while the degradation of Aß1-x seemed to be dependent on lysosomal CatB in H4 cells, but not in primary astrocytes. These findings highlight the importance of considering organelle targeting in drug development to promote Aß degradation.

Microvesicles from cerebrospinal fluid of patients with Alzheimer's disease display reduced concentrations of tau and APP protein.

Microvesicles are small membranous particles generated during cellular activation or stress. The analysis of the content and the surface of microvesicles allow conclusions about the cells they are originating from and the underlying pathology. Therefore, CSF microvesicles have been suggested to be promising targets to monitor the (etio)pathology of neurodegenerative diseases. Microvesicles in the CSF of 15 patients with Alzheimer's disease and 15 controls were analyzed by flow cytometry regarding the levels of CD3, CD4, CD45, CD64, BACE1, Aß, APP and tau. The results were replicated in a second cohort comprising 14 patients with Alzheimer's disease and 9 controls. The levels of tau and APP were reduced in microvesicles of Alzheimer's disease patients. A significant change was neither observed in the number of microvesicles nor in the expression of the other antigens. Tau and APP in microvesicles separated patients with Alzheimer's disease from controls with an AUC of 0.84 and 0.89 respectively. We conclude that tau and APP in CSF microvesicles are promising biomarkers which could directly provide information about the Alzheimer pathology on a cellular level.

Analysis of Surface Levels of IL-1 Receptors and Macrophage Scavenger Receptor I in Peripheral Immune Cells of Patients With Alzheimer Disease.

Increased concentrations of interleukin 1 (IL-1) in the cerebrospinal fluid and serum of patients with Alzheimer disease (AD) reduced phagocytic capacity point to an inflammatory activation of mononuclear phagocytes in AD. Interleukin 1 receptors (IL-1R) and the macrophage scavenger receptor I (MSRI) are important players in IL-1 signaling and phagocytosis. In 20 patients with AD and 17 controls, IL-1RI, IL-1RII, and MSRI were assessed on peripheral blood mononuclear cells by flow cytometry. IL-1ß, soluble IL-1 receptors, and IL-1R antagonist (IL-1Ra) were measured by enzyme-linked immunosorbent assay. The fraction of IL-1RI+ monocytes was increased by 10% and the expression of MSRI was reduced by 12% in AD. A 3.6% increased fraction of IL-1RI+ lymphocytes was accompanied by a 6.1% reduced expression of IL-1RII. The IL-1RI on monocytes and lymphocytes discriminated patients with AD with an accuracy of 0.79 and 0.75, respectively. The IL-1Ra was elevated in AD. Changes in the expression of IL-1 receptors and MSRI on peripheral blood cells fit to the concept of a proinflammatory state of the peripheral immune system. However, the observed differences are not strong enough to suggest their application as biomarkers for AD.

Serum neurofilament light chain in behavioral variant frontotemporal dementia.

OBJECTIVE: To determine the association of serum neurofilament light chain (NfL) with functional deterioration and brain atrophy during follow-up of patients with behavioral variant frontotemporal dementia (bvFTD). METHODS: Blood NfL levels from 74 patients with bvFTD, 26 with Alzheimer disease (AD), 17 with mild cognitive impairment (MCI), and 15 healthy controls (Con) at baseline and follow-up were determined and analyzed for the diagnostic potential in relation to functional assessment (Clinical Dementia Rating Scale Sum of Boxes [CDR-SOB], frontotemporal lobar degeneration-related CDR-SOB, Mini-Mental State Examination [MMSE]) and brain volumetry. RESULTS: At baseline, serum NfL level correlated with CSF NfL (bvFTD r = 0.706, p < 0.0001; AD/MCI r = 0.666, p = 0.0003). Highest serum levels were observed in bvFTD (p <0 0.0001 vs Con and MCI, p = 0.0078 vs AD, respectively). Discrimination of bvFTD from Con/MCI/AD was possible with 91%/74%/74% sensitivity and 79%/74%/58% specificity. At follow-up, serum NfL increased in bvFTD and AD (p = 0.0039 and p = 0.0006, respectively). At baseline and follow-up, NfL correlated with functional scores of patients with bvFTD (e.g., CDR-SOB [baseline] r = 0.4157, p = 0.0006; [follow-up] r = 0.5629, p < 0.0001) and with atrophy in the gray and white matter of many brain regions including frontal and subcortical areas (e.g., frontal lobe: r = -0.5857, p < 0.0001; 95% confidence interval -0.7415 to -0.3701). For patients with AD/MCI, NfL correlated with the functional performance as well (e.g., CDR-SOB [baseline] r = 0.6624, p < 0.0001; [follow-up] r = 0.5659, p = 0.0003) but not with regional brain volumes. CONCLUSIONS: As serum NfL correlates with functional impairment and brain atrophy in bvFTD at different disease stages, we propose it as marker of disease severity, paving the way for its future use as outcome measure for clinical trials. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with cognitive problems, serum NfL concentration discriminates bvFTD from other forms of dementia.

Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease.

BACKGROUND: A growing body of evidence suggests that the plasma concentration of the neurofilament light chain (NfL) might be considered a plasma biomarker for the screening of neurodegeneration in Alzheimer's disease (AD). METHODS: With a single molecule array method (Simoa, Quanterix), plasma NfL concentrations were measured in 99 subjects with AD at the stage of mild cognitive impairment (MCI-AD; n = 25) or at the stage of early dementia (ADD; n = 33), and in nondemented controls (n = 41); in all patients, the clinical diagnoses were in accordance with the results of the four core cerebrospinal fluid (CSF) biomarkers (amyloid ß (Aß)1-42, Aß42/40, Tau, and pTau181), interpreted according to the Erlangen Score algorithm. The influence of preanalytical storage procedures on the NfL in plasma was tested on samples exposed to six different conditions. RESULTS: NfL concentrations significantly increased in the samples exposed to more than one freezing/thawing cycle, and in those stored for 5 days at room temperature or at 4 °C. Compared with the control group of nondemented subjects (22.0 ± 12.4 pg/mL), the unadjusted plasma NfL concentration was highly significantly higher in the MCI-AD group (38.1 ± 15.9 pg/mL, p < 0.005) and even further elevated in the ADD group (49.1 ± 28.4 pg/mL; p < 0.001). A significant association between NfL and age (ρ = 0.65, p < 0.001) was observed; after correcting for age, the difference in NfL concentrations between AD and controls remained significant (p = 0.044). At the cutoff value of 25.7 pg/mL, unconditional sensitivity, specificity, and accuracy were 0.84, 0.78, and 0.82, respectively. Unadjusted correlation between plasma NfL and Mini Mental State Examination (MMSE) across all patients was moderate but significant (r = -0.49, p < 0.001). We observed an overall significant correlation between plasma NfL and the CSF biomarkers, but this correlation was not observed within the diagnostic groups. CONCLUSIONS: This study confirms increased concentrations of plasma NfL in patients with Alzheimer's disease compared with nondemented controls.

Imbalance of Circulating Th17 and Regulatory T Cells in Alzheimer's Disease: A Case Control Study.

The neuropathological hallmarks of Alzheimer's disease (AD), i.e., neuritic plaques and neurofibrillary tangles, consist of beta amyloid peptides (Aß) and hyperphosphorylated Tau. These are accompanied by reactive microglia and astrocytes in the vicinity of the neuritic plaques and by changes to the peripheral immune system, e.g., an increase of the pro-inflammatory cytokines IL-1ß, IL-6, and TNF-α in the peripheral blood. To address a potential involvement of peripheral T helper cell (Th) subsets in AD, we conducted a case control study with 54 individuals with AD dementia (n = 14), with mild cognitive impairment (MCI) due to AD (MCIAD, n = 14), with MCI unlikely due to AD (MCIother, n = 13), and controls without cognitive impairment (controls, n = 13). The proportions of CD3+CD8-IL-17A+IFNγ- Th17 cells, CD3+CD8-IL-17A-IFNγ+ Th1 cells, and CD4+CD127lowCD25+ regulatory T cells (Tregs) were assessed by flow cytometry. In addition, the correlations of the proportions of Th subsets to cerebrospinal fluid biomarkers were studied. CD3+CD8-IL-17A+IFNγ- Th17 cells were significantly increased in subjects with MCIAD compared to age- and sex-matched subjects with MCIother and controls (MCIAD mean = 1.13, SD = 0.77; MCIother mean = 0.58, SD = 0.28; and controls mean = 0.52, SD = 0.22; p = 0.008). The proportion of CD4+CD127lowCD25+ Tregs was not altered between the different groups, but it significantly positively related with the levels of total Tau and pTau181 (rTreg|totalTau = 0.43, p = 0.021, n = 28; rTreg|pTau181 = 0.46; p = 0.024, n = 28) in subjects with AD but not in nonAD controls (rTreg|totalTau = -0.51, p = 0.007, n = 26). The increase of circulating CD3+CD8-IL-17A+IFNγ- Th17 cells in the early stages of AD and the association of CD4+CD127lowCD25+ Tregs with neurodegeneration marker Tau may indicate that the adaptive immune system relates to neuropathological changes in AD.

Non-Phosphorylated Tau as a Potential Biomarker of Alzheimer's Disease: Analytical and Diagnostic Characterization.

BACKGROUND: Virtually nothing is known about a potential diagnostic role of non-phospho-epitopes of Tau (Non-P-Tau) in cerebrospinal fluid (CSF). OBJECTIVE: To establish and analytically and clinically characterize the first assay capable to measure concentrations of Non-P-Tau in human CSF. METHODS: An antibody (1G2) was developed that selectively binds to the Tau molecule non-phosphorylated at the positions T175 and T181, and was used in establishing a sandwich ELISA capable to measure Non-P-Tau in human CSF, following analytical and clinical validation of the method. RESULTS: The 1G2 antibody shows decreasing reactivity to tau peptides containing phosphorylation mainly at positions T175 and T181. Detection limit of the assay is 25 pg/ml; the coefficients of variation (CVs) of the optical densities of the repeated standard curves were between 3.6-15.9%. Median intra-assay imprecision of double measurements was 4.8%; inter-assay imprecision was in the range of 11.2% - 15.3%. Non-P-Tau concentrations are stable in the CSF samples sent to distinct laboratories under ambient temperature; inter-laboratory variation was approximately 30%. The Non-P-Tau CSF concentrations were highly significantly increased in patients with Alzheimer's disease in stage of mild cognitive impairment or dementia (AD/MCI, n = 58, 109.2±32.0 pg/mL) compared to the non-demented Controls (n = 42, 62.1±9.3 pg/mL, p < 0.001). At the cut-off of 78.3 pg/mL, the sensitivity and the specificity were 94.8% and 97.6%, respectively. CONCLUSION: For the first time, an assay is reported to reliably measure concentrations of non-phosphorylated Tau in human CSF.

Amyloidogenic amyloid-ß-peptide variants induce microbial agglutination and exert antimicrobial activity.

Amyloid-ß (Aß) peptides are the main components of the plaques found in the brains of patients with Alzheimer's disease. However, Aß peptides are also detectable in secretory compartments and peripheral blood contains a complex mixture of more than 40 different modified and/or N- and C-terminally truncated Aß peptides. Recently, anti-infective properties of Aß peptides have been reported. Here, we investigated the interaction of Aß peptides of different lengths with various bacterial strains and the yeast Candida albicans. The amyloidogenic peptides Aß1-42, Aß2-42, and Aß3p-42 but not the non-amyloidogenic peptides Aß1-40 and Aß2-40 bound to microbial surfaces. As observed by immunocytochemistry, scanning electron microscopy and Gram staining, treatment of several bacterial strains and Candida albicans with Aß peptide variants ending at position 42 (Aßx-42) caused the formation of large agglutinates. These aggregates were not detected after incubation with Aßx-40. Furthermore, Aßx-42 exerted an antimicrobial activity on all tested pathogens, killing up to 80% of microorganisms within 6 h. Aß1-40 only had a moderate antimicrobial activity against C. albicans. Agglutination of Aß1-42 was accelerated in the presence of microorganisms. These data demonstrate that the amyloidogenic Aßx-42 variants have antimicrobial activity and may therefore act as antimicrobial peptides in the immune system.

Usefulness of a Tailored eHealth Service for Informal Caregivers and Professionals in the Dementia Treatment and Care Setting: The eHealthMonitor Dementia Portal.

BACKGROUND: The European eHealthMonitor project (eHM) developed a user-sensitive and interactive Web portal for the dementia care setting called the eHM Dementia Portal (eHM-DP). It aims to provide targeted support for informal caregivers of persons with dementia and professionals. OBJECTIVE: The objective of this study was to assess the usefulness and impact of the eHM-DP service in the dementia care setting from two user perspectives: informal caregivers and professionals. METHODS: The evaluation study was conducted from June to September 2014 and followed a before-after, user-participatory, mixed-method design with questionnaires and interviews. The used intervention was the eHM-DP: an interactive Web portal for informal caregivers and professionals that was tested for a 12-week period. Primary outcomes for caregivers included empowerment, quality of life, caregiver burden, decision aid, as well as perceived usefulness and benefits of the eHM-DP. Primary outcomes for professionals involved decision aid, perceived usefulness, and benefits of the eHM-DP. RESULTS: A total of 25 informal caregivers and 6 professionals used the eHM-DP over the 12-week study period. Both professionals and informal caregivers indicated perceived benefits and support by the eHM-DP. In total, 65% (16/25) of informal caregivers would use the eHM-DP if they had access to it. Major perceived benefits were individualized information acquisition, improved interaction between informal caregivers and professionals, access to support from home, and empowerment in health-related decisions (PrepDM Score: 67.9). Professionals highlighted the improved treatment and care over the disease course (83%, 5/6) and improved health care access for people living in rural areas (67%, 4/6). However, there was no improvement in caregiver burden (Burden Scale for Family Caregivers) and quality of life (EuroQol-5D-5L) over the study period. CONCLUSIONS: Our study provides insight into the different user perspectives on an eHealth support service in the dementia treatment and care setting. These results are of importance for future developments and the uptake of eHealth solutions in the dementia domain and reinforce the importance of early user involvement. Turning to the primary target of the eHM-DP service, our findings suggest that the eHM-DP service proved to be a valuable post-diagnostic support service, in particular for the home-based care setting. Further research on a larger scale is needed to enhance the implementation in existing health care infrastructures.

Neurogranin and YKL-40: independent markers of synaptic degeneration and neuroinflammation in Alzheimer's disease.

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 Aß42 or the MMSE in AD samples. No relevant associations between YKL-40 and MMSE or the core AD biomarkers, Aß42, 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.

Depression, Anxiety, Resilience and Coping Pre and Post Kidney Transplantation - Initial Findings from the Psychiatric Impairments in Kidney Transplantation (PI-KT)-Study.

PURPOSE: Depression/anxiety, impaired Health-Related Quality of Life (HRQoL) and coping and resilience structures, are associated with increased mortality/poor outcome in chronic kidney disease (CKD) patients before (CKD/pre-KT) and after kidney (CKD-T) transplantation. Less is known about prevalence rates of psychiatric symptoms and impaired HRQoL of non-transplanted compared with transplanted patients. METHODS: In a cross-sectional study comparing 101 CKD/pre-KT patients with 151 cadaveric-transplanted (CKD-T) patients, we examined prevalence of depression/anxiety (HADS questionnaire) and coping, resilience and HRQoL (SF-12, Resilience-Scale and FKV-questionnaire). RESULTS: The prevalence of both depressive and anxiety symptoms was not significantly different between different pre-/and CKD-T patient groups. In CKD-T no significant relations of coping strategies with kidney function were identified. Furthermore, the Resilience Scales for acceptance and competence did not suggest any differences between the CKD/pre-KT and CKD-T subgroup. In the CKD/pre-KT patients, significant correlations were identified between the acceptance subscale and partnership, as well as between the competence subscale and older age/partnership. CONCLUSIONS: Both the CKD/pre-KT and CKD-T patients exhibited notable impairments in the HRQoL which which showed a comparable pattern of results. KT itself does not appear to be the main risk factor for the development of mental impairments.

Astrocytes and microglia but not neurons preferentially generate N-terminally truncated Aß peptides.

The neuropathological hallmarks of Alzheimer's disease include extracellular neuritic plaques and neurofibrillary tangles. The neuritic plaques contain ß-amyloid peptides (Aß peptides) as the major proteinaceous constituent and are surrounded by activated microglia and astrocytes as well as dystrophic neurites. N-terminally truncated forms of Aß peptides are highly prevalent in neuritic plaques, including Aß 3-x beginning at Glu eventually modified to pyroglutamate (Aß N3pE-x), Aß 2-x, Aß 4-x, and Aß 5-x. The precise origin of the different N-terminally modified Aß peptides currently remains unknown. To assess the contribution of specific cell types to the formation of different N-terminally truncated Aß peptides, supernatants from serum-free primary cell cultures of chicken neurons, astrocytes, and microglia, as well as human astrocytes, were analyzed by Aß-ELISA and one- and two-dimensional SDS-urea polyacrylamide gel electrophoresis followed by immunoblot analysis. To evaluate the contribution of ß- and γ-secretase to the generation of N-terminally modified Aß, cultured astrocytes were treated with membrane-anchored "tripartite ß-secretase (BACE1) inhibitors" and the γ-secretase inhibitor DAPT. Neurons, astrocytes, and microglia each exhibited cell type-specific patterns of secreted Aß peptides. Neurons predominantly secreted Aß peptides that begin at Asp1, whereas those released from astrocytes and microglia included high proportions of N-terminally modified Aß peptides, presumably including Aß 2/3-x and 4/5-x. The inhibition of BACE1 reduced the amount of Aß 1-x in cell culture supernatants but not the amount of Aß 2-x.