Spin scattering characteristics of nickel doped with manganese are compared to nickel doped with iron and chromium in nickel. Conclusions are made based on the spin characteristics of the nickel ...samples doped with manganese with varying percentages in a host nickel crystal. Manganese doping increases the magnetic exchange splitting of nickel, similar to doping with iron and opposite to doping with chromium. On the other hand, manganese doping behaves different from iron with respect the ratio of the majority to minority spin carriers and the ratio of their lifetimes. While iron doping affects both ratios strongly, manganese and chromium doping do not.
Alzheimer disease (AD) pathology starts with a prolonged phase of β-amyloid (Aβ) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase ...has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression.
To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aβ-positive cognitively unimpaired (CU) individuals.
This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention WRAP), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aβ pathology defined by cerebrospinal fluid (CSF) Aβ42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aβ-positive and Aβ-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aβ-positive participants were included in the main analyses.
Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort.
The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination MMSE and the modified Preclinical Alzheimer Cognitive Composite mPACC) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion.
Among 171 Aβ-positive CU participants included in the main analyses, 119 (mean SD age, 73.0 5.4 years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean SD age, 64.4 4.6 years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time.
In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
•Principal component analysis was conducted for untargeted CSF metabolites.•CSF metabolite principal components were associated with AD biomarkers such as p-tau, t-tau, Aβ42.•Tau pathology associated ...CSF metabolites were related to caffeine metabolism.
Studying the correlation between cerebrospinal fluid (CSF) metabolites and the Alzheimer's Disease (AD) biomarkers may offer a window to the alterations of the brain metabolome and unveil potential biological mechanisms underlying AD. In this analysis, 308 CSF metabolites from 338 individuals of Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center were included in a principal component analysis (PCA). The resulted principal components (PCs) were tested for association with CSF total tau (t-tau), phosphorylated tau (p-tau), amyloid β 42 (Aβ42), and Aβ42/40 ratio using linear regression models. Significant PCs were further tested with other CSF NeuroToolKit (NTK) and imaging biomarkers. Using a Bonferroni corrected p < 0.05, 5 PCs were significantly associated with CSF p-tau and t-tau and 3 PCs were significantly associated with CSF Aβ42. Pathway analysis suggested that these PCS were enriched in 6 pathways, including metabolism of caffeine and nicotinate and nicotinamide. This study provides evidence that CSF metabolites are associated with AD pathology through core AD biomarkers and other NTK markers and suggests potential pathways to follow up in future studies.
Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal ...barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using
C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.
Introduction
Blood‐based Alzheimer's disease (AD) biomarkers show promise, but pre‐analytical protocol differences may pose problems. We examined seven AD blood biomarkers (amyloid beta ...Aβ42${\rm{A\beta }}{_{42}}$, Aβ40${\rm{A}}{{{\beta}}_{40}}$, phosphorylatedtaup−tau181${\rm{phosphorylated\;tau\;p - ta}}{{\rm{u}}_{181}}$, total tau t‐tau, neurofilament light chain NfL, Aβ4240,${\rm{A}}{{{\beta}}_{\frac{{42}}{{40}}},$ and p−tau181Aβ42$\frac{{{\rm{p - ta}}{{\rm{u}}_{181}}}{{{\rm{A}}{{{\beta}}_{42}}}$) in three collection tube types (ethylenediaminetetraacetic acid EDTA plasma, heparin plasma, serum).
Methods
Plasma and serum were obtained from cerebrospinal fluid or amyloid positron emission tomography‐positive and ‐negative participants (N = 38) in the Wisconsin Registry for Alzheimer's Prevention. We modeled AD biomarker values observed in EDTA plasma versus heparin plasma and serum, and assessed correspondence with brain amyloidosis.
Results
Results suggested bias due to tube type, but crosswalks are possible for some analytes, with excellent model fit for NfL (R2${{\rm{R}}^2}\;$= 0.94), adequate for amyloid (R2${{\rm{R}}^2}\;$= 0.40‐0.69), and weaker for t‐tau (R2${{\rm{R}}^2}\;$= 0.04‐0.42) and p−tau181${\rm{p - ta}}{{\rm{u}}_{181}}$ ( R2${{\rm{R}}^2}\;$= 0.22‐0.29). Brain amyloidosis differentiated several measures, especially EDTA plasma pTau181Aβ42$\frac{{{\rm{pTa}}{{\rm{u}}_{181}}}{{{\rm{A}}{\beta _{42}}}$ (d$d\;$= 1.29).
Discussion
AD biomarker concentrations vary by tube type. However, correlations for some biomarkers support harmonization across types, suggesting cautious optimism for use in banked blood.
To examine whether the
gene variant KL-VS attenuates
associated β-amyloid (Aβ) accumulation in a late-middle-aged cohort enriched with Alzheimer disease (AD) risk factors.
Three hundred nine ...late-middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were genotyped to determine KL-VS and
status and underwent CSF sampling (n = 238) and/or
C-Pittsburgh compound B (PiB)-PET imaging (n = 183). Covariate-adjusted regression analyses were used to investigate whether
exerted expected effects on Aβ burden. Follow-up regression analyses stratified by KL-VS genotype (i.e., noncarrier vs heterozygous; there were no homozygous individuals) evaluated whether the influence of
on Aβ was different among KL-VS heterozygotes compared to noncarriers.
carriers exhibited greater Aβ burden than
-negative participants. This effect was stronger in CSF (
= -5.12,
< 0.001) compared with PiB-PET (
= 3.93,
< 0.001). In the stratified analyses, this
effect on Aβ load was recapitulated among KL-VS noncarriers (CSF:
= -5.09,
< 0.001; PiB-PET:
= 3.77,
< 0 .001). In contrast, among KL-VS heterozygotes,
-positive individuals did not exhibit higher Aβ burden than
-negative individuals (CSF:
= -1.03,
= 0.308; PiB-PET: t = 0.92,
= 0.363). These differential
effects remained after KL-VS heterozygotes and noncarriers were matched on age and sex.
In a cohort of at-risk late-middle-aged adults, KL-VS heterozygosity was associated with an abatement of
associated Aβ aggregation, suggesting KL-VS heterozygosity confers protections against
linked pathways to disease onset in AD.
Sphingomyelin (SM) levels have been associated with Alzheimer's disease (AD), but the association direction has been inconsistent and research on cerebrospinal fluid (CSF) SMs has been limited by ...sample size, breadth of SMs examined, and diversity of biomarkers available.
Here, we seek to build on our understanding of the role of SM metabolites in AD by studying a broad range of CSF SMs and biomarkers of AD, neurodegeneration, and neuroinflammation.
Leveraging two longitudinal AD cohorts with metabolome-wide CSF metabolomics data (n = 502), we analyzed the relationship between the levels of 12 CSF SMs, and AD diagnosis and biomarkers of pathology, neurodegeneration, and neuroinflammation using logistic, linear, and linear mixed effects models.
No SMs were significantly associated with AD diagnosis, mild cognitive impairment, or amyloid biomarkers. Phosphorylated tau, neurofilament light, α-synuclein, neurogranin, soluble triggering receptor expressed on myeloid cells 2, and chitinase-3-like-protein 1 were each significantly, positively associated with at least 5 of the SMs.
The associations between SMs and biomarkers of neurodegeneration and neuroinflammation, but not biomarkers of amyloid or diagnosis of AD, point to SMs as potential biomarkers for neurodegeneration and neuroinflammation that may not be AD-specific.
Introduction
We investigated whether insulin resistance (IR) was associated with longitudinal age‐related change in cognition and biomarkers of Alzheimer's disease (AD) pathology and ...neurodegeneration in middle‐aged and older adults who were non‐demented at baseline.
Methods
IR was measured with homeostatic model assessment of insulin resistance (HOMA2‐IR). Core AD‐related cerebrospinal fluid (CSF) biomarkers and cognition were assessed, respectively, on n = 212 (1 to 5 visits) and n = 1299 (1 to 6 visits). Linear mixed models tested whether HOMA2‐IR moderated age‐related change in CSF biomarkers and cognition. Linear regressions tested whether HOMA2‐IR x apolipoprotein E ε4 allele (APOE ε4) carrier status predicted amyloid beta Aβ chronicity (estimated duration of amyloid positron emission tomography PET positivity) (n = 253).
Results
Higher HOMA2‐IR was associated with greater cognitive decline but not with changes in CSF biomarkers. HOMA2‐IR x APOE4 was not related to Aβ chronicity but was significantly associated with CSF phosphorylated tau (P‐tau)181/Aβ42 level.
Discussion
In non‐demented adults IR may not be directly associated with age‐related change in AD biomarkers. Additional research is needed to determine mechanisms linking IR to cognitive decline.
Off-target binding in the skull and meninges is observed in some subjects undergoing tau positron emission tomography (PET) and could potentially differ between men and women. In this study we ...elucidate sex differences in tau off-target binding using three different tau PET tracers.
541 cognitively unimpaired amyloid-β negative participants underwent tau PET using 18Fflortaucipir (n = 165), 18FRO948 (n = 189) and 18FMK6240 (n = 187). Baseline SUVR-values were compared between females and males at the voxel level and using a region-of-interest (ROI) encompassing the skull/meninges. In addition, we assessed the cross-sectional relationship between baseline skull/meninges SUVR and age and assessed change in skull/meningeal SUVR values over time in a subsample with longitudinal data (n = 63).
Voxel-wise analysis showed higher meningeal off-target binding in women compared to men across all three tracers. The SUVRs in the skull/meningeal ROI were highest using 18FRO948, followed by 18FMK6240 and 18Fflortaucipir (p < 0.001). For all tracers, females showed higher skull/meningeal ROI retention (mean SUVR ± SD 18Fflortaucipir: 0.82 ± 0.14; 18FRO948: 1.26 ± 0.30; 18FMK6240: 1.09 ± 0.19) compared to men (18Fflortaucipir: 0.70 ± 0.11; 18FRO948: 1.10 ± 0.24; 18FMK6240: 0.97 ± 0.17) (p < 0.001). For 18Fflortaucipir and 18FRO948, off-target binding in the skull/meninges decreased with age.
There is an effect of sex on off-target retention in the meninges/skull across 18Fflortaucipir, 18FRO948, and 18FMK6240 tau PET tracers.
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