A critical and as-yet unmet need in Alzheimer's disease (AD) is the discovery of peripheral small molecule biomarkers. Given that brain pathology precedes clinical symptom onset, we set out to test ...whether metabolites in blood associated with pathology as indexed by cerebrospinal fluid (CSF) AD biomarkers.
This study analyzed 593 plasma samples selected from the European Medical Information Framework for Alzheimer's Disease Multimodal Biomarker Discovery study, of individuals who were cognitively healthy (n = 242), had mild cognitive impairment (n = 236), or had AD-type dementia (n = 115). Logistic regressions were carried out between plasma metabolites (n = 883) and CSF markers, magnetic resonance imaging, cognition, and clinical diagnosis.
Eight metabolites were associated with amyloid β and one with t-tau in CSF, these were primary fatty acid amides (PFAMs), lipokines, and amino acids. From these, PFAMs, glutamate, and aspartate also associated with hippocampal volume and memory.
PFAMs have been found increased and associated with amyloid β burden in CSF and clinical measures.
There are few updated studies on the prevalence and management of Alzheimer's disease (AD), which could be underdiagnosed or undertreated. The COVID-19 pandemic may have worsened the deficiencies in ...the diagnosis and treatment of these patients. Electronic medical records (EMR) offer an opportunity to assess the impact and management of medical processes and contingencies in the population.
To estimate AD prevalence in Spain over a 6-year period, based on treated patients, according to usual clinical practice. Additionally, to describe the management of AD-treated patients and the evolution of that treatment during the 2020 COVID-19 pandemic.
Retrospective study using the Spanish IQVIA EMR database. Patients treated with donepezil, galantamine, rivastigmine, and/or memantine were included in the study. Annual AD prevalence (2015-2020) was estimated and extrapolated to the national population level. Most frequent treatments and involved specialties were described. To assess the effect of COVID-19, the incidence of new AD cases in 2020 was calculated and compared with newly diagnosed cases in 2019.
Crude AD prevalence (2015-2020) was estimated at 760.5 per 100,000 inhabitants, and age-standardized prevalence (2020) was 664.6 (male 595.7, female 711.0). Monotherapy was the most frequent way to treat AD (86.2%), in comparison with dual therapy (13.8%); rivastigmine was the most prescribed treatment (37.3%), followed by memantine (36.4%) and donepezil (33.0%). Rivastigmine was also the most utilized medication in newly treated patients (46.7%), followed by donepezil (29.8%), although donepezil persistence was longer (22.5 vs. 20.6 months). Overall, donepezil 10 mg, rivastigmine 9.5 mg, and memantine 20 mg were the most prescribed presentations. The incidence rate of AD decreased from 148.1/100,000 (95% confidence interval CI 147.0-149.2) in 2019 to 118.4/100,000 (95% CI 117.5-119.4) in 2020.
The obtained prevalence of AD-treated patients was consistent with previous face-to-face studies. In contrast with previous studies, rivastigmine, rather than donepezil, was the most frequent treatment. A decrease in the incidence of AD-treated patients was observed during 2020 in comparison with 2019, presumably due to the significant impact of the COVID-19 pandemic on both diagnosis and treatment. EMR databases emerge as valuable tools to monitor in real time the incidence and management of medical conditions in the population, as well as to assess the health impact of global contingencies and interventions.
Plasma proteins have been widely studied as candidate biomarkers to predict brain amyloid deposition to increase recruitment efficiency in secondary prevention clinical trials for Alzheimer's ...disease. Most such biomarker studies are targeted to specific proteins or are biased toward high abundant proteins.
4001 plasma proteins were measured in two groups of participants (discovery group = 516, replication group = 365) selected from the European Medical Information Framework for Alzheimer's disease Multimodal Biomarker Discovery study, all of whom had measures of amyloid.
A panel of proteins (n = 44), along with age and apolipoprotein E (APOE) ε4, predicted brain amyloid deposition with good performance in both the discovery group (area under the curve = 0.78) and the replication group (area under the curve = 0.68). Furthermore, a causal relationship between amyloid and tau was confirmed by Mendelian randomization.
The results suggest that high-dimensional plasma protein testing could be a useful and reproducible approach for measuring brain amyloid deposition.
Introduction
This study employed an integrative system and causal inference approach to explore molecular signatures in blood and CSF, the amyloid/tau/neurodegeneration AT(N) framework, mild ...cognitive impairment (MCI) conversion to Alzheimer's disease (AD), and genetic risk for AD.
Methods
Using the European Medical Information Framework (EMIF)‐AD cohort, we measured 696 proteins in cerebrospinal fluid (n = 371), 4001 proteins in plasma (n = 972), 611 metabolites in plasma (n = 696), and genotyped whole‐blood (7,778,465 autosomal single nucleotide epolymorphisms, n = 936). We investigated associations: molecular modules to AT(N), module hubs with AD Polygenic Risk scores and APOE4 genotypes, molecular hubs to MCI conversion and probed for causality with AD using Mendelian randomization (MR).
Results
AT(N) framework associated with protein and lipid hubs. In plasma, Proprotein Convertase Subtilisin/Kexin Type 7 showed evidence for causal associations with AD. AD was causally associated with Reticulocalbin 2 and sphingomyelins, an association driven by the APOE isoform.
Discussion
This study reveals multi‐omics networks associated with AT(N) and causal AD molecular candidates.
Lumbar puncture (LP) is increasingly performed in memory units due to the usefulness of cerebrospinal fluid (CSF) biomarkers in the diagnosis of Alzheimer's disease. The feasibility of this procedure ...in this context, however, is controversial.
Our aim was to analyze the incidence of complications and their associated factors so as to determine the impact of LP in the study of CSF biomarkers of Alzheimer's disease.
In the context of a larger international initiative, we prospectively collected data from 689 participants who underwent LP in three memory units in Spain. Data included demographic factors, headache history, subjective attitude toward the procedure, patient positioning, needle characteristics, volume of CSF extracted, attempts needed, and resting time after CSF acquisition. Five to seven days after the procedure, we asked participants about complications through a semi-structured telephone interview.
No adverse events were reported in 441 (64.0%) participants. The most frequent complication was headache, reported by 171 (24.8%) subjects. It was severe in only 17 (2.5%). Headache was more frequent in younger participants and when a cutting-edge needle was used. Back pain was present in 111 (16.1%) cases, and it was associated with female gender, cutting-edge needles, increased number of attempts, and longer resting time after LP. No major complications were reported. The use of pen-point needles showed a trend toward a higher frequency of hematic CSF.
LP can be safely performed to study CSF biomarkers. The main complication is headache, associated with younger age and use of cutting-edge needles.
Introduction
Neurofilament light (NfL), chitinase‐3‐like protein 1 (YKL‐40), and neurogranin (Ng) are biomarkers for Alzheimer's disease (AD) to monitor axonal damage, astroglial activation, and ...synaptic degeneration, respectively.
Methods
We performed genome‐wide association studies (GWAS) using DNA and cerebrospinal fluid (CSF) samples from the EMIF‐AD Multimodal Biomarker Discovery study for discovery, and the Alzheimer's Disease Neuroimaging Initiative study for validation analyses. GWAS were performed for all three CSF biomarkers using linear regression models adjusting for relevant covariates.
Results
We identify novel genome‐wide significant associations between DNA variants in TMEM106B and CSF levels of NfL, and between CPOX and YKL‐40. We confirm previous work suggesting that YKL‐40 levels are associated with DNA variants in CHI3L1.
Discussion
Our study provides important new insights into the genetic architecture underlying interindividual variation in three AD‐related CSF biomarkers. In particular, our data shed light on the sequence of events regarding the initiation and progression of neuropathological processes relevant in AD.
Background
In preclinical Alzheimer’s disease (AD), amyloid accumulates in highly‐functionally connected brain regions. This selective vulnerability is related to the high neuronal fluctuations, ...typical of these regions. Dynamic functional connectivity (FC) was introduced to investigate network organization over time, with high network variations indicating regional flexibility, hence promoting functional integration. The relation of early amyloid deposition with FC dynamics remains unclear. Eigenvector centrality (EC) evaluates a node's importance in functional networks, both for the whole functional MRI time series (“static” EC) or within sliding‐windows (“dynamic” EC). We studied the association of cerebrospinal fluid (CSF) amyloid load with static and dynamic EC in non‐demented individuals from the European Prevention of Alzheimer’s Dementia (EPAD) cohort.
Methods
Data for 701 non‐demented participants were available. CSF Aβ1‐42 levels <1000 pg/mL were defined as amyloid positive (A+) (Elecsys assay). Both static and dynamic voxel‐wise EC were computed from rs‐fMRI time series. Static EC differences between A+ and A‐ participants were assessed using linear models. Standard deviation and range of dynamic EC were compared between A+ and A‐ participants within significant clusters of static EC differences, and within 10 resting‐state networks (RSN). Linear models were used to determine interaction between amyloid and cognitive performance on dynamic EC variability (Figure 1).
Results
Demographics and clinical characteristics are shown in Table 1. A+ participants showed lower static EC values in parietal and occipital clusters, and higher static EC values in a medio‐frontal cluster (Figure 2). The medio‐frontal cluster had also lower dynamic EC variability in A+ (Figure 3). The default mode (Figure 4) and the visual networks of A+ participants also showed lower dynamic EC variability (p < 0.001). Dynamic properties in the DMN and visual networks were differentially associated with cognitive domains in the A‐ and A+ groups, with lower variability found in A+ participants with higher cognitive scores (Figure 5).
Conclusion
We demonstrate that early amyloid deposition affects static and dynamic EC, possibly by reducing involvement of functional hubs in different network dynamics and functional integration, thus relating to cognitive dysfunctions. Our data suggest dynamic EC as an early biomarker of the interplay between early amyloid deposition and cognitive decline.
Abstract INTRODUCTION We aimed to unravel the underlying pathophysiology of the neurodegeneration (N) markers neurogranin (Ng), neurofilament light (NfL), and hippocampal volume (HCV), in Alzheimer's ...disease (AD) using cerebrospinal fluid (CSF) proteomics. METHODS Individuals without dementia were classified as A+ (CSF amyloid beta Aβ42), T+ (CSF phosphorylated tau181), and N+ or N− based on Ng, NfL, or HCV separately. CSF proteomics were generated and compared between groups using analysis of covariance. RESULTS Only a few individuals were A+T+Ng−. A+T+Ng+ and A+T+NfL+ showed different proteomic profiles compared to A+T+Ng− and A+T+NfL−, respectively. Both Ng+ and NfL+ were associated with neuroplasticity, though in opposite directions. Compared to A+T+HCV−, A+T+HCV+ showed few proteomic changes, associated with oxidative stress. DISCUSSION Different N markers are associated with distinct neurodegenerative processes and should not be equated. N markers may differentially complement disease staging beyond amyloid and tau. Our findings suggest that Ng may not be an optimal N marker, given its low incongruency with tau pathophysiology. Highlights In Alzheimer's disease, neurogranin (Ng)+, neurofilament light (NfL)+, and hippocampal volume (HCV)+ showed differential protein expression in cerebrospinal fluid. Ng+ and NfL+ were associated with neuroplasticity, although in opposite directions. HCV+ showed few proteomic changes, related to oxidative stress. Neurodegeneration (N) markers may differentially refine disease staging beyond amyloid and tau. Ng might not be an optimal N marker, as it relates more closely to tau.
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