In the search for biomarkers of synapse loss associated with Alzheimer's disease (AD), we used shotgun proteomics to identify a panel of 9 synaptic proteins detectable in human cerebrospinal fluid ...(CSF). Expression at the human synapse was verified using super resolution microscopy. Using SRM, we monitored the panel in CSF from 3 independent clinical cohorts. We report 6 synaptic biomarkers that demonstrate changes in preclinical AD prior to markers of neurodegeneration, which could have clinical value for assessing disease progression.
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Highlights
•Proteomic analysis of cerebrospinal fluid and identification of synaptic component.•Use of super resolution microscopy to verify synapse-specificity in human tissue.•Selective reaction monitoring MS (SRM) of synaptic panel in 3 cohorts of Alzheimer's disease cerebrospinal fluid.•Synaptic protein changes precede tau in preclinical Alzheimer's disease.
A biomarker of synapse loss, an early event in Alzheimer's disease (AD) pathophysiology that precedes neuronal death and symptom onset, would be a much-needed prognostic biomarker. With direct access to the brain interstitial fluid, the cerebrospinal fluid (CSF) is a potential source of synapse-derived proteins. In this study, we aimed to identify and validate novel CSF biomarkers of synapse loss in AD. Discovery: Combining shotgun proteomics of the CSF with an exhaustive search of the literature and public databases, we identified 251 synaptic proteins, from which we selected 22 for further study. Verification: Twelve proteins were discarded because of poor detection by Selected Reaction Monitoring (SRM). We confirmed the specific expression of 9 of the remaining proteins (Calsyntenin-1, GluR2, GluR4, Neurexin-2A, Neurexin-3A, Neuroligin-2, Syntaxin-1B, Thy-1, Vamp-2) at the human synapse using Array Tomography microscopy and biochemical fractionation methods. Exploration: Using SRM, we monitored these 9 synaptic proteins (20 peptides) in a cohort of CSF from cognitively normal controls and subjects in the pre-clinical and clinical AD stages (n = 80). Compared with controls, peptides from 8 proteins were elevated 1.3 to 1.6-fold (p < 0.04) in prodromal AD patients. Validation: Elevated levels of a GluR4 peptide at the prodromal stage were replicated (1.3-fold, p = 0.04) in an independent cohort (n = 60). Moreover, 7 proteins were reduced at preclinical stage 1 (0.6 to 0.8-fold, p < 0.04), a finding that was replicated (0.7 to 0.8-fold, p < 0.05) for 6 proteins in a third cohort (n = 38). In a cross-cohort meta-analysis, 6 synaptic proteins (Calsyntenin-1, GluR4, Neurexin-2A, Neurexin-3A, Syntaxin-1B and Thy-1) were reduced 0.8-fold (p < 0.05) in preclinical AD, changes that precede clinical symptoms and CSF markers of neurodegeneration. Therefore, these proteins could have clinical value for assessing disease progression, especially in preclinical stages of AD.
Abstract Introduction Lumbar puncture (LP) is increasingly performed in memory clinics. We investigated patient-acceptance of LP, incidence of and risk factors for post-LP complications in memory ...clinic populations. Methods We prospectively enrolled 3868 patients (50% women, age 66 ± 11 years, mini mental state examination 25 ± 5) at 23 memory clinics. We used logistic regression analysis using generalized estimated equations to investigate risk factors for post-LP complications, such as typical postlumbar puncture headache (PLPH) and back pain. Results A total of 1065 patients (31%) reported post-LP complaints; 589 patients (17%) reported back pain, 649 (19%) headache, of which 296 (9%) reported typical PLPH. Only few patients needed medical intervention: 11 (0.3%) received a blood patch, 23 (0.7%) were hospitalized. The most important risk factor for PLPH was medical history of headache. An atraumatic needle and age >65 years were preventive. Gender, rest after LP, or volume of cerebrospinal fluid had no effect. Discussions The overall risk of complications is relatively low. If risk factors shown in this study are taken into account, LPs can be safely performed in memory clinics.
The canonical case of a vortex ring interacting with a solid surface orthogonal to its symmetry axis exhibits a variety of intricate behaviours, including stretching of the primary vortex ring and ...generation of secondary vorticity, which illustrate key features of vortex interactions with boundaries. Replacing the solid boundary with a permeable screen allows for new behaviour by relaxing the no-through-flow condition, and can provide a useful analogue for the interaction of large-scale vortices with permeable structures or closely spaced obstructions. The present investigation considers the interaction of experimentally generated vortex rings with a thin permeable screen. The vortex rings were generated using a piston-in-cylinder mechanism using piston stroke-to-diameter ratios (
$L/ D$
) of 1.0 and 3.0 (nominal) with jet Reynolds numbers (
$R{e}_{j} $
) of 3000 and 6000 (nominal). Planar laser-induced fluorescence and digital particle image velocimetry (DPIV) were used to study the interaction with wire-mesh screens having surface open-area ratios (
$\phi $
) in the range 0.44–0.79. Solid surfaces (
$\phi = 0$
) and free vortex rings (
$\phi = 1$
) were also included as special cases. Measurement of the vortex trajectories showed expansion of the vortex ring diameter as it approached the boundary and generation of secondary vorticity similar to the case of a solid boundary, but the primary vortex diameter then began to contract towards the symmetry axis as the flow permeated the screen and reorganized into a transmitted vortex downstream. The trajectories were highly dependent on
$\phi $
, with little change in the incident ring trajectory for
$\phi = 0. 79$
. Measurement of the hydrodynamic impulse and kinetic energy using DPIV showed that the change between the average upstream and downstream values of these quantities also depended primarily on
$\phi $
, with a slight decrease in the relative change as
$L/ D$
and/or
${\mathit{Re}}_{j} $
were increased. The kinetic energy dissipation (
$ \mrm{\Delta} E$
) was much more sensitive to
$\phi $
, with a strongly nonlinear dependence, while the decrease in impulse (
$ \mrm{\Delta} I$
) was nearly linear in
$\phi $
. A simple model is proposed to relate
$ \mrm{\Delta} E$
and
$ \mrm{\Delta} I$
in terms of bulk flow parameters. The model incorporates the decrease in flow velocity during the interaction due to the drag force exerted by the screen on the flow.
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.
Reducing the risk of dementia can halt the worldwide increase of affected people. The multifactorial and heterogeneous nature of late‐onset dementia, including Alzheimer's disease (AD), indicates a ...potential impact of multidomain lifestyle interventions on risk reduction. The positive results of the landmark multidomain Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) support such an approach. The World‐Wide FINGERS (WW‐FINGERS), launched in 2017 and including over 25 countries, is the first global network of multidomain lifestyle intervention trials for dementia risk reduction and prevention. WW‐FINGERS aims to adapt, test, and optimize the FINGER model to reduce risk across the spectrum of cognitive decline—from at‐risk asymptomatic states to early symptomatic stages—in different geographical, cultural, and economic settings. WW‐FINGERS aims to harmonize and adapt multidomain interventions across various countries and settings, to facilitate data sharing and analysis across studies, and to promote international joint initiatives to identify globally implementable and effective preventive strategies.
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.
•Simulation of natural convection inside C-shaped cavity filled with solid obstacles.•Observation of channeling, interference and discontinuous fin-like diffusion.•Diffusion is more significant as ...the thermal conductivity of the blocks increases.
This study considers the thermo-hydraulic effects of discrete solid blocks on the natural convection inside a fluid filled, horizontally heated side-open cavity. The cavity, having adiabatic horizontal surfaces and an isothermal hot wall, is open to a vast reservoir filled with a quiescent fluid maintained at a temperature lower than the cavity wall temperature. A fixed amount of solid material is progressively distributed inside the cavity as disconnected and conductive square blocks of different numbers and sizes, forming a uniform square lattice. The ensuing natural convection process is modeled analytically considering the fluid and solid constituents inside the cavity separately, and simulated through a validated numerically approach following a parametric analysis done in terms of the Rayleigh number (105 ≤ Ra ≤ 108), the total number of blocks (9 ≤ N ≤ 144) and the solid-to-fluid thermal conductivity ratio (0.1 ≤ κ ≤ 100). The cavity aspect ratio and fluid Prandtl number are kept equal to unity, and the volume-fraction of the solid constituent is equal to 0.36. The present study evaluate the thermo-hydraulic effects of the blocks in the permanent convection process through streamlines, isotherms, hot wall Nusselt mean number and dimensionless mass flow through the fluid reservoir cavity. The blocks affect the convection process in three ways: via channeling, flow interference, and discontinuous fin-like diffusion. The most important effect is interference, which is shown to be analytically predictable. The fin-like effect is the most complex and modulates mostly by the magnitude of κ. Finally, analytical correlations are presented for averaged hot-wall Nusselt number and the nondimensional mass flow rate as useful practical tools in helping the design and analysis of similar configurations.
Machine learning (ML) may harbor the potential to capture the metabolic complexity in Alzheimer Disease (AD). Here we set out to test the performance of metabolites in blood to categorize AD when ...compared to CSF biomarkers.
This study analyzed samples from 242 cognitively normal (CN) people and 115 with AD-type dementia utilizing plasma metabolites (n = 883). Deep Learning (DL), Extreme Gradient Boosting (XGBoost) and Random Forest (RF) were used to differentiate AD from CN. These models were internally validated using Nested Cross Validation (NCV).
On the test data, DL produced the AUC of 0.85 (0.80–0.89), XGBoost produced 0.88 (0.86–0.89) and RF produced 0.85 (0.83–0.87). By comparison, CSF measures of amyloid, p-tau and t-tau (together with age and gender) produced with XGBoost the AUC values of 0.78, 0.83 and 0.87, respectively.
This study showed that plasma metabolites have the potential to match the AUC of well-established AD CSF biomarkers in a relatively small cohort. Further studies in independent cohorts are needed to validate whether this specific panel of blood metabolites can separate AD from controls, and how specific it is for AD as compared with other neurodegenerative disorders.
Abstract Mutations in three genes ( PSEN1 , PSEN2 , and APP ) have been identified in patients with early-onset (<65years) Alzheimer's disease (AD). We performed a screening for mutations in the ...coding regions of presenilins, as well as exons 16 and 17 of the APP gene in a total of 231 patients from the Iberian peninsular with a clinical diagnosis of early-onset AD (mean age at onset of 52.9 years; range 31–64). We found three novel mutations in PSEN1 , one novel mutation in PSEN2 , and a novel mutation in the APP gene. Four previously described mutations in PSEN1 were also found. The same analysis was carried in 121 elderly healthy controls from the Iberian peninsular, and a set of 130 individuals from seven African populations belonging to the Centre d’Etude du Polymorphisme Humain-Human Genome Diversity Panel (CEPH-HGDP), in order to determine the extent of normal variability in these genes. Interestingly, in the latter series, we found five new non-synonymous changes in all three genes and a presenilin 2 variant (R62H) that has been previously related to AD. In some of these mutations, the pathologic consequence is uncertain and needs further investigation. To address this question we propose and use a systematic algorithm to classify the putative pathology of AD mutations.
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.
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