#1

https://x.com/MariosGeorgakis/status/1946300683340149128?s=19

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#2

I found the paper on this:

https://www.nature.com/articles/s41591-025-03831-3

Disruption of the cerebrospinal fluid–plasma protein balance in cognitive impairment and aging

Abstract
The brain barrier system, including the choroid plexus, meninges and brain vasculature, regulates substrate transport and maintains differential protein concentrations between blood and cerebrospinal fluid (CSF). Aging and neurodegeneration disrupt brain barrier function, but proteomic studies of the effects on blood–CSF protein balance are limited. Here we used SomaScan proteomics to characterize paired CSF and plasma samples from 2,171 healthy or cognitively impaired older individuals from multiple cohorts, including the Global Neurodegeneration Proteomics Consortium. We identified proteins with correlated CSF and plasma levels that are produced primarily outside the brain and are enriched for structural domains that may enable their transport across brain barriers. CSF to plasma ratios of 848 proteins increased with aging in healthy control individuals, including complement and coagulation proteins, chemokines and proteins linked to neurodegeneration, whereas 64 protein ratios decreased with age, suggesting substrate-specific barrier regulation. Notably, elevated CSF to plasma ratios of peripherally derived or vascular-associated proteins, including DCUN1D1, MFGE8 and VEGFA, were associated with preserved cognitive function. Genome-wide association studies identified genetic loci associated with CSF to plasma ratios of 241 proteins, many of which have known disease associations, including FCN2, the collagen-like domain of which may facilitate blood–CSF transport. Overall, this work provides molecular insight into the human brain barrier system and its disruption with age and disease, with implications for the development of brain-permeable therapeutics.

and ran it through O3:

Article in one minute

Amelia Fariñas and colleagues profiled 2,171 paired cerebrospinal‑fluid (CSF) and plasma samples from three cohorts (Knight‑ADRC, Stanford and the Global Neurodegeneration Proteomics Consortium). Using the 7,288‑analyte SomaScan v4 platform they quantified 2,304 proteins in both fluids, computed individual CSF‑to‑plasma ratios, and related those ratios to age, sex, cognitive status and common genetic variation. They show that 40 % of peripherally derived proteins have higher CSF/plasma ratios with healthy ageing; men display systematically higher ratios than women; only a small, protein‑specific subset of ratios track with cognitive impairment; and 241 ratio‑protein quantitative‑trait loci (r‑pQTLs) implicate structural domains—especially collagen‑like, Sushi, Kunitz and Gla motifs—in trans‑barrier transport. (Nature, Nature)

What is genuinely novel here?

Novel element Why it matters
Proteome‑wide CSF/plasma ratios rather than separate CSF or plasma levels Provides an in‑vivo window on substrate‑specific blood–brain and blood–CSF barrier transport dynamics at scale. (Nature)
Largest paired cohort to date (n = 2,171) Triples the sample size of the next‑largest study, enabling robust replication across three centres. (Nature)
Domain‑enrichment screen (Kunitz, Sushi, collagen‑like, Gla) for high‑ratio proteins Uncovers structural “shuttle” candidates that could be engineered to ferry biologics into the brain. (Nature)
56 ratio‑specific GWAS loci not seen in CSF‑ or plasma‑only pQTLs (e.g., rs3128624 in FCN2 altering a collagen helix) Points to genetic regulators of barrier transport and highlights FCN2 as a potential prognostic marker in neuro‑inflammatory disorders. (Nature)
Identification of proteins whose higher ratios associate with preserved cognition (DCUN1D1, MFGE8, VEGFA) Challenges the notion that increased permeability is uniformly harmful and suggests candidate neuroprotective factors. (Nature)

Critical appraisal

Strengths

  • Scale & replication – Three independent cohorts with harmonised protocols and internal replication give the findings unusual robustness.
  • Ratio‑centric design – Captures transport/clearance phenomena invisible to fluid‑specific analyses; ~54 ageing‑related proteins were missed by CSF‑ or plasma‑only approaches. (Nature)
  • Integrated genetics – r‑pQTL mapping provides mechanistic anchors and translational leads (e.g., collagen‑like shuttle concept).
  • Open resource – Data released via the GNPC will be valuable for biomarker discovery well beyond dementia research.

Limitations

Issue Impact & commentary
Cross‑sectional design Limits causal inference; cannot disentangle whether ratio shifts precede, accompany or follow cognitive decline. Longitudinal sampling would help.
SomaScan constraints Aptamer binding is epitope‑dependent and semi‑quantitative; some signals (especially coagulation factors) may reflect affinity changes rather than true concentration shifts.
Barrier specificity Ratios conflate BBB, blood–CSF and glymphatic routes; without imaging or tracer studies, attributing changes to a particular barrier is speculative.
Clinical heterogeneity “Cognitive impairment” is defined by screening scores across diseases; pathology‑specific effects (e.g. amyloid, α‑synuclein) and confounders (renal function, medications) were not modelled.
Lack of functional validation The inferred transport role of domains such as Sushi or collagen‑like remains hypothetical until tested in cellular or in‑vivo shuttle assays.

Opportunities for follow‑up

  • Longitudinal ratio trajectories tied to biomarker‑confirmed Alzheimer’s and Parkinson’s conversion.
  • In‑vitro transcytosis assays and nanoparticle conjugates to validate newly flagged structural domains.
  • Mendelian‑randomisation or rare‑variant analyses to link r‑pQTLs to clinical end‑points.
  • Integration with CSF flow‑dynamics imaging and multi‑omics (metabolomics, lipids) to parse clearance versus influx mechanisms.

Bottom line

This study reframes human brain‑fluid proteomics around balance rather than abundance, offering a quantitative atlas of how proteins traverse—or fail to traverse—the ageing and diseased brain’s barrier system. Its resource value is high, its mechanistic claims are intriguing but preliminary, and its clinical relevance will depend on longitudinal and functional confirmation.

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