Chapter 15 · Learning

Reading Path: From First Principles to Research Fluency

7 min read
In this chapterPass 1: build the mapPass 2: understand the mechanismsPass 3: study specificity and mixed pathologyPass 4: measurement and translationPass 5: become a critical synthesistSuggested first 15 papersReading-note rule

This sequence uses the attached papers as anchors. Do not try to memorize every lesion on the first pass. Each pass has a different purpose.

Pass 1: build the map

Module 1 - imaging vocabulary

Read Duering et al. (STRIVE-2), focusing on the glossary, temporal evolution, mimics, and the reason for phenotype-first language. Keep STRIVE-1 available for the original definitions.

You should be able to: distinguish recent small subcortical infarct, lacune, WMH, PVS, CMB, cSS, cortical microinfarct, and atrophy without claiming etiology.

Module 2 - the two major vessel pathologies

Read Blevins et al. for brain arteriolosclerosis, then Greenberg 2026 or Charidimou 2017 for CAA.

You should be able to: draw the pial-to-penetrating vessel anatomy; explain B-ASC versus CAA histology and distribution; list overlapping downstream lesions.

Module 3 - criteria

Read Boston v2.0 and Edinburgh CT criteria. Recreate each algorithm from memory, then check the original table. Read the criteria-development methods, not only the final rules.

You should be able to: state intended population, reference standard, rule-in/rule-out goal, major exclusions, and spectrum limitations.

Pass 2: understand the mechanisms

Module 4 - disease progression

Read Koemans et al. alongside the 2026 Greenberg review.

Questions: What evidence orders amyloid deposition, physiology, non-hemorrhagic injury, and hemorrhage? Which evidence comes from hereditary rather than sporadic CAA?

Module 5 - clearance

Read van Veluw et al. 2024, then Perosa et al. 2022.

Questions: Which claims are IPAD-specific, glymphatic, or generic perivascular clearance? What does an enlarged PVS measure? What observations could result from reverse causation?

Module 6 - barrier, inflammation, and rupture

Read Kozberg et al. 2022, followed by van den Brink et al. 2024.

Questions: At what vessel grades do leakage, smooth-muscle loss, and inflammation appear? What can spatial postmortem staging establish, and what can it not establish about time?

Pass 3: study specificity and mixed pathology

Module 7 - false positives and lesion-level truth

Read Perosa et al. 2023.

Questions: How can probable CAA be false positive? Where were lesions located relative to the cortex? Why can patient-level criteria remain useful despite lesion-level etiologic overlap?

Module 8 - medial temporal lobe and co-pathology

Read the Perosa/Viswanathan medial-temporal review, Neltner/Nelson on multiregional arteriolosclerosis and hippocampal sclerosis, LATE-NC staging, and Rodríguez et al. on entorhinal vessel density.

Questions: Which associations are independent after adjustment? Which directions are plausible? How can selection into autopsy cohorts bias relationships?

Pass 4: measurement and translation

Module 9 - quantitative pathology

Read Perosa/Scherlek 2021.

Questions: How were expert labels generated? Was validation independent? What sources of stain/scanner/domain shift remain? Why retain marker-specific models?

Module 10 - in-vivo biomarkers

Read the ARTS development and MarkVCID validation papers; review the current kit protocol. Then compare ARTS with WMH volume, PSMD, free water, and CVR.

Questions: What is the exact context of use? What was the pathology reference? Does the biomarker add beyond age/sex and WMH? Has calibration been tested in your intended cohort?

Pass 5: become a critical synthesist

For every major hypothesis in docs/04_DEBATES_HYPOTHESES_OPEN_QUESTIONS.md, identify:

  1. one human tissue paper;
  2. one longitudinal human study;
  3. one experimental study;
  4. one null, conflicting, or specificity-limiting result;
  5. one experiment that would distinguish the leading explanations.

Write the result with templates/CLAIM_EVIDENCE_TEMPLATE.md. This turns reading into an evidence graph rather than a collection of summaries.

Suggested first 15 papers

  1. Duering et al. 2023 - STRIVE-2.
  2. Blevins et al. 2021 - brain arteriolosclerosis.
  3. Greenberg 2026 - current CAA overview.
  4. Charidimou et al. 2022 - Boston v2.0.
  5. Rodrigues et al. 2018 - Edinburgh CT/genetic criteria.
  6. Koemans et al. 2023 - CAA progression framework.
  7. van Veluw et al. 2024 - clearance debate.
  8. Perosa et al. 2022 - PVS-pathology spatial link.
  9. Kozberg et al. 2022 - BBB leakage/inflammation.
  10. van den Brink et al. 2024 - neuroinflammation synthesis.
  11. Perosa et al. 2023 - false-positive CAA microbleeds.
  12. Perosa/Scherlek et al. 2021 - quantitative digital pathology.
  13. Bangen et al./Arfanakis group - ARTS development.
  14. MarkVCID ARTS validation.
  15. Skrobot et al. 2016 - VCING.

Reading-note rule

Never write only "the authors found X." Record population, sample size, selection, exposure/marker, outcome/reference standard, timing, location, effect estimate with uncertainty, adjustment set, failure/missingness, and the narrowest justified conclusion.