Hypothesis

Age-related increases in myelin thickness in layer Vb of the right anterior insula sustain Von Economo neurons (VENs) by coupling axonal myelination to lactate shuttling from oligodendrocytes, thereby meeting the high metabolic demand of these large projection cells. When this myelin–metabolic support fails—due to disease‑specific disruption of oligodendrocyte function or myelin integrity—VENs degenerate despite otherwise preserved cortical thickness, producing the early interoceptive deficits seen in frontotemporal dementia (FTD). Consequently, quantitative layer‑specific myelin metrics obtained with 7‑Tesla MRI will predict interoceptive performance and systemic aging biomarkers in healthy older adults, whereas a dissociation between preserved myelin signal and VEN loss will identify pre‑symptomatic FTD.

Mechanistic Insight

VENs possess exceptionally large dendritic arbors and high firing rates, which impose a substantial ATP demand that cannot be met by somatic glycolysis alone. Recent work shows that deep cortical layers acquire compensatory myelination with age, preserving function despite overall thinning【2】. Myelin sheaths are not merely insulating; they facilitate axonal lactate transport via monocarboxylate transporters expressed in oligodendrocytes and astrocytes, providing a rapid energy substrate to active neurons【1】. In the fronto‑insular cortex, layer Vb houses VENs; age‑related myelin enrichment there could therefore supply lactate directly to VEN somata and proximal dendrites, buffering metabolic stress during normal aging. In FTD, pathogenic tau or TDP‑43 oligendropathies impair myelin integrity and lactate shuttling, uncoupling the structural myelin increase from metabolic support. The result is selective VEN loss even when myelin water fraction remains high, explaining why VENs disappear early in disease while surviving normal aging.

Testable Predictions

1. In cognitively normal participants aged 60‑85, higher myelin water fraction (MWF) in layer Vb of the right anterior insula, measured by multi‑component driven equilibrium single pulse observation of T1 and T2 (mcDESPOT) at 7 T, will correlate positively with heartbeat detection accuracy (an interoceptive task) and negatively with peripheral aging markers such as plasma IL‑6 and telomere attrition.
2. In individuals with clinically diagnosed FTD or asymptomatic carriers of progranulin mutations, MWF in the same insular layer will not differ from age‑matched controls, yet VEN density (estimated post‑mortem or via future PET ligands) will be reduced, and interoceptive performance will be disproportionately low relative to myelin metrics.
3. Longitudinally, a decline in interoceptive accuracy preceding detectable changes in MWF will predict subsequent VEN loss and conversion to FTD, whereas stable interoceptive scores alongside stable or increasing MWF will predict resilient aging.

Proposed Approach

• Acquire 7‑Tesla structural and mcDESPOT scans targeting the right anterior insula; use layer‑specific segmentation algorithms to isolate Vb.
• Collect behavioral interoceptive data (heartbeat tracking, respiratory awareness) and blood draws for cytokines, telomere length, and neurofilament light.
• Apply mixed‑effects models to test cross‑sectional associations and longitudinal trajectories.
• Validate post‑mortem in a subset of donors (including PWS brains where VEN patterning is atypical【3】) by correlating immunohistochemical VEN counts with myelin basic protein optical density and lactate transporter expression.

Implications

If confirmed, this hypothesis would reposition myelin not as a passive bystander but as an active metabolic partner that determines the fate of VENs across the adult lifespan. It would provide a non‑invasive, layer‑specific biomarker for early fronto‑insular vulnerability, bridge the gap between interoceptive decline and systemic aging, and open therapeutic avenues aimed at bolstering oligodendrocyte‑derived lactate support to protect VENs in pre‑symptomatic FTD.