Definition: 'Interstitial Fluid Volume' refers to the total volume of fluid occupying the 'extracellular space' between cells within a tissue. In the central nervous system (CNS), it is the fluid that lies between neurons, glia, and capillaries—distinct from cerebrospinal fluid (CSF) and intracellular fluid.

Physiological Role:

• Serves as a medium for:
  1. Nutrient transport
  2. Waste removal
  3. Ion exchange
  4. Intercellular signaling
• Provides mechanical support and maintains the extracellular matrix (ECM) environment.
• Interfaces dynamically with CSF through the glymphatic system and perivascular pathways.

Brain-Specific Characteristics:

• Estimated to occupy ~15–20% of total brain tissue volume under physiological conditions.
• Closely regulated by:
  1. Capillary filtration through the blood–brain barrier (BBB)
  2. Aquaporin-4 channels on astrocytic endfeet
  3. Arterial pulsatility and sleep-wake cycles (via glymphatic function)

Alterations in ISF Volume: ↑ ISF Volume:

• Idiopathic normal pressure hydrocephalus (iNPH)
• Vasogenic edema
• Aging-related extracellular matrix degradation

↓ ISF Volume:

• Cytotoxic edema (e.g., ischemic stroke)
• Cellular swelling or inflammation

Measurement Techniques:

• Spectral diffusion analysis (→ F_int)
• Diffusion MRI (indirect estimation via ADC)
• Tracer-based imaging in experimental models
• Optical or microdialysis methods in animal studies

Distinction from Related Terms:

• Interstitial fluid volume fraction (F_int):

Dimensionless ratio of ISF volume to total tissue volume.

• CSF volume: Located in ventricles and subarachnoid space; not part of ISF.
• Extracellular volume: Includes ISF + CSF + intravascular space (context-dependent).

—- In a retrospective cohort Ishida *et al.* from the University hospitals—centres in Tokyo, (e.g., Tokyo Metropolitan Geriatric Center) published in the *Journal of Magnetic Resonance Imaging* to compare interstitial fluid volume fraction (Fint) and diffusivity (Dint), derived via spectral diffusion analysis, between idiopathic normal pressure hydrocephalus (iNPH) patients and healthy controls (HCs). In iNPH patients, spectral diffusion analysis revealed increased Fint and Dint in periventricular hyperintensity (PVH) regions of the centrum semiovale (CSO) and frontal white matter (FWM), while regions outside PVH did not differ from HCs ¹⁾.

* Strengths:

• Utilizes advanced spectral diffusion with non‑negative least squares to separate Interstitial Fluid Dynamics an innovative approach.
• Well‑defined region‑based ROI analysis including CSO, FWM, lenticular nucleus (LN).
• Robust statistical treatment via Kruskal–Wallis with Dunn’s test; Spearman’s for correlations.

* Limitations & Concerns:

• Retrospective design: susceptible to selection bias, especially with mismatched age demographics (mean HC age 47.5 vs iNPH 76.9 years).
• Age confounders: ISF measures increase with age; healthy ≥60 group is younger on average and unevenly represented, raising questions about matching.
• Lack of clinical correlation: imaging findings are intriguing but lack direct linkage to symptom severity or treatment outcome.
• No intervention arm: absence of longitudinal or shunt response data means limited clinical applicability.
• Evidence level 3, Technical efficacy stage 1: preliminary. Radiological novelty, but early stage with limited validation.

Score: 5.5 / 10 Spectral diffusion yields promising imaging biomarkers for PVH-affected regions in iNPH, but substantial limitations (age confounders, lack of clinical linkage, retrospective nature) undermine its current translational value.

Spectral diffusion analysis identifies increased interstitial fluid volume and diffusivity in periventricular hyperintensity regions of elderly iNPH patients. However, due to age confounding and absence of correlation with clinical outcomes or shunt responsiveness, these metrics remain research curiosities rather than clinical tools. Prospective studies—ideally age-matched and linked to gait/cognitive improvement post-shunt—are needed before integrating into practice.

Spectral diffusion draws attention to altered ISF dynamics in iNPH, yet further longitudinal, clinically-correlated validation is required before adoption.