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  • Konstantinos Voumvourakis 1,2,*,
  • Nikolaos S. Thomaidis 3 and
  • Sotirios Tsiodras 1

Reviewer 1: Anonymous Reviewer 2: Anonymous Reviewer 3: Kakarla Ramakrishna Reviewer 4: Anonymous

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Major Comments with Reference Matching

  1. Overextension of conclusions regarding an integrated “waste clearance network”
  • The manuscript repeatedly suggests that glymphatic flow, BBB efflux, IPAD, arachnoid granulations, and cellular degradation mechanisms operate as a coordinated, interdependent clearance network. However, direct experimental evidence for functional integration among these systems is limited. Most cited studies describe each pathway independently.
  • Reference matches: [3], [59], [66], [69], [73], [90]
  • Revised example:

“These routes may be interconnected and represent a waste clearance network with complementary roles assigned to different mechanisms [3,59,66,69,73,90]. However, direct experimental evidence for functional integration is still limited.”

 

  1. Glymphatic system described as a “core mechanism” of cerebral homeostasis
  • The manuscript states that glymphatic clearance is a core mechanism of brain homeostasis, which overstates the current consensus. There are ongoing debates regarding the magnitude of convective flow in vivo, the relative contribution of diffusion vs. bulk flow, species differences, and alternative interpretations of PVS tracer movement.
  • Reference matches: [3], [7], [66], [89], [90]
  • Revised example:

“Glymphatic clearance is presented as a core mechanism of cerebral homeostasis [3,7,66,89,90], but it would be more accurate to describe it as an important contributor, acknowledging ongoing controversies.”

 

  1. Lack of balanced discussion of conflicting or critical literature
  • The review relies heavily on pro-glymphatic studies (Iliff, Xie, Nedergaard group) and does not adequately address studies questioning the magnitude of glymphatic flow, evidence supporting diffusion-dominated transport, critiques of AQP4-dependent bulk flow models, or alternative interpretations of MRI tracer kinetics.
  • Reference matches: [9], [10], [11], [12], [33], [66], [421], [466]
  • Revised example:

“A more balanced discussion should include studies questioning the magnitude of glymphatic flow, diffusion-dominated transport, critiques of AQP4-dependent bulk flow models, and alternative interpretations of MRI tracer kinetics [9,10,11,12,33,66,421,466].”

 

  1. Speculative statements regarding neurodegeneration
  • The manuscript implies causal relationships between glymphatic dysfunction and neurodegenerative diseases (AD, PD, dementia). While associations exist, causality has not been established.
  • Reference matches: [28], [29], [35], [36], [41], [42], [43], [44], [59], [81], [82], [87]
  • Revised example:

“Although associations between glymphatic dysfunction and neurodegenerative diseases (AD, PD, dementia) have been reported [28,29,35,36,41,42,43,44,59,81,82,87], causality has not been established and statements should reflect correlation rather than causation.”

 

  1. Choroid plexus section requires clarification
  • The manuscript briefly discusses CSF production by the choroid plexus but does not fully address the ongoing debate regarding extrachoroidal CSF production, CSF turnover variability, and implications for glymphatic driving forces.
  • Reference matches: [45], [46], [47], [491], [493]
  • Revised example:

“The role of the choroid plexus in glymphatic clearance is indirect and limited to CSF production [45,46,47,491,493]. The manuscript should clarify this and avoid implying a direct ‘cleaning mechanism,’ while also mentioning the debate about extrachoroidal CSF production and CSF turnover variability.”

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The author's provide a very informative, organized, and detailed review on the glymphatic system of the brain. I particularly noted a major strength in discussing the function of the glymphathic system in the context of cooperative mechanisms involved in health and disease. The prose of the writing is excellent for a broad scientific audience (experts and non-experts). 

I have a small number of recommended text edits and a citation that could be of benefit:

1) Page 3, line 115: along periarterial PVS, define PVS and delete or

"along periarterial perivascular space (PVS) also known as Virchow-Robin spaces"

2) Page 5, line 158: "Tthe" typo

3) Page 5, lines 192-194: the Dmd and Snta1 genes referenced from the literature review are describing the effect of mouse gene deletions on AQP4 mislocalization. These mouse genes should be in italics: "Dmd, Snta1". 

4) Page 6, lines 210-211: anatomical site accounts for the most of the production. Delete the first "the" to improve readability

"...anatomical site accounts for most of the production"

5) Page 7, lines 256-257: delete "the" to improve readability

"...(IPAD) pathway, arachnoid granulations and cellular degradation mechanisms."

6) Page 8, line 299, suggested "These interactions add complexity to unraveling the waste clearance network of the brain."

7) Page 9, line 367: given the negative connotation perhaps "sleep disturbances" is more consistent with the logic of the sentence.  

Citation:

I would recommend including the following citation:

DOI:

  • 10.1016/j.neuron.2024.12.014

(Santisteban & Iadecola)

 

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

The present manuscript is well written and is acceptable for publication with the following modifications:

  1. The authors have provided a clear overview of the glymphatic system. However, adding brief information on how this system is altered in various neurological diseases would enhance readability.
  2. The red text in the figure can be changed to black. Additionally, the background and blue arrows are of similar color; please use contrasting colors for better visibility.
  3. Please add a discussion on future studies that need to be carried out to achieve a better understanding of the glymphatic system.
  4. Please discuss whether this system is similar in humans and animals.
  5. Please discuss how glymphatic system dysfunction can be identified, particularly under disease conditions.
  6. Please discuss briefly about various techniques to assess the glymphatic system.

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Reviewer 4 Report

Comments and Suggestions for Authors

Review of “Mapping the Brain’s Glymphatic System”.

Short review of facts, known about glymphatic system, along to many available already (DOI 10.1016/j.isci.2022.104987, 10.1002/brx2.70011, 10.1523/JNEUROSCI.0619-21.2021). I do not see the real synthesis made from these facts, which author promised. The only figure is unclear and unprecise in details, and seems to be AI-generated. Major revision.

 

  1. Line 29: “in vivo” – please italize Latin words through the whole MS.
  2. 1: are the honeycomb structures in the picture means astrocytes? Mention needed. The fig looks AI-generated, recommend to redraw it manually. Astrocytes have another shape, and glia limitans works by astrocytic feet, not body – so the picture is incorrect in details. I do not understand the inlet in right down corner. Right wall of glia is surrounding venule, not brain parenchyma, as shown on fig (g. limitans)? Picture rises more questions, then give answers.
  3. Line 127: “CSF to enter (2) the parenchymal interstitium via aquaporin-4 channels (B) of the glia limitans”. Aquaporin-4 is channels penetrable for water, not CSF, and it allow astrocytes to swell and regulate their osmosis only. Sentence is incorrect, please rephrase to be precise in details. From the text is also unclear, how metabolites transported by glymphatic flow – just diffusion in intercellular space (ISF)? How the AQP4 helps it (g in glymphatic)?

 

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

Authors have addressed all the issues

Reviewer 4 Report

Comments and Suggestions for Authors

The Authors have resolved all my questions, and I think the MS may be accepted in present form.