Added diagnostic values of three-dimensional high-resolution proton density-weighted magnetic resonance imaging for unruptured intracranial aneurysms in the circle-of-Willis: Comparison with time-of-flight magnetic resonance angiography.

BACKGROUND: Advanced imaging methods can enhance the identification of aneurysms of the infundibula, which can reduce unnecessary follow-ups or further work-up, fear, and anxiety in patients.
PURPOSE: This study aimed to evaluate the added diagnostic value of three-dimensional proton density-weighted vessel wall magnetic resonance imaging (3D-PD MRI) in identifying aneurysms from index lesions refer to vascular bulging lesions without vessels arising from the apex, observed using volume-rendered TOF-MRA in the circle-of-Willis compared with time-of-flight magnetic resonance angiography (TOF-MRA). STUDY TYPE: Retrospective. POPULATION: A total of 299 patients who underwent 3D-PD MRI, digital subtraction angiography (DSA), and TOF-MRA between January 2012 and December 2016 were retrospectively enrolled in this study. FIELD STRENGTH/SEQUENCE: 3 Tesla, 3D-PD MRI. ASSESSMENT: Three neuroradiologists independently evaluated TOF-MRA and 3D-PD MRI combined with TOF-MRA for the determination of intracranial aneurysms in patients with index lesions within the circle of Willis. Final diagnoses were made by another neuroradiologist and neurointerventionist in consensus using DSA as the reference standard. The diagnostic performance and proportions of undetermined lesions on TOF-MRA and 3D-PD MRI with TOF-MRA were assessed based on the final diagnoses. STATISTICAL TESTS: The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of unruptured intracranial aneurysms were calculated for each imaging modality.
RESULTS: Of 452 lesions identified on volume-rendered TOF-MRA images, 173 (38%) aneurysms and 276 (61%) infundibula were finally diagnosed on DSA. 3D-PD MRI with TOF-MRA showed superior diagnostic performance (p = .001; accuracy, 85.5% versus 95.4%), superior area under the receiver operating characteristic curve over TOF-MRA (p = .001; 0.837 versus 0.947), and a lower proportion of undetermined lesions than TOF-MRA (p = .001; 25.1% versus 2.3%). DATA
CONCLUSION: For unruptured intracranial aneurysms in the circle of Willis, 3D-PD MRI can complement TOF-MRA to improve diagnostic performance and lower the proportion of undetermined lesions.

Introduction

Intracranial aneurysms occur in approximately 3%–5% of the general population [1,2]. With the increase in the demand for health checkups and accessibility to advanced imaging techniques, the detection of incidental aneurysms is increasing [3,4]. However, small infundibular dilatations are sometimes confused with true aneurysms [3,5]. Infundibula are detected on angiography or autopsy with occurrence rates ranging from 7% to 25%, and are generally considered to be benign lesions that do not require treatment or follow-up [4,6]. However, as untreated intracranial aneurysms have a risk of rupture, the fear and anxiety caused by the knowledge of having an aneurysm can affect the quality of life, and this therefore underlines the need for accurate differentiation of infundibula from aneurysms [7].

Catheterized digital subtraction angiography (DSA) is the gold standard for the definitive diagnosis of intracranial aneurysms; however, the procedure carries a risk of developing complications [8,9]. Although time-of-flight magnetic resonance angiography (TOF-MRA) is currently widely used for the screening of unruptured intracranial aneurysms owing to its noninvasiveness, the definitive diagnosis of aneurysms or infundibula can sometimes be challenging, in particular in small lesions [4]. The definitive diagnosis of small lesions suspected of being aneurysms in the circle of Willis may sometimes be challenging because of the high incidence of infundibula in the posterior communicating artery and anterior choroidal artery origin, the high incidence of anatomic variation such as fenestration in the anterior communicating arteries and the limited resolution on TOF-MRA [10-14]. High-resolution magnetic resonance imaging (HR-MRI) for vessel walls with a 3-T scanner has become a useful imaging modality for characterizing and diagnosing intracranial arterial steno-occlusive lesions, providing detailed information on vessel wall morphology [15,16] and a high correlation with DSA [17-19]. Proton density-weighted vessel wall MRI (3D-PD MRI) can depict even tiny vascular structures with high signal-to-noise ratios among commonly used vessel wall MRI sequences [20]. There was one report that demonstrated the performance of proton density images for identifying aneurysms of the infundibula. However, Kim et al. discussed that the diagnostic performance of 3D-PD MRI was found to be better than TOF-MRA only in the lesions of the posterior communicating arteries within a small population [21]. Yoon et al. found that PD-MRI can disclose the detailed location (intradural, extradural, or transdural) of paraclinoid internal carotid artery aneurysms with reference to distal dural rings without identifying aneurysms of the infundibula [22]. We hypothesized that 3D-PD MRI would be useful in accurately identifying true unruptured aneurysms from the index lesion. Therefore, this study aimed to evaluate the added diagnostic value of 3D-PD MRI in identifying aneurysms from index lesions (vascular bulging lesions without vessels arising from the apex) within the circle of Willis and thus compare between 3D-PD MRI combined with TOF-MRA and TOF-MRA alone using DSA as a reference standard.

Materials and methods

Study population

This retrospective study was approved by Asan Medical Center institutional review board, which waived the requirement for informed consent. A total of 299 patients who underwent 3D-PD MRI, DSA, and TOF-MRA between January 2012 and December 2016 were retrospectively enrolled. Patients who 1) underwent 3D-PD MRI, TOF-MRA, and DSA and 2) had index lesions (vascular bulging without vessels arising from the apex on volume-rendered TOF-MRA) and thus suspected of having intracranial aneurysms within the circle of Willis (target arteries: anterior communicating artery, bilateral A1 segment of anterior cerebral arteries, origin of bilateral ophthalmic arteries, origin of bilateral posterior communicating arteries, origin of bilateral anterior choroidal arteries, origin of bilateral superior cerebellar arteries, and top of basilar artery) were included. By contrast, patients 1) with no lesion within the target arteries on TOF-MRA (704 patients), 2) whose 3D-PD MRI scan parameters did not include the target arteries (163 patients), 3) whose 3D-PD MRI had severe artifact due to previous coil embolization or clipping that hindered evaluation of the target arteries (29 patients), and 4) whose imaging studies did not contain TOF-MRA source images (15 patients) were excluded. Finally, 452 index lesions within the circle of Willis in 299 patients were included in this study. Typical paraclinoid internal carotid artery (ICA) aneurysms with inferomedial directions were considered nontarget lesions and were not included, because it is easy to differentiate between such aneurysms and infundibula on TOF-MRA. Index lesions with an ophthalmic artery origin are lesions that appeared to be in contact with the ophthalmic arteries on volume-rendered TOF-MRA images. The mean time interval between all modalities was 29.8 days (ranges: <1 month, 203; 1–6 months, 96). Demographic and clinical data were collected by reviewing the patients’ digital medical records (Table 1). This study was reported in accordance with the Standards for Reporting of Diagnostic Accuracy Studies guidelines [23].

Table 1

Patients’ demographics and lesion details.

Variables
Final diagnosis of index lesions
Aneurysm	173 (38.0%)
Infundibulum	276 (61.0%)
No lesion	3 (1.0%)
	Index lesions	Aneurysms
Age (y) *	49.4 ± 10.2	46.8 ± 13.6
Male: Female	38:261	17:123
Size
< 3 mm	302 (66.8%)	53 (30.6%)
≥ 3mm and ≤ 5 mm	91 (20.1%)	64 (37.0%)
> 5 mm	59 (13.1%)	56 (32.4%)
Location
Posterior communicating artery	239 (52.9%)	44 (25.4%)
Ophthalmic artery	97 (21.5%)	77 (44.5%)
Anterior choroidal artery	62 (13.7%)	15 (8.7%)
Anterior communicating artery	45 (10.0%)	28 (16.2%)
Top of basilar artery	4 (0.9%)	4 (2.3%)
Superior cerebellar artery	2 (0.4%)	2 (1.15%)
Internal carotid artery bifurcation	2 (0.4%)	2 (1.15%)
Anterior cerebral artery, A1	1 (0.2%)	1 (0.6%)

* Mean ± standard deviation.

† Numbers in parentheses indicate the proportion.

Image acquisition

TOF-MRA and 3D-PD MRI were simultaneously performed using the same scanner. TOF-MRA and 3D-PD MRI were performed on 3-T MR systems (Ingenia CX with a 32-channel head coil, Philips Healthcare, Netherlands; Skyra with a 64-channel head coil, Siemens, Erlangen, Germany; Achieva with a 6-channel head coil, Philips Healthcare).

The TOF-MRA parameters were as follows: multiple overlapping thin slabs acquisition (MOTSA), 2/5/2 thin slabs (100/200/100 slices); tilted optimized nonsaturating excitation (TONE), on; magnetization transfer contrast (MTC), off; repetition time (TR), 25/22/25 ms; echo time (TE), 3.5/3.71/3.5 ms; flip angle, 20/18/20°; section thickness, 1/0.64/1 mm; matrix, 880× 880 × 100/575 × 433 × 228/880 × 880 × 100 mm; field of view (FOV), 200 × 200 × 50/230 × 173 × 137/200 × 200 × 50 mm; voxel size, 0.23 ×0.23 × 0.5/0.4 × 0.4 × 0.6/0.23 ×0.23 × 0.5 mm; number of excitations (NEX), 1/1/1; acceleration factor, 2/2/2; total acquisition time, 5 min 58 s/5 min 16 s/5 min 58 s. Maximum intensity projection (MIP) and volume rendered images were created for each data set for evaluation of the intracranial aneurysms. Initially, for each of the MIP image sets, the anterior and posterior circulations were interactively rotated around the axial and sagittal axes at 15° increments to examine for the presence of harbored aneurysms. Further arbitrary oblique projections were also obtained when necessary, to overcome vascular overlapping.

The 3D-PD MRI acquisitions were made using axial 3D turbo spin-echo sequences and 3D reconstructions with the following parameters: TR, 2000 ms; TE, 35.4/21.0/30.7 ms; flip angle, 90°/125°/90°; matrix, 640 × 640 × 150/640 × 640 × 320/640 × 640 × 100; FOV, 120 × 120 × 30/160 × 160 × 80/180 × 180 × 30 mm3; voxel size, 0.2 × 0.2 × 0.2/0.3 × 0.3 × 0.3/0.3 × 0.3 × 0.3 mm3; number of excitations, 1/2/1; total acquisition time, 12 min 36 s/5 min 10 s/5 min 38 s.

DSA was performed on a biplane system (Artis Zee, Siemens) with a diagnostic angiography catheter being introduced into the ascending aorta via the transfemoral route and navigated into the appropriate carotid or vertebral artery as decided by the neurointerventionists. With the injection of contrast media, the intracranial arteries were displayed in at least two projections (i.e., anteroposterior and lateral) and/or as 3D rotational angiography. The contrast injection rate for angiography with a catheter in ICA was 4–5 ml/s (Mark V ProVis; Medral, Warrendale, PA, USA), with a total volume of 7–8 ml and in vertebral artery was 4–5 ml/s with a total volume of 8–10 ml. DSA was performed with a 320-mm FOV and a 1024 or 2018 matrix, yielding a pixel size of 0.315 × 0.315 mm2 or 0.159 × 0.159 mm2, respectively.

Image analysis

One neuroradiologist (X.X.X. with 7 years of experience) identified index lesions (vascular bulging lesions with unclear or no demonstration of vessels arising from the apex on volume-rendered TOF-MRA images) and provided observers with anatomic location information on the index lesion. Then three neuroradiologists (X.X.X. with 2 years of experience, X.X.X. with 2 years of experience, and X.X.X. with 14 years of experience) independently classified the index lesions as definite aneurysm, infundibulum, or undetermined lesions on TOF-MRA alone (volume rendering and source images) and on 3D-PD MRI combined with TOF-MRA. They reviewed the images with 2-week intervals on TOF-MRA and 3D-PD MRI combined with TOF-MRA to avoid recall bias. The review order of the imaging methods was decided by the observer. One neuroradiologist (X.X.X. with 7 years of experience) and one neurointerventionist (X.X.X. with 5 years of experience) made the final diagnoses of the index lesions as definite aneurysm, infundibulum, or no lesion, on either DSA (n = 452) or with 3D rotational angiography (n = 324), but based on consensus. In order to classify the index lesions using TOF-MRA and 3D-PD MRI, the following criteria were applied: Aneurysm was defined as a saccular protrusion from the side wall of the cerebral arteries [24]; infundibulum was defined as a funnel-shaped vascular enlargement at the origin of the cerebral arteries [4]; undetermined lesion was defined as insufficient findings to decide on a definite diagnosis. The diameters of index lesions were manually measured on DSA using electronic calipers (X.X.X. with 2 years of experience) [25]. The image quality for TOF-MRA was assessed using the following visual scoring system: 5, excellent; 4, more than adequate for diagnosis; 3, adequate for diagnosis; 2, less than adequate for diagnosis; and 1, nondiagnostic [26]. The image analysis was performed using a picture archiving and communication system (PACS) workstation.

Statistical analysis

The summary statistics were presented as numbers and percentages for categorical variables and means with standard deviations for continuous variables. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the diagnosis of unruptured intracranial aneurysms were calculated for each imaging modality (TOF-MRA and 3D-PD MRI) and the size of the lesions was determined on a per-lesion basis. The diagnostic performance was analyzed using pooled data from three observers. The infundibula, no lesion, and undetermined lesions were not classified as aneurysm (negative result) and thus were not included in the statistical analyses. DSA was used as the reference standard to assess diagnostic performance. Diagnostic performance among imaging modalities was compared by generalized estimating equations (GEE) that accounted for the clustering of the same patient. A nonparametric method for clustered data (multiple lesions and multiple readers) proposed by Obuchowski was used to compare areas under the receiver operating characteristic (ROC) curve. The proportions of undetermined lesions were calculated and compared according to the modalities using DSA as a reference standard. 3D-PD MRI combined with TOF-MRA was compared with TOF-MRA alone in 299 patients in terms of diagnostic performance and proportions of undetermined lesions. The inter-reader agreement for the diagnosis of index lesions was evaluated using the Cohen’s kappa statistic. A κ-value <0 indicated no agreement, whereas 0–0.20, 0.21–0.40, 0.41–0.60, 0.61–0.80, and 0.81–1 indicated slight, fair, moderate, substantial, and almost perfect agreement, respectively [27]. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R version 3.4.2. Two-sided p-values less than .05 were considered significant.

Results

Of the 452 lesions identified on volume-rendered TOF-MRA images, 173 (38.0%) were diagnosed on DSA as aneurysms, 276 (61.0%) as infundibula, and 3 (1.0%) as non-lesions. The median lesion size and range were 2.5 mm and 1.0 to 20 mm, respectively (Table 1). Representative cases are illustrated in Figs 1–3.

Fig 1

A 60-year-old female who was referred from an outside hospital for incidentally found aneurysms.

TOF-MRA (a) and TOF-MRA source images (c-e) showed an index lesion around the left anterior choroidal artery origin; however, the relationship between the aneurysm and anterior choroidal artery was unclear on coronal multi-planar reconstruction (MPR) images (arrows). 3D-PD MRI clearly depicted the aneurysm and anterior choroidal artery origin on coronal MPR images (arrows) (f-h). 3D rotational angiography (b) also showed a clear relationship between the aneurysm and the anterior choroidal artery origin (arrow).

Fig 3

A 57-year-old female underwent 3D-PD MRI for evaluation of a left paraclinoid internal carotid artery aneurysm.

TOF-MRA (a) showed an index lesion around anterior choroidal artery origin of left distal ICA. However, it was difficult to diagnose the aneurysm (arrows) even on TOF-MRA source images with sagittal multi-planar reconstruction (MPR) images (c-f). The relationship between anterior choroidal artery and the index lesion was not seen clearly on sagittal MPR images of TOF-MRA (e, f). 3D-PD MRI depicted a definite aneurysm with bi-lobed shape (arrows) (g, h) and clear relationship between anterior choroidal artery and the index lesion on sagittal MPR images (i, j). 3D rotational angiography also showed a definite aneurysm with bi-lobed shape (arrow) (b).

A 66-year-old female who underwent 3D-PD MRI for evaluation of a right middle cerebral artery stenosis detected during work up for left side weakness.

TOF-MRA (a) showed an index lesion around the left distal ICA. However, it was difficult to diagnose the aneurysm due to its tiny size and nearby bone structures (arrows) (c–f) even on TOF-MRA source images with oblique coronal multi-planar reconstruction (MPR) (d-f). 3D-PD MRI depicted a definite aneurysm on oblique coronal MPR images (arrows) (g-j). DSA also showed a definite aneurysm (arrow) (b).

Diagnostic performance of TOF-MRA alone and 3D-PD MRI combined with TOF-MRA

The sensitivity, specificity, positive predictive value, and negative predictive values of TOF-MRA alone were 77.6%, 90.4%, 83.4%, and 86.7%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive values of 3D-PD MRI combined with TOF-MRA were 91.5%, 97.8%, 96.3%, and 94.9%, respectively (Table 2).

Table 2

Diagnostic performances of TOF-MRA and 3D-PD MRI combined with TOF-MRA.

TOF-MRA
	TP	TN	FP	FN	Sensitivity	Specificity	PPV	NPV	Accuracy
	403	757	80	116	77.6 (.001)	90.4 (.001)	83.4 (.001)	86.7 (.001)	85.5 (.001)
3D-PD MRI with TOF-MRA
	TP	TN	FP	FN	Sensitivity	Specificity	PPV	NPV	Accuracy
	475	819	18	44	91.5	97.8	96.3	94.9	95.4

* TOF-MRA = time-of-flight magnetic resonance angiography, 3D-PD MRI = three-dimensional high-resolution proton density-weighted magnetic resonance imaging, TP = true-positive, TN = true-negative, FP = false-positive, FN = false-negative, PPV = positive predictive value, NPV = negative predictive value, PPV = positive predictive value, NPV = negative predictive value.

† Data are percentages, and parentheses indicate p-values compared with 3D-PD MRI with TOF-MRA.

Comparison of diagnostic performance

3D-PD MRI combined with TOF-MRA showed higher diagnostic performance and AUC than TOF-MRA alone (p = .001) (Tables 2 and 3, and Fig 4). 3D-PD MRI combined with TOF-MRA showed a larger AUC compared to that of TOF-MRA alone in the ophthalmic artery origin, posterior communicating artery, anterior communicating artery, and anterior choroidal artery origin locations (p = .033 to .001).

Table 3

Comparison of diagnostic performances and proportions of undetermined lesions.

	AUC	P value
TOF-MRA	0.837 † (0.817–0.857)	.001
3D-PD MRI with TOF-MRA	0.947 † (0.934–0.958)
	Proportion	P value
TOF-MRA	25.1% †† (341/1356)	.001
3D-PD MRI with TOF-MRA	2.3% †† (31/1356)

* TOF-MRA = time-of-flight magnetic resonance angiography, 3D-PD MRI = three-dimensional high-resolution proton density-weighted magnetic resonance imaging, AUC = area under receiver operating characteristic curve.

† Data in parentheses indicate 95% confidence intervals.

†† Data in parentheses indicate numbers of lesions.

††† P-values in were calculated from comparisons with 3D-PD MRI with TOF-MRA.

Fig 4

3D-PD MRI combined with TOF-MRA (AUC = 0.837) showed higher diagnostic performance and AUC than TOF-MRA alone (AUC = 0.947) (p = .001).

Proportions of undetermined lesions

The proportions of undetermined lesions on 3D-PD MRI with TOF-MRA were lower than those on TOF-MRA alone (p = .001) (Table 3).

Interobserver agreement for identifying aneurysms from index lesions among the three observers was 0.793 (TOF-MRA, 0.679; 3D-PD MRI combined with TOF-MRA, 0.873). The mean scores for the image quality were 4.1 for TOF-MRA.

Discussion

Compared with TOF-MRA, 3D-PD MRI had added diagnostic values in identifying true aneurysms from index lesions in the circle of Willis and lower proportions of undetermined lesions. Therefore, 3D-PD MRI can play a role as a supplementary imaging modality for the diagnosis of aneurysms.

TOF-MRA showed an excellent diagnostic performance for diagnosing intracranial aneurysms [28]. However, the accurate diagnosis of intracranial aneurysms is sometimes quite challenging, especially in lesions with a small size and a high possibility of normal variation and/or infundibula [3,4]. Common locations of infundibular dilatation in intracranial arteries are the posterior communicating artery and the anterior choroidal artery; hence, it is often necessary to differentiate infundibular dilatation from small aneurysms [10,11].

HR-MRI for vessel walls is generally used for the evaluation of arterial walls in steno-occlusive lesions or aneurysms [15,16]. This study of 299 patients demonstrated the usefulness of 3D-PD MRI compared to that of TOF-MRA in identifying infundibular aneurysms in entire arterial segments of the Circle of Willis, except the paraclinoid internal carotid artery aneurysms. However, Kim et al. presented a pilot study of 82 patients investigating only the lesions of the posterior communicating arteries [21]. Therefore, 3D-PD MRI can be applied widely [21]. Therefore, 3D-PD MRI can be applied widely. In clinical practice, there have been few imaging options for the diagnosis of intracranial aneurysms beyond TOF-MRA and CTA. Thus, DSA is still mobilized for the definitive determination, despite its invasiveness with neurologic complications, radiation exposure, and iodinated contrast media [29]. Proton density imaging is a commonly used vessel wall MRI technique with a high signal-to-noise ratio that can present tiny vascular structures compared with other vessel wall MRI sequences such as T1- or T2-weighted imaging [20]. Therefore, 3D-PD MRI can depict small perforators or the relation of saccular vessel irregularity to branches such as posterior communicating or anterior choroidal artery origin better. This study thereby introduces 3D-PD MRI as another diagnostic option for intracranial aneurysms.

Recently introduced compressed sensing techniques may contribute to the enhancement of spatial resolution with preserved scan times and the reduction of scan time with preserved image quality in both TOF-MRA [30,31] and vessel wall MRI [32]. TOF-MRA with a higher resolution involving a reasonable scan time may enhance the identification of aneurysms of the infundibula even though a smaller spatial resolution can have a demerit of lower signal-to-noise ratio [33]. However, recent research on TOF-MRA has focused on the reduction of scan times, and not on the enhancement of spatial resolution [30,31]. Moreover, even 7T system shows a resolution of 0.23–0.31 mm3 [4,34]. Therefore, further studies are necessary.

This study had some limitations. First, this study was retrospective in nature and included patients from a single tertiary referral institute. The study cannot present the actual diagnostic performance of 3D-PD MRI as the index lesions evaluated in this study were those previously detected from volume-rendered TOF-MRA images. In addition, the images were not acquired using the same machines or protocols across all patients. The retrospective collection may have contributed to the severely unbalanced proportions of men and women and higher incidence of aneurysms in the general population. Second, the 3D-PD MRI may have originally been performed for the evaluation of aneurysms in other locations (paraclinoid ICA aneurysms and beyond the circle of Willis) and for steno-occlusive lesions; it was not performed for the purposes of this study. Third, this study included incidentally found unruptured intracranial aneurysms within the circle of Willis, and 66.8% of these were less than 3 mm in size. The resulting selection bias may limit the generalizability of our findings on 3D-PD MRI. Fourth, only 28.3% of DSA evaluations were performed with 3D rotational angiography to make the final decision, even though two experienced observers thoroughly reviewed the DSA to diagnose aneurysms. Fifth, the time intervals between 3D-PD MRI and DSA were variable, being up to 6 months in some cases. Hence, it remains unclear whether the changes in size and morphology did not affect the diagnostic performances. Finally, TOF-MRA was acquired with anisotropic voxels and variable parameters, and was observed to have a slightly larger spatial resolution in the z-axis. The heterogeneity of detailed parameters and differences in spatial resolutions may have affected the results of this study. Therefore, further studies involving equal imaging conditions are warranted.

Conclusions

The 3D-PD MRI can complement TOF-MRA to improve diagnostic performance and lower the proportion of undetermined lesions when identifying aneurysms from the index lesions in the circle of Willis.

(XLSX)

Click here for additional data file.

13 Jul 2020

PONE-D-20-13596

Added diagnostic values of three-dimensional high-resolution proton density-weighted magnetic resonance imaging for unruptured intracranial aneurysms in the circle-of-Willis: Comparison with time-of-flight magnetic resonance angiography.

PLOS ONE

Dear Dr. Jung,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

This manuscript was evaluated with substantial criticism, in particular with regards of omission of important recent references of very similar studies on PD imaging of intracranial aneurysms by Korean groups:

1. Kim S, Chung J, Cha J, et al. Usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo MRI in distinguishing a junctional dilatation from an intracranial aneurysm of the posterior communicating artery: a pilot study. Journal of NeuroInterventional Surgery 2020;12:315-319

2. Seon Jin Yoon, Na-Young Shin, Jae Whan Lee, Seung Kon Hu and Keun Young Park. Localization and Treatment of Unruptured Paraclinoid Aneurysms: A Proton Density MRI-based Study. J Cerebrovasc Endovasc Neurosurg. 2015;17(3):180-184

There appears to be a serious concern of dual publication of data and it appears unclear whether these are publications from the same group or not. It is not understandable why the authors did not mention these publications from colleagues on the same topic!

So we cannot accept this paper in PLOS ONE if the authors do not make clear that:

1. there is no overlap in analyzed patient cohorts between their study submitted to our journal and the other two studies published in different journal.

2. what the added values and differences in methods, analyzed endpoints/variables and results between their submitted studied and the two previously published studies was!

In addition, please answer all other comments from both authors and modify your manuscript accordingly. However, we cannot guarantee any publication if the major issue of potential dual publication cannot be solved convincingly by your answer.

==============================

Please submit your revised manuscript by Aug 27 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Stephan Meckel, MD, PhD

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2.  Please clarify in your Data availability statement how other researchers can obtain the same dataset. For PLOS ONE data sharing guidelines, please see " ext-link-type="uri" xlink:type="simple">https://journals.plos.org/plosone/s/data-availability"

3. Thank you for including your ethics statement:

"This retrospective study was approved by our institutional review board, which waived the requirement for informed consent. ".

i) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

ii) Once you have amended this statement in the Methods section of the manuscript, please add the same text to the “Ethics Statement” field of the submission form (via “Edit Submission”).

For additional information about PLOS ONE ethical requirements for human subjects research, please refer to http://journals.plos.org/plosone/s/submission-guidelines#loc-human-subjects-research.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: No

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This is an interesting original paper that quantifies with statistical analysis the improvement in diagnostic performance of the TOF-MRA combined with 3D-PD MRI with respect to the TOF-MRA performed alone for the identification of aneurysms and infundibula from the detected lesions in the circle-of-Willis. DSA is used as reference standard to verify the diagnostic outcomes. The methodology and the statistics are sufficiently detailed, and the study is properly placed in the context. The Authors clearly expose the motivation for this study and its use in the context of lifting the patient from the fear and anxiety due to the knowledge of having an aneurysm, when the probability of that lesion actually being an infundibulum is not negligible. Also, the proposed technique is completely non-invasive and would offer additional diagnostic capabilities by using it to complement other non-invasive techniques such as TOF-MRA, which used alone would have lower performance. This is an important aspect to take into consideration, since the gold standard alternative of the DSA carries important risks, as explained by the authors.

The image acquisition details used for the different diagnostic techniques are extensively provided by the Authors. However, it would be nice if more information could be added about the use of different imaging parameters with the same technique and in between the techniques, specifying if the changes are compatible with the possibility of a comparison between the techniques in terms of diagnostic capabilities. For example, can a possible change in resolution have affected the results?

A few comments for consideration:

1) At line 317 in the Discussion section the Authors mention that the time elapsed between the PD MRI and the DSA is variable and in some cases up to 6 months. Would it be possible to add an additional comment specifying how this variation could have significantly or not affected the results?

I believe it would also be important at this point to refresh the memory of the readers about the fact that the TOF-MRA and 3D-PD MRI have been performed simultaneously, thus the main comparison between TOF-MRA alone and TOF-MRA combined with 3D-PD MRI is not affected by this time issue.

Regarding the comparison with DSA instead, which would be affected by the time issue, my understanding is that if DSA was performed afterwards, and only a worsening of the situation can be considered with time, the calculated performance compared to DSA could have only been better than the shown results in the case where the DSA had been performed without waiting a long time.

2) At line 7, term “index lesions”. I see the Authors give a definition of the term at line 80 in the Introduction section but, using this term in the abstract without a definition seems confusing to me. I would suggest providing an explanation for this from the beginning.

3) Multiple times throughout the manuscript the Authors use the term “differentiating”. An instance can be found at line 81. The word "differentiating" as it is used in the sentences leads me to think that the Authors want to differentiate between the aneurysm and the index lesion, while they are actually identifying which of the index lesion is an aneurysm or an infundibulum. Therefore, I would rather use the word identifying, by saying "identifying the true unruptured aneurysms among the index lesions".

4) Line 14, “Three neuroradiologists”: after reading this in the abstract, it was confusing for me to find more people mentioned in the Materials and Methods section under Image Analysis.

5) Line 16: Is the parenthesis an explanation of what the Authors mean with aneurysm, differently from the infundibula from which instead vessel originates? As it is positioned in the sentence, it seems instead referring to the definition of index lesions.

6) End of the line 18: I think there is an “of” that would need to be deleted.

7) At line 26 and 27 the Authors use the terms “superior” and “lower”. I would suggest adding a quantification to these terms.

8) At line 57, I would suggest adding literature citations to support the two previous sentences.

9) At line 78 the Authors mention that to their knowledge, no previous study has reported the use of vessel wall MRI in differentiating intracranial aneurysms from the lesions suspected of being aneurysms.

I found a few interesting papers on the topics that may be worth referencing, even if not necessarily at line 78:

DOI: 10.7461/jcen.2015.17.3.180

DOI: 10.1136/neurintsurg-2019-015149

DOI: https://doi.org/10.3174/ajnr.A6080

DOI: https://doi.org/10.3174/ajnr.A4893

10) At line 104 the acronym “ICA” is used by the Authors, however I could not find an explanation of what the acronym stands for in the text of the manuscript.

11) Sentence starting at line 106 “Index lesions with an ophthalmic artery origin are lesions that appeared to be in contact with the ophthalmic arteries on volume-rendered TOF-MRA images.” Could the Authors clarify the purpose of this sentence and the connection to the previous and following sentences?

12) Table 1:

• Please correct the alignment of the words “Index lesions” and “Aneurysms” in the two columns.

• Under the columns referring to “Size without ophthalmic artery origin”, how were the new totals (100% of the 2 columns below) calculated?

• Under the columns referring to “Size without ophthalmic artery origin”, the second column total doesn’t add up to 100.

• Under “Location”, the second column total doesn’t add up to 100.

13) At line 119, I would suggest the word “machines” to be substituted with the word “systems”.

14) From line 126 to 128, please check the units. Why do the matrix dimensions have a unit of mm (as per my experience it should be unitless)? FOV unit should be mm^3, as well as for voxel size.

Same suggestions for line 137 to 140.

15) At lines 148-150, please check the units and dimensions.

16) At line 160 the Authors mention that the neuroradiologists reviewed the images, but it is not specified how many times they reviewed them. I believe adding this information would make clearer how the total of 1356 observations was obtained. I inferred the total from Table 2; however I couldn’t find it throughout the text.

17) At line 281 the Authors use the term “good”. I would suggest choosing a different word, as “good” can be considered as a subjective (non-quantitative) term.

Reviewer #2: The study investigates the additional diagnostic value of 3D Proton Density Imaging in the evaluation of indeterminate vessel wall lesions.

The technique seems interesting in this context, as high resolution PD-vessel images can potentially be achieved at a reasonable acquisition time (at least in 2/3 protocols).

The study, although retrospective, seems to have been carried out thoroughly and certainly includes a large number of cases, which allows a statement about the method.

The study needs a fundamental revision, in particular because important references were not mentioned, which need to be addressed.

1) The study does not mention that recently a very similar study involving PD imaging has been published (first study from Seoul):

Kim S, Chung J, Cha J, et al. Usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo MRI in distinguishing a junctional dilatation from an intracranial aneurysm of the posterior communicating artery: a pilot study. Journal of NeuroInterventional Surgery 2020;12:315-319

Seon Jin Yoon, Na-Young Shin, Jae Whan Lee, Seung Kon Hu and Keun Young Park. Localization and Treatment of Unruptured Paraclinoid Aneurysms: A Proton Density MRI-based Study. J Cerebrovasc Endovasc Neurosurg. 2015;17(3):180-184

The study submitted here must indicate whether it is a patient cohort independent of the above-mentioned studies (concern about dual publication).

The study seems to go beyond these publications both in terms of the location of the lesions and the number of cases. Please comment on the progress of your study compared to these studies.

2) L3-4: The Background paragraph needs rephrasing

3) The detection and confidence of aneurysm/infundibulum visualization is certainly a function of spatial resolution. This should be adressed in the introduction and discussion sections. TOF MRA benefits from compressed-sense techniques, improving spatial resolution at reasonable scan times. This should be adressed in the discussion, as the presented TOF technique seems not to represent latest state-of-the art technique. Please do include current references on TOF MRA imaging.

4) Is it possible to define a technique-dependent cutoff-value regarding aneurysm size based on the ROC-analysis? I suppose that this is complicated by the different resolution being used/clustered data but would increase the value of the study, as probably smaller aneurysms were detectable with additional PD-sequence compared to TOF alone.

Otherwise, it would be necessary to address the different spatial resolutions being used instead of performing a pooled analysis, the cohort size should allow this to be done.

5) Tables 2-4 need reformatting; e.g. fuse tables 3 and 4

6) L283-284: needs rephrasing, with this sentence the mentioned study is not adequately cited

7) L290-292: please change this sentence and also adress Kim S et al. Journal of NeuroInterventional Surgery 2020;12:315-319

8) L295-298: Please mention the spatial resolution/voxel size, which seems smaller compared to TOF MRA. Hypothesis: does PD MRA benefit from true isotropic acquisition (compared to TOF?) and higher CNR?

9) Please also adress aneurysm location (e.g. skull base, ca) as a relevant factor regarding aneurysm detection in the discussion section. Was detectability of „true“ aneurysms higher in these locations when using additional PD?

10) The ROC-curves are not being presented in the study, would certainly improve its value.

11) Please revise figures 1-3: mention image planes in the figure legend. The illustrations also need a general didactic revision with regard to the recognizability of the pathology.

a. Fig. 1: a,b please zoom in; 1c-h mention image plane in the figure legend

b. Fig. 2: c-j mention image plane in the figure legend

c. Fig. 3: a,b please zoom in; c-j mention image plane in the figure legend

**********

6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

21 Aug 2020

Journal Requirements

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Answer) As required, we have revised our manuscript based on the PLOS ONE style templates

2. Please clarify in your Data availability statement how other researchers can obtain the same dataset. For PLOS ONE data sharing guidelines, please see https://journals.plos.org/plosone/s/data-availability"

Answer) First, the patients enrolled in our study did not overlap with those included in the previously published articles, which may seem similar to our study; however, our study was conducted independently. Our article was already presented at previous conferences held in 2018 (European congress of Radiology 2018 and Asia-Oceanian Congress of Neuroradiology 2018); therefore, we previously commented that there was no previously published report during writing this manuscript. However, we deleted the comments declaring our study as the first report on the subject and added the corresponding references to our list in the manuscript.

3. Thank you for including your ethics statement:

"This retrospective study was approved by our institutional review board, which waived the requirement for informed consent. ".

i) Please amend your current ethics statement to include the full name of the ethics committee/institutional review board(s) that approved your specific study.

Answer) We changed the ethics statement as follows:

"This retrospective study was approved by Asan Medical Center institutional review board that waived the requirement for informed consent."

Editor’s requirements

1. This manuscript was evaluated with substantial criticism, in particular with regards of omission of important recent references of very similar studies on PD imaging of intracranial aneurysms by Korean groups:

1. Kim S, Chung J, Cha J, et al. Usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo MRI in distinguishing a junctional dilatation from an intracranial aneurysm of the posterior communicating artery: a pilot study. Journal of NeuroInterventional Surgery 2020;12:315-319

2. Seon Jin Yoon, Na-Young Shin, Jae Whan Lee, Seung Kon Hu and Keun Young Park. Localization and Treatment of Unruptured Paraclinoid Aneurysms: A Proton Density MRI-based Study. J Cerebrovasc Endovasc Neurosurg. 2015;17(3):180-184

There appears to be a serious concern of dual publication of data and it appears unclear whether these are publications from the same group or not. It is not understandable why the authors did not mention these publications from colleagues on the same topic!

So we cannot accept this paper in PLOS ONE if the authors do not make clear that:

1. there is no overlap in analyzed patient cohorts between their study submitted to our journal and the other two studies published in different journal.

2. what the added values and differences in methods, analyzed endpoints/variables and results between their submitted studied and the two previously published studies was!

Answer) Thank you for your important comment. First, the patients enrolled in our study did not overlap with those included in the two aforementioned articles because our study was conducted independently. Our article was already presented at previous conferences held in 2018 (European congress of Radiology 2018 and Asia-Oceanian Congress of Neuroradiology 2018); therefore, we previously commented that there was no previously published report during writing the manuscript. However, we deleted the comments declaring our study as the first report on the subject and added the corresponding references as follows:

“However, to our knowledge, no previous study has reported the use of vessel wall MRI in differentiating intracranial aneurysms from the lesions suspected of being aneurysms (the index lesion).” in introduction

“There was one report that demonstrated the performance of proton density images for identifying aneurysms of the infundibula. However, Kim et al. discussed that the diagnostic performance of 3D-PD MRI was found to be better than TOF-MRA only in the lesions of the posterior communicating arteries within a small population [21]. Yoon et al. found that PD-MRI can disclose the detailed location (intradural, extradural, or transdural) of paraclinoid internal carotid artery aneurysms with reference to distal dural rings without identifying aneurysms of the infundibula [22].” in Introduction.

“To our knowledge, no previous study has reported the use of vessel wall MRI in the diagnosis or differentiation of aneurysms from infundibula or normal variations.” in discussion

“This study of 299 patients demonstrated the usefulness of 3D-PD MRI compared to that of TOF-MRA in identifying infundibular aneurysms in entire arterial segments of the Circle of Willis, except the paraclinoid internal carotid artery aneurysms. However, Kim et al. presented a pilot study of 82 patients investigating only the lesions of the posterior communicating arteries [21]. Therefore, 3D-PD MRI can be applied widely.” in Discussion

Reviewers' comments:

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Answer) As written above, we have already addressed these concerns.

Reviewer #1:

This is an interesting original paper that quantifies with statistical analysis the improvement in diagnostic performance of the TOF-MRA combined with 3D-PD MRI with respect to the TOF-MRA performed alone for the identification of aneurysms and infundibula from the detected lesions in the circle-of-Willis. DSA is used as reference standard to verify the diagnostic outcomes. The methodology and the statistics are sufficiently detailed, and the study is properly placed in the context. The Authors clearly expose the motivation for this study and its use in the context of lifting the patient from the fear and anxiety due to the knowledge of having an aneurysm, when the probability of that lesion actually being an infundibulum is not negligible. Also, the proposed technique is completely non-invasive and would offer additional diagnostic capabilities by using it to complement other non-invasive techniques such as TOF-MRA, which used alone would have lower performance. This is an important aspect to take into consideration, since the gold standard alternative of the DSA carries important risks, as explained by the authors.

Answer) Thank you for your comments. Upon rechecking the data, we recognized that there was a mistake in the previously reported AUC value of TOF-MRA. We had presented 0.814 as the AUC of TOF-MRA but the correct value was 0.837 (0.817-0.857). Hence, we intend to revise the value. We apologize for this mistake.

The image acquisition details used for the different diagnostic techniques are extensively provided by the Authors. However, it would be nice if more information could be added about the use of different imaging parameters with the same technique and in between the techniques, specifying if the changes are compatible with the possibility of a comparison between the techniques in terms of diagnostic capabilities. For example, can a possible change in resolution have affected the results?

Answer) Thank you for your valuable comment. There are many factors that affect the results, such as resolution, iso- or anisometric acquisition, acceleration factors, and so on. Unfortunately, due to the limited scope of the study, we cannot comment regarding the technical issues associated with smaller portions of higher resolution images and the same imaging acquisition in most cases. However, we have started another study on the identification of aneurysms using 3D-PD MRI in view of resolution, isometric acquisitions, and acceleration factors. After analyzing the results of the new, we will be able to provide comments on this subject. I think that your suggestions are very important and insightful.

1) At line 317 in the Discussion section the Authors mention that the time elapsed between the PD MRI and the DSA is variable and in some cases up to 6 months. Would it be possible to add an additional comment specifying how this variation could have significantly or not affected the results?

I believe it would also be important at this point to refresh the memory of the readers about the fact that the TOF-MRA and 3D-PD MRI have been performed simultaneously, thus the main comparison between TOF-MRA alone and TOF-MRA combined with 3D-PD MRI is not affected by this time issue.

Regarding the comparison with DSA instead, which would be affected by the time issue, my understanding is that if DSA was performed afterwards, and only a worsening of the situation can be considered with time, the calculated performance compared to DSA could have only been better than the shown results in the case where the DSA had been performed without waiting a long time.

Answer) Thank you for your valuable comment. In most cases, DSA was performed after MRI. The time intervals between MRI and DSA can contribute to the change in size and morphology of aneurysms, which might affect detectability or diagnostic performances. For example, tiny aneurysms were not identified using MRI but were identified more easily showing growth in size and peculiar morphological changes using DSA. However, we think that the morphological changes were not dynamic especially within the 6-month interval in unruptured intracranial aneurysms. Because, rupture risk of unruptured intracranial aneurysms is known to be 1.1 – 1.3 % in average annual incidence (Natural History of Unruptured Intracranial Aneurysms A Long-term Follow-up Study Stroke 2013; Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture J Neurosurg 2008), which may mean too short interval to occur any change in size and morphology in unruptured aneurysms. However, a change in size and geometry still cannot be excluded. Hence, we wrote “it remains unclear whether the changes in size and morphology did not affect the diagnostic performances.”

2) At line 7, term “index lesions”. I see the Authors give a definition of the term at line 80 in the Introduction section but, using this term in the abstract without a definition seems confusing to me. I would suggest providing an explanation for this from the beginning.

Answer) Thank you for your comment. We added the explanation in the abstract as follows: “index lesions refer to vascular bulging lesions without vessels arising from the apex, observed using volume-rendered TOF-MRA”.

3) Multiple times throughout the manuscript the Authors use the term “differentiating”. An instance can be found at line 81. The word "differentiating" as it is used in the sentences leads me to think that the Authors want to differentiate between the aneurysm and the index lesion, while they are actually identifying which of the index lesion is an aneurysm or an infundibulum. Therefore, I would rather use the word identifying, by saying "identifying the true unruptured aneurysms among the index lesions".

Answer) Thank you for your comment. We changed “differentiating” to “identifying”.

4) Line 14, “Three neuroradiologists”: after reading this in the abstract, it was confusing for me to find more people mentioned in the Materials and Methods section under Image Analysis.

Answer) Thank you for your comments. Three neuroradiologists participated in identifying true unruptured aneurysms among the index lesions. Other two radiologists participated in identifying index lesions and reviewing DSA as a reference standard. Therefore, we changed the sentence in the Abstract to avoid confusion as follows:

“Final diagnoses were made by another neuroradiologist and neurointerventionist, in consensus, using DSA as the reference standard.” in Abstract

5) Line 16: Is the parenthesis an explanation of what the Authors mean with aneurysm, differently from the infundibula from which instead vessel originates? As it is positioned in the sentence, it seems instead referring to the definition of index lesions.

Answer) Thank you for your comments. We have explained the definition of index lesions according to your suggestion, as indicated above. Hence, we deleted the definition provided within parentheses.

“index lesions (vascular bulging lesions without vessels arising from the apex on volume-rendered TOF-MRA)”.

6) End of the line 18: I think there is an “of” that would need to be deleted.

Answer) Thank you for your detailed observation. We have deleted “of” accordingly.

7) At line 26 and 27 the Authors use the terms “superior” and “lower”. I would suggest adding a quantification to these terms.

Answer) Thank you for your suggestions. We added the specific numbers as follows:

“3D-PD MRI with TOF-MRA showed superior diagnostic performance (p=.001; accuracy, 85.5 % versus 95.4 %), superior area under the receiver operating characteristic curve over TOF-MRA (p=.001; 0.814 versus 0.947), and a lower proportion of undetermined lesions than TOF-MRA (p=.001; 25.1 % versus 2.3 %).”

8) At line 57, I would suggest adding literature citations to support the two previous sentences.

Answer) Thank you for your suggestion. We added the corresponding references as follows:

“With the increase in the demand for health checkups and accessibility of advanced imaging techniques, the detection of incidental aneurysms is increasing [3, 4].”

“However, small infundibular dilatations are sometimes confused with true aneurysms [3, 5].”

3. Sun L-J, Li Y-D, Li M-H, Wang W, Gu B-X. Aneurysm outflow angle at MRA as discriminant for accurate diagnosis and differentiation between small sidewall cerebral aneurysms and infundibula. Journal of neurointerventional surgery. 2016:neurintsurg-2016-012425.

4. Wermer MJ, van Walderveen MA, Garpebring A, van Osch MJ, Versluis MJ. 7Tesla MRA for the differentiation between intracranial aneurysms and infundibula. Magnetic Resonance Imaging. 2017;37:16-20.

5. Yang ZL, Ni QQ, Schoepf UJ, De Cecco CN, Lin H, Duguay TM, et al. Small Intracranial Aneurysms: Diagnostic Accuracy of CT Angiography. Radiology. 2017;285(3):941-52. Epub 2017/06/28. doi: 10.1148/radiol.2017162290. PubMed PMID: 28654338.

9) At line 78 the Authors mention that to their knowledge, no previous study has reported the use of vessel wall MRI in differentiating intracranial aneurysms from the lesions suspected of being aneurysms.

I found a few interesting papers on the topics that may be worth referencing, even if not necessarily at line 78:

DOI: 10.7461/jcen.2015.17.3.180

DOI: 10.1136/neurintsurg-2019-015149

DOI: https://doi.org/10.3174/ajnr.A6080

DOI: https://doi.org/10.3174/ajnr.A4893

Answer) Thank you for your important inputs that help us strengthen our study. First, the patients enrolled in our study do not overlap with those from included in the four aforementioned articles because our study was conducted independently. Our article was already presented at previous conferences held in 2018 (European congress of Radiology 2018 and Asia-Oceanian Congress of Neuroradiology 2018). Hence, we had commented that there was no previously published report upon writing the manuscript. However, because of the delayed presentation of our results, we have deleted the comments declaring no previous reports on the subject. There was one report (Surveillance of Unruptured Intracranial Saccular Aneurysms Using Noncontrast 3D-Black-Blood MRI: Comparison of 3D-TOF and Contrast-Enhanced MRA with 3D-DSA) and one review (Intracranial Vessel Wall MRI: Principles and Expert Consensus Recommendations of the American Society of Neuroradiology) about aneurysms using T1W with black-blood technique. However, as you know, the purposes of these studies were different from those of our study. Our study aimed to identify aneurysms using 3D-PD MRI and not to predict the rupture risk or measure the aneurysmal profiles. Furthermore, in detecting or identifying aneurysms, PD MRI is extremely superior to T1W with or without black-blood techniques until now. I think that T1W with or without black-blood techniques is useless in detecting aneurysms. We accordingly added references on PD-MRI and modified our manuscript as follows:

“However, to our knowledge, no previous study has reported the use of vessel wall MRI in differentiating intracranial aneurysms from the lesions suspected of being aneurysms (the index lesion).” in introduction

“There was one previous report that demonstrated the performance of proton density images in identifying aneurysms of the infundibula. However, Kim et al. presented that diagnostic performance of 3D-PD MRI was found to be better than TOF-MRA only for lesions of the posterior communicating arteries within a small population [21]. Yoon et al. found that PD-MRI can disclose the detailed location (intradural, extradural, or transdural) of paraclinoid internal carotid artery aneurysms with reference to distal dural rings without identifying aneurysms of the infundibula [22].” in Introduction.

“To our knowledge, no previous study has reported the use of vessel wall MRI in the diagnosis or differentiation of aneurysms from infundibula or normal variations.” in discussion

“This study with 299 patients demonstrated the usefulness of 3D-PD MRI compared to that of TOF-MRA in identifying infundibular aneurysms in entire arterial segments of the Circle of Willis, except the paraclinoid internal carotid artery aneurysms. However, Kim et al. presented a pilot study with 82 patients investigating only the lesions of the posterior communicating arteries [21]. Therefore, 3D-PD MRI can be applied widely.” in Discussion

10) At line 104 the acronym “ICA” is used by the Authors, however I could not find an explanation of what the acronym stands for in the text of the manuscript.

Answer) Thank you for your detailed observation and comment. We added the explanation of the first acronym as follows:

“Typical paraclinoid internal carotid artery (ICA) aneurysms”

11) Sentence starting at line 106 “Index lesions with an ophthalmic artery origin are lesions that appeared to be in contact with the ophthalmic arteries on volume-rendered TOF-MRA images.” Could the Authors clarify the purpose of this sentence and the connection to the previous and following sentences?

Answer) Thank you for your comment. In our study, paraclinoid ICA aneurysms were excluded due to the extremely small number of infundibula in the area. However, some locations could sometimes cause confusion in determining paraclinoid and ophthalmic areas. Hence, we defined ophthalmic aneurysms as we mentioned in the manuscript to differentiate it from paraclinoid ICA aneurysms.

12) Table 1:

• Please correct the alignment of the words “Index lesions” and “Aneurysms” in the two columns.

• Under the columns referring to “Size without ophthalmic artery origin”, how were the new totals (100% of the 2 columns below) calculated?

• Under the columns referring to “Size without ophthalmic artery origin”, the second column total doesn’t add up to 100.

Answer) Thank you for your observations and comments. There was a mistake in rounding off to the nearest hundredths. We intend to delete the column on size without ophthalmic artery origin because we did not analyze the lesions with or without ophthalmic artery origin.

• Under “Location”, the second column total doesn’t add up to 100.

Answer) Thank you for your comment. There was a mistake in rounding off to the nearest hundredths. We have changed the value from 1.2 to 1.15.

13) At line 119, I would suggest the word “machines” to be substituted with the word “systems”.

Answer) Thank you for your comment. As suggested, we have changed “machines” to “systems.”

14) From line 126 to 128, please check the units. Why do the matrix dimensions have a unit of mm (as per my experience it should be unitless)? FOV unit should be mm^3, as well as for voxel size.

Same suggestions for line 137 to 140.

Answer) Thank you for your suggestions. We apologize for the mistake and have accordingly removed “mm” in the matrix dimensions and changed the units to “mm3” in FOV.

15) At lines 148-150, please check the units and dimensions.

Answer) Thank you for your comment. We apologize for the mistake. We changed “mm” to “mm3” in pixel size.

16) At line 160 the Authors mention that the neuroradiologists reviewed the images, but it is not specified how many times they reviewed them. I believe adding this information would make clearer how the total of 1356 observations was obtained. I inferred the total from Table 2; however I couldn’t find it throughout the text.

Answer) Thank you for your comments. There were 299 patients and a total of 452 (173+276+3) lesions observed in the patients, which is presented in Table 1. The 1356 observations from Table 2 resulted from triplicates of 452 observations because our reviewers comprised three neuroradiologists, which has also been mentioned in the manuscript.

17) At line 281 the Authors use the term “good”. I would suggest choosing a different word, as “good” can be considered as a subjective (non-quantitative) term.

Answer) Thank you for your comment, we have changed the sentence as follows:

“3D-PD MRI can play a role as a supplementary imaging modality for the diagnosis of aneurysms.”

Reviewer #2: The study investigates the additional diagnostic value of 3D Proton Density Imaging in the evaluation of indeterminate vessel wall lesions.

The technique seems interesting in this context, as high resolution PD-vessel images can potentially be achieved at a reasonable acquisition time (at least in 2/3 protocols).

The study, although retrospective, seems to have been carried out thoroughly and certainly includes a large number of cases, which allows a statement about the method.

The study needs a fundamental revision, in particular because important references were not mentioned, which need to be addressed.

1) The study does not mention that recently a very similar study involving PD imaging has been published (first study from Seoul):

Kim S, Chung J, Cha J, et al. Usefulness of high-resolution three-dimensional proton density-weighted turbo spin-echo MRI in distinguishing a junctional dilatation from an intracranial aneurysm of the posterior communicating artery: a pilot study. Journal of NeuroInterventional Surgery 2020;12:315-319

Seon Jin Yoon, Na-Young Shin, Jae Whan Lee, Seung Kon Hu and Keun Young Park. Localization and Treatment of Unruptured Paraclinoid Aneurysms: A Proton Density MRI-based Study. J Cerebrovasc Endovasc Neurosurg. 2015;17(3):180-184

The study submitted here must indicate whether it is a patient cohort independent of the above-mentioned studies (concern about dual publication).

The study seems to go beyond these publications both in terms of the location of the lesions and the number of cases. Please comment on the progress of your study compared to these studies.

Answer) Thank you for these important comments. First, the patients enrolled in our study did not overlap with those included in the two aforementioned articles because our study was conducted independently. Our article was already presented at the previous conferences held in 2018 (European congress of Radiology 2018 and Asia-Oceanian Congress of Neuroradiology 2018); therefore, we previously commented that there was no previously published report during writing the manuscript. However, we deleted the comments declaring our study as the first report on the subject and added corresponding references as follows:

“However, to our knowledge, no previous study has reported the use of vessel wall MRI in differentiating intracranial aneurysms from the lesions suspected of being aneurysms (the index lesion).” in introduction

“There was one previous report that demonstrated the performance of proton density images for identifying aneurysms of the infundibula. However, Kim et al. discussed that the diagnostic performance of 3D-PD MRI was found to be better than TOF-MRA only in the lesions of the posterior communicating arteries within a small population [21]. Yoon et al. found that PD-MRI can disclose the detailed location (intradural, extradural, or transdural) of paraclinoid internal carotid artery aneurysms with reference to distal dural rings without identifying aneurysms from the infundibula [22].” in Introduction.

“To our knowledge, no previous study has reported the use of vessel wall MRI in the diagnosis or differentiation of aneurysms from infundibula or normal variations.” in discussion

“This study of 299 patients demonstrated the usefulness of 3D-PD MRI compared to that of TOF-MRA in identifying infundibular aneurysms in entire arterial segments of the Circle of Willis, except in paraclinoid internal carotid artery aneurysms. However, Kim et al. presented a pilot study of 82 patients investigating only the lesions of the posterior communicating arteries [21]. Therefore, 3D-PD MRI can be applied widely.” in Discussion

2) L3-4: The Background paragraph needs rephrasing

Answer) Thank you for your comments. We changed the sentences as follows:

“Advanced imaging methods can enhance the identification of aneurysms of the infundibula, which can reduce unnecessary follow-ups or further work-up, fear, and anxiety in patients.”

3) The detection and confidence of aneurysm/infundibulum visualization is certainly a function of spatial resolution. This should be adressed in the introduction and discussion sections. TOF MRA benefits from compressed-sense techniques, improving spatial resolution at reasonable scan times. This should be adressed in the discussion, as the presented TOF technique seems not to represent latest state-of-the art technique. Please do include current references on TOF MRA imaging.

Answer) Thank you for your comments. There are many factors that may affect the results, such as the resolution, iso- or anisometric acquisition, acceleration factors, and so on. The compressed sensing is also a good application for high resolution MRI and TOF-MRA. In our experience (High-Resolution Magnetic Resonance Imaging Using Compressed Sensing for Intracranial and Extracranial Arteries: Comparison with Conventional Parallel Imaging), a spatial resolution with greater than or equal to 0.2x0.2x0.2 mm3 seems difficult to apply in clinical practice with clinical 3T systems in spite of compressed sensing. As you know, recently introduced TOF-MRA sequences with compressed sensing show similar resolution as the conventional TOF-MRA, and most reports focus on the reduction of scan times. Higher resolution to conventional TOF-MRA may mean around 0.1~0.2 mm3 in acquisition voxel size not reconstructed voxel size; however, the associated decreased SNR could be problematic. Thus, it may be not easy to achieve both a higher resolution and shorter scan time simultaneously. As a result, further studies should be conducted in this regard.

“Recently introduced compressed sensing techniques may contribute to the enhancement of spatial resolution with preserved scan times and the reduction of scan time with preserved image quality in both TOF-MRA [30, 31] and vessel wall MRI [32]. TOF-MRA with a higher resolution involving a reasonable scan time may enhance the identification of aneurysms of the infundibula even though a smaller spatial resolution can have a demerit of lower signal-to-noise ratio [33]. However, recent research on TOF-MRA has focused on the reduction of scan times, and not on the enhancement of spatial resolution [30, 31]. Moreover, even 7T system shows a resolution of 0.23- 0.31 mm3 [4, 34]. Therefore, further studies are necessary.” in the Discussion

“Finally, TOF-MRA was acquired with anisotropic voxels and variable parameters, and was observed to have a slightly larger spatial resolution in the z-axis. The heterogeneity of detailed parameters and differences in spatial resolutions may have affected the results of this study. Therefore, further studies involving equal imaging conditions are warranted” in the limitations

4) Is it possible to define a technique-dependent cutoff-value regarding aneurysm size based on the ROC-analysis? I suppose that this is complicated by the different resolution being used/clustered data but would increase the value of the study, as probably smaller aneurysms were detectable with additional PD-sequence compared to TOF alone.

Otherwise, it would be necessary to address the different spatial resolutions being used instead of performing a pooled analysis, the cohort size should allow this to be done.

Answer) Thank you for your comment. We analyzed our results with a 3-mm reference but no significant differences were observed. As you observed, our data was heterogeneous in location, size, and imaging parameters, which made it difficult to analyze, compare, and stratify the results according to each issue. Thus, we opted to study imaging conditions that were similar between TOF-MRA and PD-MRI, which made it possible to analyze results in terms of location, size, etc. In addition, we added the following statement:

“Finally, TOF-MRA was acquired with anisotropic voxels and variable parameters, and was observed to have a slightly larger spatial resolution in the z-axis. The heterogeneity of detailed parameters and differences in spatial resolutions may have affected the results of this study. Therefore, further studies involving equal imaging conditions are warranted” as limitations

5) Tables 2-4 need reformatting; e.g. fuse tables 3 and 4

Answer) Thank you for your comments. We fused tables 3 and 4 as follows:

Table 3. Comparison of diagnostic performances and proportions of undetermined lesions

AUC P value

TOF-MRA 0.837

† (0.817 – 0.857) .001

3D-PD MRI with TOF-MRA 0.947

† (0.934 - 0.958)

Proportion P value

TOF-MRA 25.1%

†† (341/1356) .001

3D-PD MRI with TOF-MRA 2.3 %

†† (31/1356)

* TOF-MRA = time-of-flight magnetic resonance angiography, 3D-PD MRI = three-dimensional high-resolution proton density-weighted magnetic resonance imaging, AUC = area under the receiver operating characteristic curve.

††† P-values were calculated from comparisons between 3D-PD MRI and TOF-MRA.

6) L283-284: needs rephrasing, with this sentence the mentioned study is not adequately cited

Answer) Thank you for your comments. We have changed the references as follows:

25. Hwang SB, Kwak HS, Han YM, Chung GH. Detection of intracranial aneurysms using three-dimensional multidetector-row CT angiography: is bone subtraction necessary? Eur J Radiol. 2011;79(2):e18-23. doi: 10.1016/j.ejrad.2010.01.004. PubMed PMID: 20144517.

3. Sun L-J, Li Y-D, Li M-H, Wang W, Gu B-X. Aneurysm outflow angle at MRA as discriminant for accurate diagnosis and differentiation between small sidewall cerebral aneurysms and infundibula. Journal of neurointerventional surgery. 2016:neurintsurg-2016-012425.

4. Wermer MJ, van Walderveen MA, Garpebring A, van Osch MJ, Versluis MJ. 7Tesla MRA for the differentiation between intracranial aneurysms and infundibula. Magnetic Resonance Imaging. 2017;37:16-20.

7) L290-292: please change this sentence and also adress Kim S et al. Journal of NeuroInterventional Surgery 2020;12:315-319

Answer) Thank you for your comments. We removed the previous sentence and added new sentences with the following references:

“To our knowledge, no previous study has reported the use of vessel wall MRI in the diagnosis or differentiation of aneurysms from infundibula or normal variations.” in discussion

“This study of 299 patients demonstrated the usefulness of 3D-PD MRI compared to that of TOF-MRA in identifying infundibular aneurysms in the entire arterial segments of the Circle-of-Willis except the paraclinoid internal carotid artery aneurysms. However, Kim et al. presented a pilot study of 82 patients investigating only the lesions of the posterior communicating arteries [21]. Therefore, 3D-PD MRI can be applied widely.” in the discussion

8) L295-298: Please mention the spatial resolution/voxel size, which seems smaller compared to TOF MRA. Hypothesis: does PD MRA benefit from true isotropic acquisition (compared to TOF?) and higher CNR?

Answer) Thank you for your comment. The spatial resolution is important in identifying aneurysms. However, in our retrospective study, the resolutions were not the same between PD and TOF-MRA and among TOF-MRA sequences, as you have observed. Thus, we included this issue in the limitations as follows:

“Finally, TOF-MRA was acquired with anisotropic voxels with variable parameters and was found to have a slightly larger spatial resolution in the Z-axis. The heterogeneity of detailed parameters and differences in spatial resolutions may have affected the results of this study. Therefore, further study involving equal imaging conditions is warranted” in the limitations

9) Please also address aneurysm location (e.g. skull base, ca) as a relevant factor regarding aneurysm detection in the discussion section. Was detectability of „true“ aneurysms higher in these locations when using additional PD?

Answer) Thank you for your valuable comment. We did not analyze our results in terms of the location. Thus, we compared the diagnostic performances according to the location (Acom, oph, Pcom, AchA; we did not analyze these because of insufficient data in BA, SCA, ICA, A1) based on the AUC. A difference of AUC in the ophthalmic artery origin aneurysms was the lowest, but there were statistically significant differences across Acom, oph, Pcom, AchA. We have mentioned this issue in the discussion as follows:

“3D-PD MRI combined with TOF-MRA showed a larger AUC compared to that of TOF-MRA alone in the ophthalmic artery origin, posterior communicating artery, anterior communicating artery, and anterior choroidal artery origin locations (p=.033 to .001).” in the results.

10) The ROC-curves are not being presented in the study, would certainly improve its value.

Answer) Thank you for your suggestion. We have added the ROC curves as seen in Figure 4. In addition, during rechecking of the presented data, we noted a mistake in the AUC value of TOF-MRA. We had presented 0.814 as the AUC of TOF-MRA but the correct value was 0.837 (0.817-0.857). Thus, we intend to revise the value. We sincerely apologize for this mistake.

Fig 4. 3D-PD MRI combined with TOF-MRA (AUC= 0.837) showed higher diagnostic performance and AUC than TOF-MRA alone (AUC= 0.947) (p=.001).

11) Please revise figures 1-3: mention image planes in the figure legend. The illustrations also need a general didactic revision with regard to the recognizability of the pathology.

a. Fig. 1: a,b please zoom in; 1c-h mention image plane in the figure legend

b. Fig. 2: c-j mention image plane in the figure legend

c. Fig. 3: a,b please zoom in; c-j mention image plane in the figure legend

Answer) Thank you for your comments. We modified figure 1 and 3 using zoomed images and figure legends as follows:

Fig 1.

“A 60-year-old female was referred from an outside hospital for incidentally found aneurysms. TOF-MRA (a) and TOF-MRA source images (c-e) showed an index lesion around the left anterior choroidal artery origin; however, the relationship between the aneurysm and anterior choroidal artery was unclear on coronal multi-planar reconstruction (MPR) images (arrows). 3D-PD MRI clearly depicted the aneurysm and anterior choroidal artery origin on coronal MPR images (arrows) (f-h). 3D rotational angiography (b) also showed a clear relationship between the aneurysm and the anterior choroidal artery origin (arrow).”

Fig 2.

“A 66-year-old female underwent 3D-PD MRI for evaluation of a right middle cerebral artery stenosis detected during work up for left side weakness. TOF-MRA (a) showed an index lesion around the left distal ICA. However, it was difficult to diagnose the aneurysm due to its tiny size and nearby bone structures (arrows) (c–f) even on TOF-MRA source images with oblique coronal multi-planar reconstruction (MPR) (d-f). 3D-PD MRI depicted a definite aneurysm on oblique coronal MPR images (arrows) (g-j). DSA also showed a definite aneurysm (arrow) (b).”

Fig 3.

“A 57-year-old female underwent 3D-PD MRI for evaluation of a left paraclinoid internal carotid artery aneurysm. TOF-MRA (a) showed an index lesion around anterior choroidal artery origin of left distal ICA. However, it was difficult to diagnose the aneurysm (arrows) even on TOF-MRA source images with sagittal multi-planar reconstruction (MPR) (c-f). The relationship between anterior choroidal artery and the index lesion was not seen clearly on sagittal MPR images of TOF-MRA (e, f). 3D-PD MRI depicted a definite aneurysm with bi-lobed shape (arrows) (g, h) and clear relationship between anterior choroidal artery and the index lesion on sagittal MPR images (i, j). 3D rotational angiography also showed a definite aneurysm with bi-lobed shape (arrow) (b).”

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

18 Nov 2020

Added diagnostic values of three-dimensional high-resolution proton density-weighted magnetic resonance imaging for unruptured intracranial aneurysms in the circle-of-Willis: Comparison with time-of-flight magnetic resonance angiography.

PONE-D-20-13596R1

Dear Dr. Jung,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Nicola Toschi

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: no further comments.............................................................................................................

Reviewer #2: The authors adressed all my comments and recommendations. I only recommend correct reading by a native speaker.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

20 Nov 2020

PONE-D-20-13596R1

Added diagnostic values of three-dimensional high-resolution proton density-weighted magnetic resonance imaging for unruptured intracranial aneurysms in the circle-of-Willis: Comparison with time-of-flight magnetic resonance angiography

Dear Dr. Jung:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Nicola Toschi

Academic Editor

PLOS ONE