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"Chocolate Chip Sign" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral
Shoichiro Ando1, Rie Saito2, Sho Kitahara1
1Department of Neurology, Brain Research Institute, Niigata University, Japan.
Insights
The "Chocolate Chip Sign" on susceptibility-weighted imaging (SWI) helps diagnose HTRA1-related cerebral small vessel disease (HRSVD). This finding aids in early identification and genetic testing for this rare condition.
Area of Science:
- Neuroimaging
- Genetics
- Vascular Neurology
Background:
- HTRA1-related cerebral small vessel disease (HRSVD) is a rare genetic disorder.
- Diagnosing HRSVD is challenging due to non-specific clinical and imaging features.
- Family history may be unclear, complicating diagnosis.
Purpose of the Study:
- To investigate the utility of susceptibility-weighted imaging (SWI) in identifying diagnostic findings for HRSVD.
- To determine if SWI can differentiate HRSVD from other forms of cerebral small vessel disease (CSVD).
Main Methods:
- Retrospective study of 8 HRSVD, 12 CADASIL, and 14 sporadic CSVD patients.
- SWI analysis to count hypointense dots around the midbrain.
- Histopathologic analysis of leptomeningeal vessels in autopsied brains.
Main Results:
- Patients with HRSVD showed significantly more hypointense dots on SWI.
- The "Chocolate Chip Sign" (≥5 dots) distinguished HRSVD from CADASIL and sCSVD (AUC=0.817).
- Histopathology confirmed dilated leptomeningeal veins with type III collagen in HRSVD.
Conclusions:
- The "Chocolate Chip Sign" on SWI is a novel neuroimaging biomarker for HRSVD.
- This finding can facilitate earlier diagnosis and genetic screening for HRSVD.
- SWI offers a promising tool for diagnosing this rare genetic cerebrovascular disorder.
Background And Objectives:
HTRA1-related cerebral small vessel disease (HRSVD) is a rare hereditary form of cerebral small vessel disease (CSVD) caused by HTRA1 pathogenic variants. Diagnosing HRSVD without genetic testing is challenging because of the lack of distinctive imaging features and clinical symptoms, and even family history can be unclear in some cases with HRSVD. This study investigates whether susceptibility-weighted imaging (SWI) can identify useful diagnostic findings for HRSVD.
Methods:
This retrospective study included 8 patients with HRSVD, 12 with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and 14 with sporadic CSVD (sCSVD). Two neurologists blinded to clinical data counted the number of hypointense dots around the midbrain on SWI. Receiver operating characteristic curve analysis evaluated the optimal threshold of the number that can distinguish HRSVD and CADASIL or sCSVD. In addition, histopathologic analysis including measurement of leptomeningeal vessel diameter and type III collagen deposition was performed on autopsied brains from 3 cases each of HRSVD, CADASIL, and sCSVD and control participants.
Results:
Patients with HRSVD exhibited a significantly higher number of hypointense dots around the midbrain on SWI compared with CADASIL and sCSVD groups. A threshold of 5 or more dots, termed the "Chocolate Chip Sign," well distinguished HRSVD from CADASIL and sCSVD (area under the curve: 0.817, 95% confidence interval: 0.624-1.00). Three-dimensional SWI reconstruction and 7T MRI confirmed these dots as dilated extraparenchymal vessels. Histopathologic analysis revealed pronounced dilation of leptomeningeal veins with type III collagen accumulation specifically, in HRSVD brains.
Discussion:
The Chocolate Chip Sign on SWI represents a novel and promising neuroimaging biomarker for HRSVD. This finding holds significant potential for facilitating early diagnosis, prompting timely genetic testing, and appropriate family screening for this rare genetic disorder.
