Research Findings

2025.03.19

"Chocolate Chip Sign" on Susceptibility-Weighted Imaging: A Novel Neuroimaging Biomarker for HTRA1-Related Cerebral Small Vessel Disease

▶ Neurol Genet. 2025 Feb 26;11(2):e200237. doi: 10.1212/NXG.0000000000200237. eCollection 2025 Apr.

Ando S1, Saito R2, Kitahara S1, Uemura M1, Hatano Y1, Watanabe M3, Kato T4, Ito Y3,5, Nalini A6, Ishihara T7, Murayama S8,9, Igarashi H3, Kakita A2, Onodera O1,4.

  1. Department of Neurology, Brain Research Institute, Niigata University.
  2. Department of Pathology, Brain Research Institute, Niigata University.
  3. Center for Integrated Human Brain Science, Brain Research Institute, Niigata University.
  4. Department of Molecular Neuroscience, Brain Research Institute, Niigata University.
  5. Department of Functional Neurosurgery, Nishiniigata Chuo Hospital
  6. Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India.
  7. Advanced Treatment of Neurological Diseases Branch, Endowed Research Branch, Brain Research Institute, Niigata University.
  8. Brain Bank for Neurodevelopmental, Neurological and Psychiatric Disorders, United Graduate School of Child Development, Osaka University.
  9. Brain Bank for Aging Research (Neuropathology), Tokyo Metropolitan Institute of Geriatrics and Gerontology.

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.

*Reprinted under a CC BY NC ND 4.0 license.

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