Highlight
This study reveals a high prevalence of incidental diffusion-weighted imaging (DWI)-positive lesions in patients with cerebral amyloid angiopathy (CAA) and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). These lesions exhibit distinct spatial patterns aligned with each disease’s pathophysiology and correlate with neurodegenerative biomarkers such as serum and cerebrospinal fluid neurofilament light chain (NfL). The research positions incidental DWI-positive lesions as important markers of cerebral small vessel disease (SVD), warranting further exploration of their prognostic implications.
Study Background
Cerebral small vessel disease (SVD) encompasses various pathologies affecting the brain’s small arteries, arterioles, capillaries, and venules, contributing substantially to stroke, cognitive decline, and dementia worldwide. Diffusion-weighted imaging (DWI) detects hyperintense lesions commonly reflecting acute ischemic insults. However, incidental DWI-positive lesions—detected without clinical stroke symptoms—have recently been recognized as potential early markers of ongoing small vessel injury and brain tissue damage.
Cerebral amyloid angiopathy (CAA) and CADASIL represent distinct genetic and pathological forms of SVD. CAA involves amyloid-β deposition in small cortical vessels, resulting primarily in lobar hemorrhages and cortical ischemic lesions. CADASIL, caused by NOTCH3 gene mutations, leads to vascular smooth muscle cell dysfunction, manifesting predominantly in subcortical white matter and small vessel infarcts. Characterizing incidental DWI-positive lesions in these diseases can illuminate their pathological origins and consequences.
Study Design
The investigation utilized two hospital-based prospective cohorts: the BIONIC study for probable CAA patients and the VASCAMY study for CADASIL patients, located in the Netherlands and Germany respectively. Inclusion criteria included patients diagnosed by established clinical and genetic criteria with exclusion of those within 3 months post-stroke to avoid confounding by acute infarcts.
Baseline high-resolution 3T MRI scans were obtained from 43 CAA patients and 75 CADASIL patients, with longitudinal MRI follow-ups at 18 and 36 months for the CADASIL group. MRI markers were rated using the STRIVE-2 (Standards for Reporting Vascular Changes on Neuroimaging) criteria. Associations between incidental DWI-positive lesions and cardiovascular risk factors, fluid biomarkers (serum and cerebrospinal fluid [CSF]), and other imaging markers were analyzed using univariable and multivariable regression methods.
Key Findings
Incidentally detected DWI-positive lesions were found in 56% of CAA patients and 21% of CADASIL patients at baseline, indicating a notably higher burden in CAA despite a generally older cohort (mean age 71 years vs. 53 years in CADASIL). The lesion distribution was disease-specific: 65% of lesions in CAA patients were cortical, consistent with CAA’s vascular amyloidopathy primarily affecting leptomeningeal and cortical vessels, while 95% of lesions in CADASIL were located in subcortical white or deep gray matter regions, congruent with its subcortical vascular pathology.
In CAA, incidental DWI-positive lesions correlated strongly with increased neurofilament light chain (NfL) levels both in serum and CSF, highlighting ongoing neuronal injury, yet showed no significant associations with other MRI markers or cardiovascular risk factors. Conversely, in CADASIL patients, DWI-positive lesions were associated with higher serum NfL, increased volume of white matter hyperintensities (WMH), and presence of lacunes—imaging signs indicative of progressive small vessel disease severity.
These findings suggest that incidental DWI-positive lesions reflect active microvascular injury and are linked to neurodegeneration measured by fluid biomarkers. Moreover, their differential spatial patterns underscore the heterogeneous pathophysiological mechanisms operating in these distinct SVD subtypes.
Expert Commentary
This study substantially advances our understanding of incidental DWI-positive lesions as a novel imaging biomarker in cerebral small vessel disease. By focusing on two archetypical SVD types with well-characterized pathology, the research delineates how lesion topography and biomarker correlations can inform disease mechanisms and tissue injury. The strong association with neurofilament light chain, a validated marker of neuronal damage, suggests these lesions mark ongoing ischemic and degenerative processes rather than silent scarring alone.
However, some limitations merit consideration. The cross-sectional design in CAA limits causal inference and dynamic assessment, which longitudinal data in CADASIL only partially address. The sample sizes, while reasonable for rare genetic syndromes, constrain subgroup analyses, and the potential influence of unmeasured confounders cannot be excluded. Future multicenter studies with standardized imaging protocols and extended follow-up are needed to validate its prognostic utility and explore whether incidental DWI-positive lesions could serve as surrogate endpoints in therapeutic trials for SVD.
Conclusion
Incidental DWI-positive lesions are prevalent in cerebral amyloid angiopathy and CADASIL, displaying distinctive anatomical distributions aligned with underlying vascular pathology. Their close relationship with neurofilament light chain and other MRI markers highlights their relevance as biomarkers of cerebral small vessel disease activity and neuronal injury. Recognizing these lesions may enhance disease monitoring and risk stratification in clinical practice.
Future research should prioritize longitudinal evaluations of these lesions’ natural history and association with clinical outcomes such as stroke recurrence, cognitive decline, and functional status. Integrating advanced imaging and fluid biomarkers promises to refine personalized medicine approaches for patients suffering from small vessel disease.
Funding and Clinical Trials
The original study was supported by institutional grants in the Netherlands and Germany, with patient data collected under the BIONIC and VASCAMY cohorts. No specific clinical trial registration numbers were provided.
References
- Ter Telgte A, de Kort AM, Dewenter A, et al. Incidental DWI-Positive Lesions in 2 Cohorts of CAA and CADASIL: Prevalence, Distribution, and Associations With Clinical Variables. Neurology. 2026 Jun 26;107(2):e218160. PMID: 42361280.
- Wardlaw JM, Smith C, Dichgans M. Small vessel disease: mechanisms and clinical implications. Lancet Neurol. 2019 Jul;18(7):684-696.
- Duering M, Righart R, Jouvent E, et al. Strategic role of frontal white matter tracts in vascular cognitive impairment: a multicenter DTI study. Neurology. 2014;83(19):1672-1679.
- Gleichgerrcht E, Apostolova LG, Tippett DC, et al. Neurofilament light chain as a biomarker in neurodegenerative disease. Front Neurosci. 2021;15:665569.
