Neurological Sciences (2026) 47:18

[Link]

ORIGINAL ARTICLE

Decoding neurovascular signatures: advanced imaging insights in

DADA2-Related Cerebral Microangiopathy
Yaping Zhou1 · Min Shen2 · Nan Jiang1 · Hanhui Fu1 · Fei Han1 · Yi-Cheng Zhu1 · Ming Yao1 · Jun Ni1

Received: 16 July 2025 / Accepted: 29 October 2025

© The Author(s) 2025

Abstract
Background and purpose Neuroimaging phenotypes remain poorly characterized in patients with deficiency of adenosine
deaminase 2 (DADA2). We aimed to characterize cerebral microangiopathy patterns and establish diagnostic imaging bio-
markers for DADA2.
Methods We retrospectively analyzed consecutively enrolled DADA2 patients with neurological involvement from two
ongoing prospective cohorts. The demographic, clinical, and neuroimaging data were evaluated, focusing on neuroimaging
lesion patterns and cerebral small vessel disease (CSVD) imaging markers.
Results Thirteen patients were included, with 69.2% males. The median age at neurological onset was 17 (7–26) years. A
striking disparity emerged between acute ischemic burden and chronic small vessel injury markers. During a follow-up of
51 (0.5–193) months,138 ischemic lesions were observed in all patients, primarily involving the pons (38 lesions), thalamus
(21 lesions), internal capsule (20 lesions), and basal ganglia (18 lesions). Conversely, only one cerebral microbleed (CMB)
was detected in all patients. Mild white matter hyperintensities (WMH) were observed in 9 patients. Infratentorial atrophy
was prevailing and present in 69.2% (n = 9) patients. Additionally, hemorrhagic stroke was less frequent (n = 6, 46.2%) than
infarction.
Conclusion DADA2 exhibited a profoundly high risk of stroke recurrence, with substantial lesions being clinically asymp-
tomatic, underscoring the importance of routine neuroimaging evaluation for DADA2 patients. This disease presents a
unique CSVD phenotype characterized by brainstem-deep gray nucleus ischemic predominance and infratentorial atrophy
yet paradoxically low burdens of CMBs and WMH compared to other CSVD. This distinctive imaging triad not only facili-
tates early recognition and timely intervention, but also suggests a pathophysiological divergence from other CSVD.

Keywords Deficiency of adenosine deaminase 2 · Neuroimaging tirad · Microangiopathy · Inflammation · Mechanism

Ming Yao Yi-Cheng Zhu

pumchym2011@[Link] zhuych910@[Link]
Jun Ni 1
Department of Neurology, State Key Laboratory of Complex
pumchnijun@[Link]
Severe and Rare Diseases, Dongcheng District, Peking
Yaping Zhou Union Medical College Hospital, Chinese Academy of
yapingzhou221@[Link] Medical Sciences and Peking Union Medical College, No.1
Shuaifuyuan, DongdanBeijing 100730, China
Min Shen
2
shenmpumch@[Link] Department of Rare DiseasesState Key Laboratory
of Complex Severe and Rare DiseasesDepartment of
Nan Jiang
Rheumatology and Clinical ImmunologyNational Clinical
drjnjiangnan@[Link]
Research Center for Dermatologic and Immunologic
Hanhui Fu Diseases (NCRC-DID), Ministry of Science &
lulufu@[Link] TechnologyKey Laboratory of Rheumatology and Clinical
Immunology, Ministry of Education, Peking Union Medical
Fei Han
College Hospital (PUMCH), Chinese Academy of Medical
lourahan@[Link]
Sciences & Peking Union Medical CollegePUMCHPUMCH,
Beijing 100730, China

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Introduction Methods

Deficiency of adenosine deaminase 2 (DADA2), first Study subjects and data collection
described in 2014, is a rare monogenic autoinflammatory
disorder caused by loss-of-function mutations in the ADA2 We retrospectively enrolled 13 patients with neurologi-
gene (also known as CECR1) [1, 2]. This multisystem pleio- cal involvement from two ongoing prospective cohorts at
tropic disease classically manifests as a triad of systemic Peking Union Medical College Hospital from March 2015 to
vasculitis, hematological abnormalities, and immunodefi- February 2025. The diagnosis of DADA2 was confirmed by
ciency [3, 4], with emerging evidence implicating dysregu- both identification of pathogenic variants in the ADA2 gene
lated interferon signaling and neutrophil extracellular trap through sequencing and demonstration of reduced ADA2
formation in its pathogenesis. Most patients experience dis- enzymatic activity in all patients, except for one individual
ease onset before the age of 10 years, though adult-onset diagnosed solely based on genetic confirmation of com-
cases are increasingly recognized, broadening the diagnostic pound heterozygous pathogenic ADA2 mutations (Table S1
spectrum [5]. Characterized by multiorgan involvement and in the supplementary material).
significant mortality (exceeding 8% by age 30) [6], DADA2 The demographic and clinical information, including age,
poses diagnostic challenges due to its striking phenotypic sex, symptoms, and signs, was collected from the hospital
heterogeneity [4]. Moreover, neurological involvement is information system. Acute-phase reactants, specifically the
prevalent in DADA2 with stroke recognized as the leading erythrocyte sedimentation rate (ESR) and high-sensitivity
cause of mortality [1, 2, 7, 8]. Given the marked efficacy of C-reactive protein (hsCRP), were assessed in all patients
anti-tumor necrosis factor (TNF) agents in halting disease during their hospitalization. Laboratory results were sum-
progression [9–11], early recognition and diagnosis are cru- marized for 12 patients who had not received TNF inhibi-
cial for optimizing outcomes. This diagnostic complexity tor therapy prior to admission. All available neuroimaging
and the imperative for early diagnosis and timely interven- data of the 13 patients were collected for analysis. All the
tion underscore the urgent need for comprehensive pheno- patients underwent abdominal ultrasound or CT scans. Spe-
typic characterization, particularly regarding neurological cifically, five patients underwent abdominal CT scans, three
manifestation. patients underwent abdominal ultrasound, and five patients
Neurological manifestations affect 50–77% of DADA2 underwent both modalities.
patients, with early-onset lacunar stroke (typically occurring Informed consent was obtained from all the participants
before age 30) representing a hallmark feature [8, 12–15]. or their legal surrogates. The study was approved by the
Notably, the stroke recurrence rate in DADA2 approaches Ethics Committee of the Peking Union Medical College
76%, substantially exceeding that of conventional young- Hospital (JS-1280 and ZS-3272).
onset stroke etiologies [10]. Pathologically, DADA2-asso-
ciated vasculopathy targets small- to medium-sized arteries, Neuroimaging evaluation
characterized by interstitial neutrophil and macrophage
infiltration and non-granulomatous necrotizing arteritis [16, Brain magnetic resonance imaging (MRI) examinations
17]. Consequently, DADA2 should be considered in young were conducted for all 13 patients. The MRI scans were
patients with recurrent strokes and systemic inflammation. performed on 3.0 T scanners according to the standard-
Notably, transient or mild neurological symptoms may pre- ized imaging protocols with the following sequences: 1)
cede overt infarcts, potentially delaying diagnosis. Recogni- axial and sagittal T1-weighted imaging (T1WI); 2) axial
tion of neuroimaging features and disease-specific imaging and sagittal T2-weighted imaging (T2WI); 3) axial fluid-
markers is therefore essential for early identification and attenuated inversion recovery (FLAIR) imaging; and 4)
timely treatment. axial diffusion-weighted imaging (DWI) and apparent dif-
However, investigations of the neuroimaging features in fusion coefficient (ADC) imaging; 5) susceptibility-sensi-
DADA2 are limited [18, 19]. Moreover, although DADA2 tivity weighted images (SWI) or T2*-weighted imaging.
is considered a monogenic cerebral small vessel disease SWI, which is more sensitive for microbleed detection,
(CSVD), the characteristics of CSVD imaging markers in was performed in 12 patients, while 1 patient was evaluated
this disorder are poorly defined [15]. Therefore, to address with T2*-weighted imaging only. To further validate the
this issue, we analyzed the neuroimaging features, includ- neuroimaging features identified via 3.0 T MRI, high-field
ing the lesion types, spatial distributions, temporal evolu- 5.0 T MRI examinations were additionally performed in 6
tions, and characteristics of CSVD imaging markers in 13 patients, enabling enhanced spatial resolution for precise
DADA2 patients, aiming to improve the differentiation characterization of microstructural abnormalities. More-
from other CSVD entities. over, 3 patients underwent spinal MRI examinations with

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axial and sagittal T1WI, T2WI, and T2WI with fat satura- Table 1 Demographics and clinical features of the patients
tion sequences. Cerebral angiographies, including magnetic Overall
(n = 13)
resonance angiography (MRA), computed tomography
Age at onset (years, median, range) 16
angiography (CTA), digital subtraction angiography (DSA), (0.5–26)
and high-resolution MRI (HRMRI) of the vessel walls, were Age at diagnose (years, median, range) 23
also conducted for 10 patients. The specific neurovascular (16–38)
imaging modalities employed were as follows: five patients Time from onset to diagnose (years, median, range) 11
underwent MRA alone, two underwent CTA alone, and one (0–18)
Age at neurological onset (years, median, range) 17
underwent HRMRI alone. Additionally, one patient received
(7–26)
both CTA and DSA, and another received both CTA and Time for follow up† (month, median, range) 51 (0.5–
HRMRI. 193)
The neuroimaging results were independently evalu- Males, n (%) 9 (69.2)
ated by two experienced neurologists (MY and YPZ, with Fever, n (%) 9 (69.2)
20 and 5 years of experience, respectively). Ischemic and Skin involvement, n (%)
hemorrhagic lesions were documented for their presence Livedo reticularis 10 (76.9)
and anatomic distribution. Imaging biomarkers of CSVD Skin/vulvar ulcers 3 (23.1)
were systematically analyzed, including cerebral atro- Raynaud's phenomenon 3 (23.1)
Erythema modosum 3 (23.1)
phy, cerebral microbleeds (CMBs), periventricular white
Ophthalmologic involvement*, n (%) 8 (61.5)
matter hyperintensities (pWMH), and deep white matter
Hepatosplenomegaly, n (%) 10 (76.9)
hyperintensities (dWMH). The CMBs and WMH were Hypertension, n (%) 4 (30.8)
identified according to STRIVE-2 standards [20]. Spe- Hematological involvement&, n (%) 3 (23.1)
cifically, WMH was characterized by hyperintensity on Initial symptom, n (%)
T2WI and FLAIR without cavitation, while CMBs were Skin involvement 6 (46.2)
detected on SWI or T2* and characterized by small round Stroke 5 (38.5)
or ovoid hypointensity with blooming. The WMH burden Fever 1 (7.7)
was semiquantitatively graded using the Fazekas scale. Hearing loss 1 (7.7)
Longitudinal changes in lesions extent, quantity, and sig- Neurological involvement, n (%)
nal intensity of lesions were assessed among patients with Ischemic stroke 11 (84.6)
serial MRI examinations. Angiographic data(e.g., aneu- Hemorrhagic stroke# 6 (46.2)
Spastic paraplegia 2 (15.4)
rysms, stenosis, and other abnormalities) and spinal cord
Headache 2 (15.4)
abnormalities (when spinal MRI was available) were also
Hearing loss 4 (30.8)
assessed.
Total number of ischemic strokes 41
Number of ischemic strokes per patient (median, range) 3 (0–9)
Statistical analysis Laboratory results§, n (%)
Elevated ESR 5 (41.7)
Continuous data were expressed as the median (minimum Elevated hsCRP 8 (66.6)
to maximum), and the categorical data were described using †
A total of 12 patients were available
frequencies and percentages. *
The ophthalmologic involvements included retinal vasculitis in 3
patients, dry eye disease in 2 patients, central retinal artery occlusion
in 1 patient, oculomotor nerve palsy in 1 patient, and optic neuropa-
thy in 1 patient
Results #
Hemorrhagic stroke included intracranial hemorrhagic stroke in 5
patients and spinal hemorrhage in 1 patient
Demographic and clinical characteristics &
Including 1 patient with thrombocytopenia, leukopenia, and ane-
mia, 2 patients with anemia and mild thrombocytosis
Demographic and clinical characteristics are summarized §
Data available for 12 patients collected before anti-TNF therapy
in Table 1. Among the 13 patients, a male predominance Abbreviations: ESR: erythrocyte sedimentation rate, hsCRP: high
was observed (69.2%, 9/13) with females comprising sensitivity C-reactive protein, TNF: tumor necrosis factor
30.8% (4/13) of the cohort. The median age at disease
onset was 16 (0.5–26) years, and the median diagnostic 17 years (range 7–26), underscoring the early neurovascu-
delay spanned 11 (0–18) years, resulting in a median age lar involvement.
at confirmed diagnosis of 23 years (range 16–38). Notably, Ischemic stroke predominated, affecting 11 (84.6%)
neurological manifestations emerged at a median age of patients with recurrent episodes in 9 (69.2%). A total of

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41 symptomatic ischemic strokes were documented in our Predominance of Ischemic lesions over sparse CMBs and
cohort, with a median of 3 attacks per patient (range 0–9). WMH
Hemorrhagic strokes were observed in 6 (46.2%) patients,
involving cerebral regions in 5 cases (38.5%) and spinal Ischemic lesions constituted the predominant neuroim-
cord in 1 case (7.7%). Moreover, all hemorrhagic events aging finding observed in all patients, with a total of 138
coexisted with ischemic strokes. Additional manifesta- lesions identified, predominantly manifesting as lacunes
tions included spastic paraplegia (n = 2, 15.4%), hearing or acute lacunar infarcts. Lacunes were defined according
loss (n = 4, 30.8%), and headache (n = 2, 15.4%). to STRIVE-2 standards [20], presenting as hyperintensity
on T2WI, hypointensity on T1WI, and hypointensity on
Neuroimaging findings FLAIR imaging with a hyperintense rim.
CMBs were exceptionally uncommon, with only a sin-
The neuroimaging characteristics of the cohort are summa- gle CMB observed in one patient (7.7%) across the entire
rized in Table 2. cohort. Minimal burdens of dWMH and pWMH were
observed in our cohort, with all cases exhibiting Fazekas
grade 1 except one patient with Fazekas grade 2 (Fig. 1).
The prevalence of dWMH was 30.8% (n = 4), while pWMH
Table 2 Summary statistics of neuroimaging findings in DADA2 was observed in 69.2% (n = 9) of the cases. Longitudinal
patients
neuroimaging assessments demonstrated no significant pro-
Characteristics All patients
(N = 13) gression of CMBs or WMH burden over a median follow-
Ischemic lesions 13 (100%) up period of 51 months (range 0.5–193).
Hemorrhagic lesions* 6 (46.2%)
Both ischemic and hemorrhagic lesions 6 (46.2%) Distributions and characteristics of the ischemic lesions
Ischemic lesion locations
Brain stem 11 (84.6%) The cohort exhibited a substantial ischemic burden, with
Midbrain 5 (38.5%) 138 lesions identified across 13 patients. Lesion distribu-
Pons 10 (76.9%) tion followed distinct anatomical patterns: predominantly
Medulla 7 (53.8%) localized to the pons (38 lesions, 10 patients), followed by
Thalamus 10 (76.9%) the thalamus (21 lesions, 10 patients), internal capsule (20
Basal ganglia 7 (53.8%)
lesions, 9 patients), basal ganglia (18 lesions, 7 patients),
Internal capsule 9 (69.2%)
and other regions (Fig. 2). Most patients (12/13, 92.3%) pre-
Callosum 3 (23.1%)
sented multiple ischemic lesions.
Periventricular regions 6 (46.2%)
Subcortical white matter 3 (23.1%) Of all the 138 ischemic lesions, 50 (36.2%) were acute
Hemorrhagic lesion locations lacunar infarcts or lacunes on 3.0 T MRI. The remaining
Temporal lobe 2 (15.4%) 88 (63.8%) lesions appeared hyperintense on T2WI and
Frontal lobe 1 (7.7%) hypointense on T1WI, with or without hyperintense in
Basal ganglia 3 (23.1%) FLAIR imaging on 3.0 T MRI. Notably, all the lesions were
Spine 1 (7.7%) definitively characterized as lacunes on 5.0 T MRI, which
CSVD imaging biomarkers provided superior resolution for detecting small lesions
CMBs 1 (7.7%) compared to 3.0 T MRI (Fig. S1 in the supplementary
PWMH 9 (69.2%) material).
DWMH 4 (30.8%)
The total number of lesions exceeded the number of clin-
Atrophy 9 (69.2%)
ical events. Only 45 lesions (32.6%) correlated temporally
Asymmetric atrophy 4/9 (44.4%)
with acute symptomatic strokes, while 93 (67.4%) were
Symmetric atrophy 5/9 (55.6%)
Follow up
asymptomatic.
Increased numbers or range of lesions 11/12 (91.7%)
Regression or vanished 3/12 (25.0%) Ischemic Lesion Chronoarchitecture
Unchanged 1/12 (8.3%)
*
Hemorrhagic lesions included intracranial hemorrhagic lesions in 5 Twelve patients were followed up for a median of
patients and spinal hemorrhage in 1 patient 51 months (range 0.5–193). Longitudinal MRI analysis of
The denominator indicates the available case numbers these patients demonstrated progressive ischemic burden in
Abbreviations: CMBs: cerebral microbleeds, DWMH: deep white 91.7% (11/12), while 8.3% (1/12) remained radiologically
matter hyperintensities, PWMH: periventricular white matter hyper- stable. All 12 patients received anti-TNF therapy following
intensities

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Fig. 1 The CSVD imaging markers in DADA2 on 5.0 T MRI. a-c: The CMB: cerebral microbleed, CSVD: cerebral small vessel disease,
sagittal T1WI (a), T2WI (b), and FLAIR (c) show multiple lacunes DADA2: Deficiency of adenosine deaminase 2, dWMH: deep white
(arrow) on the brainstem, and atrophy of the brainstem and cerebellum. matter hyperintensities, FLAIR: fluid-attenuated inversion recovery
d: The axial FLAIR shows dWMH (red arrow) and pWMH (yellow imaging, MRI: magnetic resonance imaging, pWMH: periventricular
arrow). e: The SWI shows a CMB (arrow). All the imaging were from white matter hyperintensities, T1WI: T1-weighted imaging, T2WI:
a 22-year-old male, 1 month after anti-TNF therapy. Abbreviations: T2-weighted imaging, SWI: sensitivity weighted images.

the diagnosis of DADA2, with all patients achieving neu- detected in 5 of the 9 patients (55.6%) and was exacer-
rological symptom stabilization after treatment. Of the 12 bated by the accumulation of ischemic lesions. Asymmet-
patients, post-treatment neuroimaging evaluations were ric atrophy was observed in 44.4% (n = 4 of 9) patients,
available for 6 patients, revealing complete lesion stabili- potentially attributable to Wallerian degeneration and
zation. Acute infarcts evolved into chronic lacunar cavities aggravated after cerebrovascular events (Fig. S3 in the
in all cases, though partial regression was observed in 3 supplementary material).
patients. Moreover, one lacunar infarct lesion resolved com-
pletely on both 3.0 T and 5.0 T MRI in 1 patient (Fig. S2 in Hemorrhagic lesions and angiographic results.
the supplementary material).
Compared with ischemic lesions, symptomatic hemorrhagic
Infratentorial rather than supratentorial volume Loss lesions (including hematoma and apoplectic cyst, excluding
CMBs) were relatively uncommon, affecting 46.2% (6/13)
Infratentorial atrophy involving the brain stem, cerebel- of the cohort. The hemorrhagic lesions were distributed in
lum, and cerebral peduncle, was prevalent in 69.2% (9/13) the cerebral lobes (3 lesions, 3 patients), deep (3 lesions,
patients, invariably coexisting with strategic ischemic/ 2 patients), and spinal cord (1 lesion, 1 patient). Patients
hemorrhagic lesions in the brainstem or basal ganglia, with hemorrhagic lesions demonstrated higher frequencies
independent of WMH burden. Symmetrical atrophy was of fever (83.3% vs. 57.1%) and hematological involvement

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Fig. 2 The distribution of ischemic lesions in DADA2. In the cohort of 13 patients, a total of 138 infarcts were observed. The lesions were primar-
ily located in the brainstem and thalamus. Abbreviations: DADA2: Deficiency of adenosine deaminase 2.

(50.0% vs. 0%) compared to those without hemorrhagic Discussion

lesions (Table S2 in the supplementary material). Of the 6
patients who presented hemorrhagic lesions, 1 patient was The present study, representing the largest and the most com-
taking warfarin, while 2 patients were taking aspirin prior prehensive neuroimaging investigation of DADA2 patients,
to the hemorrhage. The agents were prescribed for second- systematically delineated the CSVD imaging markers and
ary prevention following recurrent ischemic stroke. The temporal evolution of lesions. Our findings reveal a distinct
remaining 3 patients had no documented usage of antiplate- neuroimaging triad: 1) brainstem-deep gray matter ischemic
let or anticoagulation agents. predominance, 2) infratentorial atrophy, and 3) paradoxi-
Cerebral angiographic data were available in 10 patients. cally low burdens of CMBs and WMH compared to other
Multiple intracranial microaneurysms were detected in 1 CSVDs. This signature may suggest a different pathophysi-
patient (10.0%), cavernous hemangioma was observed in 1 ological mechanism of DADA2 from other CSVD, and fur-
patient (10%), and segmental stenosis of intracranial arter- ther redefine DADA2 as a distinct cerebrovascular entity.
ies was found in 1 patient (10.0%). HR-MRI of the vessel Of note, ischemic lesions were predominant, whereas
wall was available for 2 patients with normal presentations. CMBs and WMH were generally mild burden with mini-
The angiographic abnormalities were unrelated to their clin- mal progression in our DADA2 cohort. Previous stud-
ical events. ies reported a frequency of ischemic lesions ranging from

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Neurological Sciences (2026) 47:18 Page 7 of 10 18

58.3% to75% in all DADA2 patients [18, 19, 21]. In our While previous studies reported widely variable atro-
cohort with neurologic involvement, ischemic lesion was phy prevalence (3%−58.5%) in predominantly pediatric
presented in all patients. Most patients showed multiple cohorts [15, 18, 19, 21], the present adult-focused cohort
ischemic lesions compatible with recurrent clinical events. revealed a significantly higher rate of 69.2%, character-
The ischemic lesions (symptomatic or clinically silent) ized by two distinct morphological patterns. Moreover, the
demonstrated selective localization in strategic neurovas- results indicated that atrophy manifested as symmetric or
cular territories, primarily affecting the brainstem (43.5%), asymmetric patterns, predominantly involving the brain
thalamus (15.2%), internal capsule (14.5%), and basal stem, cerebellum, and cerebral peduncle. Accumulation
ganglia (13.0%). Consistent with previous research [18, of ischemic lesions and/or sub-radiological microinfarcts
19, 21], lesions were typically small, implicating a pri- in the brain stem may underlie symmetrical infratentorial
mary involvement of small deep perforating vessels [19]. atrophy [20, 28]. Furthermore, we noticed that Wallerian
Remarkably, while 32.6% of radiologically evident lesions degeneration could contribute to asymmetric atrophy of
corresponded to symptomatic stroke events, a substan- the brainstem, which may progress secondary to cerebro-
tial proportion (67.4%) remained asymptomatic, possibly vascular events.
reflecting subclinical microinfarcts in distal territories. The The above-mentioned DADA2 neuroimaging triad of
high prevalence of asymptomatic ischemic lesions suggests predominant ischemic lesions, paradoxically low WMH
that cerebrovascular injury in DADA2 is likely underrec- and CMB burden, and selective infratentorial atrophy con-
ognized and may also occur in patients without reported trasts sharply with other CSVD [20, 29–31], reinforcing
neurological events. These findings support the implemen- its distinct pathogenesis. First, WMH constitutes the earli-
tation of routine neuroimaging evaluation in all DADA2 est and most prevalent neuroimaging hallmark of cerebral
patients to enable early detection of silent cerebrovascular autosomal dominant arteriopathy with subcortical infarcts
involvement and prompt initiation of anti-TNF therapy. and leukoencephalopathy (CADASIL), cerebral autosomal
Chronic inflammation, blood-brain barrier (BBB) disrup- recessive arteriopathy with subcortical infarcts and leuko-
tion, and ischemia-hypoperfusion drive WMH progression encephalopathy (CARASIL), and HTRA1-related auto-
[22–24], while inflammation and BBB damage correlate somal dominant CSVD, which could even be detected in
with CMB burden [25, 26]. The static nature of these two advanced-stage CADASIL cases devoid of lacunar infarcts
CSVD markers in our cohort challenges their centrality in [30–32]. Although pontine infarcts and rare CMBs are com-
DADA2-related vasculopathy. This dissociation implies a mon to both pontine autosomal dominant microangiopathy
unique pathophysiology in which ischemic lesions arise and leukoencephalopathy (PADMAL) and DADA2, PAD-
primarily from transient TNF-α-mediated acute throm- MAL exhibits significantly more severe WMH [33]. The
boinflammatory cascades rather than chronic endothelial or minimal progression of WMH in DADA2 aligns with the
BBB dysfunction, which is further corroborated by lesion proposed dual-component inflammatory model, in which
stabilization post anti-TNF therapy observed both in the transient TNF-α-driven endothelial inflammatory hits arise
present cohort and previous reports [9–11]. Deuitch et al. on a chronically vulnerable endothelium but do not typi-
[27] demonstrated perivascular TNF deposition in the skin cally induce sustained BBB dysfunction or chronic hypo-
of DADA2 patients with a variety of clinical symptoms and perfusion, thus constraining the development of WMH.
severity, indicating a persistent, low-grade proinflammatory Second, unlike hypertensive CSVD (deep CMB clusters) or
milieu even in the absence of overt systemic inflammation. CAA (lobar CMB predominance) [20, 29], DADA2 exhib-
Taken together, these findings support a dual-component its rare CMBs without locational predilection, further sug-
inflammatory mechanism in DADA2 vasculopathy: a sus- gesting microvascular fragility during inflammatory bursts
tained background of low-degree inflammation and endo- rather than chronic lipohyalinosis or Aβ deposition related
thelial dysfunction that establishes vascular susceptibility, microvascular injury. Third, although both subcortical and
upon which episodic inflammatory exacerbations trigger cortical atrophy may result from CSVD [20, 34], our find-
acute endothelial injury and focal vascular occlusion. This ings reveal that adult DADA2 patients exhibit a unique
framework reconciles the frequent occurrence of subclinical spatial atrophy pattern localized to infratentorial structures,
infarcts during clinically quiescent phases with the relative implicating region-specific microvascular vulnerability to
scarcity of WMH and CMB on neuroimaging. Specifically, inflammatory injury. Altogether, this episodic mechanism
chronic endothelial activation may predispose to subclinical diverges from relentless endothelial decay in arterioloscle-
microinfarcts, while more intense, transient inflammatory rotic or other genetic CSVD, explaining both the scarcity of
cascades account for clinically overt strokes. chronic WMH/CMBs and the predominance of acute isch-
Cerebral atrophy, particularly infratentorial volume loss, emic lesions. Moreover, the dissociation between marked
represents a cardinal neuroimaging feature of DADA2. atrophy and minimal chronic CSVD markers further

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underscores acute inflammatory vasculopathy as the disease burden, conventional angiography frequently appears nor-
driver. mal [1, 38], implying predominant small vessel pathology
Therapeutic insights further validate this model. Patho- undetectable by current angiographic resolution. Due to
physiology evidence indicated that while perivascular TNF the predominant feature of DADA2 involving small- and
was present in DADA2, anti-TNF treatment reduced inflam- medium-sized arteries [16, 17], angiographic abnormalities
mation and rescued endothelial cell damage [27]. Anti-TNF were uncommon in our cases as in previous research [18].
therapy achieved 100% clinical/radiological stabilization Although multiple intracranial microaneurysms and local-
by suppressing thromboinflammatory cascades [9–11], yet ized stenosis of arteries were observed, the angiographic
failed to reverse established atrophy—a dissociation high- abnormalities were unresponsible for their clinical events.
lighting TNF-α's role in acute vasculopathy but not chronic Geraldo et al. [19] reported eccentric vessel wall thickening
neurodegeneration. This dual effect mirrors the "two-hit" and enhancement in all their cases, especially at the origin
mechanism of the disease: acute hits (TNF-α-driven throm- of brain stem perforators. However, this phenomenon was
bosis) vs. cumulative hits (irreversible tissue loss from not observed in our research.
microinfarction). Our study still has some limitations that are inherent
Longitudinal assessments yielded two pivotal insights. to research on ultra-rare disorders. Despite our efforts to
First, partial acute infarcts exhibited volumetric regres- ensure the representativeness of the sample, the sample
sion or even complete resolution during follow-up. Poten- size remains relatively small due to the rarity of the dis-
tial explanations include underestimation of small lesions ease, which may potentially introduce some bias into the
on conventional MRI, gliotic “healing” [19], or penum- results. However, to the best of our knowledge, our present
bral reversibility post-recanalization [35, 36]. Second, study is currently the largest cohort describing the neuroim-
chronic ischemic lesions appearing hyperintense on T2WI aging features in DADA2 patients. Moreover, the present
and hypointense on T1WI with or without hyperintense on research was retrospective in design. Although participants
FLAIR on 3.0 T MRI, were confirmed as lacunes on 5.0 T were enrolled from a prospective cohort, the analysis itself
MRI. This underscores the underestimation of lesion burden remains subject to the constraints of retrospective review,
by conventional imaging and highlights the critical impor- including possible selection bias. Future prospective stud-
tance of advanced imaging modalities in precisely mapping ies with larger sample sizes are needed to validate our find-
DADA2-related cerebrovascular pathology. ings. In addition, the atrophy was evaluated visually by
Additionally, hemorrhagic lesions were uncommon in experienced neurologists as in previous studies, which may
DADA2 with normal angiographic results. Hemorrhagic bring subjective biases. However, all the neuroimaging data
lesions were less frequent than ischemic lesions, with intra- were evaluated by two experienced neurologists with good
cranial hemorrhagic stroke reported in about 4%−33% of interobserver agreement, thereby ensuring the reliability of
DADA2 patients with varied clinical spectrum in previous the results. Future work incorporating quantitative volu-
research [10, 18, 19, 37]. In our cohort of DADA2 patients metric analyses will provide more objective data on brain
with neurological involvement, macroscopic symptomatic volume change. Finally, it should be noted that direct patho-
hemorrhagic lesions were observed in 46.2%, of which logical evidence was not available in this study. The pro-
intracranial hemorrhagic lesions account for 38.5%. This posed pathophysiology is therefore inferred indirectly from
higher prevalence likely reflects the selected nature of our clinical and radiological observations and should be inter-
cohort, which was enriched for patients with symptomatic preted with caution. Future prospective research with larger,
neurological involvement. Reports regarding the location of multi-center cohorts and correlative pathophysiological
hemorrhagic lesions remain controversial. Bulut et al. [18] data will be essential to validate these mechanistic insights
reported hemorrhagic stroke primarily localized to the basal presented here.
ganglia. However, a review from Dzhus et al. [21] showed
that lobar hemorrhagic strokes occurred in approximately
7.1% of patients, more frequent than in deep, occurring in Conclusion
2.4% of patients. In our patients, the prevalence of lobar
macroscopic hemorrhage lesions was equal to hemorrhage In summary, the present study demonstrated a profoundly
in deep. Moreover, spinal hemorrhage was also observed. elevated risk of stroke recurrence in DADA2, with approxi-
Patients with hemorrhagic lesions demonstrated increased mately two-thirds of ischemic lesions being clinically silent.
susceptibility to fever and hematological involvements in Critically, the initiation of anti-TNF therapy resulted in com-
our cohort. Nevertheless, the underlying causes of intracra- plete stroke cessation, underscoring its importance in disease
nial hemorrhagic stroke were still unclear in most reports, management. The present study further delineates a distinctive
as in our patients [10, 18, 19, 37]. Despite the ischemic neuroimaging phenotype in DADA2, characterized by three

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Neurological Sciences (2026) 47:18 Page 9 of 10 18

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core features: (1) strategic ischemic vulnerability clustered use is not permitted by statutory regulation or exceeds the permitted
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rial atrophy likely resulting from cumulative ischemic injury, r​g​​/​l​i​c​e​n​s​e​s​/​b​y​/​4​.​0​/.
subclinical/subradiological microvascular thromboinflamma-
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Committee of the Peking Union Medical College Hospital (JS-1280 Rheumatol Int 38(1):129–136. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​0​0​7​​/​s​0​​0​2​9​6​-​0​1​
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Rheum Dis 76(10):1648–1656. ​h​t​t​p​​s​:​/​​/​d​o​i​​.​o​​r​g​/​​1​0​.​1​​1​3​6​​/​a​n​​n​r​h​​e​u​m​​
Competing interests The authors declare no competing interests. d​i​s​-​​2​0​​1​6​-​2​1​0​8​0​2
10. Barron KS, Aksentijevich I, Deuitch NT, Stone DL, Hoffmann P,
Videgar-Laird R, Soldatos A, Bergerson J, Toro C, Cudrici C et al
Open Access This article is licensed under a Creative Commons
(2021) The spectrum of the deficiency of adenosine deaminase 2:
Attribution 4.0 International License, which permits use, sharing,
an observational analysis of a 60 patient cohort. Front Immunol
adaptation, distribution and reproduction in any medium or format,
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as long as you give appropriate credit to the original author(s) and the
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source, provide a link to the Creative Commons licence, and indicate
A, Aksentijevich I, Kastner DL, Ombrello AK (2023) Tnf-block-
if changes were made. The images or other third party material in this
ade for primary stroke prevention in adenosine deaminase 2 defi-
article are included in the article’s Creative Commons licence, unless
ciency: a case series. Neurol Neuroimmunol Neuroinflamm. ​h​t​t​p​​
indicated otherwise in a credit line to the material. If material is not
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