Parkinsonism in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Clinical Features and Biomarkers
Parkinsonism in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Clinical Features and Biomarkers
Abstract
Cerebral small vessel disease (SVD) manifests with various neurological symptoms including stroke, cognitive decline, and progressive gait difficulties. This comprehensive study evaluates motor features of parkinsonism in patients with CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), assesses prevalence, and identifies potential clinical and neuroimaging markers.
🔬 Key Findings
- High Prevalence: 73% of CADASIL patients exhibited parkinsonism features, with prevalence increasing with age
- White Matter Hyperintensity (WMH): WMH volume emerged as the primary independent factor associated with parkinsonism (OR 1.04, 95% CI 1.003-1.07)
- Cortical Thinning: Significantly correlated with motor symptom severity and advanced Hoehn-Yahr stages
- Distinct from Parkinson's Disease: CADASIL patients showed significantly lower plasma α-synuclein levels and different motor symptom patterns
- Vascular Pathophysiology: Evidence suggests primarily vascular rather than α-synucleinopathy mechanism
Study Statistics
Research Background
Cerebral small vessel disease encompasses a spectrum of neurological manifestations, with gait abnormalities commonly characterized by slowed and shuffling gait resembling vascular parkinsonism. Lesions associated with parkinsonism generally affect the striatal and related motor pathways, while SVD neuroimaging marker burden can predict the risk of parkinsonism.
CADASIL, a genetic form of SVD, commonly presents with parkinsonism. However, gait difficulties are common in advanced CADASIL, yet the prevalence and characteristics of parkinsonism remain underexplored. This study hypothesized that the pathophysiology of parkinsonism in CADASIL is primarily vascular, distinct from the α-synucleinopathy seen in idiopathic Parkinson's disease.
Study Design and Methods
Patient Population
Patients from the Taiwan CADASIL Registry and idiopathic Parkinson's disease patients from the same hospital were evaluated and compared. The study enrolled 75 CADASIL patients (median age 64 years, 52% male) and 158 PD patients for comparison.
Diagnostic Criteria
In CADASIL patients, parkinsonism was diagnosed based on gait impairment, bradykinesia, or rigidity, excluding stroke-related paresis. The severity was assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS-III), with items categorized into four domains:
- Tremor
- Rigidity
- Bradykinesia
- Postural instability
Neuroimaging Assessment
MRI features were analyzed both visually and quantitatively, including:
- White matter hyperintensity (WMH) volume measurement
- Cortical thickness quantification using FreeSurfer
- Lacunes and cerebral microbleeds assessment
- Basal ganglia perivascular spaces evaluation
Biomarker Analysis
Plasma α-synuclein levels were measured using immunomagnetic reduction method. Dopaminergic imaging was performed using 99mTc-TRODAT-1 SPECT in 32 patients.
Results
Clinical Characteristics
Among 75 CADASIL patients enrolled, 55 (73%) exhibited parkinsonism features. The median UPDRS-III score was 9 (IQR 3-23), median Hoehn-Yahr stage was 1 (1-2), and median gait speed was 0.83 m/s (0.57-1.09 m/s). The median age at parkinsonism onset was 66 years (IQR 62-70 years).
| Parameter | Without Parkinsonism (n=20) | With Parkinsonism (n=55) | P-value |
|---|---|---|---|
| Age (years) | 57 (53-62) | 67 (60-73) | <0.01 |
| Cortical thickness (mm) | 2.39 (2.36-2.46) | 2.35 (2.23-2.39) | 0.02 |
| WMH volume (mL) | 20.2 (7.9-40.1) | 47.3 (31.0-60.3) | <0.01 |
| Fazekas total score | 5 (3-6) | 6 (5-6) | <0.01 |
| Basal ganglia lacune (%) | 30.0% | 60.0% | 0.03 |
Neuroimaging Findings
CADASIL patients with parkinsonism demonstrated:
- Thinner cortices (median 2.35 vs. 2.39 mm, p=0.02)
- Larger white matter hyperintensity volumes (47.3 vs. 20.2 mL, p<0.01)
- Higher prevalence of basal ganglia lacunes (60% vs. 30%, p=0.03)
- Progressive increase in WMH volume with higher Hoehn-Yahr stages
Comparison with Idiopathic Parkinson's Disease
Compared to 158 PD patients, CADASIL patients with parkinsonism exhibited:
- Lower UPDRS-III scores (median 12 vs. 18, p=0.05)
- Significantly lower tremor (0 vs. 0, p<0.01) and rigidity scores (1 vs. 4, p<0.01)
- Similar postural instability (4 vs. 4, p=0.64)
- Much lower plasma α-synuclein levels (0.08 vs. 0.95 pg/mL, p<0.01)
- Thinner cortices and more severe SVD markers
Biomarker Associations
In multivariate analysis, only WMH volume remained statistically significant as an independent factor for parkinsonism (OR 1.04, 95% CI 1.003-1.07, p=0.03). Among patients with parkinsonism, cortical thinning was associated with higher UPDRS-III scores (adjusted β -5.48, 95% CI -9.98 to -0.99) and advanced Hoehn-Yahr stages (OR 0.30, 95% CI 0.07-1.00).
Discussion and Clinical Implications
Novel Findings
This study reveals a higher prevalence of parkinsonism in CADASIL (73%) than previously reported in Italian (11%) and Korean (33%) cohorts. These discrepancies may be attributed to the older age of the current cohort, differences in NOTCH3 variants, and more thorough motor examinations.
Pathophysiological Mechanisms
Motor symptoms in CADASIL, characterized primarily by postural instability and bradykinesia with less rigidity and tremor, resemble the "lower-body" type of vascular parkinsonism. The study suggests that:
- WMH volume contributes to parkinsonism development through damage to cortico-basal ganglia-thalamus interconnecting fibers
- Cortical thinning, representing secondary neurodegeneration, correlates with motor symptom severity
- The pathophysiology is primarily vascular rather than α-synucleinopathy-related
Clinical Significance
The significantly lower plasma α-synuclein levels in CADASIL patients, which did not correlate with motor symptoms, provide strong evidence that α-synucleinopathy is not the underlying pathology. This distinction is crucial for:
- Differential diagnosis between vascular parkinsonism and idiopathic Parkinson's disease
- Treatment strategy selection
- Prognosis prediction
- Understanding disease mechanisms
Recommendations for Clinicians
Clinicians should carefully review brain MRI scans in cases of vascular parkinsonism and be aware that genetic SVD can present with parkinsonism phenotype. Features suggestive of CADASIL include:
- Disproportionately severe white matter hyperintensities
- Multiple lacunes, especially in basal ganglia
- Numerous cerebral microbleeds
- Progressive cortical thinning
- Family history of stroke or dementia
Study Limitations
- Selection bias may exist as severe cases were excluded and minor cases might have been missed
- The study enrolled predominantly NOTCH3 p.R544C variant carriers; results may not generalize to other variants
- NOTCH3 testing was not performed in PD patients
- No comparison with non-genetic vascular parkinsonism patients
- Cross-sectional design limits causal inference
Conclusions
This comprehensive study demonstrates that parkinsonism is highly prevalent (73%) in symptomatic CADASIL patients. The burden of cerebral small vessel disease, particularly white matter hyperintensity volume and cortical thinning, contributes significantly to both the development and severity of parkinsonism. The distinct biomarker profile and motor symptom pattern distinguish CADASIL-associated parkinsonism from idiopathic Parkinson's disease, supporting a primarily vascular pathophysiology.
These findings have important implications for clinical diagnosis, prognostication, and potential therapeutic approaches in CADASIL patients with motor symptoms. Future longitudinal studies are needed to establish temporal relationships and identify potential interventions to prevent or slow parkinsonism progression in CADASIL.
How to Cite This Article
Chen CH, Wang TW, Cheng YW, Chu YT, Cheng MF, Chen YF, Lin CH, Tang SC. Parkinsonism in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy: Clinical Features and Biomarkers. J Stroke. 2025;27(1):122-127. doi: 10.5853/jos.2024.03944