ObjectiveTo test the hypothesis that patients with concomitant lobar and deep intracerebral hemorrhages/microbleeds (mixed ICH) have predominantly hypertensive small vessel disease (HTN-SVD) rather than cerebral amyloid angiopathy (CAA), using in vivo amyloid imaging.MethodsEighty Asian patients with primary ICH without dementia were included in this cross-sectional study. All patients underwent brain MRI and 11C-Pittsburgh compound B (PiB)-PET imaging. The mean cortical standardized uptake value ratio (SUVR) was calculated using cerebellum as reference. Forty-six patients (57.5%) had mixed ICH. Their demographic and clinical profile as well as amyloid deposition patterns were compared to those of 13 patients with CAA-ICH and 21 patients with strictly deep microbleeds and ICH (HTN-ICH).ResultsPatients with mixed ICH were younger (62.8 ± 11.7 vs 73.3 ± 11.9 years in CAA, p = 0.006) and showed a higher rate of hypertension than patients with CAA-ICH (p < 0.001). Patients with mixed ICH had lower PiB SUVR than patients with CAA (1.06 [1.01–1.13] vs 1.43 [1.06–1.58], p = 0.003). In a multivariable logistic regression model, mixed ICH was associated with hypertension (odds ratio 8.9, 95% confidence interval 1.4–58.4, p = 0.02) and lower PiB SUVR (odds ratio 0.03, 95% confidence interval 0.001–0.87, p = 0.04) compared to CAA after adjustment for age. Compared to HTN-ICH, mixed ICH showed a similar mean age (62.8 ± 11.7 vs 60.1 ± 14.5 years in HTN-ICH) and risk factor profile (all p > 0.1). Furthermore, PiB SUVR did not differ between mixed ICH (values presented above) and HTN-ICH (1.10 [1.00–1.16], p = 0.45).Conclusions:Patients with mixed ICH have much lower amyloid load than patients with CAA-ICH, while being similar to HTN-ICH. Overall, mixed ICH is probably caused by HTN-SVD, an important finding with clinical relevance.

Parkinson’s disease is a neurodegenerative disorder with a multifactorial aetiology. Nevertheless, the genetic predisposition in many families with multi-incidence disease remains unknown. This study aimed to identify novel genes that cause familial Parkinson’s disease. Whole exome sequencing was performed in three affected members of the index family with a late-onset autosomal-dominant parkinsonism and polyneuropathy. We identified a novel heterozygous substitution c.941A&gt;C (p.Tyr314Ser) in the mitochondrial ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) gene, which co-segregates with disease within the family. Additional analysis of 699 unrelated Parkinson’s disease probands with autosomal-dominant Parkinson’s disease and 1934 patients with sporadic Parkinson’s disease revealed another two variants in UQCRC1 in the probands with familial Parkinson’s disease, c. 931A&gt;C (p.Ile311Leu) and an allele with concomitant splicing mutation (c.70-1G&gt;A) and a frameshift insertion (c.73_74insG, p.Ala25Glyfs*27). All substitutions were absent in 1077 controls and the Taiwan Biobank exome database from healthy participants (n = 1517 exomes). We then assayed the pathogenicity of the identified rare variants using CRISPR/Cas9-based knock-in human dopaminergic SH-SY5Y cell lines, Drosophila and mouse models. Mutant UQCRC1 expression leads to neurite degeneration and mitochondrial respiratory chain dysfunction in SH-SY5Y cells. UQCRC1 p.Tyr314Ser knock-in Drosophila and mouse models exhibit age-dependent locomotor defects, dopaminergic neuronal loss, peripheral neuropathy, impaired respiratory chain complex III activity and aberrant mitochondrial ultrastructures in nigral neurons. Furthermore, intraperitoneal injection of levodopa could significantly improve the motor dysfunction in UQCRC1 p.Tyr314Ser mutant knock-in mice. Taken together, our in vitro and in vivo studies support the functional pathogenicity of rare UQCRC1 variants in familial parkinsonism. Our findings expand an additional link of mitochondrial complex III dysfunction in Parkinson’s disease.

Background and Purpose: We explored whether high-degree magnetic resonance imaging–visible perivascular spaces in centrum semiovale (CSO) are more prevalent in cerebral amyloid angiopathy (CAA) than hypertensive small vessel disease and their relationship to brain amyloid retention in patients with primary intracerebral hemorrhage (ICH). Methods: One hundred and eight spontaneous ICH patients who underwent magnetic resonance imaging and Pittsburgh compound B were enrolled. Topography and severity of enlarged perivascular spaces were compared between CAA-related ICH (CAA-ICH) and hypertensive small vessel disease–related ICH (non-CAA ICH). Clinical and image characteristics associated with high-degree perivascular spaces were evaluated in univariate and multivariable analyses. Univariate and multivariable models were performed to evaluate associations between the severity of perivascular spaces in CSO and amyloid retention in CAA-ICH and non–CAA-ICH cases. Results: Patients with CAA-ICH (n=29) and non–CAA-ICH (n=79) had similar prevalence of high-degree perivascular spaces in CSO (44.8% versus 36.7%; P =0.507) and in basal ganglia (34.5% versus 51.9%; P =0.131). High-degree perivascular spaces in CSO were independently associated with the presence of lobar microbleed (odds ratio, 3.0 [95% CI, 1.1–8.0]; P =0.032). The amyloid retention was higher in those with high-degree than those with low-degree CSO-perivascular spaces in CAA-ICH (global Pittsburgh compound B standardized uptake value ratio, 1.55 [1.33–1.61] versus 1.13 [1.01–1.48]; P =0.003) but not in non–CAA-ICH. In CAA-ICH, the association between cerebral amyloid retention and the degree of perivascular spaces in CSO remained significant after adjustment for age and lobar microbleed number ( P =0.004). Conclusions: Although high-degree magnetic resonance imaging–visible perivascular spaces are equally prevalent between CAA-ICH and non–CAA-ICH in the Asian cohort, the severity of magnetic resonance imaging–visible CSO-perivascular spaces may be an indicator of higher brain amyloid deposition in patients with CAA-ICH.

Background: Promotion of hematoma resolution in a timely manner reduces intracerebral hemorrhage (ICH) brain injury induced by toxic blood components and subsequent neuroinflammation. The meningeal lymphatic system is responsible for clearance of macromolecules and pathogenic substances from the central nervous system; however, its role in intraparenchymal hematoma clearance and ICH outcomes is unknown. In the present study, we aimed to understand the contribution of the meningeal lymphatic system to ICH pathologies and to test whether pharmacological enhancement of meningeal lymphatic function promotes hematoma resolution and brain recovery after ICH. Methods: Immunofluorescence of whole-mount meninges was used to measure complexity and coverage level of meningeal lymphatic vasculature following ICH induction. Fluorescent microbeads and PKH-26-labeled erythrocytes were used to evaluate drainage function of the meningeal lymphatic system. Visudyne treatment, deep cervical lymph node ligation, and VEGF (vascular endothelial growth factor)-C injection were performed to manipulate meningeal lymphatic function. Neurobehavioral performance and hematoma volume were assayed by the cylinder test and histological measurements. Iron deposition, residual erythrocytes, neuronal loss, and astrogliosis were assessed by immunohistochemistry and antibody-based fluorescence staining. Results: Meningeal lymphangiogenesis and enhanced lymphatic drainage occurred during the late phase of ICH. Ablation and blockage of meningeal lymphatic vessels impeded hematoma clearance, whereas pharmacological enhancement of their function reduced hematoma volume, improved behavioral performance, and reduced brain residual erythrocytes, iron deposition, neuronal loss, and astroglial activation. Conclusions: Early enhancement of meningeal lymphatic function is beneficial for ICH recovery. Targeting the meningeal lymphatic system is therefore a potential therapeutic approach for treating ICH.