Stroke-related translational research

Abstract

Stroke-related translational research is multifaceted. Herein, we highlight genome-wide association studies and genetic studies of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, COL4A1 mutations, and cerebral cavernous malformations; advances in molecular biology and biomarkers; newer brain imaging research; and recovery from stroke emphasizing cell-based and other rehabilitative modalities.

Figure 1

Schematic drawing of the NOTCH3 receptor and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) mutations. A, The mature NOTCH3 receptor contains all canonical Notch motifs, including 34 epidermal growth factor-like repeats (EGFRs), 3 Lin12-Notch repeats (LNRs), a single pass transmembrane (TM) domain, and 7 Ankyrin repeats (ANKRs). NOTCH3 is cleaved between the LNRs and the TM domain and is expressed at the cell surface as an heterodimer. B, Schematic drawing of a normal EGFR with its 6 cysteine (Cys) residues (red circles) and a mutated EGFR with its odd number of cysteine residues in patients with CADASIL.

Figure 2

Generation of the P1-derived artificial chromosome (PAC)–R169C Notch3 transgenic mice. The schematic drawing shows the PAC clone that was used to generate the transgenic mice. The rat PAC clone contains the entire rat genomic Notch3 gene plus about 60 kilobase (kb) of 5′ flanking and 45 kb of 3′ flanking regulatory sequences. The cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy amino acid substitution R169C was introduced into this clone by homologous recombination.

Figure 3

Phenotype of the P1-derived artificial chromosome–R169C Notch3 transgenic mice. The neuropathological features in the mutant mice are shown. The brain artery (A [scale bar, 50μM]) and brain capillary (B [scale bar, 20μM]) were immunostained with the 5E1 antibody specific to the Notch3 extracellular domain showing the characteristic granular immunostaining indicative of microscopic aggregates of the Notch3 extracellular domain. An electron micrograph of a pial artery (C [scale bar, 1μM]) demonstrates abundant granular osmiophilic deposits (red arrowheads). Glial fibrillary acidic protein staining in the internal capsula of a 12-month-old mutant mouse (D [scale bar, 70μM]) shows astrogliosis in the white matter bundles. Hematoxylin-eosin staining in the corpus callosum (E [scale bar, 70μM]) and Klüver-Barrera Luxol fast blue staining in the internal capsula (F [scale bar, 70μM]) of a 20-month-old mutant mouse reveal vacuolization in white matter bundles as well as pallor and disorganization of the myelin. EC indicates endothelial cell; SMC, smooth muscle cell.

Figure 4

Brain magnetic resonance imaging scans of 2 COL4A1-mutated patients. Fluid-attenuated inversion recovery images (A) show diffuse and confluent white matter changes in both caudate nuclei in a 39-year-old patient. T2-gradient-echo images (B) show microbleeds and hemorrhages in both caudate nuclei in the same 39-year-old patient. C, Magnetic resonance angiography in a 47-year-old patient shows an 8-mm aneurysm on the left distal carotid artery (arrow). D, T2-gradient-echo image displays an acute hemorrhage in the left putamen in another 47-year-old patient.

Figure 5

Cartoon showing the potential brain targets of stem cells.

Figure 6

A, B, Brain scans of 2 patients. A, This patient had 37.5% of the corticospinal tract injured by stroke and had a gain of 11 points on the Fugl-Meyer (FM) scale across the period of therapy. B, This patient had 93.4% of the corticospinal tract injured by stroke and had a gain of 1 point on the FM scale across the period of therapy. C, Injury to the corticospinal tract correlates (r=−0.65, P<.002) with the change in score on the arm motor FM scale induced by robotic therapy among patients with hemiparesis in the chronic phase of stroke. Patients with milder corticospinal tract injury had greater gains from treatment. Reproduced with permission from Riley et al.