Silvia Lanfranconi

Stem cell therapy in stroke

Abstract.Recent work has focused on cell transplantation as a therapeutic option following ischemic stroke, based on animal studies showing that cells transplanted to the brain not only survive, but also lead to functional improvement. Neural degeneration after ischemia is not selective but involves different neuronal populations, as well as glial and endothelial cell types. In models of stroke, the principal mechanism by which any improvement has been observed, has been attributed to the release of trophic factors, possibly promoting endogenous repair mechanisms, reducing cell death and stimulating neurogenesis and angiogenesis. Initial human studies indicate that stem cell therapy may be technically feasible in stroke patients, however, issues still need to be addressed for use in human subjects.

COL4A1 Mutations as a Monogenic Cause of Cerebral Small Vessel Disease A Systematic Review

Background and Purpose— A number of single gene disorders can cause cerebral small vessel disease. Mutations in the COL4A1 gene encoding the type IV collagen alpha 1 chain, which are already associated with porencephaly and infantile hemiparesis, have been recently recognized as a further monogenic cause of small vessel disease that can present in adulthood. Methods— We performed a systematic review of published data from 1966 to January 8, 2010 to characterize the features of small vessel disease seen with COL4A1 mutations. Results— We identified a total of 52 mutation carriers. A history of stroke was reported in 9 subjects (17.3%); in 6 cases it was attributable to subcortical hemorrhage and in 3 cases it was attributable to lacunar infarction. Stroke often occurred as first presentation of the disease, with a mean age of onset of 36.1 (SD, 12.95; range, 14-49). Hemorrhages, often recurrent, have been associated with physical trauma and activity and anticoagulant therapy. Brain imaging showed frequent leukoaraiosis (63.5%), microbleeds that are usually subcortical (52.9%), lacunar infarction (13.5%), and dilated perivascular spaces (19.2%). Extensive leukoaraiosis was seen in a number of asymptomatic adult mutation carriers. Asymptomatic intracranial aneurysms were common (44.4% of 18 with angiography). Migraine (with and without aura) was reported in 10 subjects, with a mean age at onset of 31.7. Systemic features are also frequent, affecting the eye (10/21, 47.6%), kidney (15.4%), and muscle (15.4%). Conclusions— COL4A1 is a further cause of familial vasculopathy and may present with stroke, ischemic as well as hemorrhagic, in adult life and with radiological features of leukoaraiosis and microbleeds.

Antiplatelets vs anticoagulation for dissection: CADISS nonrandomized arm and meta-analysis

Objective: To present the results of the nonrandomized arm of the Cervical Artery Dissection in Stroke Study (CADISS-NR) trial, comparing anticoagulation and antiplatelets for prevention of recurrent stroke after carotid and vertebral dissection, and perform a meta-analysis of these results with previously published studies comparing the 2 therapeutic strategies. Methods: A total of 88 patients from 22 centers with extracranial carotid and vertebral dissection were recruited within 1 month of symptom onset. The primary endpoint was recurrent stroke at 3 months. A systematic review was performed, and results of published studies included in a meta-analysis with the CADISS-NR results. Results: In CADISS-NR, one patient in each group had recurrent ischemic stroke (antiplatelet 1/59 [1.69% ], anticoagulation 1/28 [3.57%]). At the primary endpoint of 3 months, 3 (5.08%) antiplatelet patients had recurrent TIA, compared with none in the anticoagulation group. For meta-analysis, there were data from 40 nonrandomized studies including 1,636 patients. There was no significant difference between the 2 treatments in recurrent stroke risk (antiplatelet 13/499 [2.6%], anticoagulant 20/1,137 [1.8%], odds ratio [OR] 1.49) or risk of death (antiplatelet 5/499 [1.00%], anticoagulant 9/1,137 [0.80%], OR 1.27). Conclusion: There is no evidence for superiority of anticoagulation or antiplatelet therapy in prevention of stoke after carotid and vertebral artery dissection; however, all data are from nonrandomized studies and randomized studies are required. The nonrandomized CADISS data show a lower rate of recurrent stroke than reported in some previous studies. Clinical Trial Registration Information: www.dissection.co.uk, ISRNCTN44555237. Neurology® 2012;79:686–689

Brain Atrophy and Cerebral Small Vessel Disease A Prospective Follow-Up Study

Background and Purpose— Cerebral small vessel disease (SVD) is the most common cause of vascular dementia. Interest in the use of surrogate markers is increasing. The aims of this study were to determine if brain volume was different between patients with SVD and control subjects, whether it correlated with cognition in SVD, and whether changes in brain volume could be detected during prospective follow-up. Methods— Thirty-five patients (mean age, 68.8 years) who had a lacunar stroke and radiological evidence of confluent leukoaraiosis and 70 age- and gender-matched control subjects were recruited. Whole-brain T1-weighted imaging and neuropsychological testing were performed after 1 year on all patients and after 2 years for the control subjects. Fully automated software was used to determine brain volume and percentage brain volume change. An executive function score was derived. Results— There was a significant difference in brain volume between the patients with SVD and control subjects (mean±SD [mL] 1529±84 versus 1573±69, P=0.019). In the patients with SVD, there was a significant association between brain volume and executive function (r=0.501, P<0.05). The mean±SD yearly brain atrophy rate for patients with SVD and control subjects was significantly different (−0.914%±0.8% versus −0.498%±0.4%, respectively, P=0.017). No change in executive function score was detected over this period. Conclusions— Brain volume is reduced in SVD and a decline is detectable prospectively. The correlation with executive function at a cross-sectional level and the change in brain volume with time are both promising for the use of brain atrophy as a surrogate marker of SVD progression.

Inclusion body myopathy and frontotemporal dementia caused by a novel VCP mutation

Hereditary inclusion body myopathy (IBM) with Pagets disease of the bone (PDB) and frontotemporal dementia (FTD) is a rare autosomal dominant disease caused by mutations in the valosin-containing protein (VCP) gene. We report a novel heterozygous VCP gene mutation (R159C) in a 69-year-old Italian patient presenting with slowly progressive muscle weakness of the distal upper and proximal lower limbs since the age of 50 years, 18 years later FTD supervened. No dementia or myopathies were revealed in the family history covering two generations. Degenerative changes and rimmed vacuoles together with VCP- and ubiquitin-positive cytoplasmic and nuclear aggregates were observed at the muscle biopsy. Several elements support the pathogenic role of the R159C VCP gene mutation: the occurrence at the same codon of a different, previously identified pathogenic mutation within a VCP gene mutational hot-spot, the histopathological and biochemical evidence of muscle VCP accumulation and the combined clinical presentation of IBM and FTD. These findings suggest VCP gene investigation even in apparently sporadic cases.

Growth factors in ischemic stroke

•  Background •  Search strategies •  Haematopoietic growth factors •  Granulocyte colony‐stimulating factor ‐  G‐CSF and experimental stroke ‐  G‐CSF and human stroke ‐  Ongoing studies ‐  Current evidence and future perspectives •  Erythropoietin ‐  EPO and experimental stroke ‐  EPO and human stroke ‐  Ongoing studies ‐  Current evidence and future perspectives •  Granulocyte‐macrophage colony‐stimulating factor ‐  GM‐CSF and experimental stroke ‐  GM‐CSF and human stroke ‐  Current evidence and future perspectives •  Vascular endothelial growth factor ‐  VEGF and experimental stroke ‐  VEGF and human stroke ‐  Ongoing studies ‐  Current evidence and future perspectives •  Stromal cell‐derived factor‐1 ‐  SDF‐1 in experimental stroke ‐  Current evidence and future perspectives •  Stem cell factor ‐  Current evidence and future perspectives •  Other growth factors: neurotrophins ‐  Brain–derived neurotrophic factor ‐  Current evidence and future perspectives ‐  Basic fibroblast growth factor ‐  Current evidence and future perspectives ‐  Insulin‐like growth factor 1 ‐  Current evidence and future perspectives ‐  Glial cell line‐derived neurotrophic factor ‐  Current evidence and future perspectives ‐  Heparin‐binding EGF‐like growth factor ‐  Current evidence and future perspectives •  Discussion

17q25 Locus Is Associated With White Matter Hyperintensity Volume in Ischemic Stroke, But Not With Lacunar Stroke Status

Background and Purpose— Recently, a novel locus at 17q25 was associated with white matter hyperintensities (WMH) on MRI in stroke-free individuals. We aimed to replicate the association with WMH volume (WMHV) in patients with ischemic stroke. If the association acts by promoting a small vessel arteriopathy, it might be expected to also associate with lacunar stroke. Methods— We quantified WMH on MRI in the stroke-free hemisphere of 2588 ischemic stroke cases. Association between WMHV and 6 single-nucleotide polymorphisms at chromosome 17q25 was assessed by linear regression. These single-nucleotide polymorphisms were also investigated for association with lacunar stroke in 1854 cases and 51 939 stroke-free controls from METASTROKE. Meta-analyses with previous reports and a genetic risk score approach were applied to identify other novel WMHV risk variants and uncover shared genetic contributions to WMHV in community participants without stroke and ischemic stroke. Results— Single-nucleotide polymorphisms at 17q25 were associated with WMHV in ischemic stroke, the most significant being rs9894383 (P=0.0006). In contrast, there was no association between any single-nucleotide polymorphism and lacunar stroke. A genetic risk score analysis revealed further genetic components to WMHV shared between community participants without stroke and ischemic stroke. Conclusions— This study provides support for an association between the 17q25 locus and WMH. In contrast, it is not associated with lacunar stroke, suggesting that the association does not act by promoting small-vessel arteriopathy or the same arteriopathy responsible for lacunar infarction.

Genome-wide meta-analysis of cerebral white matter hyperintensities in patients with stroke

Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10−6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p = 2.2 × 10−8; rs941898 [EVL], p = 4.0 × 10−8; rs962888 [C1QL1], p = 1.1 × 10−8; rs9515201 [COL4A2], p = 6.9 × 10−9). Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Neurological features of Fabry disease: clinical, pathophysiological aspects and therapy

Fabry disease is a multisystem, X‐linked, lysosomal storage disorder caused by a mutation in the GLA gene on chromosome Xq22 resulting in alpha‐galactosidase A enzyme (α‐Gal A) deficiency. Neurological manifestations other than cerebrovascular accidents include small fibre neuropathy and dysautonomic disorders, which may be the presenting clinical features in a proportion of patients. An atypical disease onset may be misdiagnosed until the emergence of a more typical clinical picture, characterized by chronic renal and cardiac failure. Thus, neurologists should consider Fabry disease in differential diagnosis and provide an appropriate diagnostic work up. This review focuses on central and peripheral nervous system involving available diagnostic tools and diagnostic work up in Fabry disease. It also covers the most recent evidence regarding enzyme replacement therapy.

Genetic architecture of white matter hyperintensities differs in hypertensive and nonhypertensive ischemic stroke

Background and Purpose— Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. Methods— WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. Results— A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10−5); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). Conclusions— A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.