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Epigenetics in Stroke: II. RNA Regulatory Circuitry
Qureshi and MehlerArticle examine the role of novel non–protein-coding RNA in the nervous system and highlight emerging evidence that implicates RNA-based networks in the molecular pathophysiology of stroke. They also describe RNA editing, a related epigenetic mechanism that is partly responsible for generating the exquisite degrees of environmental responsiveness and molecular diversity that characterize non–protein-coding RNA. In addition, they discuss the development of future therapeutic strategies for locus-specific and genome-wide regulation of genes and functional gene networks through the modulation of RNA transcription, posttranscriptional RNA processing (eg, RNA modifications, quality control, intracellular trafficking, local and long-distance intercellular transport), and RNA translation.
Plane and colleaguesArticle indicate that minocycline is a clinically available antibiotic and anti-inflammatory drug that also demonstrates neuroprotective properties in a variety of experimental models of neurological diseases. There have, thus far, been more than 300 publications on minocycline neuroprotection, including a growing number of human studies. Their purpose here is to critically review the biological basis and translational potential of this action of minocycline on the nervous system.
CD8+ T Cells in FTY720-Treated Patients With Multiple Sclerosis
Johnson et alArticle define the capacity of peripheral blood CD8+ T cells of patients with multiple sclerosis (MS) who receive fingolimod (FTY720) to migrate in response to chemokines that contribute to trafficking into the central nervous system. In vitro addition of active (phosphorylated) FTY720 (FTY720P) increased migration of CD8+ T cells from untreated donor patients to CXCL12 and CCL2. Therapy with FTY720 results in a subset of CD8+ T cells with distinct functional migratory properties that dominate the peripheral circulation. The expected forthcoming use of FTY720 as a sustained therapy in multiple sclerosis will clarify how this redistribution of lymphocyte populations affects the overall process of immune surveillance. Editorial perspective is provided by Michael K. Racke, MD. Article
In vitro treatment with phosphorylated FTY720 (FTY720P) enhances migration of CD8+ T cells to CXCL12 and CCL2 chemokines. The CD8+ T cells isolated from untreated donors were treated with vehicle or 1mM FTY720P before migration to CXCL12 (10 ng/mL; n = 8) (A) or CCL2 (0.25 mg/mL; n = 5) (B) chemokine. Results are reported as total number of cells migrated as quantified by flow cytometry. The spontaneous migration rate for each group reflects the vehicle-treated cells that migrated in the absence of chemokine. In vitro migration results represent mean (SEM) values. * P < .001. † P < .05.
Persistence With Stroke Prevention Medications
Bushnell and colleaguesArticle measure longitudinal use of stroke prevention medications following stroke hospital discharge. They hypothesized that a combination of patient, provider, and system-level factors influence medication-taking behavior. They report that one-quarter of patients with stroke reported discontinuing 1 or more of their prescribed regimen of secondary prevention medications within 3 months of hospitalization for an acute stroke. Several modifiable factors associated with regimen persistence were identified and could be targets for improving long-term secondary stroke prevention.
Autophagy Markers in Parkinson Disease Brains
Alvarez-Erviti et alArticle investigate chaperone-mediated autophagy (CMA) in the pathogenesis of Parkinson disease (PD). Lysosomal-associated membrane protein 2A and heat shock cognate 70 protein levels were compared in the substantia nigra and amygdala of PD, Alzheimer disease, and control brain samples. To provide insight into the turnover of α-synuclein, degradation pathways for this protein were studied in a dopaminergic cell line. The expression levels of the CMA proteins lysosomal-associated membrane protein 2A and heat shock cognate 70 were significantly reduced in the substantia nigra and amygdala of individuals with PD compared with age-matched Alzheimer disease and control samples. These findings suggest that there is reduced CMA activity in PD brain, provide evidence for the role of autophagy in PD pathogenesis and Lewy body formation, and suggest that this pathway may be a suitable therapeutic target in PD.
Meta-analysis Confirms CR1, CLU, and PICALM as Alzheimer Disease Risk Loci
Jun and colleaguesArticle determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer disease (AD) and whether risk of AD associated withthese genes is influenced by APOE genotypes. They find that unadjusted CLU (odds ratio [OR], 0.91; 95% confidence interval [CI], 0.85-0.96 for single-nucleotide polymorphism [SNP] rs11136000), CR1 (OR, 1.14; CI, 1.07-1.22 for SNP rs3818361), and PICALM (OR, 0.89; CI, 0.84-0.94 for SNP rs3851179) were associated with AD in white individuals. They confirm in a completely independent data set that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4–positive subjects. Thus, APOE and PICALM synergistically interact.
Plasma β-Amyloid and Cognitive Decline
Cosentino et alArticle determine if plasma β-amyloid (Aβ) levels (1) can be linked to specific cognitive changes that constitute conversion to Alzheimer disease and (2) correspond to cognitive change independent of dementia. They find that high baseline levels of plasma Aβ42 (P = .01) and Aβ40 (P = .01) and decreasing/relatively stable Aβ42 (P = .01) were associated with faster decline in multiple cognitive domains. In those who remained cognitively healthy, high levels of baseline plasma Aβ42 (P = .01) and decreasing/relatively stable plasma Aβ42 (P = .01) were associated with faster cognitive decline, primarily in memory.
Higher HDL-C in Elderly Persons and Lower Risk of Late-Onset Alzheimer Disease
Reitz and colleaguesArticle examine the association of lipids with Alzheimer disease in 1130 elderly individuals without cognitive impairment at baseline using Cox proportional hazards models. They report that higher levels of high-density lipoprotein cholesterol (HDL-C) (>55 mg/dL) were associated with a decreased risk of both probable and possible AD and probable Alzheimer disease compared with lower HDL-C levels (hazard ratio, 0.4; 95% confidence interval, 0.2-0.9; P = .03 and hazard ratio, 0.4; 95% confidence interval, 0.2-0.9; P = .02).
Analyzing Histopathological Features of Rare Charcot-Marie-Tooth Neuropathies to Unravel Their Pathogenesis
Benedetti et alArticle characterize a large cohort of patients with demyelinating, axonal, and intermediate forms of Charcot-Marie-Tooth disease. They found mutations in 40% of patients. Among identified changes, 7 represent new mutations occurring in the MPZ, GJB1, EGR2, MFN2, NEFL, and HSBP1/HSP27 genes. Histopathology performed in selected cases revealed morphological features that correlated with the molecular diagnosis and provided evidence of the underlying pathogenetic mechanism.
Validation of Consensus Panel Diagnosis in Dementia
Gabel and colleaguesArticle have determined conditions that improve consensus panel diagnosis. The consensus protocol using trainees and experts surpassed the accuracy of individual expert diagnoses when clinical information elicited diverse judgments. In these situations, consensus was 3.5 times more likely to produce positive than negative changes in the accuracy and diagnostic certainty of individual panelists. A rule that forced group consensus was at least as accurate as majority and unanimity rules.
This Month in Archives of Neurology. Arch Neurol. 2010;67(12):1431–1432. doi:10.1001/archneurol.2010.307
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