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Itoh, Takayuki; Pleasure, David
doi: 10.1001/jamaneurol.2014.2346pmid: 25364864
This viewpoint focuses on the technological advances in nucleotide sequencing and genetic engineering and on our deepening understanding of the molecular processes underlying Schwann cell–axon interactions and axonal degeneration.
Yu, Lei; Chibnik, Lori B.; Srivastava, Gyan P.; Pochet, Nathalie; Yang, Jingyun; Xu, Jishu; Kozubek, James; Obholzer, Nikolaus; Leurgans, Sue E.; Schneider, Julie A.; Meissner, Alexander; De Jager, Philip L.; Bennett, David A.
Lin, Feng-Cheng; Tsai, Ching-Piao; Kuang-Wu Lee, Johnny; Wu, Ming-Tsang; Tzu-Chi Lee, Charles
doi: 10.1001/jamaneurol.2014.3367pmid: 25383557
ImportanceAlthough several studies have shown that use of angiotensin-converting enzyme inhibitors (ACEIs) potentially decreased amyotrophic lateral sclerosis (ALS) risk in animal models, to our knowledge, there has been no human study in the literature discussing this issue. ObjectiveTo investigate the association between the use of ACEIs and the risk for developing ALS. Design, Setting, and ParticipantsThis case-control study was conducted using the total population of Taiwanese citizens seen in general medical practice; therefore, the findings can be applied to the general population. The case group comprised 729 patients with newly diagnosed ALS and a severely disabling disease certificate between January 1, 2002, and December 31, 2008. These cases were compared with 14 580 sex-, age-, residence-, and insurance premium–matched control individuals. ExposuresUse of ACEIs was analyzed using a conditional logistic regression model that controlled for other antihypertensives, aspirin, steroids, nonsteroidal anti-inflammatory drugs, Charlson Comorbidity Index score, length of hospital stay, and number of outpatient visits. The cumulative defined daily dose (cDDD), which indicates the exposed duration of drug use, was estimated as the sum of dispensed DDD of drug and compared with the risk for ALS. Main Outcomes and MeasuresAll patients with ALS fulfilled El Escorial criteria in this study. Medical claim data past 1 to 5 years of ALS first diagnosis date for patients and claim data from their matched control individuals were included in the analysis. ResultsThere was a dose-dependent inverse association between ACEI use and the risk for developing ALS. When compared with patients who did not use ACEIs, the adjusted odds ratios were 0.83 (95% CI, 0.65-1.07; P = .15) for the group prescribed ACEIs lower than 449.5 of the cDDD and 0.43 cDDD (95% CI, 0.26-0.72; P = .001) for the group with a cumulative ACEI use of greater than 449.5 cDDD. The association was most predominant in men older than 55 years. Conclusions and RelevanceUse of ACEIs exhibited a dose-dependent inverse association with ALS. This study demonstrated a 57% risk reduction in the chance for developing ALS in people who used ACEIs greater than 449.5 cDDD in 4 years.
Showing 1 to 10 of 32 Articles
doi: 10.1001/jamaneurol.2014.3049pmid: 25365775
ImportanceRecent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown. ObjectiveTo examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies. Design, Setting, and ParticipantsOngoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old. ExposuresDNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay. Main Outcomes and MeasuresPathological diagnosis of AD by National Institute on Aging–Reagan criteria following a standard postmortem examination. ResultsOverall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load. Conclusions and RelevanceBrain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.
ImportanceThe effectiveness of intravenous thrombolysis in acute ischemic stroke is time dependent. The effects are likely to be highest if the time from symptom onset to treatment is within 60 minutes, termed the golden hour. ObjectiveTo determine the achievable rate of golden hour thrombolysis in prehospital care and its effect on outcome. Design, Setting, and ParticipantsThe prospective controlled Prehospital Acute Neurological Treatment and Optimization of Medical Care in Stroke study was conducted in Berlin, Germany, within an established infrastructure for stroke care. Weeks were randomized according to the availability of a specialized ambulance (stroke emergency mobile unit (STEMO) from May 1, 2011, through January 31, 2013. We included 6182 consecutive adult patients for whom a stroke dispatch (44.1% male; mean [SD] age, 73.9 [15.0] years) or regular care (45.0% male; mean [SD] age, 74.2 [14.9] years) were included. InterventionsThe STEMO was deployed when the dispatchers suspected an acute stroke during emergency calls. If STEMO was not available (during control weeks, when the unit was already in operation, or during maintenance), patients received conventional care. The STEMO is equipped with a computed tomographic scanner plus a point-of-care laboratory and telemedicine connection. The unit is staffed with a neurologist trained in emergency medicine, a paramedic, and a technician. Thrombolysis was started in STEMO if a stroke was confirmed and no contraindication was found. Main Outcomes and MeasuresRates of golden hour thrombolysis, 7- and 90-day mortality, secondary intracerebral hemorrhage, and discharge home. ResultsThrombolysis rates in ischemic stroke were 200 of 614 patients (32.6%) when STEMO was deployed and 330 of 1497 patients (22.0%) when conventional care was administered (P < .001). Among all patients who received thrombolysis, the proportion of golden hour thrombolysis was 6-fold higher after STEMO deployment (62 of 200 patients [31.0%] vs 16 of 330 [4.9%]; P < .01). Compared with patients with a longer time from symptom onset to treatment, patients who received golden hour thrombolysis had no higher risks for 7- or 90-day mortality (adjusted odds ratios, 0.38 [95% CI, 0.09-1.70]; P = .21 and 0.69 [95% CI, 0.32-1.53]; P = .36) and were more likely to be discharged home (adjusted odds ratio, 1.93 [95% CI, 1.09-3.41]; P = .02). Conclusions and RelevanceThe use of STEMO increases the percentage of patients receiving thrombolysis within the golden hour. Golden hour thrombolysis entails no risk to the patients’ safety and is associated with better short-term outcomes. Trial Registrationclinicaltrials.gov Identifier: NCT01382862
ImportanceVaricella-zoster virus (VZV) infections increasingly are reported in patients with multiple sclerosis (MS) and constitute an area of significant concern, especially with the advent of more disease-modifying treatments in MS that affect T-cell–mediated immunity. ObjectiveTo assess the incidence, risk factors, and clinical characteristics of VZV infections in fingolimod-treated patients and provide recommendations for prevention and management. Design, Setting, and ParticipantsRates of VZV infections in fingolimod clinical trials are based on pooled data from the completed controlled phases 2 and 3 studies (3916 participants) and ongoing uncontrolled extension phases (3553 participants). Male and female patients aged 18 through 55 years (18-60 years for the phase 2 studies) and diagnosed as having relapsing-remitting MS were eligible to participate in these studies. In the postmarketing setting, reporting rates since 2010 were evaluated. InterventionsIn clinical trials, patients received fingolimod at a dosage of 0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the postmarketing setting, all patients received fingolimod, 0.5 mg/d (total exposure of 54 000 patient-years at the time of analysis). Main Outcomes and MeasuresCalculation of the incidence rate of VZV infection per 1000 patient-years was based on the reporting of adverse events in the trials and the postmarketing setting. ResultsOverall, in clinical trials, VZV rates of infection were low but higher with fingolimod compared with placebo (11 vs 6 per 1000 patient-years). A similar rate was confirmed in the ongoing extension studies. Rates reported in the postmarketing settings were comparable (7 per 1000 patient-years) and remained stable over time. Disproportionality in reporting herpes zoster infection was higher for patients receiving fingolimod compared with those receiving other disease-modifying treatments (empirical Bayes geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of serious herpes zoster infections was not higher than the proportion for other treatments (empirical Bayes geometric mean, 1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses might be a risk factor for VZV reactivation. Conclusions and RelevanceRates of VZV infections in clinical trials were low with fingolimod, 0.5 mg/d, but higher than in placebo recipients. Rates reported in the postmarketing setting are comparable. We found no sign of risk accumulation with longer exposure. Serious or complicated cases of herpes zoster were uncommon. We recommend establishing the patient’s VZV immune status before initiating fingolimod therapy and immunization for patients susceptible to primary VZV infection. Routine antiviral prophylaxis is not needed, but using concomitant pulsed corticosteroid therapy beyond 3 to 5 days requires an individual risk-benefit assessment. Vigilance to identify early VZV symptoms is important to allow timely antiviral treatment.