Archives of neurology最新文献

Objective: To evaluate the association of risk and age at onset (AAO) of Alzheimer disease (AD) with single-nucleotide polymorphisms (SNPs) in the chromosome 19 region including apolipoprotein E (APOE) and a repeat-length polymorphism in TOMM40 (poly-T, rs10524523).

Design: Conditional logistic regression models and survival analysis.

Setting: Fifteen genome-wide association study data sets assembled by the Alzheimer's Disease Genetics Consortium.

Participants: Eleven thousand eight hundred forty AD cases and 10 931 cognitively normal elderly controls.

Main outcome measures: Association of AD risk and AAO with genotyped and imputed SNPs located in an 800-Mb region including APOE in the entire Alzheimer's Disease Genetics Consortium data set and with the TOMM40 poly-T marker genotyped in a subset of 1256 cases and 1605 controls.

Results: In models adjusting for APOE ε4, no SNPs in the entire region were significantly associated with AAO at P.001. Rs10524523 was not significantly associated with AD or AAO in models adjusting for APOE genotype or within the subset of ε3/ε3 subjects.

Conclusions: APOE alleles ε2, ε3, and ε4 account for essentially all the inherited risk of AD associated with this region. Other variants including a poly-T track in TOMM40 are not independent risk or AAO loci.

Objective: To examine the association between day of admission and measures of the quality and safety of the care received by patients with stroke.

Design: Retrospective cohort study of patients admitted to hospitals with stroke (codes I60-I64 from the International Statistical Classification of Diseases and Related Health Problems, Tenth Version) from April 1, 2009, through March 31, 2010.

Setting: English National Health Service public hospitals.

Patients: PATIENTS during the study period accounted for 93 621 admissions. We used logistic regression to adjust the outcome measures for case mix.

Main outcome measures: Quality and safety measurements using 6 indicators spanning the hospital care pathway, from timely brain scans to emergency readmissions after discharge.

Results: Performance across 5 of the 6 measures was significantly lower on weekends (confidence level, 99%). One of the largest disparities was seen in rates of same-day brain scans, which were 43.1% on weekends compared with 47.6% on weekdays (unadjusted odds ratio, 0.83 [95% CI, 0.81-0.86]). In particular, the rate of 7-day in-hospital mortality for Sunday admissions was 11.0% (adjusted odds ratio, 1.26 [95% CI, 1.16-1.37], with Monday used as a reference) compared with a mean of 8.9% for weekday admissions.

Conclusions: Strong evidence suggests that, nationally, stroke patients admitted on weekends are less likely to receive urgent treatments and have worse outcomes across a range of indicators. Although we adjusted the results for case mix, we cannot rule out some of the effect being due to unmeasured differences in patients admitted on weekends compared with weekdays. The findings suggest that approximately 350 in-hospital deaths each year within 7 days are potentially avoidable, and an additional 650 people could be discharged to their usual place of residence within 56 days if the performance seen on weekdays was replicated on weekends.

Objective: To determine the genetic basis of an unexplained multisystem neurological disorder affecting 2 siblings.

Design: Case reports and whole-exome DNA sequencing.

Setting: Neurogenetics clinic, Institute of Genetic Medicine, Newcastle upon Tyne, England.

Patients: Two adult siblings with a sensorimotor neuropathy, ataxia, and spasticity.

Main outcome measures: Clinical, neurophysiological, imaging, and genetic data.

Results: Novel compound heterozygous frameshift mutations were detected in the SACS gene of both siblings, predicted to drastically truncate the sacsin protein.

Conclusions: Whole-exome sequencing rapidly defined the genetic cause of the disorder, expanding the clinical phenotype associated with SACS mutations to include a severe sensorimotor neuropathy.

Objective: To assess the impact of fingolimod (FTY720) therapy on magnetic resonance imaging measures of inflammatory activity and tissue damage in patients participating in a 2-year, placebo-controlled, phase 3 study.

Design: Patients with active relapsing-remitting multiple sclerosis were randomized to receive fingolimod, 0.5 mg; fingolimod, 1.25 mg; or placebo for 2 years. Standardized magnetic resonance imaging scans were obtained at months 0, 6, 12, and 24 and centrally evaluated for number and volume of T1 gadolinium-enhancing, T2 hyperintense, and T1 hypointense lesions and for percentage of brain volume change. Findings were compared across subgroups by treatment and baseline characteristics.

Setting: Worldwide, multicenter clinical trial.

Patients: Patients were part of the fingolimod FTY720 Research Evaluating Effects of Daily Oral Therapy in Multiple Sclerosis (FREEDOMS) clinical trial for relapsing-remitting multiple sclerosis (N=1272).

Main outcome measures: We measured the effect of therapy on acute inflammatory activity, burden of disease, and irreversible loss of brain volume.

Results: Fingolimod therapy resulted in rapid and sustained reductions in inflammatory lesion activity as assessed by gadolinium-enhancing and new/newly enlarged T2 lesions after 6, 12, and 24 months of therapy (P.001, all comparisons vs placebo). Changes in T2 hyperintense and T1 hypointense lesion volume also significantly favored fingolimod (P.05, all comparisons). Fingolimod, 0.5 mg (licensed dose), significantly reduced brain volume loss during months 0 to 6, 0 to 12, 12 to 24, and 0 to 24 (P.05, all comparisons) vs placebo, and subgroup analyses confirmed these effects over 2 years irrespective of the presence/absence of gadolinium-enhancing lesions, T2 lesion load, previous treatment status, or level of disability.

Conclusion: These results, coupled with the significant reductions in relapse rates and disability progression reported previously, support the positive impact on long-term disease evolution.

Trial registration: clinicaltrials.gov Identifier: NCT00289978

Traumatic brain injury (TBI) is among the earliest illnesses described in human history and remains a major source of morbidity and mortality in the modern era. It is estimated that 2% of the US population lives with long-term disabilities due to a prior TBI, and incidence and prevalence rates are even higher in developing countries. One of the most feared long-term consequences of TBIs is dementia, as multiple epidemiologic studies show that experiencing a TBI in early or midlife is associated with an increased risk of dementia in late life. The best data indicate that moderate and severe TBIs increase risk of dementia between 2- and 4-fold. It is less clear whether mild TBIs such as brief concussions result in increased dementia risk, in part because mild head injuries are often not well documented and retrospective studies have recall bias. However, it has been observed for many years that multiple mild TBIs as experienced by professional boxers are associated with a high risk of chronic traumatic encephalopathy (CTE), a type of dementia with distinctive clinical and pathologic features. The recent recognition that CTE is common in retired professional football and hockey players has rekindled interest in this condition, as has the recognition that military personnel also experience high rates of mild TBIs and may have a similar syndrome. It is presently unknown whether dementia in TBI survivors is pathophysiologically similar to Alzheimer disease, CTE, or some other entity. Such information is critical for developing preventive and treatment strategies for a common cause of acquired dementia. Herein, we will review the epidemiologic data linking TBI and dementia, existing clinical and pathologic data, and will identify areas where future research is needed.

Background: Shortening of chromosomal telomeres is a consequence of cell division and is a biological factor related to cellular aging and potentially to more rapid organismal biological aging.

Objective: To determine whether shorter telomere length (TL), as measured in human blood samples, is associated with the development of Alzheimer disease and mortality.

Design: We studied available stored leukocyte DNA from a community-based study of aging using realtime polymerase chain reaction analysis to determine mean TL in our modification of a method measuring the ratio of telomere sequence to single-copy gene sequence.

Setting: A multiethnic community-based study of aging and dementia.

Participants: One thousand nine hundred eighty-three subjects 65 years or older. Mean (SD) age at blood draw was 78.3 (6.9) years; at death, 86.0 (7.4) years. Median follow-up for mortality was 9.3 years; 190 (9.6%) developed incident dementia.

Results: The TL was inversely related to age and shorter in men than women. Persons dying during follow-up had a shorter TL compared with survivors (mean [SD], 6218 [819] vs 6491 [881] base pairs [bp] [P.001]), even after adjustment for age, sex, education, and apolipoprotein E genotype. Individuals who developed dementia had significantly shorter TL (mean [SD], 6131 [798] bp for prevalent cases and 6315 [817] bp for incident cases) compared with those remaining dementia-free (6431 [864] bp). Cox-regression analyses showed that shorter TL was a risk for earlier onset of dementia (P=.05), but stratified analyses for sex showed that this association of age at onset of dementia with shorter TL was significant in women only.

Conclusion: Our findings suggest that shortened leukocyte TL is associated with risks for dementia and mortality and may therefore be a marker of biological aging.

Objective: To identify plasma biomarkers for the diagnosis of Alzheimer disease (AD).

Design: Baseline plasma screening of 151 multiplexed analytes combined with targeted biomarker and clinical pathology data.

Setting: General community-based, prospective, longitudinal study of aging.

Participants: A total of 754 healthy individuals serving as controls and 207 participants with AD from the Australian Imaging Biomarker and Lifestyle study (AIBL) cohort with identified biomarkers that were validated in 58 healthy controls and 112 individuals with AD from the Alzheimer Disease Neuroimaging Initiative (ADNI) cohort.

Results: A biomarker panel was identified that included markers significantly increased (cortisol, pancreatic polypeptide, insulinlike growth factor binding protein 2, β(2) microglobulin, vascular cell adhesion molecule 1, carcinoembryonic antigen, matrix metalloprotein 2, CD40, macrophage inflammatory protein 1α, superoxide dismutase, and homocysteine) and decreased (apolipoprotein E, epidermal growth factor receptor, hemoglobin, calcium, zinc, interleukin 17, and albumin) in AD. Cross-validated accuracy measures from the AIBL cohort reached a mean (SD) of 85% (3.0%) for sensitivity and specificity and 93% (3.0) for the area under the receiver operating characteristic curve. A second validation using the ADNI cohort attained accuracy measures of 80% (3.0%) for sensitivity and specificity and 85% (3.0) for area under the receiver operating characteristic curve.

Conclusions: This study identified a panel of plasma biomarkers that distinguish individuals with AD from cognitively healthy control subjects with high sensitivity and specificity. Cross-validation within the AIBL cohort and further validation within the ADNI cohort provides strong evidence that the identified biomarkers are important for AD diagnosis.

Objective: To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS).

Design: Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy.

Patients: The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin.

Interventions: Statin effects on in vitro and in vivo interferon-beta-induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity.

Results: In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P < .001), interferon regulatory factor 1 protein by 30% (P=.006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy-induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium- dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation.

Conclusions: High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease.