Citations

ABSTRACT Many people with rapid eye movement (REM) sleep behavior disorder (RBD) have an underlying synucleinopathy, the most common of which is Lewy body disease. Identifying additional abnormal clinical features may help in identifying those at greater risk of evolving to a more severe syndrome. Because gait disorders are common in the synucleinopathies, early abnormalities in gait in those with RBD could help in identifying those at increased risk of developing overt parkinsonism and/or cognitive impairment. We identified 42 probable RBD subjects and 492 controls using the Mayo Sleep Questionnaire and assessed gait velocity, cadence, and stride dynamics with an automated gait analysis system. Cases and controls were similar in age (79.9 ± 4.7 and 80.1 ± 4.7, P = 0.74), Unified Parkinson's Disease Rating Scale Part III (UPDRS) score (3.3 ± 5.5 and 1.9 ± 4.1, P = 0.21) and Mini–Mental State Examination scores (27.2 ± 1.9 and 27.7 ± 1.6, P = 0.10). A diagnosis of probable RBD was associated with decreased velocity (−7.9 cm/s; 95% confidence interval [CI], −13.8 to −2.0; P < 0.01), cadence (−4.4 steps/min; 95% CI, −7.6 to −1.3; P < 0.01), significantly increased double limb support variability (30%; 95% CI, 6–60; P = 0.01), and greater stride time variability (29%; 95% CI, 2–63; P = 0.03) and swing time variability (46%; 95% CI, 15–84; P < 0.01). Probable RBD is associated with subtle gait changes prior to overt clinical parkinsonism. Diagnosis of probable RBD supplemented by gait analysis may help as a screening tool for disorders of α‐synuclein. © 2013 International Parkinson and Movement Disorder Society

Objective: To summarize the pharmacology, development, and clinical application of sorafenib, a specific tyrosine kinase and vascular growth factor inhibitor, for the treatment of renal cell carcinoma (RCC). Data Sources: Clinical literature, including both primary studies and review articles, was obtained by searching MEDLINE (1966–May 2006), using the search terms BAY 43-9006, sorafenib, renal cell carcinoma, and tyrosine kinase inhibitor. Additional information was supplied by the manufacturer, Bayer HealthCare Pharmaceuticals. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to sorafenib were analyzed. An evaluation of the research exploring sorafenib as a potential therapy for RCC was conducted. Relevant information was then selected and is reviewed in this article. Data Synthesis: Knowledge of the cellular abnormalities that can cause solid tumors has led to the development of medications that block these pathways. Sorafenib is an oral tyrosine kinase inhibitor that both blocks the Raf kinase pathway and inhibits vascular growth factors. Phase I and II trials have demonstrated that sorafenib has activity against RCC. Dermatologic reactions (rash, desquamation), fatigue, and hypertension have been the most commonly seen treatment-related adverse events. Sorafenib received FDA approval in December 2005 for treatment of advanced RCC. Conclusions: Sorafenib is a novel oral tyrosine kinase inhibitor effective in the treatment of RCC.

Introduction The successful treatment of intracranial aneurysms is dependent on a full understanding of the anatomic relationship of a given aneurysm to its parent artery(s) and nearby branches. Furthermore, new endovascular technologies are often limited by size constraints. Currently, there is no complete atlas describing diameters for each major intracranial arterial segment. We sought to obtain these data by performing a systematic analysis of selected cerebral angiography images from the International Study of Unruptured Intracranial Aneurysms (ISUIA). Methods Four hundred and forty-five patients with unruptured intracranial aneurysms from the ISUIA database were reviewed. Using previously described techniques, artery diameters were measured for all arteries involved in the aneurysm neck for each patient. Results Measurements were obtained from 695 different aneurysm-associated arterial segments among 445 patient angiograms (mean 1.6 measurements per aneurysm). Artery diameters, mean, median, SEM and IQRs based upon the different arterial segments are presented. Conclusions This angiographic almanac of aneurysm-associated intracranial arterial diameters may be of benefit in establishing standard norms through which devices, protocols and research aims may be developed.

Objective The newly proposed National Institute on Aging–Alzheimer's Association (NIA‐AA) criteria for mild cognitive impairment (MCI) due to Alzheimer disease (AD) suggest a combination of clinical features and biomarker measures, but their performance in the community is not known. Methods The Mayo Clinic Study of Aging (MCSA) is a population‐based longitudinal study of nondemented subjects in Olmsted County, Minnesota. A sample of 154 MCI subjects from the MCSA was compared to a sample of 58 amnestic MCI subjects from the Alzheimer's Disease Neuroimaging Initiative 1 (ADNI‐1) to assess the applicability of the criteria in both settings and to assess their outcomes. Results Fourteen percent of MCSA and 16% of ADNI‐1 of subjects were biomarker negative. In addition, 14% of MCSA and 12% of ADNI‐1 subjects had evidence for amyloid deposition only, whereas 43% of MCSA and 55% of ADNI‐1 subjects had evidence for amyloid deposition plus neurodegeneration (magnetic resonance imaging atrophy, fluorodeoxyglucose positron emission tomography hypometabolism, or both). However, a considerable number of subjects had biomarkers inconsistent with the proposed AD model; for example, 29% of MCSA subjects and 17% of ADNI‐1 subjects had evidence for neurodegeneration without amyloid deposition. These subjects may not be on an AD pathway. Neurodegeneration appears to be a key factor in predicting progression relative to amyloid deposition alone. Interpretation The NIA‐AA criteria apply to most MCI subjects in both the community and clinical trials settings; however, a sizeable proportion of subjects had conflicting biomarkers, which may be very important and need to be explored. Ann Neurol 2013;74:199–208

Objective Knowledge of potentially modifiable risk factors for neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) is important. This study longitudinally explores modifiable vascular risk factors for NPS in AD. Methods Participants enrolled in the Cache County Study on Memory in Aging with no dementia at baseline were subsequently assessed over three additional waves, and those with incident (new onset) dementia were invited to join the Dementia Progression Study for longitudinal follow‐up. A total of 327 participants with incident AD were identified and assessed for the following vascular factors: atrial fibrillation, hypertension, diabetes mellitus, angina, coronary artery bypass surgery, myocardial infarction, cerebrovascular accident, and use of antihypertensive or diabetes medicines. A vascular index (VI) was also calculated. NPS were assessed over time using the Neuropsychiatric Inventory (NPI). Affective and Psychotic symptom clusters were assessed separately. The association between vascular factors and change in NPI total score was analyzed using linear mixed model and in symptom clusters using a random effects model. Results No individual vascular risk factors or the VI significantly predicted change in any individual NPS. The use of antihypertensive medications more than four times per week was associated with higher total NPI and Affective cluster scores. Conclusions Use of antihypertensive medication was associated with higher total NPI and Affective cluster scores. The results of this study do not otherwise support vascular risk factors as modifiers of longitudinal change in NPS in AD. Copyright © 2013 John Wiley & Sons, Ltd.

Abstract Purpose: We set out to identify Stearoyl-CoA desaturase 1 (SCD1) as a novel molecular target in clear cell renal cell carcinoma (ccRCC) and examine its role in tumor cell growth and viability in vitro and in vivo independently as well as in combination with current U.S. Food and Drug Administration (FDA)-approved regimens. Experimental Design: Patient normal and ccRCC tissue samples and cell lines were examined for SCD1 expression. Genetic knockdown models and targeted inhibition of SCD1 through use of a small molecule inhibitor, A939572, were analyzed for growth, apoptosis, and alterations in gene expression using gene array analysis. Therapeutic models of synergy were evaluated utilizing pharmacologic inhibition of SCD1 with the tyrosine kinase inhibitors (TKI) sunitinib and pazopanib, and the mTOR inhibitor temsirolimus. Results: Our studies identify increased SCD1 expression in all stages of ccRCC. Both genetic knockdown and pharmacologic inhibition of SCD1 decreased tumor cell proliferation and induced apoptosis in vitro and in vivo. Upon gene array, quantitative real-time PCR, and protein analysis of A939572-treated or SCD1 lentiviral knockdown samples, induction of endoplasmic reticulum stress response signaling was observed, providing mechanistic insight for SCD1 activity in ccRCC. Furthermore, combinatorial application of A939572 with temsirolimus synergistically inhibited tumor growth in vitro and in vivo. Conclusions: Increased SCD1 expression supports ccRCC viability and therefore we propose it as a novel molecular target for therapy either independently or in combination with an mTOR inhibitor for patients whose disease cannot be remedied with surgical intervention, such as in cases of advanced or metastatic disease. Clin Cancer Res; 19(9); 2368–80. ©2013 AACR.

AbstractBackgroundType 2 diabetes may increase the risk of amnestic mild cognitive impairment (aMCI) through Alzheimer's disease (AD)‐related and vascular pathology and may also increase the risk of nonamnestic MCI (naMCI) through vascular disease mechanisms. We examined the association of type 2 diabetes with mild cognitive impairment (MCI) and MCI subtype (aMCI and naMCI) overall and by sex.MethodsParticipants were Olmsted County, Minnesota residents (70 years and older) enrolled in a prospective, population‐based study. At baseline and every 15 months thereafter, participants were evaluated using the Clinical Dementia Rating scale, a neurological evaluation, and neuropsychological testing for a diagnosis of normal cognition, MCI, and dementia by a consensus panel. Type 2 diabetes was ascertained from the medical records of participants at baseline.ResultsOver a median 4.0 years of follow‐up, 348 of 1450 subjects developed MCI. Type 2 diabetes was associated (hazard ratio [95% confidence interval]) with MCI (1.39 [1.08–1.79]), aMCI (1.58 [1.17–2.15]; multiple domain: 1.58 [1.01–2.47]; single domain: 1.49 [1.09–2.05]), and the hazard ratio for naMCI was elevated (1.37 [0.84–2.24]). Diabetes was strongly associated with multiple‐domain aMCI in men (2.42 [1.31–4.48]) and an elevated risk of multiple domain naMCI in men (2.11 [0.70–6.33]), and with single domain naMCI in women (2.32 [1.04–5.20]).ConclusionsDiabetes was associated with an increased risk of MCI in elderly persons. The association of diabetes with MCI may vary with subtype, number of domains, and sex. Prevention and control of diabetes may reduce the risk of MCI and Alzheimer's disease.