Sarcopenia is associated with increased wait-list mortality, but a standard definition is lacking. In this retrospective study, we sought to determine the optimal definition of sarcopenia in end-stage liver disease (ESLD) patients awaiting liver transplantation (LT). Included were 396 patients newly listed for LT in 2012 at 5 North American transplant centers. All computed tomography scans were read by 2 individuals with interobserver correlation of 98%. Using image analysis software, the total cross-sectional area (cm2) of abdominal skeletal muscle at the third lumbar vertebra was measured. The skeletal muscle index (SMI), which normalizes muscle area to patient height, was then calculated. The primary outcome was wait-list mortality, defined as death on the waiting list or removal from the waiting list for reasons of clinical deterioration. Sex-specific potential cutoff values to define sarcopenia were determined with a grid search guided by log-rank test statistics. Optimal search methods identified potential cutoffs to detect survival differences between groups. The overall median SMI was 47.6 cm2/m2: 50.0 in men and 42.0 in women. At a median of 8.8 months follow-up, mortality was 25% in men and 36% in women. Patients who died had lower SMI than those who survived (45.6 versus 48.5 cm2/m2; P < 0.001), and SMI was associated with wait-list mortality (hazard ratio, 0.95; P < 0.001). Optimal search method yielded SMI cutoffs of 50 cm2/m2 for men and 39 cm2/m2 for women; these cutoff values best combined statistical significance with a sufficient number of events to detect survival differences between groups. In conclusion, we recommend that an SMI < 50 cm2/m2 for men and < 39 cm2/m2 for women be used to define sarcopenia in patients with ESLD awaiting LT.
Synaptic dysfunction occurs early in senile dementias, presumably as a result of decreased levels of functional synaptic proteins as found in autopsied brains of patients with Alzheimer's disease (AD) or frontotemporal dementia (FTD). Plasma neuronal-derived exosomes (NDEs) were recovered by precipitation and immunoabsorption from 12 patients with AD, 16 with FTD, and 28 controls in a cross-sectional study, and from 9 patients with AD, 10 with FTD, and 19 controls in a longitudinal study. Six synaptic proteins in NDE extracts were quantified by ELISAs and normalized for exosome amounts. NDE levels of synaptophysin, synaptopodin, synaptotagmin-2, and neurogranin were significantly lower in patients with FTD and AD than in controls, but those of growth-associated protein 43 and synapsin 1 were reduced only in patients with AD. Functionally relevant phosphorylation of synapsin 1 serine 9 was reduced in patients with FTD and AD, although total synapsin 1 protein was higher in FTD than in controls. NDE levels of synaptotagmin, synaptophysin, and neurogranin were decreased years before dementia in patients with FTD and AD. NDE levels of synaptopodin, synaptotagmin, and synaptophysin, but not of amyloid β-peptide 42 or P-T181-tau, were correlated significantly with cognition assessed by mini-mental state examination or AD assessment scale-cognitive subscale. NDE synaptic proteins may be useful preclinical indices and progression measures in senile dementias.-Goetzl, E. J., Kapogiannis, D., Schwartz, J. B., Lobach, I. V., Goetzl, L., Abner, E. L., Jicha, G. A., Karydas, A. M., Boxer, A., Miller, B. L. Decreased synaptic proteins in neuronal exosomes of frontotemporal dementia and Alzheimer's disease.
Background There is no angiographically demonstrable obstructive coronary artery disease (CAD) in a significant minority of patients with myocardial infarction (MI), particularly women. We sought to determine mechanism(s) of MI in this setting using multiple imaging techniques. Methods and Results Women with MI were enrolled prospectively, prior to angiography if possible. Women with ≥50% angiographic stenosis or use of vasospastic agents were excluded. Intravascular ultrasound (IVUS) was performed during angiography and cardiac magnetic resonance imaging (CMR) within one week. Fifty women (age 57±13 years) had median peak troponin 1.60 ng/ml; 11 had ST elevation. Median diameter stenosis of the worst lesion was 20% by angiography; 15 patients (30%) had normal angiograms. Plaque disruption was observed in 16/42 patients (38%) undergoing IVUS. There were abnormal myocardial CMR findings in 26/44 patients (59%) undergoing CMR: late gadolinium enhancement (LGE) in 17 and T2 signal hyperintensity indicating edema in 9 additional patients. The most common LGE pattern was ischemic (transmural/subendocardial). Non-ischemic LGE patterns (midmyocardial/subepicardial) were also observed. LGE was infrequent with plaque disruption but T2 signal hyperintensity was common with plaque disruption. Conclusions Plaque rupture and ulceration are common in women with MI without angiographically demonstrable obstructive CAD. LGE is also common in this cohort of women, with an ischemic pattern of injury most evident. Vasospasm and embolism are possible mechanisms of ischemic LGE without plaque disruption. IVUS and CMR provide complementary mechanistic insights in female MI patients without obstructive CAD and may be useful in identifying potential etiologies and therapies.
Highlights d Discovery of 107 mutations in the RNA helicase DDX3X causing cortical malformations d Clinical severity is linked to reduced helicase activity and RNA-protein granules d Ddx3x is required in neural progenitors to produce cortical neurons during development d Severe missense mutations cause polymicrogyria and impair translation of targets
Summary Background Davunetide (AL-108, NAP) is an eightamino acid peptide that promotes microtubule stability and decreases tau phosphorylation in pre-clinical studies. Since PSP is tightly linked to tau pathology, davunetide could be an effective treatment for PSP.The goals of this study were to evaluate the efficacy and safety of davunetide in PSP. Methods A phase 2/3 double-blind, parallel group, clinical trial of davunetide 30 mg or placebo (randomized 1:1) administered intranasally twice daily for 52 weeks was conducted at 48centers. Participants met modifiedNNIPPS criteria for possible or probable PSP. Co-primary endpointswere the change from baseline in PSP Rating Scale (PSPRS) and Schwab and England ADL(SEADL) scale at up to 52 weeks. Data from all individuals who received at least one dose of medication and had a post-baseline efficacy assessment were compared using a rank-based method.Secondary outcomes included the Clinical Global Impression of Change (CGIC) and the change in regional brain volumeon MRI. Clinicaltrials.gov identifier: NCT01110720. Findings 360 participants were screened, 313 were randomized and 243 (77.6%) completed the study. There were no group differences in PSPRS (mean difference: 0.49 [95% CI: −1.5, 2.5], p = 0.72) or SEADL (1% [−2, 4%], p = 0.76) change from baseline (CFB) and mean 52 week CFB PSPRS scores were similar between the davunetide (11.3 [9.8,12.8]) and placebo groups (10.9 [9.1, 13.0]). There wereno differences in any of the secondary or exploratory endpoints. There were 11deaths in the davunetide group and tenin the placebo group. There were more nasal adverse events in the davunetide group. Interpretation Davunetide is well tolerated but is not an effective treatment for PSP. Clinical trials of disease modifying therapy are feasible in PSP and should be pursued with other promising tau-directed therapies. Funding Allon Therapeutics
Objective In multiple sclerosis (MS) cerebral gray matter (GM) atrophy correlates more strongly than white matter (WM) atrophy with disability. The corresponding relationships in the spinal cord (SC) are unknown due to technical limitations in assessing SCGM atrophy. Using phase sensitive inversion recovery (PSIR) MRI, we determined the association of the SCGM and SCWM areas with MS disability and disease type. Methods 113 MS patients and 20 healthy controls were examined at 3T with a PSIR sequence acquired at the C2/C3 disc level. Two independent, clinically-masked readers measured the cord WM and GM areas. Correlations between cord areas and Expanded Disability Status Score (EDSS) were determined. Differences in areas between groups were assessed with age and sex as covariates. Results Relapsing (R) MS patients showed smaller SCGM areas than age and sex matched controls (p=0.008) without significant differences in SCWM areas. Progressive MS patients showed smaller SCGM and SCWM areas compared to RMS patients (all p≤0.004). SCGM, SCWM, and whole cord areas inversely correlated with EDSS (rho: −0.60, −0.32, −0.42, respectively; all p≤0.001). SCGM area was the strongest correlate of disability in multivariate models including brain GM and WM volumes, FLAIR lesion load, T1-lesion load, SCWM area, number of spinal cord T2 lesions, age, sex, disease duration. Brain and spinal GM independently contributed to EDSS. Interpretation SCGM atrophy is detectable in-vivo in absence of WM atrophy in RMS. It is more pronounced in progressive than RMS and contributes more to patient disability than spinal cord WM or brain GM atrophy.
In primary progressive aphasia (PPA), speech and language difficulties are caused by neurodegeneration of specific brain networks. In the nonfluent/agrammatic variant (nfvPPA), motor speech and grammatical deficits are associated with atrophy in a left fronto-insularstriatal network previously implicated in speech production. In vivo dissection of the crossing white matter (WM) tracts within this "speech production network" is complex and has rarely been performed in health or in PPA. We hypothesized that damage to these tracts would be specific to nfvPPA and would correlate with differential aspects of the patients' fluency abilities. We prospectively studied 25 PPA and 21 healthy individuals who underwent extensive cognitive testing and 3 T MRI. Using residual bootstrap Q-ball probabilistic tractography on high angular resolution diffusion-weighted imaging (HARDI), we reconstructed pathways connecting posterior inferior frontal, inferior premotor, insula, supplementary motor area (SMA) complex, striatum, and standard ventral and dorsal language pathways. We extracted tract-specific diffusion tensor imaging (DTI) metrics to assess changes across PPA variants and perform brainbehavioral correlations. Significant WM changes in the left intrafrontal and frontostriatal pathways were found in nfvPPA, but not in the semantic or logopenic variants. Correlations between tract-specific DTI metrics with cognitive scores confirmed the specific involvement of this anterior-dorsal network in fluency and suggested a preferential role of a posterior premotor-SMA pathway in motor speech. This study shows that left WM pathways connecting the speech production network are selectively damaged in nfvPPA and suggests that different tracts within this system are involved in subcomponents of fluency. These findings emphasize the emerging role of diffusion imaging in the differential diagnosis of neurodegenerative diseases.
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