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"Stern, Michael G"
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When you wish upon a well
When Amber makes a wish for her father to spend more time with her and less with Sofia, she inadvertently turns Sofia into a cat, and must find a way to get Sofia back to normal.
Book
Tau Positron-Emission Tomography in Former National Football League Players
Twenty-six former NFL players with cognitive and behavioral symptoms were compared with controls by means of tau PET. Tau deposition was found in the temporal, superior frontal, and left parietal regions, similar to the neuropathological findings in chronic traumatic encephalopathy.
Journal Article
Comparison of Warfarin and Aspirin for Symptomatic Intracranial Arterial Stenosis
Stroke or transient ischemic attack due to intracranial arterial stenosis is usually treated with warfarin. The results of the current trial refute this practice and suggest that warfarin results in an increased mortality rate. Aspirin (1300 mg per day) is the recommended therapy.
The results of this trial suggest that warfarin for intracranial arterial stenosis results in an increased mortality rate. Aspirin is the recommended therapy.
Atherosclerotic stenosis of the major intracranial arteries is an important cause of stroke, especially in blacks, Asians, and Hispanics.
1
–
3
Of the 900,000 strokes or transient ischemic attacks that occur each year in the United States,
4
,
5
approximately 70,000 to 90,000 are caused by intracranial arterial stenosis.
3
The risk of recurrent stroke in these patients may be as high as 15 percent per year.
6
,
7
Despite their high risk of stroke, there are no prospective studies comparing antithrombotic therapies in these patients. Anticoagulation was first used to treat intracranial arterial stenosis in 1955,
8
and subsequent, retrospective studies suggested that warfarin . . .
Journal Article
Club Cell Secretory Protein Deficiency Leads to Altered Lung Function
CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.
To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.
Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16
mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.
We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness to methacholine challenge from 11 years throughout young adult life. Similarly, CC16
mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-type mice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16
mice had significantly elevated gene expression of procollagen type I, procollagen type III, and α-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.
Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.
Journal Article
Independent effects of white matter hyperintensities on cognitive, neuropsychiatric, and functional decline: a longitudinal investigation using the National Alzheimer’s Coordinating Center Uniform Data Set
Background
Longitudinal investigations are needed to improve understanding of the contributions of cerebral small vessel disease to the clinical manifestation of Alzheimer’s disease, particularly in the early disease stages. This study leveraged the National Alzheimer’s Coordinating Center Uniform Data Set to longitudinally examine the association between white matter hyperintensities and neuropsychological, neuropsychiatric, and functional decline among participants with normal cognition.
Methods
The sample included 465 participants from the National Alzheimer’s Coordinating Center Uniform Data Set who had quantitated volume of white matter hyperintensities from fluid-attenuated inversion recovery MRI, had normal cognition at the time of their MRI, and were administered the National Alzheimer’s Coordinating Center Uniform Data Set neuropsychological test battery within 1 year of study evaluation and had at least two post-MRI time points of clinical data. Neuropsychiatric status was assessed by the Geriatric Depression Scale-15 and Neuropsychiatric Inventory-Questionnaire. Clinical Dementia Rating Sum of Boxes defined functional status. For participants subsequently diagnosed with mild cognitive impairment (MCI) or dementia, their impairment must have been attributed to Alzheimer’s disease (AD) to evaluate the relationships between WMH and the clinical presentation of AD.
Results
Of the 465 participants, 56 converted to MCI or AD dementia (average follow-up = 5 years). Among the 465 participants, generalized estimating equations controlling for age, sex, race, education,
APOE ε4
, and total brain and hippocampal volume showed that higher baseline log-white matter hyperintensities predicted accelerated decline on the following neuropsychological tests in rank order of effect size: Trails B (
p
< 0.01), Digit Symbol Coding (
p
< 0.01), Logical Memory Immediate Recall (
p
= 0.02), Trail Making A (
p
< 0.01), and Semantic Fluency (
p
< 0.01). White matter hyperintensities predicted increases in Clinical Dementia Rating Sum of Boxes (
p
< 0.01) and Geriatric Depression Scale-15 scores (
p
= 0.01). Effect sizes were comparable to total brain and hippocampal volume. White matter hyperintensities did not predict diagnostic conversion. All effects also remained after including individuals with non-AD suspected etiologies for those who converted to MCI or dementia.
Conclusions
In this baseline cognitively normal sample, greater white matter hyperintensities were associated with accelerated cognitive, neuropsychiatric, and functional decline independent of traditional risk factors and MRI biomarkers for Alzheimer’s disease.
Journal Article
Optimal blood tau species for the detection of Alzheimer’s disease neuropathology: an immunoprecipitation mass spectrometry and autopsy study
Plasma-to-autopsy studies are essential for validation of blood biomarkers and understanding their relation to Alzheimer’s disease (AD) pathology. Few such studies have been done on phosphorylated tau (p-tau) and those that exist have made limited or no comparison of the different p-tau variants. This study is the first to use immunoprecipitation mass spectrometry (IP-MS) to compare the accuracy of eight different plasma tau species in predicting autopsy-confirmed AD. The sample included 123 participants (AD = 69, non-AD = 54) from the Boston University Alzheimer’s disease Research Center who had an available ante-mortem plasma sample and donated their brain. Plasma samples proximate to death were analyzed by targeted IP-MS for six different tryptic phosphorylated (p-tau-181, 199, 202, 205, 217, 231), and two non-phosphorylated tau (195–205, 212–221) peptides. NIA-Reagan Institute criteria were used for the neuropathological diagnosis of AD. Binary logistic regressions tested the association between each plasma peptide and autopsy-confirmed AD status. Area under the receiver operating curve (AUC) statistics were generated using predicted probabilities from the logistic regression models. Odds Ratio (OR) was used to study associations between the different plasma tau species and CERAD and Braak classifications. All tau species were increased in AD compared to non-AD, but p-tau217, p-tau205 and p-tau231 showed the highest fold-changes. Plasma p-tau217 (AUC = 89.8), p-tau231 (AUC = 83.4), and p-tau205 (AUC = 81.3) all had excellent accuracy in discriminating AD from non-AD brain donors, even among those with CDR < 1). Furthermore, p-tau217, p-tau205 and p-tau231 showed the highest ORs with both CERAD (OR
p-tau217
= 15.29, OR
p-tau205
= 5.05 and OR
p-tau231
= 3.86) and Braak staging (OR
p-tau217
= 14.29, OR
p-tau205
= 5.27 and OR
p-tau231
= 4.02) but presented increased levels at different amyloid and tau stages determined by neuropathological examination. Our findings support plasma p-tau217 as the most promising p-tau species for detecting AD brain pathology. Plasma p-tau231 and p-tau205 may additionally function as markers for different stages of the disease.
Journal Article
Global analysis of protein phosphorylation in yeast
Protein phosphorylation is estimated to affect 30% of the proteome and is a major regulatory mechanism that controls many basic cellular processes. Until recently, our biochemical understanding of protein phosphorylation on a global scale has been extremely limited; only one half of the yeast kinases have known in vivo substrates and the phosphorylating kinase is known for less than 160 phosphoproteins. Here we describe, with the use of proteome chip technology, the in vitro substrates recognized by most yeast protein kinases: we identified over 4,000 phosphorylation events involving 1,325 different proteins. These substrates represent a broad spectrum of different biochemical functions and cellular roles. Distinct sets of substrates were recognized by each protein kinase, including closely related kinases of the protein kinase A family and four cyclin-dependent kinases that vary only in their cyclin subunits. Although many substrates reside in the same cellular compartment or belong to the same functional category as their phosphorylating kinase, many others do not, indicating possible new roles for several kinases. Furthermore, integration of the phosphorylation results with protein-protein interaction and transcription factor binding data revealed novel regulatory modules. Our phosphorylation results have been assembled into a first-generation phosphorylation map for yeast. Because many yeast proteins and pathways are conserved, these results will provide insights into the mechanisms and roles of protein phosphorylation in many eukaryotes.
Journal Article
LRO-LAMP Observations of the LCROSS Impact Plume
On 9 October 2009, the Lunar Crater Observation and Sensing Satellite (LCROSS) sent a kinetic impactor to strike Cabeus crater, on a mission to search for water ice and other volatiles expected to be trapped in lunar polar soils. The Lyman Alpha Mapping Project (LAMP) ultraviolet spectrograph onboard the Lunar Reconnaissance Orbiter (LRO) observed the plume generated by the LCROSS impact as far-ultraviolet emissions from the fluorescence of sunlight by molecular hydrogen and carbon monoxide, plus resonantly scattered sunlight from atomic mercury, with contributions from calcium and magnesium. The observed light curve is well simulated by the expansion of a vapor cloud at a temperature of approximately 1000 kelvin, containing approximately 570 kilograms (kg) of carbon monoxide, approximately 140 kg of molecular hydrogen, approximately 160 kg of calcium, approximately 120 kg of mercury, and approximately 40 kg of magnesium.
Journal Article
Age at First Exposure to Repetitive Head Impacts Is Associated with Smaller Thalamic Volumes in Former Professional American Football Players
Thalamic atrophy has been associated with exposure to repetitive head impacts (RHI) in professional fighters. The aim of this study is to investigate whether or not age at first exposure (AFE) to RHI is associated with thalamic volume in symptomatic former National Football League (NFL) players at risk for chronic traumatic encephalopathy (CTE). Eighty-six symptomatic former NFL players (mean age = 54.9 ± 7.9 years) were included. T1-weighted data were acquired on a 3T magnetic resonance imager, and thalamic volumes were derived using FreeSurfer. Mood and behavior, psychomotor speed, and visual and verbal memory were assessed. The association between thalamic volume and AFE to playing football and to number of years playing was calculated. Decreased thalamic volume was associated with more years of play (left: p = 0.03; right: p = 0.03). Younger AFE was associated with decreased right thalamic volume (p = 0.014). This association remained significant after adjusting for total years of play. Decreased left thalamic volume was associated with worse visual memory (p = 0.014), whereas increased right thalamic volume was associated with fewer mood and behavior symptoms (p = 0.003). In our sample of symptomatic former NFL players at risk for CTE, total years of play and AFE were associated with decreased thalamic volume. The effect of AFE on right thalamic volume was almost twice as strong as the effect of total years of play. Our findings confirm previous reports of an association between thalamic volume and exposure to RHI. They suggest further that younger AFE may result in smaller thalamic volume later in life.
Journal Article
Olfactory Function and Associated Clinical Correlates in Former National Football League Players
Professional American football players incur thousands of repetitive head impacts (RHIs) throughout their lifetime. The long-term consequences of RHI are not well characterized, but may include olfactory dysfunction. RHI has been associated with changes to brain regions involved in olfaction, and olfactory impairment is common after traumatic brain injury. Olfactory dysfunction is a frequent early sequelae of neurodegenerative diseases (e.g., Alzheimer's disease), and RHI is associated with the neurodegenerative disease, chronic traumatic encephalopathy (CTE). We examined olfaction, and its association with clinical measures, in former National Football League (NFL) players. Ninety-five former NFL players (ages 40–69) and 28 same-age controls completed a neuropsychological and neuropsychiatric evaluation as part of a National Institutes of Health–funded study. The Brief Smell Identification Test (B-SIT) assessed olfaction. Principal component analysis generated a four-factor structure of the clinical measures: behavioral/mood, psychomotor speed/executive function, and verbal and visual memory. Former NFL players had worse B-SIT scores relative to controls (p = 0.0096). A B-SIT cutoff of 11 had the greatest accuracy (c-statistic = 0.61) and specificity (79%) for discriminating former NFL players from controls. In the former NFL players, lower B-SIT scores correlated with greater behavioral/mood impairment (p = 0.0254) and worse psychomotor speed/executive functioning (p = 0.0464) after controlling for age and education. Former NFL players exhibited lower olfactory test scores relative to controls, and poorer olfactory test performance was associated with worse neuropsychological and neuropsychiatric functioning. Future work that uses more-comprehensive tests of olfaction and structural and functioning neuroimaging may improve understanding on the association between RHI and olfaction.
Journal Article