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1.  Pharmacotherapy of Traumatic Brain Injury: State of the Science and the Road Forward: Report of the Department of Defense Neurotrauma Pharmacology Workgroup 
Journal of Neurotrauma  2014;31(2):135-158.
Abstract
Despite substantial investments by government, philanthropic, and commercial sources over the past several decades, traumatic brain injury (TBI) remains an unmet medical need and a major source of disability and mortality in both developed and developing societies. The U.S. Department of Defense neurotrauma research portfolio contains more than 500 research projects funded at more than $700 million and is aimed at developing interventions that mitigate the effects of trauma to the nervous system and lead to improved quality of life outcomes. A key area of this portfolio focuses on the need for effective pharmacological approaches for treating patients with TBI and its associated symptoms. The Neurotrauma Pharmacology Workgroup was established by the U.S. Army Medical Research and Materiel Command (USAMRMC) with the overarching goal of providing a strategic research plan for developing pharmacological treatments that improve clinical outcomes after TBI. To inform this plan, the Workgroup (a) assessed the current state of the science and ongoing research and (b) identified research gaps to inform future development of research priorities for the neurotrauma research portfolio. The Workgroup identified the six most critical research priority areas in the field of pharmacological treatment for persons with TBI. The priority areas represent parallel efforts needed to advance clinical care; each requires independent effort and sufficient investment. These priority areas will help the USAMRMC and other funding agencies strategically guide their research portfolios to ensure the development of effective pharmacological approaches for treating patients with TBI.
doi:10.1089/neu.2013.3019
PMCID: PMC3900003  PMID: 23968241
animal studies; head trauma; human studies; pharmacology; traumatic brain injury
2.  Acute Biomarkers of Traumatic Brain Injury: Relationship between Plasma Levels of Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein 
Journal of Neurotrauma  2014;31(1):19-25.
Abstract
Biomarkers are important for accurate diagnosis of complex disorders such as traumatic brain injury (TBI). For a complex and multifaceted condition such as TBI, it is likely that a single biomarker will not reflect the full spectrum of the response of brain tissue to injury. Ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are among of the most widely studied biomarkers for TBI. Because UCH-L1 and GFAP measure distinct molecular events, we hypothesized that analysis of both biomarkers would be superior to analysis of each alone for the diagnosis and prognosis of TBI. Serum levels of UCH-L1 and GFAP were measured in a cohort of 206 patients with TBI enrolled in a multicenter observational study (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI]). Levels of the two biomarkers were weakly correlated to each other (r=0.364). Each biomarker in isolation had good sensitivity and sensitivity for discriminating between TBI patients and healthy controls (area under the curve [AUC] 0.87 and 0.91 for UCH-L1 and GFAP, respectively). When biomarkers were combined, superior sensitivity and specificity for diagnosing TBI was obtained (AUC 0.94). Both biomarkers discriminated between TBI patients with intracranial lesions on CT scan and those without such lesions, but GFAP measures were significantly more sensitive and specific (AUC 0.88 vs. 0.71 for UCH-L1). For association with outcome 3 months after injury, neither biomarker had adequate sensitivity and specificity (AUC 0.65–0.74, for GFAP, and 0.59–0.80 for UCH-L1, depending upon Glasgow Outcome Scale Extended [GOS-E] threshold used). Our results support a role for multiple biomarker measurements in TBI research. (ClinicalTrials.gov Identifier NCT01565551)
doi:10.1089/neu.2013.3040
PMCID: PMC3880090  PMID: 23865516
biomarker; common data elements; human studies; TBI
3.  Masters Athletes Exhibit Larger Regional Brain Volume and Better Cognitive Performance than Sedentary Older Adults 
Journal of magnetic resonance imaging : JMRI  2013;38(5):10.1002/jmri.24085.
Purpose
To investigate differences in the age-related decline in brain tissue concentration between Masters athletes and sedentary older adults.
Materials and Methods
Twelve Masters athletes (MA) (3 females, age=72.4±5.6yrs, endurance training>15yrs), 12 sedentary elderly (SE) similar in age and educational level (4 females, age=74.6±4.3yrs), and 9 young controls (YC)(4 females, age=27.2±3.6yrs) participated. T1-weighted-high-resolution (1×1×1mm3) images were acquired. Voxel-based analysis was conducted to identify clusters showing tissue concentration differences with t-tests. Cognitive function was assessed using a standard clinical battery focused on executive function and memory.
Results
Two Masters athletes and 2 sedentary elderly were unable to complete MRI study. Both SE and MA showed lower GM concentrations than YC in the superior, inferior and middle frontal gyrus, superior temporal gyrus, postcentral gyrus and the cingulate gyrus (PFDR-corrected<0.001) and lower WM concentrations in the inferior frontal gyrus and precentral gyrus (PFDR-corrected<0.005). Notably, MA showed higher GM and WM concentrations than SE in the sub-gyral, cuneus, and precuneus regions related to visuospatial function, motor control, and working memory (PFDR-corrected<0.005). After controlling for estimated intelligence, MA outperformed SE on tasks of letter (p<0.01) and category (p<0.05) fluency.
Conclusion
Life-long exercise may confer benefits to some aspects of executive function and age-related brain tissue loss in the regions related to visuospatial function, motor control, and working memory in older adults.
doi:10.1002/jmri.24085
PMCID: PMC3812419  PMID: 23908143
Aging; brain; cognition; exercise; MRI
4.  A randomized, placebo-controlled proof-of-concept, crossover trial of phenytoin for hydrocortisone-induced declarative memory changes 
Journal of affective disorders  2013;150(2):551-558.
Background
Corticosteroid excess is associated with declarative memory impairment and hippocampal atrophy. These findings are clinically important because approximately 1% of the population receives prescription corticosteroids at any time, and major depressive disorder is associated with elevated cortisol levels and hippocampal atrophy. In animals, hippocampal changes with corticosteroids are blocked by phenytoin. The objective of the current study was to extend these preclinical findings to humans. We examined whether phenytoin attenuated the effects of hydrocortisone on declarative memory. Functional magnetic resonance imaging (fMRI) assessed task-related hippocampal activation.
Methods
A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in 17 healthy adult volunteers. Participants received hydrocortisone (2.5 days), phenytoin (3.5 days), both medications together, or placebo, with 21-day washouts between conditions. Differences between treatments were estimated using a mixed-effects repeated measures analysis.
Results
Fifteen participants had data from at least two treatment conditions and were used in the analysis. Basal cortisol levels negatively correlated with fMRI BOLD activation in the para-hippocampus with a similar trend observed in the hippocampus. Decrease in declarative memory with hydrocortisone was blocked with concomitant phenytoin administration. Relative to the placebo condition, a significant decrease in hippocampal BOLD activation was observed with hydrocortisone and phenytoin alone, and the two medications in combination. Declarative memory did not show significant correlations with hippocampal activation.
Limitations
The modest sample size, which limited our statistical power, was a limitation.
Conclusions
Findings from this pilot study suggest phenytoin attenuated effects of corticosteroids memory in humans, but potentiated the reduction in hippocampal activation.
doi:10.1016/j.jad.2013.01.038
PMCID: PMC3689865  PMID: 23453674
anticonvulsant; corticosteroid; fMRI; cognition; hippocampus
5.  Clinical Phenotype of Dementia after Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(13):1117-1122.
Abstract
Traumatic brain injury (TBI) in early to mid-life is associated with an increased risk of dementia in late life. It is unclear whether TBI results in acceleration of Alzheimer's disease (AD)-like pathology or has features of another dementing condition, such as chronic traumatic encephalopathy, which is associated with more-prominent mood, behavior, and motor disturbances than AD. Data from the National Alzheimer's Coordinating Center (NACC) Uniform Data Set was obtained over a 5-year period. Categorical data were analyzed using Fisher's exact test. Continuous parametric data were analyzed using the Student's t-test. Nonparametric data were analyzed using Mann-Whitney's test. Overall, 877 individuals with dementia who had sustained TBI were identified in the NACC database. Only TBI with chronic deficit or dysfunction was associated with increased risk of dementia. Patients with dementia after TBI (n=62) were significantly more likely to experience depression, anxiety, irritability, and motor disorders than patients with probable AD. Autopsy data were available for 20 of the 62 TBI patients. Of the patients with TBI, 62% met National Institute of Aging-Reagan Institute “high likelihood” criteria for AD. We conclude that TBI with chronic deficit or dysfunction is associated with an increased odds ratio for dementia. Clinically, patients with dementia associated with TBI were more likely to have symptoms of depression, agitation, irritability, and motor dysfunction than patients with probable AD. These findings suggest that dementia in individuals with a history of TBI may be distinct from AD.
doi:10.1089/neu.2012.2638
PMCID: PMC3705947  PMID: 23374007
Alzheimer's disease; chronic traumatic encephalopathy; National Alzheimer's Coordinating Center
6.  Risk Factors for β-Amyloid Deposition in Healthy Aging 
JAMA neurology  2013;70(5):600-606.
Importance
Identifying risk factors for increased β-amyloid (Aβ) deposition is important for targeting individuals most at risk for developing Alzheimer disease and informing clinical practice concerning prevention and early detection.
Objective
To investigate risk factors for Aβ deposition in cognitively healthy middle-aged and older adults. Specifically, we hypothesized that individuals with a vascular risk factor such as hypertension, in combination with a genetic risk factor for Alzheimer disease (apolipoprotein E ε4 allele), would show greater amyloid burden than those without such risk.
Design
Cross-sectional study.
Setting
General community.
Participants
One hundred eighteen well-screened and cognitively normal adults, aged 47 to 89 years. Participants were classified in the hypertension group if they reported a medical diagnosis of hypertension or if blood pressure exceeded 140 mm Hg systolic/90 mm Hg diastolic, as measured across 7 occasions at the time of study.
Intervention
Participants underwent Aβ positron emission tomography imaging with radiotracer fluorine 18–labeled florbetapir. Participants were genotyped for apolipoprotein E and were classified as ε4+ or ε4−.
Main Outcome Measure
Amyloid burden.
Results
Participants in the hypertension group with at least 1 ε4 allele showed significantly greater amyloid burden than those with only 1 risk factor or no risk factors. Furthermore, increased pulse pressure was strongly associated with increased mean cortical amyloid level for subjects with at least 1 ε4 allele.
Conclusions and Relevance
Vascular disease is a prevalent age-related condition that is highly responsive to both behavioral modification and medical treatment. Proper control and prevention of risk factors such as hypertension earlier in the life span may be one potential mechanism to ameliorate or delay neuropathological brain changes with aging.
doi:10.1001/jamaneurol.2013.1342
PMCID: PMC3968915  PMID: 23553344
7.  C9ORF72 hexanucleotide repeat expansions in clinical Alzheimer’s disease 
JAMA neurology  2013;70(6):736-741.
Objective
Hexanucleotide repeat expansions in C9ORF72 underlie a significant fraction of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). This study investigates the frequency of C9ORF72 repeat expansions in clinically diagnosed late-onset Alzheimer’s disease (AD).
Design, setting and patients
This case-control study genotyped the C9ORF72 repeat expansion in 872 unrelated familial AD cases and 888 controls recruited as part of the NIA-LOAD cohort, a multi-site collaboration studying 1000 families with two or more individuals clinically diagnosed with late-onset-AD.
Main Outcome Measure
We determined the presence or absence of the C9ORF72 repeat expansion by repeat-primed PCR, the length of the longest non-expanded allele, segregation of the genotype with disease, and clinical features of repeat expansion carriers.
Results
Three families showed large C9ORF72 hexanucleotide repeat expansions. Two additional families carried more than 30 repeats. Segregation with disease could be demonstrated in 3 families. One affected expansion carrier had neuropathology compatible with AD. In the NIA-LOAD series, the C9ORF72 repeat expansions constituted the second most common pathogenic mutation, just behind the PSEN1 A79V mutation, highlighting the heterogeneity of clinical presentations associated with repeat expansions.
Interpretation
C9ORF72 repeat expansions explain a small proportion of patients with a clinical presentation indistinguishable from AD, and highlight the necessity of screening “FTD genes” in clinical AD cases with strong family history.
doi:10.1001/2013.jamaneurol.537
PMCID: PMC3681841  PMID: 23588422
8.  Distinctive disruption patterns of white matter tracts in Alzheimer’s disease with full diffusion tensor characterization 
Neurobiology of Aging  2011;33(9):2029-2045.
To characterize the white matter structural changes at the tract level and tract group level, comprehensive analysis with four metrics derived from DTI, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AxD) and radial diffusivity (RD), was conducted. Tract groups, namely limbic, commissural, association and projection tracts, include white matter tracts of similar functions. DTI data were acquired from 61 subjects (26 AD, 11 subjects with amnestic mild cognitive impairment or aMCI, 24 age-matched controls). An atlas-based approach was used to survey 30 major cerebral white matter tracts with the measurements of FA, MD, AxD and RD. Regional cortical atrophy and cognitive functions of AD patients were also measured to correlate with the structural changes of white matter. Synchronized structural changes of cingulum bundle and fornix, both of which are part of limbic tract group, were revealed. Widespread yet distinctive structural changes were found in limbic, commissural, association and projection tract groups between control and AD subjects. Specifically, FA, MD and RD of limbic tracts, FA, MD, AxD and RD of commissural tracts, MD, AxD and RD of association tracts and MD and AxD of projection tracts are significantly different between AD patients and control subjects. In contrast, the comparison between aMCI and control subjects shows disruption only in the limbic and commissural tract groups of aMCI subjects. MD values of all tract groups of AD patients are significantly correlated to cognitive functions. Difference between AD and control and that between MCI and control indicates a progression pattern of white matter disruption from limbic and commissural tract group to other tract groups. High correlation between FA, MD and RD measurements from limbic tracts and cortical atrophy suggests the disruption of the limbic tract group is caused by the neuronal damage.
doi:10.1016/j.neurobiolaging.2011.06.027
PMCID: PMC3227739  PMID: 21872362
Alzheimer’s disease; atlas; DTI; white matter tract; tract group; biomarker
9.  Regional changes of cortical mean diffusivities with aging after correction of partial volume effects 
NeuroImage  2012;62(3):1705-1716.
Accurately measuring the cortical mean diffusivity (MD) derived from diffusion tensor imaging (DTI) at the comprehensive lobe, gyral and voxel level of young, elderly healthy brains and those with Alzheimer's disease (AD) may provide insights on heterogeneous cortical microstructural changes caused by aging and AD. Due to partial volume effects (PVE), the measurement of cortical MD is overestimated with contamination of cerebrospinal fluid (CSF). The bias is especially severe for aging and AD brains because of significant cortical thinning of these brains. In this study, we aimed to quantitatively characterize the unbiased regional cortical MD changes due to aging and AD and delineate the effects of cortical thinning of elderly healthy and AD groups on MD measurements. DTI and T1-weighted images of 14 young, 15 elderly healthy subjects and 17 AD patients were acquired. With the parcellated cortical gyri and lobes from T1 weighted image transformed to DTI, regional cortical MD of all subjects before and after PVE correction were measured. CSF contamination model was used to correct bias of MD caused by PVE. Compared to cortical MD of young group, significant increases of corrected MD for elderly healthy and AD groups were found only in frontal and limbic regions, respectively, while there were significant increases of uncorrected MD all over the cortex. Uncorrected MD are significantly higher in limbic and temporal gyri in AD group, compared to those in elderly healthy group but higher MD only remained in limbic gyri after PVE correction. Cortical thickness was also measured for all groups. The correlation slopes between cortical MD and thickness for elderly healthy and AD groups were significantly decreased after PVE correction compared to before correction while no significant change of correlation slope was detected for young group. It suggests that the cortical thinning in elderly healthy and AD groups is a significant contributor to the bias of uncorrected cortical MD measurement. The established comprehensive unbiased cortical MD profiles of young, elderly healthy subjects and AD patients at the lobe, gyral and voxel level may serve as clinical references for cortical microstructure.
doi:10.1016/j.neuroimage.2012.05.082
PMCID: PMC3574164  PMID: 22683383
DTI; Cortex; Mean diffusivity; Aging; Alzheimer's disease; Unbiased; Partial volume effects
10.  Dementia Resulting From Traumatic Brain Injury 
Archives of neurology  2012;69(10):1245-1251.
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.
doi:10.1001/archneurol.2011.3747
PMCID: PMC3716376  PMID: 22776913
11.  Predicting missing biomarker data in a longitudinal study of Alzheimer disease 
Lo, Raymond Y. | Jagust, William J. | Aisen, Paul | Jack, Clifford R. | Toga, Arthur W. | Beckett, Laurel | Gamst, Anthony | Soares, Holly | C. Green, Robert | Montine, Tom | Thomas, Ronald G. | Donohue, Michael | Walter, Sarah | Dale, Anders | Bernstein, Matthew | Felmlee, Joel | Fox, Nick | Thompson, Paul | Schuff, Norbert | Alexander, Gene | DeCarli, Charles | Bandy, Dan | Chen, Kewei | Morris, John | Lee, Virginia M.-Y. | Korecka, Magdalena | Crawford, Karen | Neu, Scott | Harvey, Danielle | Kornak, John | Saykin, Andrew J. | Foroud, Tatiana M. | Potkin, Steven | Shen, Li | Buckholtz, Neil | Kaye, Jeffrey | Dolen, Sara | Quinn, Joseph | Schneider, Lon | Pawluczyk, Sonia | Spann, Bryan M. | Brewer, James | Vanderswag, Helen | Heidebrink, Judith L. | Lord, Joanne L. | Petersen, Ronald | Johnson, Kris | Doody, Rachelle S. | Villanueva-Meyer, Javier | Chowdhury, Munir | Stern, Yaakov | Honig, Lawrence S. | Bell, Karen L. | Morris, John C. | Mintun, Mark A. | Schneider, Stacy | Marson, Daniel | Griffith, Randall | Clark, David | Grossman, Hillel | Tang, Cheuk | Marzloff, George | Toledo-Morrell, Leylade | Shah, Raj C. | Duara, Ranjan | Varon, Daniel | Roberts, Peggy | Albert, Marilyn S. | Pedroso, Julia | Toroney, Jaimie | Rusinek, Henry | de Leon, Mony J | De Santi, Susan M | Doraiswamy, P. Murali | Petrella, Jeffrey R. | Aiello, Marilyn | Clark, Christopher M. | Pham, Cassie | Nunez, Jessica | Smith, Charles D. | Given, Curtis A. | Hardy, Peter | Lopez, Oscar L. | Oakley, MaryAnn | Simpson, Donna M. | Ismail, M. Saleem | Brand, Connie | Richard, Jennifer | Mulnard, Ruth A. | Thai, Gaby | Mc-Adams-Ortiz, Catherine | Diaz-Arrastia, Ramon | Martin-Cook, Kristen | DeVous, Michael | Levey, Allan I. | Lah, James J. | Cellar, Janet S. | Burns, Jeffrey M. | Anderson, Heather S. | Laubinger, Mary M. | Bartzokis, George | Silverman, Daniel H.S. | Lu, Po H. | Graff-Radford MBBCH, Neill R | Parfitt, Francine | Johnson, Heather | Farlow, Martin | Herring, Scott | Hake, Ann M. | van Dyck, Christopher H. | MacAvoy, Martha G. | Benincasa, Amanda L. | Chertkow, Howard | Bergman, Howard | Hosein, Chris | Black, Sandra | Graham, Simon | Caldwell, Curtis | Hsiung, Ging-Yuek Robin | Feldman, Howard | Assaly, Michele | Kertesz, Andrew | Rogers, John | Trost, Dick | Bernick, Charles | Munic, Donna | Wu, Chuang-Kuo | Johnson, Nancy | Mesulam, Marsel | Sadowsky, Carl | Martinez, Walter | Villena, Teresa | Turner, Scott | Johnson, Kathleen B. | Behan, Kelly E. | Sperling, Reisa A. | Rentz, Dorene M. | Johnson, Keith A. | Rosen, Allyson | Tinklenberg, Jared | Ashford, Wes | Sabbagh, Marwan | Connor, Donald | Jacobson, Sandra | Killiany, Ronald | Norbash, Alexander | Nair, Anil | Obisesan, Thomas O. | Jayam-Trouth, Annapurni | Wang, Paul | Lerner, Alan | Hudson, Leon | Ogrocki, Paula | DeCarli, Charles | Fletcher, Evan | Carmichael, Owen | Kittur, Smita | Mirje, Seema | Borrie, Michael | Lee, T-Y | Bartha, Dr Rob | Johnson, Sterling | Asthana, Sanjay | Carlsson, Cynthia M. | Potkin, Steven G. | Preda, Adrian | Nguyen, Dana | Tariot, Pierre | Fleisher, Adam | Reeder, Stephanie | Bates, Vernice | Capote, Horacio | Rainka, Michelle | Hendin, Barry A. | Scharre, Douglas W. | Kataki, Maria | Zimmerman, Earl A. | Celmins, Dzintra | Brown, Alice D. | Gandy, Sam | Marenberg, Marjorie E. | Rovner, Barry W. | Pearlson, Godfrey | Anderson, Karen | Saykin, Andrew J. | Santulli, Robert B. | Englert, Jessica | Williamson, Jeff D. | Sink, Kaycee M. | Watkins, Franklin | Ott, Brian R. | Wu, Chuang-Kuo | Cohen, Ronald | Salloway, Stephen | Malloy, Paul | Correia, Stephen | Rosen, Howard J. | Miller, Bruce L. | Mintzer, Jacobo
Neurology  2012;78(18):1376-1382.
Objective:
To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD).
Methods:
The Alzheimer's Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI.
Results:
CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ42. Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD.
Conclusion:
The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.
doi:10.1212/WNL.0b013e318253d5b3
PMCID: PMC3345787  PMID: 22491869
12.  A Comprehensive Reliability Assessment of Quantitative Diffusion Tensor Tractography 
NeuroImage  2011;60(2):1127-1138.
Diffusion tensor tractography is increasingly used to examine structural connectivity in the brain in various conditions, but its test-retest reliability is understudied. The main purposes of this study were to evaluate 1) the reliability of quantitative measurements of diffusion tensor tractography and 2) the effect on reliability of the number of gradient sampling directions and scan repetition. Images were acquired from ten healthy participants. Ten fiber regions of nine major fiber tracts were reconstructed and quantified using six fiber variables. Intra- and inter-session reliabilities were estimated using intraclass correlation coefficient (ICC) and coefficient of variation (CV), and compared to pinpoint major error sources. Additional pairwise comparisons were made between the reliability of images with 30 directions and NEX 2 (DTI30-2), 30 directions and NEX 1 (DTI30-1), and 15 directions and NEX 2 (DTI15-2) to determine whether increasing gradient directions and scan repetition improved reliability. Of the 60 tractography measurements, 43 showed intersession CV ≤ 10%, ICC ≥ .70, or both for DTI30-2, 40 measurements for DTI30-1, and 37 for DTI15-2. Most of the reliable measurements were associated with the tracts corpus callosum, cingulum, cerebral peduncular fibers, uncinate fasciculus, and arcuate fasciculus. These reliable measurements included factional anisotropy (FA) and mean diffusivity of all 10 fiber regions. Intersession reliability was significantly worse than intra-session reliability for FA, mean length, and tract volume measurements from DTI15-2, indicating that the combination of MRI signal variation and physiological noise/change over time was the major error source for this sequence. Increasing the number of gradient directions from 15 to 30 while controlling the scan time, significantly affected values for all six variables and reduced intersession variability for mean length and tract volume measurements. Additionally, while increasing scan repetition from 1 to 2 had no significant effect on the reliability for DTI with 30 directions, this significantly reduced the upward bias in FA values from all 10 fiber regions and fiber count, mean length, and tract volume measurements from 5-7 fiber regions. In conclusion, diffusion tensor tractography provided many measurements with high test-retest reliability across different fiber variables and various fiber tracts even for images with 15 directions (NEX 2). Increasing the number of gradient directions from 15 to 30 with equivalent scan time reduced variability whereas increasing repetition from 1 to 2 for 30-direction DTI improved the accuracy of tractography measurements.
doi:10.1016/j.neuroimage.2011.12.062
PMCID: PMC3468740  PMID: 22227883
reliability; diffusion tensor imaging; tractography; variability; white matter; fiber tracts
13.  Forebrain-dominant deficit in cerebrovascular reactivity in Alzheimer’s Disease 
Neurobiology of aging  2010;33(1):75-82.
Epidemiologic evidence and postmortem studies of cerebral amyloid angiopathy suggest that vascular dysfunction may play an important role in the pathogenesis of Alzheimer’s Disease (AD). However, alterations in vascular function under in vivo conditions are poorly understood. In this study, we assessed cerebrovascular-reactivity (CVR) in AD patients and age-matched controls using CO2-inhalation while simultaneously acquiring Blood-Oxygenation-Level-Dependent (BOLD) MR images. Compared to controls, AD patients had widespread reduction in CVR in the rostral brain including prefrontal, anterior cingulate, and insular cortex (p<0.01). The deficits could not be explained by cardiovascular risk factors. The spatial distribution of the CVR deficits differed drastically from the regions of cerebral blood flow (CBF) deficits, which were found in temporal and parietal cortices. Individuals with greater CVR deficit tended to have a greater volume of leukoaraiosis as seen on FLAIR MRI (p=0.004). Our data suggest that early AD subjects have evidence of significant forebrain vascular contractility deficits. The localization, while differing from CBF findings, appears to be spatially similar to PIB amyloid imaging findings.
doi:10.1016/j.neurobiolaging.2010.02.005
PMCID: PMC2896562  PMID: 20359779
Alzheimer’s Disease; Vascular function; Cerebrovascular reactivity; Magnetic Resonance Imaging; Cerebral blood flow
14.  Regionally Selective Atrophy after Traumatic Axonal Injury 
Archives of neurology  2010;67(11):1336-1344.
Objectives
To determine the spatial distribution of cortical and subcortical volume loss in patients with diffuse traumatic axonal injury and to assess the relationship between regional atrophy and functional outcome.
Design
Prospective imaging study. Longitudinal changes in global and regional brain volumes were assessed using high-resolution magnetic resonance imaging (MRI)-based morphometric analysis.
Setting
Inpatient traumatic brain injury unit
Patients or Other Participants
Twenty-five patients with diffuse traumatic axonal injury and 22 age- and sex-matched controls.
Main Outcome Measure
Changes in global and regional brain volumes between initial and follow-up MRI were used to assess the spatial distribution of post-traumatic volume loss. The Glasgow Outcome Scale – Extended was the primary measure of functional outcome.
Results
Patients underwent substantial global atrophy with mean brain parenchymal volume loss of 4.5% (95% Confidence Interval: 2.7 – 6.3%). Decreases in volume (at a false discovery rate of 0.05) were seen in several brain regions including the amygdala, hippocampus, thalamus, corpus callosum, putamen, precuneus, postcentral gyrus, paracentral lobule, and parietal and frontal cortices, while other regions such as the caudate and inferior temporal cortex were relatively resistant to atrophy. Loss of whole brain parenchymal volume was predictive of long-term disability, as was atrophy of particular brain regions including the inferior parietal cortex, pars orbitalis, pericalcarine cortex, and supramarginal gyrus.
Conclusion
Traumatic axonal injury leads to substantial post-traumatic atrophy that is regionally selective rather than diffuse, and volume loss in certain regions may have prognostic value for functional recovery.
doi:10.1001/archneurol.2010.149
PMCID: PMC3465162  PMID: 20625067
15.  The Relation between Inflammation and Neuropsychological Test Performance 
Background. Considerable research documents an association between pro- and anti-inflammatory markers and Alzheimer's disease (AD), yet the differential relation between these markers and neuropsychological functioning in AD and nondemented controls has received less attention. The current study sought to evaluate the relationship between peripheral markers of inflammation (both pro- and anti-inflammatory) and neuropsychological functioning through the Texas Alzheimer's Research and Care Consortium (TARCC) cohort. Methods. There were 320 participants (Probable AD n = 124, Controls n = 196) in the TARCC Longitudinal Research Cohort available for analysis. Regression analyses were utilized to examine the relation between proinflammatory and anti-inflammatory markers and neuropsychological functioning. Follow-up analyses were conducted separately by case versus control status. Results. Proinflammatory and anti-inflammatory markers were found to be associated with neuropsychological testing. Third tertile proinflammatory markers were negatively associated with measures of attention and language, and anti-inflammatory markers were positively associated with measures of immediate verbal memory and delayed verbal and visual memory. Conclusions. These findings support the link between peripheral inflammatory markers and neuropsychological functioning and suggest the utility of examining profiles of inflammatory markers in the future.
doi:10.1155/2012/703871
PMCID: PMC3449133  PMID: 23008797
16.  A Blood-Based Algorithm for the Detection of Alzheimer's Disease 
Background
We previously created a serum-based algorithm that yielded excellent diagnostic accuracy in Alzheimer's disease. The current project was designed to refine that algorithm by reducing the number of serum proteins and by including clinical labs. The link between the biomarker risk score and neuropsychological performance was also examined.
Methods
Serum-protein multiplex biomarker data from 197 patients diagnosed with Alzheimer's disease and 203 cognitively normal controls from the Texas Alzheimer's Research Consortium were analyzed. The 30 markers identified as the most important from our initial analyses and clinical labs were utilized to create the algorithm.
Results
The 30-protein risk score yielded a sensitivity, specificity, and AUC of 0.88, 0.82, and 0.91, respectively. When combined with demographic data and clinical labs, the algorithm yielded a sensitivity, specificity, and AUC of 0.89, 0.85, and 0.94, respectively. In linear regression models, the biomarker risk score was most strongly related to neuropsychological tests of language and memory.
Conclusions
Our previously published diagnostic algorithm can be restricted to only 30 serum proteins and still retain excellent diagnostic accuracy. Additionally, the revised biomarker risk score is significantly related to neuropsychological test performance.
doi:10.1159/000330750
PMCID: PMC3169374  PMID: 21865746
Algorithm, blood-based; Alzheimer's disease; Diagnosis
17.  Natural History of Headache after Traumatic Brain Injury 
Journal of Neurotrauma  2011;28(9):1719-1725.
Abstract
Headache is one of the most common persisting symptoms after traumatic brain injury (TBI). Yet there is a paucity of prospective longitudinal studies of the incidence and prevalence of headache in a sample with a range of injury severity. We sought to describe the natural history of headache in the first year after TBI, and to determine the roles of prior history of headache, sex, and severity of TBI as risk factors for post-traumatic headache. A cohort of 452 acute, consecutive patients admitted to inpatient rehabilitation services with TBI were enrolled during their inpatient rehabilitation from February 2008 to June 2009. Subjects were enrolled across 7 acute rehabilitation centers designated as TBI Model Systems centers. They were prospectively assessed by structured interviews prior to inpatient rehabilitation discharge, and at 3, 6, and 12 months after injury. Results of this natural history study suggest that 71% of participants reported headache during the first year after injury. The prevalence of headache remained high over the first year, with more than 41% of participants reporting headache at 3, 6, and 12 months post-injury. Persons with a pre-injury history of headache (p<0.001) and females (p<0.01) were significantly more likely to report headache. The incidence of headache had no relation to TBI severity (p=0.67). Overall, headache is common in the first year after TBI, independent of the severity of injury range examined in this study. Use of the International Classification of Headache Disorders criteria requiring onset of headache within 1 week of injury underestimates rates of post-traumatic headache. Better understanding of the natural history of headache including timing, type, and risk factors should aid in the design of treatment studies to prevent or reduce the chronicity of headache and its disruptive effects on quality of life.
doi:10.1089/neu.2011.1914
PMCID: PMC3172878  PMID: 21732765
headache; natural history; traumatic brain injury
18.  Serum Granulocyte Colony-Stimulating Factor and Alzheimer's Disease 
Background
Granulocyte colony-stimulating factor (G-CSF) promotes the survival and function of neutrophils. G-CSF is also a neurotrophic factor, increasing neuroplasticity and suppressing apoptosis.
Methods
We analyzed G-CSF levels in 197 patients with probable Alzheimer's disease (AD) and 203 cognitively normal controls (NCs) from a longitudinal study by the Texas Alzheimer's Research and Care Consortium (TARCC). Data were analyzed by regression with adjustment for age, education, gender and APOE4 status.
Results
Serum G-CSF was significantly lower in AD patients than in NCs (β = −0.073; p = 0.008). However, among AD patients, higher serum G-CSF was significantly associated with increased disease severity, as indicated by lower Mini-Mental State Examination scores (β = −0.178; p = 0.014) and higher scores on the global Clinical Dementia Rating (CDR) scale (β = 0.170; p = 0.018) and CDR Sum of Boxes (β = 0.157; p = 0.035).
Conclusions
G-CSF appears to have a complex relationship with AD pathogenesis and may reflect different pathophysiologic processes at different illness stages.
doi:10.1159/000341780
PMCID: PMC3457029  PMID: 23012618
Granulocyte colony-stimulating factor; Alzheimer's disease; Inflammation; Serum proteins; Mini-Mental State Examination; Clinical Dementia Rating-Sum of Boxes
19.  Plasma 24S-hydroxycholesterol and other oxysterols in acute closed head injury 
Brain Injury  2008;22(7-8):611-615.
Primary objective
To determine if plasma levels of 24S-hydroxycholesterol, the primary catabolite of brain cholesterol, provide a measure of axonal damage in acute brain trauma.
Research design
Determination of plasma 24S-hydroxycholesterol in a series of persons admitted to an intensive care unit for treatment of closed head injury.
Methods and procedures
Levels of 24-S-hydroxycholesterol, 27-hydroxycholesterol, lathosterol and total cholesterol were measured in peripheral blood from 38 persons from 14–55 years of age treated by craniotomy and ventriculostomy for intractable intracerebral hypertension. Severity of brain injury was estimated by the Glasgow Coma Scale (range = 3–13, median = 6 points) and overall injury by the Injury Severity Scale (range = 10–48, median = 29). All subjects were intubated and anaesthetized with intravenous propofol. Plasma sterol levels were compared with those of age-matched control subjects.
Outcomes and results
There was no significant increase in plasma 24-S-hydroxycholesterol in subjects with head injury, but measures of peripheral cholesterol synthesis were markedly reduced as compared with values for age-matched normal control subjects.
Conclusion
Plasma 24S-hydroxycholesterol levels do not change with severe closed head injury.
doi:10.1080/02699050802196037
PMCID: PMC3399688  PMID: 18568715
Closed head injury; 24-S-hydroxycholesterol; oxysterols
20.  Elevated Serum Pesticide Levels and Risk of Parkinson Disease 
Archives of Neurology  2009;66(7):870-875.
Background
Exposure to pesticides has been reported to increase the risk of Parkinson disease (PD), but identification of the specific pesticides is lacking. Three studies have found elevated levels of organochlorine pesticides in postmortem PD brains.
Objective
To determine whether elevated levels of organochlorine pesticides are present in the serum of patients with PD.
Design
Case-control study.
Setting
An academic medical center.
Participants
Fifty patients with PD, 43 controls, and 20 patients with Alzheimer disease.
Main Outcome Measures
Levels of 16 organochlorine pesticides in serum samples.
Results
β-Hexachlorocyclohexane (β-HCH) was more often detectable in patients with PD (76%) compared with controls (40%) and patients with Alzheimer disease (30%). The median level of β-HCH was higher in patients with PD compared with controls and patients with Alzheimer disease. There were no marked differences in detection between controls and patients with PD concerning any of the other 15 organochlorine pesticides. Finally, we observed a significant odds ratio for the presence of β-HCH in serum to predict a diagnosis of PD vs control (odds ratio, 4.39; 95% confidence interval, 1.67–11.6) and PD vs Alzheimer disease (odds ratio, 5.20), which provides further evidence for the apparent association between serum β-HCH and PD.
Conclusions
These data suggest that β-HCH is associated with a diagnosis of PD. Further research is warranted regarding the potential role of β-HCH as a etiologic agent for some cases of PD.
doi:10.1001/archneurol.2009.89
PMCID: PMC3383784  PMID: 19597089
23.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
Objective
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Design
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Setting
Academic medical centers
Patients
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Results
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Conclusions
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
doi:10.1001/archneurol.2010.295
PMCID: PMC3058918  PMID: 21059987
24.  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families 
PLoS ONE  2012;7(2):e31039.
Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10−5; OR = 2.21; 95%CI = 1.49–3.28) or an unselected population of 12,481 samples (p = 6.82×10−5; OR = 2.19; 95%CI = 1.347–3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.
doi:10.1371/journal.pone.0031039
PMCID: PMC3270040  PMID: 22312439
25.  Serum Brain-Derived Neurotrophic Factor Levels Are Specifically Associated with Memory Performance among Alzheimer's Disease Cases 
Aims
Our purpose was to study the link between serum brain-derived neurotrophic factor (BDNF) levels and neuropsychological functioning through the Texas Alzheimer's Research Consortium cohort.
Methods
A total of 399 participants [probable Alzheimer's disease (AD) n = 198, controls n = 201] were available for analysis. The BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels and neuropsychological functioning.
Results
There were no significant mean differences in BDNF levels between cases and controls. In the AD group, the BDNF levels were significantly negatively associated with the scores on immediate [B = −0.07 (0.02), t = −3.55, p = 0.001] and delayed [B = −0.05 (0.02), t = −2.79, p = 0.01] verbal memory and immediate [B = −0.12 (0.05), t = −2.70, p = 0.01] visual memory. No other neuropsychological variables were significantly related to the BDNF levels. The BDNF levels were not significantly related to the neuropsychological test scores in the control group.
Conclusions
Increased serum BDNF levels were associated with poorer visual and verbal memory, but only among AD cases. The current findings point toward an upregulation of serum BDNF as one possible mechanism linked to memory disturbances in AD though it does not appear to be linked to disease severity.
doi:10.1159/000321980
PMCID: PMC3019366  PMID: 21135555
Alzheimer's disease; Biomarkers; Brain-derived neurotrophic factor; Cognition; Neuropsychology; Aging

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