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1.  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.
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.
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.
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.
PMCID: PMC3812419  PMID: 23908143
Aging; brain; cognition; exercise; MRI
2.  Older Adults with Amnestic Mild Cognitive Impairment Exhibit Exacerbated Gait Slowing under Dual-Task Challenges 
Current Alzheimer research  2014;11(5):494-500.
With age, performance of motor tasks becomes more reliant on cognitive resources to compensate for the structural and functional declines in the motor control regions in the brain. We hypothesized that participants with amnestic mild cognitive impairment (aMCI) are more prone to motor dysfunctions than cognitively normal older adults under dual-task conditions where competitive demands challenge cognitive functions while performing a motor task simultaneously.
Sixteen aMCI participants (females=9, age=64±5yrs, clinical dementia rating score=0.5) and 10 age- and education-matched cognitively normal adults (females=5, age=62±6yrs) participated. Using a 10-meter-walk test (10MW), gait velocity was recorded at baseline and under 4 different dual-task (DT) conditions designed to challenge working memory, executive function, and episodic memory. Specifically, DT1: verbal fluency; DT2: 5-digit backward span; DT3: serial-7 subtraction; and DT4: 3-item delayed recall. Physical function was measured by Timed Up-and-Go (TUG), simple reaction time (RT) to a free-falling yardstick, and functional reach (FR).
No difference was found in physical functions, aerobic fitness, and exercise cardiopulmonary responses between aMCI participants and controls. However, aMCI participants showed more pronounced gait slowing from baseline when compared to the controls (p<0.05; p=0.001; p<0.001; p<0.001, respectively).
Our finding supports the theory of shared resource of motor and cognitive control. Participants with aMCI manifested more gait slowing than cognitively-normal older adults under DT conditions, with the largest differences during tests of working and episodic memory. The outcome of dual-task assessment shows promise as a potential marker for detection of aMCI and early Alzheimer disease.
PMCID: PMC4082490  PMID: 24801217
Dual-task; early detection; gait; mild cognitive impairment; motor control
3.  Depressive symptoms and white matter dysfunction in retired NFL players with concussion history 
Neurology  2013;81(1):25-32.
To determine whether correlates of white matter integrity can provide general as well as specific insight into the chronic effects of head injury coupled with depression symptom expression in professional football players.
We studied 26 retired National Football League (NFL) athletes who underwent diffusion tensor imaging (DTI) scanning. Depressive symptom severity was measured using the Beck Depression Inventory II (BDI-II) including affective, cognitive, and somatic subfactor scores (Buckley 3-factor model). Fractional anisotropy (FA) maps were processed using tract-based spatial statistics from FSL. Correlations between FA and BDI-II scores were assessed using both voxel-wise and region of interest (ROI) techniques, with ROIs that corresponded to white matter tracts. Tracts demonstrating significant correlations were further evaluated using a receiver operating characteristic curve that utilized the mean FA to distinguish depressed from nondepressed subjects.
Voxel-wise analysis identified widely distributed voxels that negatively correlated with total BDI-II and cognitive and somatic subfactors, with voxels correlating with the affective component (p < 0.05 corrected) localized to frontal regions. Four tract ROIs negatively correlated (p < 0.01) with total BDI-II: forceps minor, right frontal aslant tract, right uncinate fasciculus, and left superior longitudinal fasciculus. FA of the forceps minor differentiated depressed from nondepressed athletes with 100% sensitivity and 95% specificity.
Depressive symptoms in retired NFL athletes correlate negatively with FA using either an unbiased voxel-wise or an ROI-based, tract-wise approach. DTI is a promising biomarker for depression in this population.
PMCID: PMC3770203  PMID: 23709590
4.  Neuroimaging of Cognitive Dysfunction and Depression in Aging Retired NFL Players: A cross-sectional study 
JAMA neurology  2013;70(3):326-335.
To assess for the presence of cognitive impairment and depression in aging former NFL players, and identify neuroimaging correlates of these dysfunctions.
Comparison of aging NFL players with cognitive impairment and depression to those without these dysfunctions and with matched healthy controls
Research center in the North Texas region of the United States.
We performed a cross-sectional study of retired professional football players with and without a history of concussion recruited from the North Texas region, along with age-, education-, and IQ-matched controls. We studied thirty-four retired NFL players (mean age 62) neurologically and neuropsychologically. A subset of 26 also underwent detailed neuroimaging; imaging data in this subset were compared to imaging data acquired in 26 healthy matched controls.
Main Outcome Measures
Neuropsychological measures, clinical diagnoses of depression, neuroimaging measures of white matter pathology, and a measure of cerebral blood flow (CBF).
Of the 34 participants, 20 were cognitively normal, 4 were diagnosed with a fixed cognitive deficit, 8 with Mild Cognitive Impairment, and 2 with dementia; 8 were diagnosed with depression. Of the subgroup in which neuroimaging data were acquired, cognitively impaired (CI) participants showed greatest deficits on tests of naming, word finding, and visual/verbal episodic memory. We found significant differences in white matter abnormalities in CI players and depressed players compared to their respective controls. Regional blood flow differences in the CI group (left temporal pole, inferior parietal lobule, superior temporal gyrus) corresponded to regions associated with impaired neurocognitive performance (problems with memory, naming and word finding).
Cognitive deficits and depression appear to be more common in aging NFL players compared to controls. These deficits are correlated with white matter abnormalities and changes in regional CBF.
PMCID: PMC4016798  PMID: 23303193
concussion; memory; depression; cognition; NFL; white matter; DTI; ASL; aging
5.  Predictive Pursuit Association with Deficits in Working Memory in Psychosis 
Biological psychiatry  2012;72(9):752-757.
Deficits in smooth pursuit eye movements (SPEM) are an established phenotype for schizophrenia (SZ) and are being investigated as a potential liability marker for bipolar disorder. While the molecular determinants of this deficit are still unclear, research has verified deficits in predictive pursuit mechanisms in SZ. Because predictive pursuit may depend on the working memory system, we have hypothesized a relationship between the two in healthy controls (HC) and SZ, and here examine whether it extends to psychotic bipolar disorder (BDP).
Volunteers with SZ (n = 38), BDP (n = 31), and HC (n = 32), performed a novel eye movement task to assess predictive pursuit as well as a standard visuospatial measure of working memory.
Individuals with SZ and BDP both showed reduced predictive pursuit gain compared with HC (p <.05). Moreover, each patient group showed worse performance in visuospatial working memory compared to controls (p <.05). A strong correlation (r = .53, p =.007) was found between predictive pursuit gain and working memory in HC, a relationship that showed a trend correlation within the BDP group but not among SZ.
Individuals with SZ and BDP showed similar deficits in predictive pursuit, suggesting that this alteration could be a characteristic trait of the psychosis domain. The correlation between predictive pursuit and working memory in HC supports the assumption that working memory is related to predictive pursuit eye movements; however, the degradation of working memory in people with psychosis disrupts its association with eye tracking behavior.
PMCID: PMC3427716  PMID: 22554452
psychosis; schizophrenia; bipolar disorder; smooth pursuit eye movement; predictive pursuit; working memory
6.  Motor Symptoms at Onset of Parkinson Disease and Risk for Cognitive Impairment and Depression 
To determine if side and type of initial motor symptoms in Parkinson disease predict risk for later development of cognitive impairment or depressive symptoms.
We recruited 124 nondemented patients with Parkinson disease to participate in a cohort study of cognitive function and depressive symptoms that used validated neuropsychological tests and a depressive symptom inventory. We first reviewed the patients’ charts to determine their initial motor symptom and side of onset, and then classified the patients into 4 groups: right-side onset tremor, right-side onset bradykinesia/rigidity, left-side onset tremor, and left-side onset bradykinesia/rigidity. We excluded patients with bilateral symptom onset. We used analysis of variance on neuropsychological test performance and depressive symptoms to determine if group classification affected risk of cognitive impairment or depressive symptoms. We controlled our analyses for disease duration and motor severity as measured by the Unified Parkinson Disease Rating Scale Part III motor score.
There were no differences in any cognitive measure by side and type of initial motor symptoms. The right-side onset tremor group had the lowest depressive symptom scores, and no patient in any group reported severe depressive symptoms.
Our findings suggest that patterns of nigral cell loss correlating to the initial side and type of motor symptoms in Parkinson disease are not related to the risk of later cognitive impairment. By contrast, patients with right-side onset of tremor appear to have a lower risk of depressive symptoms than patients with other presentations.
PMCID: PMC3477612  PMID: 22960435
7.  Donepezil effects on hippocampal and prefrontal functional connectivity in Alzheimer’s disease: Preliminary report 
Journal of Alzheimer's disease : JAD  2012;31(0 3):S221-S226.
We used functional connectivity magnetic resonance imaging (fcMRI) to investigate changes in interhemispheric brain connectivity in 11 patients with mild Alzheimer’s disease (AD) following eight weeks of treatment with the cholinesterase inhibitor donepezil. We examined functional connectivity between four homologous temporal, frontal, and occipital regions. These regions were selected to represent sites of AD neuropathology, sites of donepezil-related brain activation change in prior studies, and sites that are minimally affected by the pathologic changes of AD. Based on previous findings of selective, localized frontal responses to donepezil, we predicted that frontal connectivity would be most strongly impacted by treatment. Of the areas we examined, we found that treatment had a significant effect only on functional connectivity between right and left dorsolateral prefrontal cortices. Implications for understanding the impact of donepezil treatment on brain functioning and behavior in patients with AD are discussed. This preliminary report suggests that fcMRI may provide a useful index of treatment outcome in diseases affecting brain connectivity. Future research should investigate these treatment-related changes in larger samples of patients and age-matched controls.
PMCID: PMC3749074  PMID: 22886013
Alzheimer’s disease; donepezil; functional connectivity; dorsolateral prefrontal cortex; hippocampus
8.  Consumer Acceptability of Brief Videoconference-based Neuropsychological Assessment in Older Individuals with and without Cognitive Impairment 
The Clinical neuropsychologist  2013;27(5):808-817.
Growing evidence suggests that neuropsychological assessment via videoconference shows good agreement with traditional in-person assessment. However, there are few published studies regarding patient acceptability of this methodology, particularly in individuals with cognitive impairment. In this study we sought to evaluate patient preferences and acceptability of teleneuropsychology to further shed light on the viability of this cognitive assessment medium. We examined acceptability of videoconference-based neuropsychological assessment among healthy aging individuals and in subjects with mild cognitive impairment or early stage Alzheimer disease. We found that teleneuropsychology appears to be well accepted by consumers. Our results reflected 98% satisfaction, and roughly 2/3 of participants indicated no preference between traditional face-to-face testing and examination by teleneuropsychology. Furthermore, even participants with cognitive impairment showed good acceptability of teleneuropsychological assessment. In conjunction with the preliminary data on reliability and validity from this growing literature, these results support teleneuropsychology as a viable and acceptable method for assessing cognitive functioning, and show promise for the implementation and utilization of this cognitive assessment medium in clinical and research settings.
PMCID: PMC3692573  PMID: 23607729
9.  Assessment of cognition in early dementia 
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
PMCID: PMC3613863  PMID: 23559893
10.  A Blood-Based Algorithm for the Detection of Alzheimer's Disease 
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.
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.
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.
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.
PMCID: PMC3169374  PMID: 21865746
Algorithm, blood-based; Alzheimer's disease; Diagnosis
11.  Staging Dementia Using Clinical Dementia Rating Scale Sum of Boxes Scores 
Archives of neurology  2008;65(8):1091-1095.
The Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB) score is commonly used, although the utility regarding this score in staging dementia severity is not well established.
To investigate the effectiveness of CDRSOB scores in staging dementia severity compared with the global CDR score.
Retrospective study.
Texas Alzheimer's Research Consortium minimum data set cohort.
A total of 1577 participants (110 controls, 202 patients with mild cognitive impairment, and 1265 patients with probable Alzheimer disease) were available for analysis.
Main Outcome Measures
Receiver operating characteristic curves were generated from a derivation sample to determine optimal cutoff scores and ranges, which were then applied to the validation sample.
Optimal ranges of CDR-SOB scores corresponding to the global CDR scores were 0.5 to 4.0 for a global score of 0.5, 4.5 to 9.0 for a global score of 1.O, 9.5 to 15.5 for a global score of 2.0, and 16.0 to 18.0 for a global score of 3.0. When applied to the validation sample, κ scores ranged from 0.86 to 0.94 (P <.001 for all), with 93.0% of the participants falling within the new staging categories.
The CDR-SOB score compares well with the global CDR score for dementia staging. Owing to the increased range of values, the CDR-SOB score offers several advantages over the global score, including increased utility in tracking changes within and between stages of dementia severity. Interpretive guidelines for CDR-SOB scores are provided.
PMCID: PMC3409562  PMID: 18695059
12.  Diffusion Tensor Imaging Biomarkers for Traumatic Axonal Injury: Analysis of Three Analytic Methods 
Traumatic axonal injury (TAI) is a common mechanism of traumatic brain injury not readily identified using conventional neuroimaging modalities. Novel imaging modalities such as diffusion tensor imaging (DTI) can detect microstructural compromise in white matter (WM) in various clinical populations including TAI. DTI-derived data can be analyzed using global methods (i.e., WM histogram or voxel based approaches) or a regional approach (i.e., tractography). While each of these methods produce qualitatively comparable results, it is not clear which is most useful in clinical research and ultimately in clinical practice. This study compared three methods of analyzing DTI-derived data with regard to detection of WM injury and their association with clinical outcomes. Thirty patients with TAI and 19 demographically similar normal controls were scanned using a 3T magnet. Patients were scanned approximately eight months post-injury, and underwent an outcomes assessment at that time. Histogram analysis of FA and MD showed global WM integrity differences between patients and controls. Voxel-based and tractography analyses showed significant decreases in FA within centroaxial structures involved in TAI. All three techniques were associated with functional and cognitive outcomes. DTI measures of microstructural integrity appear robust, as the three analysis techniques studied showed adequate utility for detecting WM injury.
PMCID: PMC3097093  PMID: 21070694
DTI; DAI; Traumatic Brain Injury; memory; Tractography; cognitive outcomes
13.  Brain-Derived Neurotrophic Factor Levels in Alzheimer's Disease 
The current search for biomarkers that are diagnostic and/or prognostic of Alzheimer's disease (AD) is of vital importance given the rapidly aging population. It was recently reported that brain derived neurotrophic factor (BDNF) fluctuated according to AD severity, suggesting that BDNF might have utility for diagnostics and monitoring of therapeutic efficacy. The current study sought to examine whether BDNF levels varied according to AD severity, as previously reported.
There were 196 participants (Probable AD n = 98, Controls n = 98) in the Texas Alzheimer's Research Consortium (TARC) Longitudinal Research Cohort available for analysis. BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels, MMSE, and CDR scores adjusting for age and gender.
In adjusted models, BDNF levels did not distinguish between AD patients and normal controls and did not significantly predict AD severity or global cognitive functioning.
These findings do not support the notion that BDNF serves as a diagnostic marker for AD or disease severity. It is likely that the most accurate approach to identifying biomarkers of AD will be through an algorithmic approach that combines multiple markers reflective of various pathways.
PMCID: PMC2787708  PMID: 19363274
Alzheimer's disease; Biomarkers; BDNF; Dementia Severity; Clinical Dementia Rating
NeuroRehabilitation  2009;24(1):75-85.
Neuropsychological evaluations conducted in the United States and abroad commonly include the use of tests translated from English to Spanish. The use of translated naming tests for evaluating predominately Spanish-speakers has recently been challenged on the grounds that translating test items may compromise a test’s construct validity. The Texas Spanish Naming Test (TNT) has been developed in Spanish specifically for use with Spanish-speakers; however, it is unlikely patients from diverse Spanish-speaking geographical regions will perform uniformly on a naming test. The present study evaluated and compared the internal consistency and patterns of item-difficulty and -discrimination for the TNT and two commonly used translated naming tests in three countries (i.e., United States, Colombia, Spain). Two hundred fifty two subjects (126 demented, 116 nondemented) across three countries were administered the TNT, Modified Boston Naming Test-Spanish, and the naming subtest from the CERAD. The TNT demonstrated superior internal consistency to its counterparts, a superior item difficulty pattern than the CERAD naming test, and a superior item discrimination pattern than the MBNT-S across countries. Overall, all three Spanish naming tests differentiated nondemented and moderately demented individuals, but the results suggest the items of the TNT are most appropriate to use with Spanish-speakers. Preliminary normative data for the three tests examined in each country are provided.
PMCID: PMC2666471  PMID: 19208960
15.  Can a Direct IADL Measure Detect Deficits in Persons with MCI? 
Current Alzheimer research  2009;6(1):48-51.
To determine if a direct measure of instrumental activities of daily living (IADL) scale designed for use with dementia patients can detect differences between persons with mild cognitive impairment (MCI) and normal elderly control subjects (NC).
This study used cross-sectional and longitudinal IADL scale data from MCI and NC subjects followed at an Alzheimer’s Disease Center.
On a 52-point scale, MCI subjects (n = 30) scored significantly lower than NC subjects (n = 30) on the IADL scale (total score 47.17 vs. 48.77 points; t (58) = 2.34, p = .011) and its Memory subscale (5.27 vs. 6.6 points; t (58) = 3.29, p = .002).Examination of annualized IADL scale change scores revealed that 50% of MCI subjects had declined by one point, compared with 29% of NC.
A direct IADL measure for dementia patients is able to detect small differences between MCI and NC and cross-sectionally and longitudinally, but does not distinguish between groups.
PMCID: PMC2655701  PMID: 19199874
Mild cognitive impairment; IADL; texas functional living scale

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