Identification of Factors in Moderate-Severe TBI Related to a Functional Decline in Cognition Decades After Injury.

OBJECTIVE: To investigate whether a functional decline in cognitive activities decades after moderate-to-severe traumatic brain injury (m-sTBI) might relate to injury features and/or lifetime health factors, some of which may emerge as consequences of the injury. DESIGN: Secondary analysis of the TBI Model Systems National Database, a prospective, multi-center, longitudinal study of patients with m-sTBI. SETTING: TBI Model Systems Centers. PARTICIPANTS: Included were 732 participants rated on the cognitive subscale of the Functional Independence Measure (FIM Cognitive), a metric for everyday cognitive skills, across 3 time points out to 20 years (visits at 2-, 10-, and 20-year follow-ups; N=732). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): FIM Cognitive Scale. Injury characteristics such as timing and features pertaining to severity and health-related factors (eg, alcohol use, socioeconomic status) were examined to discriminate stable from declining participants on the FIM Cognitive Scale using logistic regression. RESULTS: At 20 years post-injury, there was a low base rate of FIM Cognitive decline (11%, n=78), with most being stable or having meaningful improvement (89%, n=654). Older age at injury, longer duration of post-traumatic amnesia, and presence of repetitive seizures were significant predictors of FIM Cognitive decline in the final model (area under the curve=0.75), while multiple health-related factors that can represent independent co-morbidities or possible consequences of injury were not. CONCLUSION(S): The strongest contributors to reported functional decline in cognitive activities later-in-life were related to acute characteristics of m-sTBI and experiencing post-traumatic seizures. Future studies are needed integrating functional with performance-based cognitive assessments to affirm conclusions and identify the timeline and trajectory of cognitive decline.

Hippocampal and rostral anterior cingulate blood flow is associated with affective symptoms in chronic traumatic brain injury.

OBJECTIVE: The purpose of this study was to assess cerebral blood flow (CBF) and its association with self-reported symptoms in chronic traumatic brain injury (TBI). PARTICIPANTS: Sixteen participants with mild to severe TBI and persistent self-reported neurological symptoms, 6 to 72 months post-injury were included. For comparison, 16 age- and gender-matched healthy normal control participants were also included. MAIN MEASURES: Regional CBF and brain volume were assessed using pseudo-continuous Arterial Spin Labeling (PCASL) and T1-weighted data respectively. Cognitive function and self-reported symptoms were assessed in TBI participants using the national institutes of health (NIH) Toolbox Cognition Battery and Patient-Reported Outcome Measurement Information System respectively. Associations between CBF and cognitive function, symptoms were assessed. RESULTS: Global CBF and regional brain volumes were similar between groups, but region of interest (ROI) analysis revealed lower CBF bilaterally in the thalamus, hippocampus, left caudate, and left amygdala in the TBI group. Voxel-wise analysis revealed that CBF in the hippocampus, parahippocampus, rostral anterior cingulate, inferior frontal gyrus, and other temporal regions were negatively associated with self-reported anger, anxiety, and depression symptoms. Furthermore, region of interest (ROI) analysis revealed that hippocampal and rostral anterior cingulate CBF were negatively associated with symptoms of fatigue, anxiety, depression, and sleep issues. CONCLUSION: Regional CBF deficit was observed in the group with chronic TBI compared to the normal control (NC) group despite similar volume of cerebral structures. The observed negative correlation between regional CBF and affective symptoms suggests that CBF-targeted intervention may potentially improve affective symptoms and quality of life after TBI, which needs to be assessed in future studies.

One-Year Aerobic Exercise Reduced Carotid Arterial Stiffness and Increased Cerebral Blood Flow in Amnestic Mild Cognitive Impairment.

BACKGROUND: Central arterial stiffness and brain hypoperfusion are emerging risk factors of Alzheimer's disease (AD). Aerobic exercise training (AET) may improve central arterial stiffness and brain perfusion. OBJECTIVE: To investigate the effects of AET on central arterial stiffness and cerebral blood flow (CBF) in patients with amnestic mild cognitive impairment (MCI), a prodromal stage of AD. METHODS: This is a proof-of-concept, randomized controlled trial that assigned 70 amnestic MCI patients into a 12-month program of moderate-to-vigorous AET or stretching-and-toning (SAT) intervention. Carotid ß-stiffness index and CBF were measured by color-coded duplex ultrasonography and applanation tonometry. Total CBF was measured as the sum of CBF from both the internal carotid and vertebral arteries, and divided by total brain tissue mass assessed with MRI to obtain normalized CBF (nCBF). Episodic memory and executive function were assessed using standard neuropsychological tests (CVLT-II and D-KEFS). Changes in cardiorespiratory fitness were measured by peak oxygen uptake (VO2peak). RESULTS: Total 48 patients (29 in SAT and 19 in AET) were completed one-year training. AET improved VO2peak, decreased carotid ß-stiffness index and CBF pulsatility, and increased nCBF. Changes in VO2peak were associated positively with changes in nCBF (r = 0.388, p = 0.034) and negatively with carotid ß-stiffness index (r = -0.418, p = 0.007) and CBF pulsatility (r = -0.400, p = 0.014). Decreases in carotid ß-stiffness were associated with increases in cerebral perfusion (r = -0.494, p = 0.003). AET effects on cognitive performance were minimal compared with SAT. CONCLUSION: AET reduced central arterial stiffness and increased CBF which may precede its effects on neurocognitive function in patients with MCI.

Carotid Stiffness is Associated with Brain Amyloid-ß Burden in Amnestic Mild Cognitive Impairment.

BACKGROUND: Vascular dysfunction has been implicated in the onset and progression of Alzheimer's disease (AD), yet the relationship of arterial stiffening with brain amyloid-ß (Aß) burden in at risk patients is unclear. OBJECTIVE: We aimed to determine the relationship of aortic and carotid arterial stiffening with Aß burden in patients with amnestic mild cognitive impairment (aMCI), a proposed transitional stage between normal aging and AD. METHODS: Thirty-two older adults with aMCI underwent 18Florbetapir PET amyloid imaging to ascertain Aß burden via standardized uptake value ratio (SUVR). Carotid-femoral pulse wave velocity (cfPWV), which reflects aortic stiffness, and carotid ß stiffness index and distensibility, which reflect local cerebral arterial stiffness, thus having direct impact on the cerebral circulation, were measured using applanation tonometry and ultrasonography. RESULTS: Region-of-interest based analysis showed that precuneus and mean cortex Aß SUVR were correlated positively with carotid ß stiffness index and negatively with carotid distensibility after adjusting for age, sex, mean arterial pressure (MAP), pulse pressure (PP), and APOE4 status. Whole-brain voxel-wise analysis showed that Aß SUVR was positively correlated with carotid ß stiffness index, and negatively with carotid distensibility at the precuneus/cingulate gyrus after multiple comparison correction. cfPWV was not correlated with Aß SUVR. CONCLUSIONS: Carotid rather than aortic stiffening was independently associated with brain Aß burden in patients with aMCI after adjusting for age, sex, MAP, PP, and APOE4 status. These findings provide evidence that arterial stiffening, particularly carotid artery stiffening, may contribute to AD pathology in patients with aMCI.

The test-retest reliability of three computerized neurocognitive tests used in the assessment of sport concussion.

Computerized neurocognitive tests (CNTs) are widely used at all competitive levels of sport to assess sport concussion (SC). Whereas there are multiple CNTs available, little is known about how some of the most popular platforms compare. The purpose of this study was to investigate the test-retest reliability of the Automated Neuropsychological Assessment Metrics (ANAM), Concussion Vital Signs (CVS) and the Immediate Postconcussion and Cognitive Testing battery (ImPACT) using clinically relevant time points in healthy college-age participants. Participants were healthy college-age students (N=128) randomly assigned into one of three groups which were administered ANAM, CVS, or ImPACT at Days 1, 45 and 50. Intraclass correlation coefficients (ICCs) and Pearson correlations were used to assess reliability of the various CNT scores and subtest scores between time points. Participants were tested approximately 47.1±2.75days after time point 1 and approximately 7.0±2.45days after time point 2. ICC values ranged from 0.18 (Procedural Reaction Time) to 0.53 (Mathematical Processing and Simple Reaction Time 1) for ANAM, 0.14 (Continuous Performance Test) to 0.85 (Reaction Time) for CVS, and 0.19 (Verbal Memory) to 0.89 (Visual Motor Speed) for ImPACT. Significant improvements (p<0.05) across time were observed for (7/10) CNS Vital Signs composite scores, but no additional significant changes in performance were observed for the remaining CNTs. Overall, weak to strong reliability coefficients for ANAM, CVS, and ImPACT were observed when using clinically relevant time points of repeated administration.

Use of the Montreal Cognitive Assessment and Alzheimer's Disease-8 as cognitive screening measures in Parkinson's disease.

OBJECTIVE: To examine the sensitivity and specificity of the Montreal Cognitive Assessment (MoCA), a brief cognitive screening measure previously validated for use in Parkinson's disease (PD), and Alzheimer's Disease-8 (AD8), an eight-item informant report used to screen for dementia, but not yet validated for use in PD, to identify cognitive impairment in a sample of 111 patients with PD. METHODS: Cognitive impairment was determined based on a battery of neuropsychological measures, excluding the MoCA and AD8. Classification rates of both the MoCA and AD8 in identifying cognitive impairment were examined using logistic regression and receiver operator characteristic (ROC) analysis. Optimal cutoff scores were determined to maximize sensitivity and specificity. RESULTS: The MoCA correctly classified 78.4% of participants (p < 0.001), and ROC analysis yielded an area under the curve (AUC) of 0.82. A MoCA cutoff score of <25 yielded optimal sensitivity (0.77) and specificity (0.79) for identifying PD patients with cognitive impairment. Similar analyses for the AD8 were statistically nonsignificant, although the classification rate was 70.5%, with an AUC of 0.50. CONCLUSIONS: These results provide additional support for the MoCA, but not the AD8, in identifying cognitive impairment in patients with PD.

Central artery stiffness, baroreflex sensitivity, and brain white matter neuronal fiber integrity in older adults.

Cerebral hypoperfusion elevates the risk of brain white matter (WM) lesions and cognitive impairment. Central artery stiffness impairs baroreflex, which controls systemic arterial perfusion, and may deteriorate neuronal fiber integrity of brain WM. The purpose of this study was to examine the associations among brain WM neuronal fiber integrity, baroreflex sensitivity (BRS), and central artery stiffness in older adults. Fifty-four adults (65 ± 6 years) with normal cognitive function or mild cognitive impairment (MCI) were tested. The neuronal fiber integrity of brain WM was assessed from diffusion metrics acquired by diffusion tensor imaging. BRS was measured in response to acute changes in blood pressure induced by bolus injections of vasoactive drugs. Central artery stiffness was measured by carotid-femoral pulse wave velocity (cfPWV). The WM diffusion metrics including fractional anisotropy (FA) and radial (RD) and axial (AD) diffusivities, BRS, and cfPWV were not different between the control and MCI groups. Thus, the data from both groups were combined for subsequent analyses. Across WM, fiber tracts with decreased FA and increased RD were associated with lower BRS and higher cfPWV, with many of the areas presenting spatial overlap. In particular, the BRS assessed during hypotension was strongly correlated with FA and RD when compared with hypertension. Executive function performance was associated with FA and RD in the areas that correlated with cfPWV and BRS. These findings suggest that baroreflex-mediated control of systemic arterial perfusion, especially during hypotension, may play a crucial role in maintaining neuronal fiber integrity of brain WM in older adults.

Teleneuropsychology: evidence for video teleconference-based neuropsychological assessment.

The use of videoconference technology to deliver health care diagnostics and treatment continues to grow at a rapid pace. Telepsychiatry and telepsychology applications are well-accepted by patients and providers, and both diagnostic and treatment outcomes have generally been similar to traditional face-to-face interactions. Preliminary applications of videoconference-based neuropsychological assessment (teleneuropsychology) have yielded promising results in the feasibility and reliability of several standard tests, although large-scale studies are lacking. This investigation was conducted to determine the reliability of video teleconference (VTC) - based neuropsychological assessment using a brief battery of standard neuropsychological tests commonly used in the evaluation of known or suspected dementia. Tests included the Mini-Mental State Examination (MMSE), Hopkins Verbal Learning Test-Revised, Digit Span forward and backward, short form Boston Naming Test, Letter and Category Fluency, and Clock Drawing. Tests were administered via VTC and in-person to subjects, counterbalanced using alternate test forms and standard instructions. Two hundred two adult subjects were tested in both rural and urban settings, including 83 with cognitive impairment and 119 healthy controls. We found highly similar results across VTC and in-person conditions, with significant intraclass correlations (mean=.74; range: 0.55-0.91) between test scores. Findings remained consistent in subjects with or without cognitive impairment and in persons with MMSE scores as low as 15. VTC-based neuropsychological testing is a valid and reliable alternative to traditional face-to-face assessment using selected measures. More VTC-based studies using additional tests in different populations are needed to fully explore the utility of this new testing medium.

Elevated CNS inflammation in patients with preclinical Alzheimer's disease.

Alzheimer's disease (AD) is a progressive, neurodegenerative disease that may involve inflammatory responses in the central nervous system (CNS). Our objective was to determine whether patients with amnestic mild cognitive impairment (aMCI), a preclinical stage of AD, have inflammatory characteristics similar to patients with multiple sclerosis (MS), a known CNS inflammatory disease. The frequency of lymphocytes and levels of pro-inflammatory cytokines in the cerebrospinal fluid of aMCI patients was comparable to MS patients or patients at high risk to develop MS. Thus, brain inflammation occurs early at the preclinical stage of AD and may have an important role in pathology.

Depressive symptoms and concussions in aging retired NFL players.

We examined the relationship between a remote history of concussions with current symptoms of depression in retired professional athletes. Thirty retired National Football League (NFL) athletes with a history of concussion and 29 age- and IQ-matched controls without a history of concussion were recruited. We found a significant correlation between the number of lifetime concussions and depressive symptom severity using the Beck Depression Inventory II. Upon investigating a three-factor model of depressive symptoms (affective, cognitive, and somatic; Buckley et al., 2001) from the BDI-II, the cognitive factor was the only factor that was significantly related to concussions. In general, NFL players endorsed more symptoms of depression on all three Buckley factors compared with matched controls. Findings suggest that the number of self-reported concussions may be related to later depressive symptomology (particularly cognitive symptoms of depression).

Expanding the ecological validity of WAIS-IV and WMS-IV with the Texas functional living scale.

Assessment of functional status is an important aspect of clinical evaluation. As part of the standardization of the Wechsler Adult Intelligence Scale-Fourth Edition (WAIS-IV) and Wechsler Memory Scale-Fourth Edition (WMS-IV), participants completed the Texas Functional Living Scale (TFLS), a measure of Instrumental Activities of Daily Living. The relationships between TFLS and WAIS-IV and WMS-IV were examined in both normally developing and clinical samples. In general, the highest correlations were between TFLS and measures of general cognitive ability (WAIS-IV FSIQ [Full Scale IQ] and GAI [General Ability Index]) and working memory (WAIS-IV WMI [Working Memory Index] and WMS-IV VWMI [Visual Working Memory Index]). Across the clinical populations, working memory subtests were generally strongly related to TFLS performance, although this relationship was more consistent with WAIS-IV than WMS-IV. Contrast scaled scores are presented for the TFLS based on WAIS-IV or WMS-IV performance. These scores allow the evaluation of functional abilities within the context of cognitive and memory ability, enhancing and expanding the utility of the WAIS-IV and WMS-IV.

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 3 Tesla magnet. Patients were scanned approximately eight months postinjury, and underwent an outcomes assessment at that time. Histogram analysis of fractional anisotropy (FA) and mean diffusivity 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.

The CERAD Neuropsychologic Battery Total Score and the progression of Alzheimer disease.

OBJECTIVE: To establish the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychologic battery as a valid measure of cognitive progression in Alzheimer disease (AD) by deriving annualized CERAD Total Change Scores and corresponding confidence intervals in AD and controls from which to define clinically meaningful change. METHOD: Subjects included 383 normal control (NC) and 655 AD subjects with serial data from the CERAD registry database. Annualized CERAD Total Change Scores were derived and Reliable Change Indexes (RCIs) calculated to establish statistically reliable change values. CERAD Change Scores were compared with annualized change scores from the Mini-Mental State Examination (MMSE), Clinical Dementia Rating Scale (CDR) Sum of Boxes, and Blessed Dementia Rating Scale (BDRS). RESULTS: For the CERAD Total Score, the AD sample showed significantly greater decline than the NC sample over the 4-year interval, with AD subjects declining an average of 22.2 points compared with the NCs' improving an average 2.8 points from baseline to last visit [Group x Time interaction [F(4,1031)=246.08, P<0.001)]. By Visit 3, the majority of AD subjects (65.2%) showed a degree of cognitive decline that fell outside the RCI. CERAD Change Scores significantly correlated (P<0.001) with MMSE (r=-0.66), CDR (r=-0.42), and BDRS (r=-0.38) change scores. CONCLUSION: Results support the utility of the CERAD Total Score as a measure of AD progression and provide comparative data for annualized change in CERAD Total Score and other summary measures.

A direct functional measure to help ascertain optimal level of residential care.

A brieF direct measure oF daily living skills might help place cognitively impaired elders in suitable living environments. In this study, the Test oF Everyday Functional Abilities (TEFA) as a possible adjunctive measure was investigated. The authors recruited 77 cognitively impaired persons in independent living (IL; N = 26), assisted living (AL; N = 25), and dementia special care (SC; N = 26) units. Participants in IL and AL were administered the TEFA and other instruments at baseline and every 6 months over 18 months and when transFerred to a higher level oF care. Special care subjects were administered the same instruments only at baseline. The TEFA clearly separated IL, AL, and SC residents (P < .0001). A TEFA score >50 suggests adequate Functional competence For IL; a score From 30 to 40 adequate Functional competence For AL; and a score oF <30 probable need For an SC unit in the absence oF a capable spouse.

Patterns of verbal memory performance in mild cognitive impairment, Alzheimer disease, and normal aging.

OBJECTIVE: Individuals with mild cognitive impairment (MCI) typically demonstrate memory loss that falls between normal aging (NA) and Alzheimer disease (AD), but little is known about the pattern of memory dysfunction in MCI. METHOD: To explore this issue, California Verbal Learning Test (CVLT) performance was examined across groups of MCI, AD, and NA. RESULTS: MCI subjects displayed a pattern of deficits closely resembling that of AD, characterized by reduced learning, rapid forgetting, increased recency recall, elevated intrusion errors, and poor recognition discriminability with increased false-positives. MCI performance was significantly worse than that of controls and better than that of AD patients across memory indices. Although qualitative analysis of CVLT profiles may be useful in individual cases, discriminant function analysis revealed that delayed recall and total learning were the best aspects of learning/memory on the CVLT in differentiating MCI, AD, and NA. CONCLUSIONS: These findings support the position that amnestic MCI represents an early point of decline on the continuum of AD that is different from normal aging.

Association between Dementia Rating Scale performance and neurocognitive domains in Alzheimer's disease.

The Dementia Rating Scale (DRS; Mattis, 1976, 1988) is commonly used in the assessment of dementia, although little is known about the relationship of performance on this test to specific cognitive deficits in Alzheimer's disease (AD). Additionally, cognitive profiles have not been investigated across different levels of dementia as determined by the DRS. A sample of 133 individuals diagnosed with possible or probable AD was administered the DRS as part of a comprehensive neuropsychological evaluation. Composite scores for the cognitive domains of attention, executive functioning, visuospatial skills, language abilities, immediate recall, and delayed memory were derived by averaging demographically corrected T scores of key measures. Individual domain scores were also averaged to develop a global index score. Pearson correlations between composite and total DRS scores were highly significant (p<.001) for all domains and the global index score, with the exception of delayed memory, which showed a floor effect. When the sample was divided into mild and moderate-to-severe groups to examine the effects of disease severity on the relationship between the DRS and standard neurocognitive domain scores, the resulting mean neuropsychological profile scores were significantly different while maintaining a parallel pattern of impairment across domains. Results demonstrate the relationship between the DRS and standard cognitive domain functions, which appears to underscore the validity and robustness of the DRS in characterizing patterns of cognitive impairment across the AD spectrum.

Comparative analysis of qualitative verbal fluency performance in normal elderly and demented populations.

Verbal fluency tasks are commonly used in the assessment of patients with known or suspected dementia. Whereas total word production is often analyzed, less attention has been paid to qualitative aspects of verbal fluency performance. The purpose of this study was to examine the diagnostic utility of a qualitative scoring technique for semantic and phonemic fluency tasks in individuals with Alzheimer's disease (AD), Parkinson's disease (PD) with and without dementia, and in a group of older normal controls (ONC). In addition to total words produced, the groups were compared on their use of clustering (i.e., ratio of words generated within subcategories) and switching (i.e., frequency of shifts between clusters) strategies as originally defined by Troyer et al. (1997a). In terms of total number of words produced, controls were superior to the AD and demented PD subjects, who performed similarly. A similar trend was found in relation to switching and clustering scores. PD patients without dementia performed similar to the ONC group on semantic fluency, but were impaired relative to controls on all phonemic fluency variables (i.e., total words produced, clustering, switching). Discriminant function analyses using the three fluency variables revealed that total words was equal to or surpassed the other variables in distinguishing the groups, suggesting that these qualitative verbal fluency features may not provide significant additional information in terms of diagnostic utility.

Normal aging and forgetting rates on the Wechsler Memory Scale-Revised.

The deleterious effects of aging on various cognitive abilities are widely recognized, yet little is known regarding what constitutes "normal" memory test performance in individuals over the age of 74. In this study, forgetting rates for verbal and nonverbal material from the Wechsler Memory Scale-Revised (WMS-R) were examined in groups of older healthy individuals, age 50-70 and 75-95. Despite equivalent scores on measures of global cognitive status and attention/ concentration, the older group demonstrated significantly more rapid forgetting rates on the Visual Reproduction, Verbal Paired Associates, and Visual Paired Associates subtests of the WMS-R. Although patients with Alzheimer's disease also evidence very rapid forgetting on some subtests, the severity and pattern of losses appears useful in differentiating "abnormal" forgetting from that exhibited by normal elderly subjects. Preliminary normative data for normal elderly subjects on the WMS-R are presented, and the need for appropriate norms for elderly individuals is discussed.