Gene Expression Alterations in Peripheral Blood Following Sport-Related Concussion in a Prospective Cohort of Collegiate Athletes: A Concussion Assessment, Research and Education (CARE) Consortium Study.

BACKGROUND: Molecular-based approaches to understanding concussion pathophysiology provide complex biological information that can advance concussion research and identify potential diagnostic and/or prognostic biomarkers of injury. OBJECTIVE: The aim of this study was to identify gene expression changes in peripheral blood that are initiated following concussion and are relevant to concussion response and recovery. METHODS: We analyzed whole blood transcriptomes in a large cohort of concussed and control collegiate athletes who were participating in the multicenter prospective cohort Concussion Assessment, Research, and Education (CARE) Consortium study. Blood samples were collected from collegiate athletes at preseason (baseline), within 6 h of concussion injury, and at four additional prescribed time points spanning 24 h to 6 months post-injury. RNA sequencing was performed on samples from 230 concussed, 130 contact control, and 102 non-contact control athletes. Differential gene expression and deconvolution analysis were performed at each time point relative to baseline. RESULTS: Cytokine and immune response signaling pathways were activated immediately after concussion, but at later time points these pathways appeared to be suppressed relative to the contact control group. We also found that the proportion of neutrophils increased and natural killer cells decreased in the blood following concussion. CONCLUSIONS: Transcriptome signatures in the blood reflect the known pathophysiology of concussion and may be useful for defining the immediate biological response and the time course for recovery. In addition, the identified immune response pathways and changes in immune cell type proportions following a concussion may inform future treatment strategies.

A protein panel in cerebrospinal fluid for diagnostic and predictive assessment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease with heterogenous pathophysiological changes that develop years before the onset of clinical symptoms. These preclinical changes have generated considerable interest in identifying markers for the pathophysiological mechanisms linked to AD and AD-related disorders (ADRD). On the basis of our prior work integrating cerebrospinal fluid (CSF) and brain proteome networks, we developed a reliable and high-throughput mass spectrometry-selected reaction monitoring assay that targets 48 key proteins altered in CSF. To test the diagnostic utility of these proteins and compare them with existing AD biomarkers, CSF collected at baseline visits was assayed from 706 participants recruited from the Alzheimer's Disease Neuroimaging Initiative. We found that the targeted CSF panel of 48 proteins (CSF 48 panel) performed at least as well as existing AD CSF biomarkers (Aß42, tTau, and pTau181) for predicting clinical diagnosis, FDG PET, hippocampal volume, and measures of cognitive and dementia severity. In addition, for each of those outcomes, the CSF 48 panel plus the existing AD CSF biomarkers significantly improved diagnostic performance. Furthermore, the CSF 48 panel plus existing AD CSF biomarkers significantly improved predictions for changes in FDG PET, hippocampal volume, and measures of cognitive decline and dementia severity compared with either measure alone. A potential reason for these improvements is that the CSF 48 panel reflects a range of altered biology observed in AD/ADRD. In conclusion, we show that the CSF 48 panel complements existing AD CSF biomarkers to improve diagnosis and predict future cognitive decline and dementia severity.

MIND food and speed of processing training in older adults with low education, the MINDSpeed Alzheimer's disease prevention pilot trial.

BACKGROUND: Multiple national organizations and leaders have called for increased attention to dementia prevention in those most vulnerable, for example persons with limited formal education. Prevention recommendations have included calls for multicomponent interventions that have the potential to improve both underlying neurobiological health and the ability to function despite neurobiological pathology, or what has been termed cognitive reserve. OBJECTIVES: Test feasibility, treatment modifier, mechanism, and cognitive function effects of a multicomponent intervention consisting of foods high in polyphenols (i.e., MIND foods) to target neurobiological health, and speed of processing training to enhance cognitive reserve. We refer to this multicomponent intervention as MINDSpeed. DESIGN: MINDSpeed is being evaluated in a 2 × 2 randomized factorial design with 180 participants residing independently in a large Midwestern city. Qualifying participants are 60 years of age or older with no evidence of dementia, and who have completed 12 years or less of education. All participants receive a study-issued iPad to access the custom study application that enables participants, depending on randomization, to select either control or MIND food, and to play online cognitive games, either speed of processing or control games. METHODS: All participants complete informed consent and baseline assessment, including urine and blood samples. Additionally, up to 90 participants will complete neuroimaging. Assessments are repeated immediately following 12 weeks of active intervention, and at 24 weeks post-randomization. The primary outcome is an executive cognitive composite score. Secondary outcomes include oxidative stress, pro-inflammatory cytokines, and neuroimaging-captured structural and functional metrics of the hippocampus and cortical brain regions. SUMMARY: MINDSpeed is the first study to evaluate the multicomponent intervention of high polyphenol intake and speed of processing training. It is also one of the first dementia prevention trials to target older adults with low education. The results of the study will guide future dementia prevention efforts and trials in high risk populations.

Stability of MRI metrics in the advanced research core of the NCAA-DoD concussion assessment, research and education (CARE) consortium.

The NCAA-DoD Concussion Assessment, Research, and Education (CARE) consortium is performing a large-scale, comprehensive study of sport related concussions in college student-athletes and military service academy cadets. The CARE "Advanced Research Core" (ARC), is focused on executing a cutting-edge investigative protocol on a subset of the overall CARE athlete population. Here, we present the details of the CARE ARC MRI acquisition and processing protocol along with preliminary analyzes of within-subject, between-site, and between-subject stability across a variety of MRI biomarkers. Two experimental datasets were utilized for this analysis. First, two "human phantom" subjects were imaged multiple times at each of the four CARE ARC imaging sites, which utilize equipment from two imaging vendors. Additionally, a control cohort of healthy athletes participating in non-contact sports were enrolled in the study at each CARE ARC site and imaged at four time points. Multiple morphological image contrasts were acquired in each MRI exam; along with quantitative diffusion, functional, perfusion, and relaxometry imaging metrics. As expected, the imaging markers were found to have varying levels of stability throughout the brain. Importantly, between-subject variance was generally found to be greater than within-subject and between-site variance. These results lend support to the expectation that cross-site and cross-vendor advanced quantitative MRI metrics can be utilized to improve analytic power in assessing sensitive neurological variations; such as those effects hypothesized to occur in sports-related-concussion. This stability analysis provides a crucial foundation for further work utilizing this expansive dataset, which will ultimately be freely available through the Federal Interagency Traumatic Brain Injury Research Informatics System.

Reliable change in neuropsychological assessment of breast cancer survivors.

BACKGROUND: The purpose of this study was to enhance the current understanding and interpretation of longitudinal change on tests of neurocognitive function in individuals with cancer. Scores on standard neuropsychological instruments may be impacted by practice effects and other random forms of error. METHODS: The current study assessed the test-retest reliability of several tests and overarching cognitive domains comprising a neurocognitive battery typical of those used for research and clinical evaluation using relevant time frames. Practice effect-adjusted reliable change confidence intervals for test-retest difference scores based on a sample of patient-matched healthy controls are provided. RESULTS: By applying reliable change confidence intervals to scores from two samples of breast cancer patients at post-treatment follow-up assessment, meaningful levels of detectable change in cognitive functioning in breast cancer survivors were ascertained and indicate that standardized neuropsychological instruments may be subject to limitations in detection of subtle cognitive dysfunction over clinically relevant intervals, especially in patient samples with average to above average range baseline functioning. CONCLUSIONS: These results are discussed in relation to reported prevalence of cognitive change in breast cancer patients along with recommendations for study designs that enhance detection of treatment effects.

Relationship between the Montreal Cognitive Assessment and Mini-mental State Examination for assessment of mild cognitive impairment in older adults.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) was developed to enable earlier detection of mild cognitive impairment (MCI) relative to familiar multi-domain tests like the Mini-Mental State Exam (MMSE). Clinicians need to better understand the relationship between MoCA and MMSE scores. METHODS: For this cross-sectional study, we analyzed 219 healthy control (HC), 299 MCI, and 100 Alzheimer's disease (AD) dementia cases from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-GO/2 database to evaluate MMSE and MoCA score distributions and select MoCA values to capture early and late MCI cases. Stepwise variable selection in logistic regression evaluated relative value of four test domains for separating MCI from HC. Functional Activities Questionnaire (FAQ) was evaluated as a strategy to separate dementia from MCI. Equi-percentile equating produced a translation grid for MoCA against MMSE scores. Receiver Operating Characteristic (ROC) analyses evaluated lower cutoff scores for capturing the most MCI cases. RESULTS: Most dementia cases scored abnormally, while MCI and HC score distributions overlapped on each test. Most MCI cases scored ≥ 17 on MoCA (96.3%) and ≥ 24 on MMSE (98.3%). The ceiling effect (28-30 points) for MCI and HC was less using MoCA (18.1%) versus MMSE (71.4%). MoCA and MMSE scores correlated most for dementia (r = 0.86; versus MCI r = 0.60; HC r = 0.43). Equi-percentile equating showed a MoCA score of 18 was equivalent to MMSE of 24. ROC analysis found MoCA ≥ 17 as the cutoff between MCI and dementia that emphasized high sensitivity (92.3%) to capture MCI cases. The core and orientation domains in both tests best distinguished HC from MCI groups, whereas comprehension/executive function and attention/calculation were not helpful. Mean FAQ scores were significantly higher and a greater proportion had abnormal FAQ scores in dementia than MCI and HC. CONCLUSIONS: MoCA and MMSE were more similar for dementia cases, but MoCA distributes MCI cases across a broader score range with less ceiling effect. A cutoff of ≥ 17 on the MoCA may help capture early and late MCI cases; depending on the level of sensitivity desired, ≥ 18 or 19 could be used. Functional assessment can help exclude dementia cases. MoCA scores are translatable to the MMSE to facilitate comparison.

Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: the impact of APOE and smoking.

PURPOSE: This study examined the association of post-treatment changes in cognitive performance, apolipoprotein E (APOE), and smoking in breast cancer patients treated with adjuvant therapy. PARTICIPANTS AND METHODS: Breast cancer patients treated with chemotherapy (N = 55, age = 51.9 ± 7.1, education = 15.7 ± 2.6) were evaluated with a battery of neuropsychological tests prior to chemotherapy and at 1, 6, and 18 months post-chemotherapy. Matched groups of breast cancer patients not exposed to chemotherapy (N = 68, age = 56.8 ± 8.3, education = 14.8 ± 2.2) and healthy controls (N = 43, age = 53.0 ± 10.1, education = 15.2 ± 2.6) were evaluated at similar intervals. APOE epsilon 4 carrier status (APOE4+) and smoking history were also evaluated. RESULTS: The detrimental effect of APOE4+ genotype on post-treatment cognitive functioning was moderated by smoking history, that is, patients without a smoking history had significantly lower performance on measures of processing speed and working memory compared with those with a smoking history and healthy controls. Exploratory analyses revealed that APOE4+ patients without a smoking history who were exposed to chemotherapy showed a decline in performance in processing speed, compared with patients with a smoking history. A similar but less pronounced pattern was seen in the no chemotherapy group (primarily endocrine treatment). For working memory, the APOE4+ by smoking interaction was observed in the no chemotherapy group only. CONCLUSIONS: The association between APOE status, breast cancer treatment, and cognitive functioning was moderated by smoking history suggesting that both chemotherapy and endocrine therapy interact with APOE status and smoking to influence cognition. A putative mechanism is that smoking corrects a deficit in nicotinic receptor functioning and dopamine levels in APOE4+ individuals.

Longitudinal assessment of cognitive changes associated with adjuvant treatment for breast cancer: impact of age and cognitive reserve.

PURPOSE: To examine the impact of age and cognitive reserve on cognitive functioning in patients with breast cancer who are receiving adjuvant treatments. PATIENTS AND METHODS: Patients with breast cancer exposed to chemotherapy (n = 60; mean age, 51.7 years) were evaluated with a battery of neuropsychological and psychological tests before treatment and at 1, 6, and 18 months after treatment. Patients not exposed to chemotherapy (n = 72; mean age, 56.6 years) and healthy controls (n = 45; mean age, 52.9 years) were assessed at matched intervals. RESULTS: Mixed-effects modeling revealed significant effects for the Processing Speed and Verbal Ability domains. For Processing Speed, a three-way interaction among treatment group, age, and baseline cognitive reserve (P < .001) revealed that older patients with lower baseline cognitive reserve who were exposed to chemotherapy had lower performance on Processing Speed compared with patients not exposed to chemotherapy (P = .003) and controls (P < .001). A significant group by time interaction for Verbal Ability (P = .01) suggested that the healthy controls and no chemotherapy groups improved over time. The chemotherapy group failed to improve at 1 month after treatment but improved during the last two follow-up assessments. Exploratory analyses suggested a negative effect of tamoxifen on Processing Speed (P = .036) and Verbal Memory (P = .05) in the no-chemotherapy group. CONCLUSION: These data demonstrated that age and pretreatment cognitive reserve were related to post-treatment decline in Processing Speed in women exposed to chemotherapy and that chemotherapy had a short-term impact on Verbal Ability. Exploratory analysis of the impact of tamoxifen suggests that this pattern of results may be due to a combination of chemotherapy and tamoxifen.

A survey of neuropsychologists' practices and perspectives regarding the assessment of judgment ability.

Judgment is an important aspect of cognitive and real-world functioning that is commonly assessed during neuropsychological evaluations. This study utilized a brief, online survey to examine neuropsychologists' practices and perspectives regarding available judgment instruments. Participants (n = 290, 17% response rate) were randomly selected members of the International Neuropsychological Society and the National Academy of Neuropsychology. Respondents rank-ordered the following issues that should be incorporated into assessments of judgment (from most to least important): safety, ability to perform activities of daily living, and problem solving/decision making about medical, financial, social/ethical, and legal matters. A majority of respondents reported that they "often" or "always" assessed judgment when evaluating patients with traumatic brain injury (89%), dementia (87%), and psychiatric disorders (70%). Surprisingly, the top-ranked instruments were not tests of judgment per se, and included the WAIS-III Comprehension, Wisconsin Card Sorting Test, and WAIS-III Similarities. Further, 61% of respondents were slightly confident, and only 23% were very confident, in their ability to assess a patient's judgment skills with their current tests. The overwhelming majority (87%) of respondents perceived a need for improved measures. Overall results indicate use of varied techniques by neuropsychologists to evaluate judgment and suggest the need for additional tests of this cognitive domain.