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Item The association of bone, fingernail and blood manganese with cognitive and olfactory function in Chinese workers(Elsevier, 2019-05-20) Rolle-McFarland, Danelle; Liu, Yingzi; Mostafaei, Farshad; Zauber, S. Elizabeth; Zhou, Yuanzhong; Li, Yan; Fan, Quiyan; Zheng, Wei; Nie, Linda H.; Wells, Ellen M.; Neurology, School of MedicineOccupational manganese (Mn) exposure has been associated with cognitive and olfactory dysfunction; however, few studies have incorporated cumulative biomarkers of Mn exposure such as bone Mn (BnMn). Our goal was to assess the cross-sectional association between BnMn, blood Mn (BMn), and fingernail Mn (FMn) with cognitive and olfactory function among Mn-exposed workers. A transportable in vivo neutron activation analysis (IVNAA) system was designed and utilized to assess BnMn among 60 Chinese workers. BMn and FMn were measured using inductively coupled plasma mass spectrometry. Cognitive and olfactory function was assessed using Animal and Fruit Naming tests, World Health Organization/University of California-Los Angeles Auditory Verbal Learning Test (AVLT) and the University of Pennsylvania Smell Identification Test (UPSIT). Additional data were obtained via questionnaire. Regression models adjusted for age, education, factory of employment, and smoking status (UPSIT only), were used to assess the relationship between Mn biomarkers and test scores. In adjusted models, increasing BnMn was significantly associated with decreased performance on average AVLT scores [β (95% confidence interval (CI)) = -0.65 (-1.21, -0.09)] and Animal Naming scores [β (95% CI) = -1.54 (-3.00, -0.07)]. Increasing FMn was significantly associated with reduced performance measured by the average AVLT [β (95% CI) = -0.35 (-0.70, -0.006)] and the difference in AVLT scores [β (95% CI) = -0.40 (-0.77, -0.03)]. BMn was not significantly associated with any test scores; no significant associations were observed with Fruit Naming or UPSIT tests. BnMn and FMn, but not BMn, are associated with cognitive function in Mn-exposed workers. None of theItem Associations between Suicidal Thoughts and Behaviors and Genetic Liability for Cognitive Performance, Depression, and Risk-Taking in a High-Risk Sample(Karger, 2021) Johnson, Emma C.; Aliev, Fazil; Meyers, Jacquelyn L.; Salvatore, Jessica E.; Tillman, Rebecca; Chang, Yoonhoo; Docherty, Anna R.; Bogdan, Ryan; Acion, Laura; Chan, Grace; Chorlian, David B.; Kamarajan, Chella; Kuperman, Samuel; Pandey, Ashwini; Plawecki, Martin H.; Schuckit, Marc; Tischfield, Jay; Edenberg, Howard J.; Bucholz, Kathleen K.; Nurnberger, John I.; Porjesz, Bernice; Hesselbrock, Victor; Dick, Danielle M.; Kramer, John R.; Agrawal, Arpana; Psychiatry, School of MedicineBackground: Suicidal thoughts and behaviors (STBs) and nonsuicidal self-injury (NSSI) behaviors are moderately heritable and may reflect an underlying predisposition to depression, impulsivity, and cognitive vulnerabilities to varying degrees. Objectives: We aimed to estimate the degrees of association between genetic liability to depression, impulsivity, and cognitive performance and STBs and NSSI in a high-risk sample. Methods: We used data on 7,482 individuals of European ancestry and 3,359 individuals of African ancestry from the Collaborative Study on the Genetics of Alcoholism to examine the links between polygenic scores (PGSs) for depression, impulsivity/risk-taking, and cognitive performance with 3 self-reported indices of STBs (suicidal ideation, persistent suicidal ideation defined as ideation occurring on at least 7 consecutive days, and suicide attempt) and with NSSI. Results: The PGS for depression was significantly associated with all 4 primary self-harm measures, explaining 0.6-2.5% of the variance. The PGS for risk-taking behaviors was also associated with all 4 self-harm behaviors in baseline models, but was no longer associated after controlling for a lifetime measure of DSM-IV alcohol dependence and abuse symptom counts. Polygenic predisposition for cognitive performance was negatively associated with suicide attempts (q = 3.8e-4) but was not significantly associated with suicidal ideation nor NSSI. We did not find any significant associations in the African ancestry subset, likely due to smaller sample sizes. Conclusions: Our results encourage the study of STB as transdiagnostic outcomes that show genetic overlap with a range of risk factors.Item Cognitive function prior to systemic therapy and subsequent well-being in older breast cancer survivors: longitudinal findings from the Thinking and Living with Cancer Study(Wiley, 2020-06) Kobayashi, Lindsay C.; Cohen, Harvey Jay; Zhai, Wanting; Zhou, Xingtao; Small, Brent J.; Luta, George; Hurria, Arti; Carroll, Judith; Tometich, Danielle; McDonald, Brenna C.; Graham, Deena; Jim, Heather S.L.; Jacobsen, Paul; Root, James C.; Saykin, Andrew J.; Ahles, Tim A.; Mandelblatt, Jeanne; Radiology and Imaging Sciences, School of MedicineObjective: To investigate the relationships between self-reported and objectively measured cognitive function prior to systemic therapy and subsequent well-being outcomes over 24 months in older breast cancer survivors. Methods: Data were from 397 women aged 60 to 98 diagnosed with non-metastatic breast cancer in the Thinking and Living with Cancer Study recruited from 2010-2016. Cognitive function was measured at baseline (following surgery, prior to systemic therapy) using neuropsychological assessments of attention, processing speed, and executive function (APE), learning and memory (LM), and the self-reported FACT-Cog scale. Well-being was measured using the FACT-G functional, physical, social, and emotional well-being domain scales at baseline and 12 and 24 months later, scaled from 0 (low) to 100 (high). Linear mixed-effects models assessed the relationships between each of baseline APE, LM, and FACT-Cog quartiles with well-being scores over 24 months, adjusted for confounding variables. Results: At baseline, older survivors in the lowest APE, LM, and FACT-Cog score quartiles experienced poorer global well-being than those in the highest quartiles. At 24 months, older survivors tended to improve in well-being, and there were no differences according to baseline APE or LM scores. At 24 months, mean global well-being was 80.3 (95% CI: 76.2-84.3) among those in the lowest vs 86.6 (95% CI: 83.1-90.1) in the highest FACT-cog quartile, a clinically meaningful difference of 6.3 points (95% CI: 1.5-11.1). Conclusions: Among older breast cancer survivors, self-reported, but not objective cognitive impairments, were associated with lower global well-being over the first 2 years of survivorship.Item COMT Val 158 Met polymorphism is associated with nonverbal cognition following mild traumatic brain injury(Springer, 2016-01) Winker, Ethan A.; Yue, John K.; McAllister, Thomas W.; Temkin, Nancy R.; Oh, Sam S.; Burchard, Esteban G.; Hu, Donglei; Ferguson, Adam R.; Lingsma, Hester F.; Burke, John F.; Sorani, Marco D.; Rosand, Jonathan; Yuh, Esther L.; Barber, Jason; Tarapore, Phiroz E.; Gardner, Raquel C.; Sharma, Sourabh; Satris, Gabriela G.; Eng, Celeste; Puccio, Ava M.; Wang, Kevin K.W.; Mukherjee, Pratik; Valadka, Alex B.; Okonkwo, David O.; Diaz-Arrastia, Ramon; Manley, Geoffrey T.; Department of Psychiatry, IU School of MedicineMild traumatic brain injury (mTBI) results in variable clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism in catechol-o-methyltransferase (COMT), an enzyme which degrades catecholamine neurotransmitters, may influence cognitive deficits following moderate and/or severe head trauma. However, this has been disputed, and its role in mTBI has not been studied. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val (158) Met polymorphism influences outcome on a cognitive battery 6 months following mTBI--Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), Trail Making Test (TMT) Trail B minus Trail A time, and California Verbal Learning Test, Second Edition Trial 1-5 Standard Score (CVLT-II). All patients had an emergency department Glasgow Coma Scale (GCS) of 13-15, no acute intracranial pathology on head CT, and no polytrauma as defined by an Abbreviated Injury Scale (AIS) score of ≥3 in any extracranial region. Results in 100 subjects aged 40.9 (SD 15.2) years (COMT Met (158) /Met (158) 29 %, Met (158) /Val (158) 47 %, Val (158) /Val (158) 24 %) show that the COMT Met (158) allele (mean 101.6 ± SE 2.1) associates with higher nonverbal processing speed on the WAIS-PSI when compared to Val (158) /Val (158) homozygotes (93.8 ± SE 3.0) after controlling for demographics and injury severity (mean increase 7.9 points, 95 % CI [1.4 to 14.3], p = 0.017). The COMT Val (158) Met polymorphism did not associate with mental flexibility on the TMT or with verbal learning on the CVLT-II. Hence, COMT Val (158) Met may preferentially modulate nonverbal cognition following uncomplicated mTBI.Registry: ClinicalTrials.gov Identifier NCT01565551.Item Design and baseline characteristics of the Cognitive and Aerobic Resilience for the Brain (CARB) study(Elsevier, 2023-08) Tam, Joyce W.; Khurshid, Kiran; Sprague, Briana; Clark, Daniel O.; Xu, Huiping; Moser, Lyndsi R.; Miller, Douglas K.; Considine, Robert; Callahan, Christopher M.; Garringer, Holly J.; Rexroth, Daniel; Unverzagt, Frederick W.; Pathology and Laboratory Medicine, School of MedicineBackground Treatments that delay progression of cognitive impairment in older adults are of great public health significance. This manuscript outlines the protocol, recruitment, baseline characteristics, and retention for a randomized controlled trial of cognitive and aerobic physical training to improve cognition in individuals with subjective cognitive dysfunction, the “Cognitive and Aerobic Resilience for the Brain” (CARB) study. Methods Community-dwelling, older adults with self-reported memory loss were randomly assigned to receive either computer-based cognitive training, aerobic physical training, combined cognitive and physical training, or education control. Treatment was delivered 2- to 3-times per week in 45- to 90-min sessions for 12 weeks by trained facilitators videoconferencing into subject's home. Outcome assessments of were taken at the baseline, immediately following training, and 3-months after training. Results 191 subjects were randomized into the trial (mean age, 75.5 years; 68% female; 20% non-white; mean education, 15.1 years; 30% with 1+ APOE e4 allele). The sample was generally obese, hypertensive, and many were diabetic, while cognition, self-reported mood, and activities of daily living were in the normal range. There was excellent retention throughout the trial. Interventions were completed at high rates, participants found the treatments acceptable and enjoyable, and outcome assessments were completed at high rates. Conclusions This study was designed to determine the feasibility of recruiting, intervening, and documenting response to treatment in a population at risk for progressive cognitive decline. Older adults with self-reported memory loss were enrolled in high numbers and were well engaged with the intervention and outcome assessments.Item Dietary patterns are associated with cognitive function in the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort.(Cambridge UP, 2016) Pearson, Keith E.; Wadley, Virginia G.; McClure, Leslie A.; Shikany, James M.; Unverzagt, Fred W.; Judd, Suzanne E.; Department of Psychiatry, IU School of MedicineIdentifying factors that contribute to the preservation of cognitive function is imperative to maintaining quality of life in advanced years. Of modifiable risk factors, diet quality has emerged as a promising candidate to make an impact on cognition. The objective of this study was to evaluate associations between empirically derived dietary patterns and cognitive function. This study included 18 080 black and white participants aged 45 years and older from the REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Principal component analysis on data from the Block98 FFQ yielded five dietary patterns: convenience, plant-based, sweets/fats, Southern, and alcohol/salads. Incident cognitive impairment was defined as shifting from intact cognitive status (score >4) at first assessment to impaired cognitive status (score ≤4) at latest assessment, measured by the Six-Item Screener. Learning, memory and executive function were evaluated with the Word List Learning, Word List Delayed Recall, and animal fluency assessments. In fully adjusted models, greater consumption of the alcohol/salads pattern was associated with lower odds of incident cognitive impairment (highest quintile (Q5) v. lowest quintile (Q1): OR 0·68; 95 % CI 0·56, 0·84; P for trend 0·0005). Greater consumption of the alcohol/salads pattern was associated with higher scores on all domain-specific assessments and greater consumption of the plant-based pattern was associated with higher scores in learning and memory. Greater consumption of the Southern pattern was associated with lower scores on each domain-specific assessment (all P < 0·05). In conclusion, dietary patterns including plant-based foods and alcohol intake were associated with higher cognitive scores, and a pattern including fried food and processed meat typical of a Southern diet was associated with lower scores.Item Do subjective or objective cognitive measures better predict social network type among older adults?(Taylor & Francis, 2022) Roth, Adam R.; Peng, Siyun; Coleman, Max E.; Apostolova, Liana G.; Perry, Brea L.; Radiology and Imaging Sciences, School of MedicineA large literature highlights the link between cognitive function and social networks in later life. Yet there remains uncertainty about the factors driving this relationship. In the present study, we use measures of subjective cognitive decline and clinical cognitive assessments on a sample of older adults to investigate whether the relationship between cognitive function and social networks is driven by psychosocial factors. We found a consistent link between clinical cognitive assessments and social network type, but no association between subjective concerns of cognitive decline and networks. Participants who exhibited signs of clinical cognitive impairment were more likely to have restricted networks (i.e., smaller networks consisting of fewer contacts, more interconnectivity, and less social diversity) compared to their cognitively normal counterparts, regardless of subjective measures of cognitive decline—both from the participant’s perspective and study partner’s perspective. These findings suggest that neither cognitively impaired older adults nor their network members appear to consciously dissolve social ties on the basis of perceived cognitive decline. However, it remains unclear whether the association between clinical cognitive impairment and social network type indicates the protective nature of social networks against cognitive decline or a subconscious process leading to social contraction.Item The Feasibility of Telephone-Administered Cognitive Testing in Individuals 1 and 2 Years after Inpatient Rehabilitation for Traumatic Brain Injury(Mary Ann Liebert, 2018-05-15) Dams-O'Connor, Kristen; Sy, Karla Therese L.; Landau, Alexandra; Bodien, Yelena; Dikmen, Sureyya; Felix, Elizabeth R.; Giacino, Joseph T.; Gibbons, Laura; Hammond, Flora M.; Hart, Tessa; Johnson-Greene, Doug; Lengenfelder, Jeannie; Lequerica, Anthony; Newman, Jody; Novack, Thomas; O'Neil-Pirozzi, Therese M.; Whiteneck, Gale; Physical Medicine and Rehabilitation, School of MedicineTraumatic brain injury (TBI) often results in cognitive impairment, and trajectories of cognitive functioning can vary tremendously over time across survivors. Traditional approaches to measuring cognitive performance require face-to-face administration of a battery of objective neuropsychological tests, which can be time- and labor-intensive. There are numerous clinical and research contexts in which in-person testing is undesirable or unfeasible, including clinical monitoring of older adults or individuals with disability for whom travel is challenging, and epidemiological studies of geographically dispersed participants. A telephone-based method for measuring cognition could conserve resources and improve efficiency. The objective of this study is to examine the feasibility and usefulness of the Brief Test of Adult Cognition by Telephone (BTACT) among individuals who are 1 and 2 years post-moderate-to-severe TBI. A total of 463 individuals participated in the study at Year 1 post-injury, and 386 participated at Year 2. The sample was mostly male (73%) and white (59%), with an average age of (mean ± standard deviation) 47.9 ± 20.9 years, and 73% experienced a duration of post-traumatic amnesia (PTA) greater than 7 days. A majority of participants were able to complete the BTACT subtests (61-69% and 56-64% for Years 1 and 2 respectively); score imputation for those unable to complete a test due to severity of cognitive impairment yields complete data for 74-79% of the sample. BTACT subtests showed expected changes between Years 1-2, and summary scores demonstrated expected associations with injury severity, employment status, and cognitive status as measured by the Functional Independence Measure. Results indicate it is feasible, efficient, and useful to measure cognition over the telephone among individuals with moderate-severe TBI.Item Functionally-detected cognitive impairment in high school football players without clinically-diagnosed concussion(Mary Ann Liebert, Inc., 2014-02) Talavage, Thomas M.; Nauman, Eric A.; Breedlove, Evan L.; Yoruk, Umit; Dye, Anne E.; Morigaki, Katherine E.; Feuer, Henry; Leverenz, Larry J.; Department of Medicine, IU School of MedicineHead trauma and concussion in football players have recently received considerable media attention. Postmortem evidence suggests that accrual of damage to the brain may occur with repeated blows to the head, even when the individual blows fail to produce clinical symptoms. There is an urgent need for improved detection and characterization of head trauma to reduce future injury risk and promote development of new therapies. In this study we examined neurological performance and health in the presence of head collision events in high school football players, using longitudinal measures of collision events (the HIT(™) System), neurocognitive testing (ImPACT(™)), and functional magnetic resonance imaging MRI (fMRI). Longitudinal assessment (including baseline) was conducted in 11 young men (ages 15-19 years) participating on the varsity and junior varsity football teams at a single high school. We expected and observed subjects in two previously described categories: (1) no clinically-diagnosed concussion and no changes in neurological behavior, and (2) clinically-diagnosed concussion with changes in neurological behavior. Additionally, we observed players in a previously undiscovered third category, who exhibited no clinically-observed symptoms associated with concussion, but who demonstrated measurable neurocognitive (primarily visual working memory) and neurophysiological (altered activation in the dorsolateral prefrontal cortex [DLPFC]) impairments. This new category was associated with significantly higher numbers of head collision events to the top-front of the head, directly above the DLPFC. The discovery of this new category suggests that more players are suffering neurological injury than are currently being detected using traditional concussion-assessment tools. These individuals are unlikely to undergo clinical evaluation, and thus may continue to participate in football-related activities, even when changes in brain physiology (and potential brain damage) are present, which will increase the risk of future neurological injury.Item Neuron-specific ablation of eIF5A or deoxyhypusine synthase leads to impairments in growth, viability, neurodevelopment, and cognitive functions in mice(Elsevier, 2021) Kar, Rajesh Kumar; Hanner, Ashleigh S.; Starost, Matthew F.; Springer, Danielle; Mastracci, Teresa L.; Mirmira, Raghavendra G.; Park, Myung Hee; Biology, School of ScienceEukaryotic initiation factor 5A (eIF5A)†, ‡ is an essential protein that requires a unique amino acid, hypusine, for its activity. Hypusine is formed exclusively in eIF5A post-translationally via two enzymes, deoxyhypusine synthase (DHPS) and deoxyhypusine hydroxylase. Each of the genes encoding these proteins, Eif5a, Dhps, and Dohh, is required for mouse embryonic development. Variants in EIF5A or DHPS were recently identified as the genetic basis underlying certain rare neurodevelopmental disorders in humans. To investigate the roles of eIF5A and DHPS in brain development, we generated four conditional KO mouse strains using the Emx1-Cre or Camk2a-Cre strains and examined the effects of temporal- and region-specific deletion of Eif5a or Dhps. The conditional deletion of Dhps or Eif5a by Emx1 promotor–driven Cre expression (E9.5, in the cortex and hippocampus) led to gross defects in forebrain development, reduced growth, and premature death. On the other hand, the conditional deletion of Dhps or Eif5a by Camk2a promoter–driven Cre expression (postnatal, mainly in the CA1 region of the hippocampus) did not lead to global developmental defects; rather, these KO animals exhibited severe impairment in spatial learning, contextual learning, and memory when subjected to the Morris water maze and a contextual learning test. In both models, the Dhps-KO mice displayed more severe impairment than their Eif5a-KO counterparts. The observed defects in the brain, global development, or cognitive functions most likely result from translation errors due to a deficiency in active, hypusinated eIF5A. Our study underscores the important roles of eIF5A and DHPS in neurodevelopment.