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Item 5. Collaborative Study on the Genetics of Alcoholism: Functional genomics(Wiley, 2023) Gameiro-Ros, Isabel; Popova, Dina; Prytkova, Iya; Pang, Zhiping P.; Liu, Yunlong; Dick, Danielle; Bucholz, Kathleen K.; Agrawal, Arpana; Porjesz, Bernice; Goate, Alison M.; Xuei, Xiaoling; Kamarajan, Chella; COGA Collaborators; Tischfield, Jay A.; Edenberg, Howard J.; Slesinger, Paul A.; Hart, Ronald P.; Medical and Molecular Genetics, School of MedicineAlcohol Use Disorder is a complex genetic disorder, involving genetic, neural, and environmental factors, and their interactions. The Collaborative Study on the Genetics of Alcoholism (COGA) has been investigating these factors and identified putative alcohol use disorder risk genes through genome-wide association studies. In this review, we describe advances made by COGA in elucidating the functional changes induced by alcohol use disorder risk genes using multimodal approaches with human cell lines and brain tissue. These studies involve investigating gene regulation in lymphoblastoid cells from COGA participants and in post-mortem brain tissues. High throughput reporter assays are being used to identify single nucleotide polymorphisms in which alternate alleles differ in driving gene expression. Specific single nucleotide polymorphisms (both coding or noncoding) have been modeled using induced pluripotent stem cells derived from COGA participants to evaluate the effects of genetic variants on transcriptomics, neuronal excitability, synaptic physiology, and the response to ethanol in human neurons from individuals with and without alcohol use disorder. We provide a perspective on future studies, such as using polygenic risk scores and populations of induced pluripotent stem cell-derived neurons to identify signaling pathways related with responses to alcohol. Starting with genes or loci associated with alcohol use disorder, COGA has demonstrated that integration of multimodal data within COGA participants and functional studies can reveal mechanisms linking genomic variants with alcohol use disorder, and potential targets for future treatments.Item A role for zinc transporter gene SLC39A12 in the nervous system and beyond(Elsevier, 2021) Davis, Danielle N.; Strong, Morgan D.; Chambers, Emily; Hart, Matthew D.; Bettaieb, Ahmed; Clarke, Stephen L.; Smith, Brenda J.; Stoecker, Barbara J.; Lucas, Edralin A.; Lin, Dingbo; Chowanadisai, Winyoo; Obstetrics and Gynecology, School of MedicineThe SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.Item The accumulation of phenothiazine derivatives in rat brain and plasma after repeated dosage(1968) Mahju, Mohammad AnisItem Alexa, let's train now! - A systematic review and classification approach to digital and home-based physical training interventions aiming to support healthy cognitive aging(Elsevier, 2023) Herold, Fabian; Theobald, Paula; Gronwald, Thomas; Kaushal, Navin; Zou, Liye; de Bruin, Eling D.; Bherer, Louis; Müller, Notger G.; Health Sciences, School of Health and Human SciencesBackground There is mounting evidence that regular physical activity is an important prerequisite for healthy cognitive aging. Consequently, the finding that almost one-third of the adult population does not reach the recommended level of regular physical activity calls for further public health actions. In this context, digital and home-based physical training interventions might be a promising alternative to center-based intervention programs. Thus, this systematic review aimed to summarize the current state of the literature on the effects of digital and home-based physical training interventions on adult cognitive performance. Methods In this pre-registered systematic review (PROSPERO; ID: CRD42022320031), 5 electronic databases (PubMed, Web of Science, PsycInfo, SPORTDiscus, and Cochrane Library) were searched by 2 independent researchers (FH and PT) to identify eligible studies investigating the effects of digital and home-based physical training interventions on cognitive performance in adults. The systematic literature search yielded 8258 records (extra 17 records from other sources), of which 27 controlled trials were considered relevant. Two reviewers (FH and PT) independently extracted data and assessed the risk of bias using a modified version of the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX scale). Results Of the 27 reviewed studies, 15 reported positive effects on cognitive and motor-cognitive outcomes (i.e., performance improvements in measures of executive functions, working memory, and choice stepping reaction test), and a considerable heterogeneity concerning study-related, population-related, and intervention-related characteristics was noticed. A more detailed analysis suggests that, in particular, interventions using online classes and technology-based exercise devices (i.e., step-based exergames) can improve cognitive performance in healthy older adults. Approximately one-half of the reviewed studies were rated as having a high risk of bias with respect to completion adherence (≤85%) and monitoring of the level of regular physical activity in the control group. Conclusion The current state of evidence concerning the effectiveness of digital and home-based physical training interventions is mixed overall, though there is limited evidence that specific types of digital and home-based physical training interventions (e.g., online classes and step-based exergames) can be an effective strategy for improving cognitive performance in older adults. However, due to the limited number of available studies, future high-quality studies are needed to buttress this assumption empirically and to allow for more solid and nuanced conclusions.Item Alzheimer disease brain atrophy subtypes are associated with cognition and rate of decline(American Academy of Neurology, 2017-11-21) Risacher, Shannon L.; Anderson, Wesley H.; Charil, Arnaud; Castelluccio, Peter F.; Shcherbinin, Sergey; Saykin, Andrew J.; Schwarz, Adam J.; Radiology and Imaging Sciences, School of MedicineOBJECTIVE: To test the hypothesis that cortical and hippocampal volumes, measured in vivo from volumetric MRI (vMRI) scans, could be used to identify variant subtypes of Alzheimer disease (AD) and to prospectively predict the rate of clinical decline. METHODS: Amyloid-positive participants with AD from the Alzheimer's Disease Neuroimaging Initiative (ADNI) 1 and ADNI2 with baseline MRI scans (n = 229) and 2-year clinical follow-up (n = 100) were included. AD subtypes (hippocampal sparing [HpSpMRI], limbic predominant [LPMRI], typical AD [tADMRI]) were defined according to an algorithm analogous to one recently proposed for tau neuropathology. Relationships between baseline hippocampal volume to cortical volume ratio (HV:CTV) and clinical variables were examined by both continuous regression and categorical models. RESULTS: When participants were divided categorically, the HpSpMRI group showed significantly more AD-like hypometabolism on 18F-fluorodeoxyglucose-PET (p < 0.05) and poorer baseline executive function (p < 0.001). Other baseline clinical measures did not differ across the 3 groups. Participants with HpSpMRI also showed faster subsequent clinical decline than participants with LPMRI on the Alzheimer's Disease Assessment Scale, 13-Item Subscale (ADAS-Cog13), Mini-Mental State Examination (MMSE), and Functional Assessment Questionnaire (all p < 0.05) and tADMRI on the MMSE and Clinical Dementia Rating Sum of Boxes (CDR-SB) (both p < 0.05). Finally, a larger HV:CTV was associated with poorer baseline executive function and a faster slope of decline in CDR-SB, MMSE, and ADAS-Cog13 score (p < 0.05). These associations were driven mostly by the amount of cortical rather than hippocampal atrophy. CONCLUSIONS: AD subtypes with phenotypes consistent with those observed with tau neuropathology can be identified in vivo with vMRI. An increased HV:CTV ratio was predictive of faster clinical decline in participants with AD who were clinically indistinguishable at baseline except for a greater dysexecutive presentation.Item Alzheimer's Disease Narratives and the Myth of Human Being(2012-12-11) Rieske, Tegan Echo; Schultz, Jane E.; Johnson, Karen Ramsay; Tilley, John J.The ‘loss of self’ trope is a pervasive shorthand for the prototypical process of Alzheimer's disease (AD) in the popular imagination. Turned into an effect of disease, the disappearance of the self accommodates a biomedical story of progressive deterioration and the further medicalization of AD, a process which has been storied as an organic pathology affecting the brain or, more recently, a matter of genetic calamity. This biomedical discourse of AD provides a generic framework for the disease and is reproduced in its illness narratives. The disappearance of self is a mythic element in AD narratives; it necessarily assumes the existence of a singular and coherent entity which, from the outside, can be counted as both belonging to and representing an individual person. The loss of self, as the rhetorical locus of AD narrative, limits the privatization of the experience and reinscribes cultural storylines---storylines about what it means to be a human person. The loss of self as it occurs in AD narratives functions most effectively in reasserting the presence of the human self, in contrast to an anonymous, inhuman nonself; as AD discourse details a loss of self, it necessarily follows that the thing which is lost (the self) always already existed. The private, narrative self of individual experience thus functions as proxy to a collective human identity predicated upon exceptionalism: an escape from nature and the conditions of the corporeal environment.Item Anatomy Nights: An international public engagement event increases audience knowledge of brain anatomy(PLOS, 2022-06-09) Sanders, Katherine A.; Philp, Janet A.C.; Jordan, Crispin Y.; Cale, Andrew S.; Cunningham, Claire L.; Organ, Jason M.; Anatomy, Cell Biology and Physiology, School of MedicineAnatomy Nights is an international public engagement event created to bring anatomy and anatomists back to public spaces with the goal of increasing the public's understanding of their own anatomy by comparison with non-human tissues. The event consists of a 30-minute mini-lecture on the anatomy of a specific anatomical organ followed by a dissection of animal tissues to demonstrate the same organ anatomy. Before and after the lecture and dissection, participants complete research surveys designed to assess prior knowledge and knowledge gained as a result of participation in the event, respectively. This study reports the results of Anatomy Nights brain events held at four different venues in the UK and USA in 2018 and 2019. Two general questions were asked of the data: 1) Do participant post-event test scores differ from pre-event scores; and 2) Are there differences in participant scores based on location, educational background, and career. We addressed these questions using a combination of generalized linear models (R's glm function; R version 4.1.0 [R Core Team, 2014]) that assumed a binomial distribution and implemented a logit link function, as well as likelihood estimates to compare models. Survey data from 91 participants indicate that scores improve on post-event tests compared to pre-event tests, and these results hold irrespective of location, educational background, and career. In the pre-event tests, participants performed well on naming structures with an English name (frontal lobe and brainstem), and showed signs of improvement on other anatomical names in the post-test. Despite this improvement in knowledge, we found no evidence that participation in Anatomy Nights improved participants' ability to apply this knowledge to neuroanatomical contexts (e.g., stroke).Item The apéritif effect: Alcohol's effects on the brain's response to food aromas in women(Wiley Blackwell (John Wiley & Sons), 2015-07) Eiler, William J. A.; Džemidžić, Mario; Case, K. Rose; Soeurt, Christina M.; Armstrong, Cheryl L. H.; Mattes, Richard D.; O'Connor, Sean J.; Harezlak, Jaroslaw; Acton, Anthony J.; Considine, Robert V.; Kareken, David A.; Department of Neurology, IU School of MedicineOBJECTIVE: Consuming alcohol prior to a meal (an apéritif) increases food consumption. This greater food consumption may result from increased activity in brain regions that mediate reward and regulate feeding behavior. Using functional magnetic resonance imaging, we evaluated the blood oxygenation level dependent (BOLD) response to the food aromas of either roast beef or Italian meat sauce following pharmacokinetically controlled intravenous infusion of alcohol. METHODS: BOLD activation to food aromas in non-obese women (n = 35) was evaluated once during intravenous infusion of 6% v/v EtOH, clamped at a steady-state breath alcohol concentration of 50 mg%, and once during infusion of saline using matching pump rates. Ad libitum intake of roast beef with noodles or Italian meat sauce with pasta following imaging was recorded. RESULTS: BOLD activation to food relative to non-food odors in the hypothalamic area was increased during alcohol pre-load when compared to saline. Food consumption was significantly greater, and levels of ghrelin were reduced, following alcohol. CONCLUSIONS: An alcohol pre-load increased food consumption and potentiated differences between food and non-food BOLD responses in the region of the hypothalamus. The hypothalamus may mediate the interplay of alcohol and responses to food cues, thus playing a role in the apéritif phenomenon.Item Apolipoprotein ε4 Is Associated with Lower Brain Volume in Cognitively Normal Chinese but Not White Older Adults(PLoS, 2016-06-17) Yokoyama, Jennifer S.; Lee, Allen K.L.; Takada, Leonel T.; Busovaca, Edgar; Bonham, Luke W.; Chao, Steven Z.; Tse, Marian; He, Jing; Schwarz, Christopher G.; Carmichael, Owen T.; Matthews, Brandy R.; Karydas, Anna; Weiner, Michael W.; Coppola, Giovanni; DeCarli, Charles S.; Miller, Bruce L.; Rosen, Howard J.; Department of Neurology, IU School of MedicineStudying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.Item Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults(American Medical Association, 2016-06-01) Risacher, Shannon Leigh; McDonald, Brenna C.; Tallman, Eileen F.; West, John D.; Farlow, Martin R.; Unverzagt, Fredrick W.; Gao, Sujuan; Boustani, Malaz; Crane, Paul K.; Petersen, Ronald C.; Jack, Clifford R.; Jagust, William J.; Aisen, Paul S.; Weiner, Michael W.; Saykin, Andrew J.; Department of Radiology and Imaging Sciences, School of MedicineIMPORTANCE: The use of anticholinergic (AC) medication is linked to cognitive impairment and an increased risk of dementia. To our knowledge, this is the first study to investigate the association between AC medication use and neuroimaging biomarkers of brain metabolism and atrophy as a proxy for understanding the underlying biology of the clinical effects of AC medications. OBJECTIVE: To assess the association between AC medication use and cognition, glucose metabolism, and brain atrophy in cognitively normal older adults from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Indiana Memory and Aging Study (IMAS). DESIGN, SETTING, AND PARTICIPANTS: The ADNI and IMAS are longitudinal studies with cognitive, neuroimaging, and other data collected at regular intervals in clinical and academic research settings. For the participants in the ADNI, visits are repeated 3, 6, and 12 months after the baseline visit and then annually. For the participants in the IMAS, visits are repeated every 18 months after the baseline visit (402 cognitively normal older adults in the ADNI and 49 cognitively normal older adults in the IMAS were included in the present analysis). Participants were either taking (hereafter referred to as the AC+ participants [52 from the ADNI and 8 from the IMAS]) or not taking (hereafter referred to as the AC- participants [350 from the ADNI and 41 from the IMAS]) at least 1 medication with medium or high AC activity. Data analysis for this study was performed in November 2015. MAIN OUTCOMES AND MEASURES: Cognitive scores, mean fludeoxyglucose F 18 standardized uptake value ratio (participants from the ADNI only), and brain atrophy measures from structural magnetic resonance imaging were compared between AC+ participants and AC- participants after adjusting for potential confounders. The total AC burden score was calculated and was related to target measures. The association of AC use and longitudinal clinical decline (mean [SD] follow-up period, 32.1 [24.7] months [range, 6-108 months]) was examined using Cox regression. RESULTS: The 52 AC+ participants (mean [SD] age, 73.3 [6.6] years) from the ADNI showed lower mean scores on Weschler Memory Scale-Revised Logical Memory Immediate Recall (raw mean scores: 13.27 for AC+ participants and 14.16 for AC- participants; P = .04) and the Trail Making Test Part B (raw mean scores: 97.85 seconds for AC+ participants and 82.61 seconds for AC- participants; P = .04) and a lower executive function composite score (raw mean scores: 0.58 for AC+ participants and 0.78 for AC- participants; P = .04) than the 350 AC- participants (mean [SD] age, 73.3 [5.8] years) from the ADNI. Reduced total cortical volume and temporal lobe cortical thickness and greater lateral ventricle and inferior lateral ventricle volumes were seen in the AC+ participants relative to the AC- participants. CONCLUSIONS AND RELEVANCE: The use of AC medication was associated with increased brain atrophy and dysfunction and clinical decline. Thus, use of AC medication among older adults should likely be discouraged if alternative therapies are available.