Browsing by Author "Brosch, Jared R."
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Item A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer's disease(Springer Nature, 2021) Salloway, Stephen; Farlow, Martin; McDade, Eric; Clifford, David B.; Wang, Guoqiao; Llibre-Guerra, Jorge J.; Hitchcock, Janice M.; Mills, Susan L.; Santacruz, Anna M.; Aschenbrenner, Andrew J.; Hassenstab, Jason; Benzinger, Tammie L.S.; Gordon, Brian A.; Fagan, Anne M.; Coalier, Kelley A.; Cruchaga, Carlos; Goate, Alison A.; Perrin, Richard J.; Xiong, Chengjie; Li, Yan; Morris, John C.; Snider, B. Joy; Mummery, Catherine; Surti, G. Mustafa; Hannequin, Didier; Wallon, David; Berman, Sarah B.; Lah, James J.; Jimenez-Velazquez, Ivonne Z.; Roberson, Erik D.; van Dyck, Christopher H.; Honig, Lawrence S.; Sánchez-Valle, Raquel; Brooks, William S.; Gauthier, Serge; Galasko, Douglas R.; Masters, Colin L.; Brosch, Jared R.; Hsiung, Ging-Yuek Robin; Jayadev, Suman; Formaglio, Maité; Masellis, Mario; Clarnette, Roger; Pariente, Jérémie; Dubois, Bruno; Pasquier, Florence; Jack, Clifford R., Jr.; Koeppe, Robert; Snyder, Peter J.; Aisen, Paul S.; Thomas, Ronald G.; Berry, Scott M.; Wendelberger, Barbara A.; Andersen, Scott W.; Holdridge, Karen C.; Mintun, Mark A.; Yaari, Roy; Sims, John R.; Baudler, Monika; Delmar, Paul; Doody, Rachelle S.; Fontoura, Paulo; Giacobino, Caroline; Kerchner, Geoffrey A.; Bateman, Randall J.; Dominantly Inherited Alzheimer Network–Trials Unit; Neurology, School of MedicineDominantly inherited Alzheimer's disease (DIAD) causes predictable biological changes decades before the onset of clinical symptoms, enabling testing of interventions in the asymptomatic and symptomatic stages to delay or slow disease progression. We conducted a randomized, placebo-controlled, multi-arm trial of gantenerumab or solanezumab in participants with DIAD across asymptomatic and symptomatic disease stages. Mutation carriers were assigned 3:1 to either drug or placebo and received treatment for 4-7 years. The primary outcome was a cognitive end point; secondary outcomes included clinical, cognitive, imaging and fluid biomarker measures. Fifty-two participants carrying a mutation were assigned to receive gantenerumab, 52 solanezumab and 40 placebo. Both drugs engaged their Aβ targets but neither demonstrated a beneficial effect on cognitive measures compared to controls. The solanezumab-treated group showed a greater cognitive decline on some measures and did not show benefits on downstream biomarkers. Gantenerumab significantly reduced amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. Amyloid-related imaging abnormalities edema was observed in 19.2% (3 out of 11 were mildly symptomatic) of the gantenerumab group, 2.5% of the placebo group and 0% of the solanezumab group. Gantenerumab and solanezumab did not slow cognitive decline in symptomatic DIAD. The asymptomatic groups showed no cognitive decline; symptomatic participants had declined before reaching the target doses.Item Amyloid and Tau Pathology are Associated with Cerebral Blood Flow in a Mixed Sample of Nondemented Older Adults with and without Vascular Risk Factors for Alzheimer’s Disease(Elsevier, 2023) Swinford, Cecily G.; Risacher, Shannon L.; Vosmeier, Aaron; Deardorff, Rachael; Chumin, Evgeny J.; Dzemidzic, Mario; Wu, Yu-Chien; Gao, Sujuan; McDonald, Brenna C.; Yoder, Karmen K.; Unverzagt, Frederick W.; Wang, Sophia; Farlow, Martin R.; Brosch, Jared R.; Clark, David G.; Apostolova, Liana G.; Sims, Justin; Wang, Danny J.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineIdentification of biomarkers for the early stages of Alzheimer's disease (AD) is an imperative step in developing effective treatments. Cerebral blood flow (CBF) is a potential early biomarker for AD; generally, older adults with AD have decreased CBF compared to normally aging peers. CBF deviates as the disease process and symptoms progress. However, further characterization of the relationships between CBF and AD risk factors and pathologies is still needed. We assessed the relationships between CBF quantified by arterial spin-labeled magnetic resonance imaging, hypertension, APOEε4, and tau and amyloid positron emission tomography in 77 older adults: cognitively normal, subjective cognitive decline, and mild cognitive impairment. Tau and amyloid aggregation were related to altered CBF, and some of these relationships were dependent on hypertension or APOEε4 status. Our findings suggest a complex relationship between risk factors, AD pathologies, and CBF that warrants future studies of CBF as a potential early biomarker for AD.Item Association Between MIND Diet Score and Cortical Thickness in an Aging Population(Wiley, 2025-01-09) Dempsey, Desarae A.; Apostolova, Liana G.; Brosch, Jared R.; Clark, David G.; Farlow, Martin R.; Mathew, Sunu; Unverzagt, Frederick; Wang, Sophia; Gao, Sujuan; Clark, Daniel; Saykin, Andrew J.; Risacher, Shannon L.; Neurology, School of MedicineBackground The Mediterranean diet has been associated with decreased brain atrophy (Staubo et al. 2016,Alz&Dem), but the MIND (Mediterranean‐Dietary Approaches to Stop Hypertension (DASH) Intervention for Neurodegenerative Delay) diet, designed for dementia prevention (Morris et al. 2015, Alz&Dem), remains underexplored for its impact on brain atrophy. We investigated the MIND diet’s association with cortical thickness (CT) in the Indiana Alzheimer’s Disease Research Center (IADRC) sample. Methods 134 participants (49 CN, 45 SCD, 30 MCI, 10 AD/other) completed a self‐report MIND diet questionnaire at the IADRC, which was coded into high, medium, or low intake groups for each food (5 ‘unhealthy’ food groups were reverse scored) and completed an MRI scan on a 3T scanner. The cortical surface was parcellated using FreeSurfer v6. We selected two regions of interest (ROIs) reflecting AD‐associated neurodegeneration: temporal and global CT. We examined the association of MIND diet scores (0‐15) and food groups with CT using regression models adjusted for age, sex, race, education, and diagnosis. Results Higher MIND diet scores were associated with greater mean temporal CT (r = 0.269, p = 0.002) and greater mean global CT (r = 0.230, p = 0.008). In multivariable‐adjusted models, the association persisted for temporal but not global CT. Among the 15 food components, greater olive oil (r = 0.034, p<0.001), fish (r = 0.181, p = 0.040), beans (r = 0.237, p = 0.008), and nuts (r = 0.214, p = 0.014), and reduced fast food intake (r = 0.188, p = 0.035) were significantly associated with temporal CT. These associations, except for nuts, remained significant in multivariable‐adjusted models, with an additional relationship found for chicken (r = 0.189, p = 0.038). Among the 15 food components, greater olive oil (r = 0.243, p = 0.008), and beans (0.180, p = 0.044), and reduced fast food (r = 0.212, p = 0.017) were significantly associated with global CT. Only reduced fast food retained significance in the multivariable‐adjusted models. Conclusions Greater adherence to the MIND diet was associated with greater CT in both global and temporal regions. Specific components, including increased olive oil, beans, nuts, fish, and reduced fast food, showed significant associations with CT, suggesting elements within the diet driving this association. These findings highlight the potential neuroprotective effects of the MIND diet, emphasizing the importance of dietary patterns in preserving brain health during aging.Item Association of Brain Volume and Retinal Thickness in the Early Stages of Alzheimer’s Disease(IOS Press, 2023) Mathew, Sunu; WuDunn, Darrell; Mackay, Devin D.; Vosmeier, Aaron; Tallman, Eileen F.; Deardorff, Rachael; Harris, Alon; Farlow, Martin R.; Brosch, Jared R.; Gao, Sujuan; Apostolova, Liana G.; Saykin, Andrew J.; Risacher, Shannon L.; Radiology and Imaging Sciences, School of MedicineBackground: The eye has been considered a 'window to the brain,' and several neurological diseases including neurodegenerative conditions like Alzheimer's disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r = 0.235 p = 0.046, left eye r = 0.244, p = 0.037), temporal lobe (right eye r = 0.242 p = 0.039, left eye r = 0.290, p = 0.013), hippocampal (right eye r = 0.320 p = 0.005, left eye r = 0.306, p = 0.008), amygdala (left eye r = 0.332, p = 0.004), and occipital lobe (right eye r = 0.264 p = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD.Item CYP1B1-RMDN2 Alzheimer's disease endophenotype locus identified for cerebral tau PET(Springer Nature, 2024-09-20) Nho, Kwangsik; Risacher, Shannon L.; Apostolova, Liana G.; Bice, Paula J.; Brosch, Jared R.; Deardorff, Rachael; Faber, Kelley; Farlow, Martin R.; Foroud, Tatiana; Gao, Sujuan; Rosewood, Thea; Kim, Jun Pyo; Nudelman, Kelly; Yu, Meichen; Aisen, Paul; Sperling, Reisa; Hooli, Basavaraj; Shcherbinin, Sergey; Svaldi, Diana; Jack, Clifford R., Jr.; Jagust, William J.; Landau, Susan; Vasanthakumar, Aparna; Waring, Jeffrey F.; Doré, Vincent; Laws, Simon M.; Masters, Colin L.; Porter, Tenielle; Rowe, Christopher C.; Villemagne, Victor L.; Dumitrescu, Logan; Hohman, Timothy J.; Libby, Julia B.; Mormino, Elizabeth; Buckley, Rachel F.; Johnson, Keith; Yang, Hyun-Sik; Petersen, Ronald C.; Ramanan, Vijay K.; Ertekin-Taner, Nilüfer; Vemuri, Prashanthi; Cohen, Ann D.; Fan, Kang-Hsien; Kamboh, M. Ilyas; Lopez, Oscar L.; Bennett, David A.; Ali, Muhammad; Benzinger, Tammie; Cruchaga, Carlos; Hobbs, Diana; De Jager, Philip L.; Fujita, Masashi; Jadhav, Vaishnavi; Lamb, Bruce T.; Tsai, Andy P.; Castanho, Isabel; Mill, Jonathan; Weiner, Michael W.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI); Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN); Australian Imaging, Biomarker & Lifestyle Study (AIBL); Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineDetermining the genetic architecture of Alzheimer's disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.Item Every hit matters: White matter diffusivity changes in high school football athletes are correlated with repetitive head acceleration event exposure(Elsevier, 2019-07-16) Jang, Ikbeom; Chun, Il Yong; Brosch, Jared R.; Bari, Sumra; Zou, Yukai; Cummiskey, Brian R.; Lee, Taylor A.; Lycke, Roy J.; Poole, Victoria N.; Shenk, Trey E.; Svaldi, Diana O.; Tamer, Gregory G., Jr.; Dydak, Ulrike; Leverenz, Larry J.; Nauman, Eric A.; Talavage, Thomas M.; Neurology, School of MedicineRecent evidence of short-term alterations in brain physiology associated with repeated exposure to moderate intensity subconcussive head acceleration events (HAEs), prompts the question whether these alterations represent an underlying neural injury. A retrospective analysis combining counts of experienced HAEs and longitudinal diffusion-weighted imaging explored whether greater exposure to incident mechanical forces was associated with traditional diffusion-based measures of neural injury-reduced fractional anisotropy (FA) and increased mean diffusivity (MD). Brains of high school athletes (N = 61) participating in American football exhibited greater spatial extents (or volumes) experiencing substantial changes (increases and decreases) in both FA and MD than brains of peers who do not participate in collision-based sports (N = 15). Further, the spatial extents of the football athlete brain exhibiting traditional diffusion-based markers of neural injury were found to be significantly correlated with the cumulative exposure to HAEs having peak translational acceleration exceeding 20 g. This finding demonstrates that subconcussive HAEs induce low-level neurotrauma, with prolonged exposure producing greater accumulation of neural damage. The duration and extent of recovery associated with periods in which athletes do not experience subconcussive HAEs now represents a priority for future study, such that appropriate participation and training schedules may be developed to minimize the risk of long-term neurological dysfunction.Item Head injury is associated with tau deposition on PET in MCI and AD patients(Wiley, 2021-08-24) Risacher, Shannon L.; West, John D.; Deardorff, Rachael; Gao, Sujuan; Farlow, Martin R.; Brosch, Jared R.; Apostolova, Liana G.; McAllister, Thomas W.; Wu, Yu-Chien; Jagust, William J.; Landau, Susan M.; Weiner, Michael W.; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineIntroduction: Head injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important. Methods: Cognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid and [18F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study. Results: Sixty-three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta-positive individuals with history of HI with LOC. Discussion: These findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.Item Implementing Digital Cognitive Assessments to Detect Cognitive Impairment: Results from the Davos Alzheimer’s Collaborative Early Detection Program(Wiley, 2025-01-09) MacLeod, Tim; Murray, James F.; dos Santos Filho, Otelo Corrêa; de Sá Paiva Lima, Marcilea Dias; Govia, Ishtar; Robinson, Janelle; Kowa, Hisatomo; Morimoto, Kohei; López-Ortega, Mariana; McKean, Alison; Ritchie, Craig; Baksh, Magda R.; Smith, Steven R.; Willis, Deanna R.; Brosch, Jared R.; Small, Seamus; Martin, Tammy; Selzler, Katherine J.; Medicine, School of MedicineBackground: Cognitive impairment is frequently undetected or undiagnosed in the early stages. To increase the rates of detecting cognitive impairment, the Early Detection program of the Davos Alzheimer’s Collaborative System Preparedness (DAC‐SP) implemented digital cognitive assessments (DCA) in primary care and other non‐specialty settings. Methods: The DAC‐SP Early Detection program was initiated in 2021 in seven healthcare systems across six countries. Sites were able to choose from several DCAs, and clinicians were provided training, including recognizing signs and symptoms of cognitive decline, and provided with post‐diagnostic support. Patients were eligible for a DCA if they were over 60 years of age, able to hear and see well enough to complete the assessments, and had no prior diagnosis of dementia. The DCA tools included Linus Health’s Core Cognitive Evaluation, Cogstate Cognigram, and Cogstate Brief Battery. Results: The DCA results across the seven sites are presented in Table 1. There was notable variability in the number of patients screened across sites, which could be attributed to multiple factors (i.e., number of clinics onboarded/trained, additional testing for language and culture appropriateness of DCA tool prior to deployment, reduction in the number of elderly people visiting clinics during the COVID‐19 pandemic, available time of clinicians, etc.). The rate of cognitive impairment (abnormal and borderline) was also numerically higher at sites outside the US, independent of the DCA tool used. However, this study was not designed to evaluate operating characteristics of DCA tools, so further research is needed. Approximately 60% of the patients in the DAC‐SP Early Detection program tested abnormal or borderline for cognitive issues, suggesting the need for additional clinical assessment and follow‐up. Conclusion: Findings from the DAC‐SP Early Detection program demonstrated a DCA can be implemented in existing patient care workflows, including primary care settings, and across healthcare systems globally with different resource settings. Adoption of DCAs in clinical practice can help improve the ability to detect symptoms of cognitive impairment and provide much needed earlier screening and care for patients and their families.Item Journal Club: comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology.(American Academy of Neurology, 2014-03-04) Brosch, Jared R.; Matthews, Brandy R.; Department of Neurology, IU School of MedicineAdvances in neuroimaging, biomarkers, and clinical data have led to the hypothesis that the pathologic process of Alzheimer dementia begins decades prior to functional decline and diagnosis.1–3 High-profile clinical trial results have shown that biomarker changes can be made via pharmacologic intervention; however, the timing of this intervention has likely been too late to impact the cascade of neurodegenerative changes.4,5 In “Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology” by Monsell et al.,6 neuropathologic and clinical data were used to determine the risk of developing clinically significant cognitive impairment. This work represents a significant contribution because it examines a large cohort of autopsy data, which includes patients with Alzheimer dementia neuropathology who were clinically normal or diagnosed with mild cognitive impairment and Alzheimer-type dementia. The authors report a 3-fold increase in the risk of cognitive symptoms in association with quantifiable increases in neurofibrillary tangle pathology. Additionally, several other factors including APOE gene status, history of depression, and age impacted the clinical presentation. The ultimate goal of this investigation and similar studies is to facilitate the early and accurate identification of those at risk of developing Alzheimer dementia, such that potentially disease-modifying therapies may be considered.Item A novel SNCA E83Q mutation in a case of dementia with Lewy bodies and atypical frontotemporal lobar degeneration(Wiley, 2020-12) Kapasi, Alifiya; Brosch, Jared R.; Nudelman, Kelly N.; Agrawal, Sonal; Foroud, Tatiana M.; Schneider, Julie A.; Neurology, School of MedicineIn this case report, we discuss a patient presenting with parkinsonism followed by a non-amnestic dementia with aphasic clinical features, as well as frontal dysexecutive syndrome. There was a family history of dementia with an autopsy diagnosis of "Pick's disease" in the proband's father. Neuroimaging of the patient revealed focal and severe temporal lobe and lesser frontoparietal lobe atrophy. At autopsy, there was severe frontotemporal lobar degeneration. Histologic evaluation revealed an absence of tau or transactivation response DNA-binding protein of 43 kDa (TDP) pathology but rather severe Lewy body deposition in the affected cortices. Genetic phenotyping revealed a novel missense mutation (p.E83Q) in exon 4 of the gene encoding α-synuclein (SNCA). This case study presents a patient with a novel SNCA E83Q mutation associated with widespread Lewy body pathology with prominent severe atrophy of the frontotemporal lobes and corresponding cognitive impairment.