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Item Age-dependent formation of TMEM106B amyloid filaments in human brains(Springer Nature, 2022) Schweighauser, Manuel; Arseni, Diana; Bacioglu, Mehtap; Huang, Melissa; Lövestam, Sofia; Shi, Yang; Yang, Yang; Zhang, Wenjuan; Kotecha, Abhay; Garringer, Holly J.; Vidal, Ruben; Hallinan, Grace I.; Newell, Kathy L.; Tarutani, Airi; Murayama, Shigeo; Miyazaki, Masayuki; Saito, Yuko; Yoshida, Mari; Hasegawa, Kazuko; Lashley, Tammaryn; Revesz, Tamas; Kovacs, Gabor G.; van Swieten, John; Takao, Masaki; Hasegawa, Masato; Ghetti, Bernardino; Spillantini, Maria Grazia; Ryskeldi-Falcon, Benjamin; Murzin, Alexey G.; Goedert, Michel; Scheres, Sjors H.W.; Pathology and Laboratory Medicine, School of MedicineMany age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.Item Amyloid seeding of transthyretin by ex vivo cardiac fibrils and its inhibition(National Academy of Sciences, 2018-07-17) Saelices, Lorena; Chung, Kevin; Lee, Ji H.; Cohn, Whitaker; Whitelegge, Julian P.; Benson, Merrill D.; Eisenberg, David S.; Pathology and Laboratory Medicine, School of MedicineEach of the 30 human amyloid diseases is associated with the aggregation of a particular precursor protein into amyloid fibrils. In transthyretin amyloidosis (ATTR), mutant or wild-type forms of the serum carrier protein transthyretin (TTR), synthesized and secreted by the liver, convert to amyloid fibrils deposited in the heart and other organs. The current standard of care for hereditary ATTR is liver transplantation, which replaces the mutant TTR gene with the wild-type gene. However, the procedure is often followed by cardiac deposition of wild-type TTR secreted by the new liver. Here we find that amyloid fibrils extracted from autopsied and explanted hearts of ATTR patients robustly seed wild-type TTR into amyloid fibrils in vitro. Cardiac-derived ATTR seeds can accelerate fibril formation of wild-type and monomeric TTR at acidic pH and under physiological conditions, respectively. We show that this seeding is inhibited by peptides designed to complement structures of TTR fibrils. These inhibitors cap fibril growth, suggesting an approach for halting progression of ATTR.Item Association of brain amyloidosis with the incidence and frequency of neuropsychiatric symptoms in ADNI: a multisite observational cohort study(BMJ Journals, 2019-12-18) Goukasian, Naira; Hwang, Kristy S.; Romero, Tamineh; Grotts, Jonathan; Do, Triet M.; Groh, Jenna R.; Bateman, Daniel R.; Apostolova, Liana G.; Neurology, School of MedicineObjective To investigate the relationship between amyloid burden and frequency of existing and incidence of new neuropsychiatric symptoms (NPS) in elderly with and without cognitive decline. Methods 275 cognitively normal controls (NC), 100 subjective memory complaint (SMC), 559 mild cognitive impairment (MCI) and 143 Alzheimer’s disease dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative received (18F)-florbetapir positron emission tomography (PET) scans. Yearly neuropsychiatric inventory (Neuropsychiatric Inventory (NPI)/NPI-Questionnaire) data were collected from the study partners at each visit. Mean standard uptake volume ratios (SUVR) normalised to whole cerebellum were obtained. Positive amyloid PET scan was defined as mean SUVR ≥1.17. Fisher’s exact test was used to compare frequency and incidence between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate of neuropsychiatric symptoms (NPS) between amyloid positive and amyloid negative subjects. Survival analyses were used to estimate hazard ratios for developing the most common NPS by amyloid status. Results No differences in NPS frequency were seen between amyloid positive and amyloid negative NC, SMC, MCI or dementia groups. MCI subjects with amyloid pathology however tended to have greater frequency x severity (FxS) of anxiety, hallucinations, delusions, apathy, disinhibition, irritability, aberrant motor behavior, and appetite, but not agitation, depression, night-time disturbances, or elation. MCI subjects with amyloid pathology were at greater risk for developing apathy, anxiety and agitation over time. Baseline presence of agitation and apathy and new onset agitation, irritability and apathy predicted faster conversion to dementia among MCI subjects. Conclusions Amyloid pathology is associated with greater rate of development of new NPS in MCI. Anxiety and delusions are significant predictors of amyloid pathology. Agitation, irritability and apathy are significant predictors for conversion from MCI to dementia.Item Cardiac amyloidosis‐A review of current literature for the practicing physician(Wiley, 2021-03) Ash, Samantha; Shorer, Eran; Ramgobin, Devyani; Vo, Maique; Gibbons, Jonathan; Golamari, Reshma; Jain, Rahul; Jain, Rohit; Medicine, School of MedicineThe amyloidoses are a family of diseases in which misfolded precursor proteins aggregate to form amyloid and deposit in body tissues. A very serious yet underrecognized form of this disease is cardiac amyloidosis, in which amyloid deposits into the extracellular space of the myocardium, resulting in thickening and stiffening of ventricular walls with resultant heart failure and conductive dysfunction. This review provides a discussion of the pathogenesis and clinical presentation of cardiac amyloidosis subtypes, as well as an up-to-date approach to diagnosis and treatment. Significant progress has been made in recent years regarding diagnosis and treatment of this condition, but prognosis remains heavily reliant on early detection of the disease. Two types of precursor protein are responsible for most cardiac amyloidosis cases: transthyretin amyloid, and immunoglobulin-derived light chain amyloid. An early diagnosis of cardiac amyloidosis can allow for novel treatment modalities to be initiated with the potential to improve prognosis.Item Cerebral amyloidosis associated with cognitive decline in autosomal dominant Alzheimer disease(American Academy of Neurology, 2015-09) Wang, Fen; Gordon, Brian A.; Ryman, Davis C.; Ma, Shengmei; Xiong, Chengjie; Hassenstab, Jason; Goate, Alison; Fagan, Anne M.; Cairns, Nigel J.; Marcus, Daniel S.; McDade, Eric; Ringman, John M.; Graff-Radford, Neill R.; Ghetti, Bernardino; Farlow, Martin R.; Sperling, Reisa; Salloway, Steve; Schofield, Peter R.; Masters, Colin L.; Martins, Ralph N.; Rossor, Martin N. N.; Jucker, Mathias; Danek, Adrian; Förster, Stefan; Lane, Christopher A.S.; Morris, John C.; Benzinger, Tammie L. S.; Bateman, Randall J.; Department of Neurology, IU School of MedicineOBJECTIVE: To investigate the associations of cerebral amyloidosis with concurrent cognitive performance and with longitudinal cognitive decline in asymptomatic and symptomatic stages of autosomal dominant Alzheimer disease (ADAD). METHODS: Two hundred sixty-three participants enrolled in the Dominantly Inherited Alzheimer Network observational study underwent neuropsychological evaluation as well as PET scans with Pittsburgh compound B. One hundred twenty-one participants completed at least 1 follow-up neuropsychological evaluation. Four composite cognitive measures representing global cognition, episodic memory, language, and working memory were generated using z scores from a battery of 13 standard neuropsychological tests. General linear mixed-effects models were used to investigate the relationship between baseline cerebral amyloidosis and baseline cognitive performance and whether baseline cerebral amyloidosis predicts cognitive change over time (mean follow-up 2.32 years ± 0.92, range 0.89-4.19) after controlling for estimated years from expected symptom onset, APOE ε4 allelic status, and education. RESULTS: In asymptomatic mutation carriers, amyloid burden was not associated with baseline cognitive functioning but was significantly predictive of longitudinal decline in episodic memory. In symptomatic mutation carriers, cerebral amyloidosis was correlated with worse baseline performance in multiple cognitive composites and predicted greater decline over time in global cognition, working memory, and Mini-Mental State Examination. CONCLUSIONS: Cerebral amyloidosis predicts longitudinal episodic memory decline in presymptomatic ADAD and multidomain cognitive decline in symptomatic ADAD. These findings imply that amyloidosis in the brain is an indicator of early cognitive decline and provides a useful outcome measure for early assessment and prevention treatment trials.Item Clinical Outcomes of Percutaneous Coronary Intervention in Amyloidosis, Sarcoidosis, and Hemochromatosis(Elsevier, 2023-12-30) Hussain, Bilal; Malik, Hamza; Mamas, Mamas A.; Desai, Rupak; Aggarwal, Vikas; Kumar, Gautam; Alraies, M. Chadi; Kalra, Ankur; Paul, Timir K.; Medicine, School of MedicineBackground: Infiltrative diseases (IDs), including amyloidosis, sarcoidosis, and hemochromatosis, are characterized by abnormal cellular infiltration in multiple organs, including the heart. The prognosis of percutaneous coronary intervention (PCI) patients with underlying IDs has not been well-studied. We evaluated the prevalence of IDs in patients undergoing PCI and their association with post-PCI outcomes. Methods: The National Inpatient Sample (NIS) 2016-2020 database was used to identify PCI patients with ICD-10 codes for a retrospective analysis. PCI patients were then divided into those with and without underlying IDs, which included amyloidosis, sarcoidosis, and hemochromatosis. Multivariable logistic regression was performed for composite post-PCI outcomes analyses. Results: Among 2,360,860 patients admitted to undergo PCI, 7855 patients had underlying IDs. The highest prevalence was observed for sarcoidosis (0.2%) followed by hemochromatosis (0.07%) and amyloidosis (0.04%). Underlying amyloidosis was associated with worse composite post-PCI outcomes (odds ratio [OR], 1.6; 95% CI, 1.1-2.44; P = .02), including higher in-hospital mortality (OR, 1.9; 95% CI, 1.1-3.4; P = .04), higher risk of intra/post-PCI stroke (OR, 4.0; 95% CI, 1.1-16.0; P = .04), but not major bleeding (OR, 2.2; 95% CI, 0.97-5.03; P = .058). In contrast, underlying sarcoidosis (OR, 1.1; 95% CI, 0.87-1.41; P = .4), and hemochromatosis (OR, 1.18; 95% CI, 0.77-1.8; P = .44) were not associated with composite post-PCI outcomes. Amyloidosis patients undergoing PCI also had higher hospitalization charges ($212,123 vs $141,137; P = .03) and longer length of stay (8.2 vs 3.9 days; P < .001). Conclusions: Underlying amyloidosis was associated with worse post-PCI outcomes including higher in-hospital mortality, intra/post-PCI stroke, and socioeconomic burden. A multidisciplinary approach and future studies are needed to investigate the screening and treatment strategies in these patients.Item Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease(American Medical Association, 2022) Young, Christina B.; Winer, Joseph R.; Younes, Kyan; Cody, Karly A.; Betthauser, Tobey J.; Johnson, Sterling C.; Schultz, Aaron; Sperling, Reisa A.; Greicius, Michael D.; Cobos, Inma; Poston, Kathleen L.; Mormino, Elizabeth C.; Alzheimer’s Disease Neuroimaging Initiative; Harvard Aging Brain Study; Radiology and Imaging Sciences, School of MedicineImportance: Characterization of early tau deposition in individuals with preclinical Alzheimer disease (AD) is critical for prevention trials that aim to select individuals at risk for AD and halt the progression of disease. Objective: To evaluate the prevalence of cortical tau positron emission tomography (PET) heterogeneity in a large cohort of clinically unimpaired older adults with elevated β-amyloid (A+). Design, setting, and participants: This cross-sectional study examined prerandomized tau PET, amyloid PET, structural magnetic resonance imaging, demographic, and cognitive data from the Anti-Amyloid Treatment in Asymptomatic AD (A4) Study from April 2014 to December 2017. Follow-up analyses used observational tau PET data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Harvard Aging Brain Study (HABS), and the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (together hereinafter referred to as Wisconsin) to evaluate consistency. Participants were clinically unimpaired at the study visit closest to the tau PET scan and had available amyloid and tau PET data (A4 Study, n = 447; ADNI, n = 433; HABS, n = 190; and Wisconsin, n = 328). No participants who met eligibility criteria were excluded. Data were analyzed from May 11, 2021, to January 25, 2022. Main outcomes and measures: Individuals with preclinical AD with heterogeneous cortical tau PET patterns (A+T cortical+) were identified by examining asymmetrical cortical tau signal and disproportionate cortical tau signal relative to medial temporal lobe (MTL) tau. Voxelwise tau patterns, amyloid, neurodegeneration, cognition, and demographic characteristics were examined. Results: The 447 A4 participants (A+ group, 392; and normal β-amyloid group, 55), with a mean (SD) age of 71.8 (4.8) years, included 239 women (54%). A total of 36 individuals in the A+ group (9% of the A+ group) exhibited heterogeneous cortical tau patterns and were further categorized into 3 subtypes: asymmetrical left, precuneus dominant, and asymmetrical right. A total of 116 individuals in the A+ group (30% of the A+ group) showed elevated MTL tau (A+T MTL+). Individuals in the A+T cortical+ group were younger than those in the A+T MTL+ group (t61.867 = -2.597; P = .03). Across the A+T cortical+ and A+T MTL+ groups, increased regional tau was associated with reduced hippocampal volume and MTL thickness but not with cortical thickness. Memory scores were comparable between the A+T cortical+ and A+T MTL+ groups, whereas executive functioning scores were lower for the A+T cortical+ group than for the A+T MTL+ group. The prevalence of the A+T cortical+ group and tau patterns within the A+T cortical+ group were consistent in ADNI, HABS, and Wisconsin. Conclusions and relevance: This study suggests that early tau deposition may follow multiple trajectories during preclinical AD and may involve several cortical regions. Staging procedures, especially those based on neuropathology, that assume a uniform trajectory across individuals are insufficient for disease monitoring with tau imaging.Item Effects of SPI1-mediated transcriptome remodeling on Alzheimer's disease-related phenotypes in mouse models of Aβ amyloidosis(Springer Nature, 2024-05-11) Kim, Byungwook; Dabin, Luke Child; Tate, Mason Douglas; Karahan, Hande; Sharify, Ahmad Daniel; Acri, Dominic J.; Al-Amin, Md Mamun; Philtjens, Stéphanie; Smith, Daniel Curtis; Wijeratne, H. R. Sagara; Park, Jung Hyun; Jucker, Mathias; Kim, Jungsu; Medical and Molecular Genetics, School of MedicineSPI1 was recently reported as a genetic risk factor for Alzheimer's disease (AD) in large-scale genome-wide association studies. However, it is unknown whether SPI1 should be downregulated or increased to have therapeutic benefits. To investigate the effect of modulating SPI1 levels on AD pathogenesis, we performed extensive biochemical, histological, and transcriptomic analyses using both Spi1-knockdown and Spi1-overexpression mouse models. Here, we show that the knockdown of Spi1 expression significantly exacerbates insoluble amyloid-β (Aβ) levels, amyloid plaque deposition, and gliosis. Conversely, overexpression of Spi1 significantly ameliorates these phenotypes and dystrophic neurites. Further mechanistic studies using targeted and single-cell transcriptomics approaches demonstrate that altered Spi1 expression modulates several pathways, such as immune response pathways and complement system. Our data suggest that transcriptional reprogramming by targeting transcription factors, like Spi1, might hold promise as a therapeutic strategy. This approach could potentially expand the current landscape of druggable targets for AD.Item Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk(PLOS, 2022-05-26) Ali, Muhammad; Sung, Yun Ju; Wang, Fengxian; Fernández, Maria V.; Morris, John C.; Fagan, Anne M.; Blennow, Kaj; Zetterberg, Henrik; Heslegrave, Amanda; Johansson, Per M.; Svensson, Johan; Nellgård, Bengt; Lleó, Alberto; Alcolea, Daniel; Clarimon, Jordi; Rami, Lorena; Molinuevo, José Luis; Suárez-Calvet, Marc; Morenas-Rodríguez, Estrella; Kleinberger, Gernot; Haass, Christian; Ewers, Michael; Levin, Johannes; Farlow, Martin R.; Perrin, Richard J.; Alzheimer’s Disease Neuroimaging Initiative (ADNI); Dominantly Inherited Alzheimer Network (DIAN); Cruchaga, Carlos; Neurology, School of MedicineTwo genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.Item Ligand conjugated antisense oligonucleotide for the treatment of transthyretin amyloidosis: preclinical and phase 1 data(Wiley, 2021) Viney, Nicholas J.; Guo, Shuling; Tai, Li-Jung; Baker, Brenda F.; Aghajan, Mariam; Jung, Shiangtung W.; Yu, Rosie Z.; Booten, Sheri; Murray, Heather; Machemer, Todd; Burel, Sebastien; Murray, Sue; Buchele, Gustavo; Tsimikas, Sotirios; Schneider, Eugene; Geary, Richard S.; Benson, Merrill D.; Monia, Brett P.; Medicine, School of MedicineAims: Amyloidogenic transthyretin (ATTR) amyloidosis is a fatal disease characterized by progressive cardiomyopathy and/or polyneuropathy. AKCEA-TTR-LRx (ION-682884) is a ligand-conjugated antisense drug designed for receptor-mediated uptake by hepatocytes, the primary source of circulating transthyretin (TTR). Enhanced delivery of the antisense pharmacophore is expected to increase drug potency and support lower, less frequent dosing in treatment. Methods and results: AKCEA-TTR-LRx demonstrated an approximate 50-fold and 30-fold increase in potency compared with the unconjugated antisense drug, inotersen, in human hepatocyte cell culture and mice expressing a mutated human genomic TTR sequence, respectively. This increase in potency was supported by a preferential distribution of AKCEA-TTR-LRx to liver hepatocytes in the transgenic hTTR mouse model. A randomized, placebo-controlled, phase 1 study was conducted to evaluate AKCEA-TTR-LRx in healthy volunteers (ClinicalTrials.gov: NCT03728634). Eligible participants were assigned to one of three multiple-dose cohorts (45, 60, and 90 mg) or a single-dose cohort (120 mg), and then randomized 10:2 (active : placebo) to receive a total of 4 SC doses (Day 1, 29, 57, and 85) in the multiple-dose cohorts or 1 SC dose in the single-dose cohort. The primary endpoint was safety and tolerability; pharmacokinetics and pharmacodynamics were secondary endpoints. All randomized participants completed treatment. No serious adverse events were reported. In the multiple-dose cohorts, AKCEA-TTR-LRx reduced TTR levels from baseline to 2 weeks after the last dose of 45, 60, or 90 mg by a mean (SD) of -85.7% (8.0), -90.5% (7.4), and -93.8% (3.4), compared with -5.9% (14.0) for pooled placebo (P < 0.001). A maximum mean (SD) reduction in TTR levels of -86.3% (6.5) from baseline was achieved after a single dose of 120 mg AKCEA-TTR-LRx . Conclusions: These findings suggest an improved safety and tolerability profile with the increase in potency achieved by productive receptor-mediated uptake of AKCEA-TTR-LRx by hepatocytes and supports further development of AKCEA-TTR-LRx for the treatment of ATTR polyneuropathy and cardiomyopathy.