LEA TENENHOLZ GRINBERG
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Patologia, Faculdade de Medicina - Docente
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
LIM/22 - Laboratório de Patolologia Cardiovascular, Hospital das Clínicas, Faculdade de Medicina
67 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 67
- Selective Vulnerability of Brainstem Nuclei in Distinct Tauopathies: A Postmortem Study(2018) ESER, Rana A.; EHRENBERG, Alexander J.; PETERSEN, Cathrine; DUNLOP, Sara; MEJIA, Maria B.; SUEMOTO, Claudia K.; WALSH, Christine M.; RAJANA, Hima; OH, Jun; THEOFILAS, Panos; SEELEY, William W.; MILLER, Bruce L.; NEYLAN, Thomas C.; HEINSEN, Helmut; GRINBERG, Lea T.The brainstem nuclei of the reticular formation (RF) are critical for regulating homeostasis, behavior, and cognition. RF degenerates in tauopathies including Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Although the burden of phopho-tau inclusion is high across these diseases, suggesting a similar vulnerability pattern, a distinct RF-associated clinical phenotype in these diseases indicates the opposite. To compare patterns of RF selective vulnerability to tauopathies, we analyzed 5 RF nuclei in tissue from 14 AD, 14 CBD, 10 PSP, and 3 control cases. Multidimensional quantitative analysis unraveled discernable differences on how these nuclei are vulnerable to AD, CBD, and PSP. For instance, PSP and CBD accrued more tau inclusions than AD in locus coeruleus, suggesting a lower vulnerability to AD. However, locus coeruleus neuronal loss in AD was so extreme that few neurons remained to develop aggregates. Likewise, tau burden in gigantocellular nucleus was low in AD and high in PSP, but few GABAergic neurons were present in AD. This challenges the hypothesis that gigantocellular nucleus neuronal loss underlies REM behavioral disorders because REM behavioral disorders rarely manifests in AD. This study provides foundation for characterizing the clinical consequences of RF degeneration in tauopathies and guiding customized treatment.
conferenceObject NEUROBIOLOGICAL BASIS OF SLEEP DISTURBANCES IN TAUOPATHIES: HUMAN WAKE-PROMOTING NEURONS DEGENERATE MORE IN ALZHEIMER'S DISEASE(2019) OH, Jun; ESER, Rana A.; EHRENBERG, Alexander J.; MORALES, Dulce; PETERSEN, Cathrine; THEOFILAS, Panos; RESENDE, Elisa; COSME, Celica; SEELEY, William W.; SPINA, Salvatore; WALSH, Christine M.; NEYLAN, Thomas C.; MILLER, Bruce L.; BITTENCOURT, Jackson C.; GRINBERG, Lea T.- Quantifying the accretion of hyperphosphorylated tau in the locus coeruleus and dorsal raphe nucleus: the pathological building blocks of early Alzheimer's disease(2017) EHRENBERG, A. J.; NGUY, A. K.; THEOFILAS, P.; DUNLOP, S.; SUEMOTO, C. K.; ALHO, A. T. Di Lorenzo; LEITE, R. P.; RODRIGUEZ, R. Diehl; MEJIA, M. B.; RUEB, U.; FARFEL, J. M.; FERRETTI-REBUSTINI, R. E. de Lucena; NASCIMENTO, C. F.; NITRINI, R.; PASQUALLUCCI, C. A.; JACOB-FILHO, W.; MILLER, B.; SEELEY, W. W.; HEINSEN, H.; GRINBERG, L. T.AimsHyperphosphorylated tau neuronal cytoplasmic inclusions (ht-NCI) are the best protein correlate of clinical decline in Alzheimer's disease (AD). Qualitative evidence identifies ht-NCI accumulating in the isodendritic core before the entorhinal cortex. Here, we used unbiased stereology to quantify ht-NCI burden in the locus coeruleus (LC) and dorsal raphe nucleus (DRN), aiming to characterize the impact of AD pathology in these nuclei with a focus on early stages.MethodsWe utilized unbiased stereology in a sample of 48 well-characterized subjects enriched for controls and early AD stages. ht-NCI counts were estimated in 60-m-thick sections immunostained for p-tau throughout LC and DRN. Data were integrated with unbiased estimates of LC and DRN neuronal population for a subset of cases.ResultsIn Braak stage 0, 7.9% and 2.6% of neurons in LC and DRN, respectively, harbour ht-NCIs. Although the number of ht-NCI+ neurons significantly increased by about 1.9x between Braak stages 0 to I in LC (P = 0.02), we failed to detect any significant difference between Braak stage I and II. Also, the number of ht-NCI+ neurons remained stable in DRN between all stages 0 and II. Finally, the differential susceptibility to tau inclusions among nuclear subdivisions was more notable in LC than in DRN.ConclusionsLC and DRN neurons exhibited ht-NCI during AD precortical stages. The ht-NCI increases along AD progression on both nuclei, but quantitative changes in LC precede DRN changes.
- Primary age-related tauopathy (PART): a common pathology associated with human aging(2014) CRARY, John F.; TROJANOWSKI, John Q.; SCHNEIDER, Julie A.; ABISAMBRA, Jose F.; ABNER, Erin L.; ALAFUZOFF, Irina; ARNOLD, Steven E.; ATTEMS, Johannes; BEACH, Thomas G.; BIGIO, Eileen H.; CAIRNS, Nigel J.; DICKSON, Dennis W.; GEARING, Marla; GRINBERG, Lea T.; HOF, Patrick R.; HYMAN, Bradley T.; JELLINGER, Kurt; JICHA, Gregory A.; KOVACS, Gabor G.; KNOPMAN, David S.; KOFLER, Julia; KUKULL, Walter A.; MACKENZIE, Ian R.; MASLIAH, Eliezer; MCKEE, Ann; MONTINE, Thomas J.; MURRAY, Melissa E.; NELTNER, Janna H.; SANTA-MARIA, Ismael; SEELEY, William W.; SERRANO-POZO, Alberto; SHELANSKI, Michael L.; STEIN, Thor; TAKAO, Masaki; THAL, Dietmar R.; TOLEDO, Jonathan B.; TRONCOSO, Juan C.; VONSATTEL, Jean Paul; III, Charles L. White; WISNIEWSKI, Thomas; WOLTJER, Randall L.; YAMADA, Masahito; NELSON, Peter T.We recommend a new term, ""primary age-related tauopathy"" (PART), to describe a pathology that is commonly observed in the brains of aged individuals. Many autopsy studies have reported brains with neurofibrillary tangles (NFTs) that are indistinguishable from those of Alzheimer's disease (AD), in the absence of amyloid (A beta) plaques. For these ""NFT+/A beta-aEuroe brains, for which formal criteria for AD neuropathologic changes are not met, the NFTs are mostly restricted to structures in the medial temporal lobe, basal forebrain, brainstem, and olfactory areas (bulb and cortex). Symptoms in persons with PART usually range from normal to amnestic cognitive changes, with only a minority exhibiting profound impairment. Because cognitive impairment is often mild, existing clinicopathologic designations, such as ""tangle-only dementia"" and ""tangle-predominant senile dementia"", are imprecise and not appropriate for most subjects. PART is almost universally detectable at autopsy among elderly individuals, yet this pathological process cannot be specifically identified pre-mortem at the present time. Improved biomarkers and tau imaging may enable diagnosis of PART in clinical settings in the future. Indeed, recent studies have identified a common biomarker profile consisting of temporal lobe atrophy and tauopathy without evidence of A beta accumulation. For both researchers and clinicians, a revised nomenclature will raise awareness of this extremely common pathologic change while providing a conceptual foundation for future studies. Prior reports that have elucidated features of the pathologic entity we refer to as PART are discussed, and working neuropathological diagnostic criteria are proposed.
- Fmr1 exon 14 skipping in late embryonic development of the rat forebrain(2022) CORREA-VELLOSO, Juliana C.; LINARDI, Alessandra M.; GLASER, Talita; VELLOSO, Fernando J.; RIVAS, Maria P.; LEITE, Renata E. P.; GRINBERG, Lea T.; ULRICH, Henning; AKINS, Michael R.; CHIAVEGATTO, Silvana; HADDAD, Luciana A.Background Fragile X syndrome, the major cause of inherited intellectual disability among men, is due to deficiency of the synaptic functional regulator FMR1 protein (FMRP), encoded by the FMRP translational regulator 1 (FMR1) gene. FMR1 alternative splicing produces distinct transcripts that may consequently impact FMRP functional roles. In transcripts without exon 14 the translational reading frame is shifted. For deepening current knowledge of the differential expression of Fmr1 exon 14 along the rat nervous system development, we conducted a descriptive study employing quantitative RT-PCR and BLAST of RNA-Seq datasets. Results We observed in the rat forebrain progressive decline of total Fmr1 mRNA from E11 to P112 albeit an elevation on P3; and exon-14 skipping in E17-E20 with downregulation of the resulting mRNA. We tested if the reduced detection of messages without exon 14 could be explained by nonsense-mediated mRNA decay (NMD) vulnerability, but knocking down UPF1, a major component of this pathway, did not increase their quantities. Conversely, it significantly decreased FMR1 mRNA having exon 13 joined with either exon 14 or exon 15 site A. Conclusions The forebrain in the third embryonic week of the rat development is a period with significant skipping of Fmr1 exon 14. This alternative splicing event chronologically precedes a reduction of total Fmr1 mRNA, suggesting that it may be part of combinatorial mechanisms downregulating the gene's expression in the late embryonic period. The decay of FMR1 mRNA without exon 14 should be mediated by a pathway different from NMD. Finally, we provide evidence of FMR1 mRNA stabilization by UPF1, likely depending on FMRP.
- Hyperphosphorylated Tau in Mesial Temporal Lobe Epilepsy: a Neuropathological and Cognitive Study(2023) TOSCANO, Eliana C. B.; VIEIRA, Erica L. M.; GRINBERG, Lea T.; ROCHA, Natalia P.; BRANT, Joseane A. S.; PARADELA, Regina S.; GIANNETTI, Alexandre V.; SUEMOTO, Claudia K.; LEITE, Renata E. P.; NITRINI, Ricardo; RACHID, Milene A.; TEIXEIRA, Antonio L.Temporal lobe epilepsy (TLE) often courses with cognitive deficits, but its underlying neuronal basis remains unclear. Confluent data suggest that epilepsy share pathophysiological mechanisms with neurodegenerative diseases. However, as most studies analyze subjects 60 years old and older, it is challenging to rule out that neurodegenerative changes arise from age-related mechanisms rather than epilepsy in these individuals. To fill this gap, we conducted a neuropathological investigation of the hippocampal formation of 22 adults with mesial TLE and 20 age-and sex-matched controls (both younger than 60 years). Moreover, we interrogated the relationship between these neuropathological metrics and cognitive performance. Hippocampal formation extracted from patients with drug-resistant mesial TLE undergoing surgery and postmortem non-sclerotic hippocampal formation of clinically and neuropathologically controls underwent immunohistochemistry against amyloid beta (A beta), hyperphosphorylated tau (p-tau), and TAR DNA-binding protein-43 (TDP-43) proteins, followed by quantitative analysis. Patients underwent a comprehensive neuropsychological evaluation prior to surgery. TLE hippocampi showed a significantly higher burden of p-tau than controls, whereas A beta deposits and abnormal inclusions of TDP-43 were absent in both groups. Patients with hippocampal sclerosis (HS) type 2 had higher immunostaining for p-tau than patients with HS type 1. In addition, p-tau burden was associated with impairment in attention tasks and seizures frequency. In this series of adults younger than 60 years-old, the increase of p-tau burden associated with higher frequency of seizures and attention impairment suggests the involvement of tau pathology as a potential contributor to cognitive deficits in mesial TLE.
- p Deep learning for Alzheimer's disease: Mapping large-scale histological tau protein for neuroimaging biomarker validation(2022) USHIZIMA, Daniela; CHEN, Yuheng; ALEGRO, Maryana; OVANDO, Dulce; ESER, Rana; LEE, WingHung; POON, Kinson; SHANKAR, Anubhav; KANTAMNENI, Namrata; SATRAWADA, Shruti; AMARO JUNIOR, Edson; HEINSEN, Helmut; TOSUN, Duygu; GRINBERG, Lea T.Abnormal tau inclusions are hallmarks of Alzheimer's disease and predictors of clinical decline. Several tau PET tracers are available for neurodegenerative disease research, opening avenues for molecular diagnosis in vivo. However, few have been approved for clinical use. Understanding the neurobiological basis of PET signal validation remains problematic because it requires a large-scale, voxel-to-voxel correlation between PET and (immuno) histological signals. Large dimensionality of whole human brains, tissue deformation impacting co-registration, and computing requirements to process terabytes of information preclude proper validation. We developed a computational pipeline to identify and segment particles of interest in billion-pixel digital pathology images to generate quantitative, 3D density maps. The proposed convolutional neural network for immunohistochemistry samples, IHCNet, is at the pipeline's core. We have successfully processed and immunostained over 500 slides from two whole human brains with three phospho-tau antibodies (AT100, AT8, and MC1), spanning several terabytes of images. Our artificial neural network estimated tau inclusion from brain images, which performs with ROC AUC of 0.87, 0.85, and 0.91 for AT100, AT8, and MC1, respectively. Introspection studies further assessed the ability of our trained model to learn tau-related features. We present an end-to-end pipeline to create terabytes-large 3D tau inclusion density maps co-registered to MRI as a means to facilitate validation of PET tracers.
- 4-Repeat tau seeds and templating subtypes as brain and CSF biomarkers of frontotemporal lobar degeneration (vol 52, pg 127, 2019)(2020) SAIJO, Eri; II, Michael A. Metrick; KOGA, Shunsuke; PARCHI, Piero; LITVAN, Irene; SPINA, Salvatore; BOXER, Adam; ROJAS, Julio C.; GALASKO, Douglas; KRAUS, Allison; ROSSI, Marcello; NEWELL, Kathy; ZANUSSO, Gianluigi; GRINBERG, Lea T.; SEELEY, William W.; GHETTI, Bernardino; DICKSON, Dennis W.; CAUGHEY, Byron
- Post-mortem assessment in vascular dementia: advances and aspirations(2016) MCALEESE, Kirsty E.; ALAFUZOFF, Irina; CHARIDIMOU, Andreas; REUCK, Jacques De; GRINBERG, Lea T.; HAINSWORTH, Atticus H.; HORTOBAGYI, Tibor; INCE, Paul; JELLINGER, Kurt; GAO, Jing; KALARIA, Raj N.; KOVACS, Gabor G.; KOVARI, Eniko; LOVE, Seth; POPOVIC, Mara; SKROBOT, Olivia; TAIPA, Ricardo; THAL, Dietmar R.; WERRING, David; WHARTON, Stephen B.; ATTEMS, JohannesBackground: Cerebrovascular lesions are a frequent finding in the elderly population. However, the impact of these lesions on cognitive performance, the prevalence of vascular dementia, and the pathophysiology behind characteristic in vivo imaging findings are subject to controversy. Moreover, there are no standardised criteria for the neuropathological assessment of cerebrovascular disease or its related lesions in human post-mortem brains, and conventional histological techniques may indeed be insufficient to fully reflect the consequences of cerebrovascular disease. Discussion: Here, we review and discuss both the neuropathological and in vivo imaging characteristics of cerebrovascular disease, prevalence rates of vascular dementia, and clinico-pathological correlations. We also discuss the frequent comorbidity of cerebrovascular pathology and Alzheimer's disease pathology, as well as the difficult and controversial issue of clinically differentiating between Alzheimer's disease, vascular dementia and mixed Alzheimer's disease/vascular dementia. Finally, we consider additional novel approaches to complement and enhance current post-mortem assessment of cerebral human tissue. Conclusion: Elucidation of the pathophysiology of cerebrovascular disease, clarification of characteristic findings of in vivo imaging and knowledge about the impact of combined pathologies are needed to improve the diagnostic accuracy of clinical diagnoses.
- Frequency of LATE neuropathologic change across the spectrum of Alzheimer's disease neuropathology: combined data from 13 community-based or population-based autopsy cohorts(2022) NELSON, Peter T.; BRAYNE, Carol; FLANAGAN, Margaret E.; ABNER, Erin L.; AGRAWAL, Sonal; ATTEMS, Johannes; CASTELLANI, Rudolph J.; CORRADA, Maria M.; CYKOWSKI, Matthew D.; DI, Jing; DICKSON, Dennis W.; DUGGER, Brittany N.; ERVIN, John F.; FLEMING, Jane; GRAFF-RADFORD, Jonathan; GRINBERG, Lea T.; HOKKANEN, Suvi R. K.; HUNTER, Sally; KAPASI, Alifiya; KAWAS, Claudia H.; KEAGE, Hannah A. D.; KEENE, C. Dirk; KERO, Mia; KNOPMAN, David S.; KOURI, Naomi; KOVACS, Gabor G.; LABUZAN, Sydney A.; LARSON, Eric B.; LATIMER, Caitlin S.; LEITE, Renata E. P.; MATCHETT, Billie J.; MATTHEWS, Fiona E.; MERRICK, Richard; MONTINE, Thomas J.; MURRAY, Melissa E.; MYLLYKANGAS, Liisa; NAG, Sukriti; NELSON, Ruth S.; NELTNER, Janna H.; NGUYEN, Aivi T.; PETERSEN, Ronald C.; POLVIKOSKI, Tuomo; REICHARD, R. Ross; RODRIGUEZ, Roberta D.; SUEMOTO, Claudia K.; WANG, Shih-Hsiu J.; WHARTON, Stephen B.; WHITE, Lon; SCHNEIDER, Julie A.Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and Alzheimer's disease neuropathologic change (ADNC) are each associated with substantial cognitive impairment in aging populations. However, the prevalence of LATE-NC across the full range of ADNC remains uncertain. To address this knowledge gap, neuropathologic, genetic, and clinical data were compiled from 13 high-quality community- and population-based longitudinal studies. Participants were recruited from United States (8 cohorts, including one focusing on Japanese-American men), United Kingdom (2 cohorts), Brazil, Austria, and Finland. The total number of participants included was 6196, and the average age of death was 88.1 years. Not all data were available on each individual and there were differences between the cohorts in study designs and the amount of missing data. Among those with known cognitive status before death (n = 5665), 43.0% were cognitively normal, 14.9% had MCI, and 42.4% had dementia-broadly consistent with epidemiologic data in this age group. Approximately 99% of participants (n = 6125) had available CERAD neuritic amyloid plaque score data. In this subsample, 39.4% had autopsy-confirmed LATE-NC of any stage. Among brains with ""frequent"" neuritic amyloid plaques, 54.9% had comorbid LATE-NC, whereas in brains with no detected neuritic amyloid plaques, 27.0% had LATE-NC. Data on LATE-NC stages were available for 3803 participants, of which 25% had LATE-NC stage > 1 (associated with cognitive impairment). In the subset of individuals with Thal A beta phase = 0 (lacking detectable A beta plaques), the brains with LATE-NC had relatively more severe primary age-related tauopathy (PART). A total of 3267 participants had available clinical data relevant to frontotemporal dementia (FTD), and none were given the clinical diagnosis of definite FTD nor the pathological diagnosis of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In the 10 cohorts with detailed neurocognitive assessments proximal to death, cognition tended to be worse with LATE-NC across the full spectrum of ADNC severity. This study provided a credible estimate of the current prevalence of LATE-NC in advanced age. LATE-NC was seen in almost 40% of participants and often, but not always, coexisted with Alzheimer's disease neuropathology.