Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study

Rodriguez, Roberta Diehl; Suemoto, Cláudia Kimie; Molina, Mariana; Nascimento, Camila; Leite, Renata Elaine Paraízo; Ferretti-Rebustini, Renata Eloah de Lucena; Farfel, José Marcelo; Heinsen, Helmut; Nitrini, Ricardo; Uéda, Kenji; Pasqualucci, Carlos Augusto; Jacob‐Filho, Wilson; Yaffe, Kristine; Grinberg, Lea T.

doi:10.1093/jnen/nlw034

Cited by 64 publications

(60 citation statements)

References 70 publications

(99 reference statements)

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“…Likewise, AGD, a common age-related tauopathy [44], failed to worsen cognitive scores. Other studies suggest that AGD can actually represent a protective factor against AD spread [85].…”

Section: Discussionmentioning

confidence: 99%

“…We also collected comprehensive clinical and neuropathological data that allowed us to develop the NPC score and investigate its association with cognitive and neuropsychiatric scales. Moreover, we investigated the association between clinical symptoms and AGD, which has not been fully explored in other series [44]. In addition, the BBBABSG is a community-based autopsy study, which allows for the collection of a large number of brains from individuals with normal cognition and also an opportunity to study participants with dementia of unknown etiology.…”

Section: Discussionmentioning

confidence: 99%

“…The diagnosis of argyrophilic grain disease (AGD) was based on the presence of abundant phosphorylated tau-positive grains in the CA1 sector of the hippocampus; pretangles, especially in the hippocampal CA2 sector; and oligodendrocytes with coiled bodies in the hippocampal/temporal white matter [44]. Lewy-type pathology was classified according to the Braak et al staging scheme for PD [40].…”

Section: Methodsmentioning

confidence: 99%

“…We had first planned to include in the multivariate model only the variables that were associated with dementia status in univariate analyses. However, following peer review request, we included all neuropathological variables measured in this study in a multivariate ordinal logistic regression model that had the three categories of cognitive status (normal, questionable dementia, and dementia) as the dependent variable, since these variables have been associated with higher risk of dementia in several studies [9,10,19,44,47]. The ordinal logistic model was adjusted for age, sex, and education.…”

Section: Methodsmentioning

confidence: 99%

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Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

et al. 2017

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BackgroundClinicopathological studies are important in determining the brain lesions underlying dementia. Although almost 60% of individuals with dementia live in developing countries, few clinicopathological studies focus on these individuals. We investigated the frequency of neurodegenerative and vascular-related neuropathological lesions in 1,092 Brazilian admixed older adults, their correlation with cognitive and neuropsychiatric symptoms, and the accuracy of dementia subtype diagnosis.Methods and findingsIn this cross-sectional study, we describe clinical and neuropathological variables related to cognitive impairment in 1,092 participants (mean age = 74 y, 49% male, 69% white, and mean education = 4 y). Cognitive function was investigated using the Clinical Dementia Rating (CDR) and the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE); neuropsychiatric symptoms were evaluated using the Neuropsychiatric Inventory (NPI). Associations between neuropathological lesions and cognitive impairment were investigated using ordinal logistic regression. We developed a neuropathological comorbidity (NPC) score and compared it to CDR, IQCODE, and NPI scores. We also described and compared the frequency of neuropathological diagnosis to clinical diagnosis of dementia subtype. Forty-four percent of the sample met criteria for neuropathological diagnosis. Among these participants, 50% had neuropathological diagnoses of Alzheimer disease (AD), and 35% of vascular dementia (VaD). Neurofibrillary tangles (NFTs), hippocampal sclerosis, lacunar infarcts, hyaline atherosclerosis, siderocalcinosis, and Lewy body disease were independently associated with cognitive impairment. Higher NPC scores were associated with worse scores in the CDR sum of boxes (β = 1.33, 95% CI 1.20–1.46), IQCODE (β = 0.14, 95% CI 0.13–0.16), and NPI (β = 1.74, 95% CI = 1.33–2.16). Compared to neuropathological diagnoses, clinical diagnosis had high sensitivity to AD and high specificity to dementia with Lewy body/Parkinson dementia. The major limitation of our study is the lack of clinical follow-up of participants during life.ConclusionsNFT deposition, vascular lesions, and high NPC scorewere associated with cognitive impairment in a unique Brazilian sample with low education. Our results confirm the high prevalence of neuropathological diagnosis in older adults and the mismatch between clinical and neuropathological diagnoses.

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“…Likewise, AGD, a common age-related tauopathy [44], failed to worsen cognitive scores. Other studies suggest that AGD can actually represent a protective factor against AD spread [85].…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

et al. 2017

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“…The brain samples used in this study contained a broad burden of AD-type pathology and were selected to be free from non-AD pathology including Lewy body disease, TDP-43 proteinopathies, primary tauopathies, and cerebrovascular changes. Argyrophilic grain disease (AGD) was not an exclusion criterion based on its high prevalence and lack of correlation with significant clinical symptoms [69][70][71] . In total, the cohort included 10 cases who underwent snRNAseq, representing Braak stages 0, 2 and 6, all ApoE 3/3, and 26 cases who underwent neuroanatomical analysis, representing Braak stages 0-6 3, 25 , ranging from 2-5 individuals per Braak stage.…”

Section: Online Methods Post-mortem Cohortmentioning

confidence: 99%

Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

Leng

Eser

et al. 2020

Preprint

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Alzheimer's disease (AD) is characterized by the selective vulnerability of specific neuronal populations, the molecular signatures of which are largely unknown. To identify and characterize selectively vulnerable neuronal populations, we used single-nucleus RNA sequencing to profile the caudal entorhinal cortex and the superior frontal gyrus -brain regions where neurofibrillary inclusions and neuronal loss occur early and late in AD, respectively -from individuals spanning the neuropathological progression of AD. We identified RORB as a marker of selectively vulnerable excitatory neurons in the entorhinal cortex, and subsequently validated their depletion and selective susceptibility to neurofibrillary inclusions during disease progression using quantitative neuropathological methods. We also discovered an astrocyte subpopulation, likely representing reactive astrocytes, characterized by decreased expression of genes involved in homeostatic functions. Our characterization of selectively vulnerable neurons in AD paves the way for future mechanistic studies of selective vulnerability and potential therapeutic strategies for enhancing neuronal resilience. MAIN TEXTSelective vulnerability is a fundamental feature of neurodegenerative diseases, in which different neuronal populations show a gradient of susceptibility to degeneration 1, 2 . Selective vulnerability at the network level has been extensively explored in Alzheimer's disease (AD) 3-5 , currently the leading cause of dementia and lacking in effective therapies. However, little is known about the mechanisms underlying selective vulnerability at the cellular level in AD, which could provide insight into disease mechanisms and lead to therapeutic strategies.The entorhinal cortex (EC), an allocortex, is one of the first cortical brain regions to exhibit neuronal loss in AD 6 . Neurons in the external EC layers, especially in layer II (also known as alpha clusters of the lamina principalis externa, abbreviated "Pre-alpha") 7 , accumulate taupositive neurofibrillary changes and die early on in the course of AD 8-13 . However, these selectively vulnerable neurons have yet to be characterized extensively at the molecular level. Furthermore, it is unknown whether there are differences in vulnerability among subpopulations of these neurons. Although rodent models of AD have offered some insights [14][15][16] , the human brain has unique features with regard to cellular physiology, composition and aging [17][18][19] , limiting the extrapoloation of findings from animal models to address selective vulnerability.Previous studies have combined laser capture microdissection with microarray analysis of gene expression 20, 21 to characterize EC neurons in AD, but focused on disease-related changes in gene expression, rather than selective vulnerability. More recently, single-nucleus RNA-sequencing (snRNA-seq) has enabled large-scale characterization of transcriptomic profiles of individual cells from post-mortem human brain tissue 22, 23 . However, snRNA-seq studies of AD p...

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A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies

Imbimbo

Ippati

Watling

et al. 2021

Alzheimer's & Dementia

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Introduction: Primary tauopathies are neurological disorders in which tau protein deposition is the predominant pathological feature. Alzheimer's disease is a secondary tauopathy with tau forming hyperphosphorylated insoluble aggregates. Tau pathology can propagate from region to region in the brain, while alterations in tau processing may impair tau physiological functions. Methods:We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts, and ClnicalTrials.gov. Results:The past 15 years have seen >30 drugs interfering with tau aggregation, processing, and accumulation reaching the clinic. Initial results with tau aggregation inhibitors and anti-tau monoclonal antibodies have not shown clinical efficacy. Discussion:The reasons for these clinical failures are unclear but could be linked to the clearing of physiological forms of tau by non-specific drugs. Research is now concentrating efforts on developing reliable translational animal models and selective compounds targeting specific tau epitopes, neurotoxic tau aggregates, and posttranslational tau modifications.

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Argyrophilic Grain Disease: Demographics, Clinical, and Neuropathological Features From a Large Autopsy Study

Cited by 64 publications

References 70 publications

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

Neuropathological diagnoses and clinical correlates in older adults in Brazil: A cross-sectional study

Molecular characterization of selectively vulnerable neurons in Alzheimer’s Disease

A critical appraisal of tau‐targeting therapies for primary and secondary tauopathies

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