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Article ; Online: Autopsy Human Brain Dissection Protocol for Common Age-Related Neurodegenerative Disorders.

Sonnen, Joshua A

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2515, Page(s) 255–279

Abstract: Age-related neurodegenerative disorders are common causes of dementia-associated morbidity and mortality in populations throughout the world. Standardized, protocol-based methods for the examination and diagnosis of these disorders allow direct ... ...

Abstract	Age-related neurodegenerative disorders are common causes of dementia-associated morbidity and mortality in populations throughout the world. Standardized, protocol-based methods for the examination and diagnosis of these disorders allow direct comparison between human cohorts and play a key role in understanding how these disorders impact our population. Further understanding of these protocols and harmonization with animal and in vitro investigative techniques is imperative to demonstrate relevance to human disease. The following is a concise protocol for the examination of human whole brain autopsy samples, with and without spinal cord, for the examination of neurodegenerative disorders. The following protocol is designed to provide samples appropriate for most neurodegenerative diseases. The collection of both fresh-frozen and formalin-fixed tissues is described.This guide presumes general knowledge of neuroanatomy of the human central nervous system. Tissue processing, detailed histological techniques and complete diagnostic examination of the brain is beyond the scope of this chapter; however, a limited evaluation appropriate for the evaluation of neurodegenerative disease is described here. Diagnostic protocols for the most common causes of dementia-associated, age-related neurodegenerative disorders are also summarized.
MeSH term(s)	Autopsy ; Brain/pathology ; Dementia/diagnosis ; Dementia/etiology ; Dementia/pathology ; Humans ; Neurodegenerative Diseases/diagnosis ; Neurodegenerative Diseases/pathology ; Spinal Cord/pathology
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2409-8_16
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Article ; Online: Amyloid-PET in cerebral amyloid angiopathy: Detecting vascular amyloid deposits, not just blood.

Raposo, Nicolas / Sonnen, Joshua A

Neurology

2017 Volume 89, Issue 14, Page(s) 1437–1438

MeSH term(s)	Amyloid/metabolism ; Amyloid beta-Peptides/metabolism ; Amyloidosis/diagnostic imaging ; Amyloidosis/pathology ; Humans ; Peripheral Vascular Diseases/diagnostic imaging ; Positron-Emission Tomography
Chemical Substances	Amyloid ; Amyloid beta-Peptides
Language	English
Publishing date	2017-08-30
Publishing country	United States
Document type	Editorial
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000004548
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Article ; Online: Association Between Sepsis and Microvascular Brain Injury.

Ehlenbach, William J / Sonnen, Joshua A / Montine, Thomas J / Larson, Eric B

Critical care medicine

2019 Volume 47, Issue 11, Page(s) 1531–1538

Abstract: Objectives: Many survivors of sepsis suffer long-term cognitive impairment, but the mechanisms of this association remain unknown. The objective of this study was to determine whether sepsis is associated with cerebral microinfarcts on brain autopsy.: ...

Abstract	Objectives: Many survivors of sepsis suffer long-term cognitive impairment, but the mechanisms of this association remain unknown. The objective of this study was to determine whether sepsis is associated with cerebral microinfarcts on brain autopsy. Design: Retrospective cohort study. Setting and subjects: Five-hundred twenty-nine participants of the Adult Changes in Thought, a population-based prospective cohort study of older adults carried out in Kaiser Permanente Washington greater than or equal to 65 years old without dementia at study entry and who underwent brain autopsy. Measurements and main results: Late-life sepsis hospitalization was identified using administrative data. We identified 89 individuals with greater than or equal to 1 sepsis hospitalization during study participation, 80 of whom survived hospitalization and died a median of 169 days after discharge. Thirty percent of participants with one or more sepsis hospitalization had greater than two microinfarcts, compared with 19% participants without (χ p = 0.02); 20% of those with sepsis hospitalization had greater than two microinfarcts in the cerebral cortex, compared with 10% of those without (χ p = 0.01). The adjusted relative risk of greater than two microinfarcts was 1.61 (95% CI, 1.01-2.57; p = 0.04); the relative risk for having greater than two microinfarcts in the cerebral cortex was 2.12 (95% CI, 1.12-4.02; p = 0.02). There was no difference in Braak stage for neurofibrillary tangles or consortium to establish a registry for Alzheimer's disease score for neuritic plaques between, but Lewy bodies were less significantly common in those with sepsis. Conclusions: Sepsis was specifically associated with moderate to severe vascular brain injury as assessed by microvascular infarcts. This association was stronger for microinfarcts within the cerebral cortex, with those who experienced severe sepsis hospitalization being more than twice as likely to have evidence of moderate to severe cerebral cortical injury in adjusted analyses. Further study to identify mechanisms for the association of sepsis and microinfarcts is needed.
MeSH term(s)	Aged ; Aged, 80 and over ; Autopsy ; Brain/pathology ; Brain Infarction/pathology ; Cohort Studies ; Female ; Hospitalization ; Humans ; Intracranial Arteriosclerosis/pathology ; Male ; Retrospective Studies ; Sepsis/epidemiology ; Washington/epidemiology
Language	English
Publishing date	2019-08-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0000000000003924
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Article ; Online: Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.

Tamaki, Yoshitaka / Ross, Jay P / Alipour, Paria / Castonguay, Charles-Étienne / Li, Boting / Catoire, Helene / Rochefort, Daniel / Urushitani, Makoto / Takahashi, Ryosuke / Sonnen, Joshua A / Stifani, Stefano / Dion, Patrick A / Rouleau, Guy A

PLoS genetics

2023 Volume 19, Issue 2, Page(s) e1010606

Abstract: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) ... ...

Abstract	Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.
MeSH term(s)	Humans ; Amyotrophic Lateral Sclerosis/pathology ; Spinal Cord/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Prions/metabolism ; Organoids/metabolism
Chemical Substances	DNA-Binding Proteins ; Prions
Language	English
Publishing date	2023-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2186725-2
ISSN	1553-7404 ; 1553-7390
ISSN (online)	1553-7404
ISSN	1553-7390
DOI	10.1371/journal.pgen.1010606
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Article ; Online: Microinfarcts are common and strongly related to dementia in the oldest-old: The 90+ study.

Corrada, María M / Sonnen, Joshua A / Kim, Ronald C / Kawas, Claudia H

Alzheimer's & dementia : the journal of the Alzheimer's Association

2016 Volume 12, Issue 8, Page(s) 900–908

Abstract: Introduction: We estimated the prevalence of microinfarcts and their association with dementia in a cohort of oldest-old participants.: Methods: Participants were from The 90+ Study, a population-based study of people 90 years and older. Dementia ... ...

Abstract	Introduction: We estimated the prevalence of microinfarcts and their association with dementia in a cohort of oldest-old participants. Methods: Participants were from The 90+ Study, a population-based study of people 90 years and older. Dementia diagnoses were assigned postmortem during a consensus conference. Microinfarcts were evaluated in six brain regions. Results: At death, the 213 participants were on average 97 years old, 69% were women, and 52% had dementia. Of the participants, 51% had microinfarcts and 17% had 3+ microinfarcts. The odds ratio (OR) for dementia was similar for 3+ microinfarcts (OR = 4.75, P < .01) and tangle stage V-VI (OR = 4.70, P < .001). Only microinfarcts in cortical regions (other than occipital) were associated to dementia. Discussion: In this oldest-old cohort, microinfarcts are common and contribute independently and similarly in magnitude to dementia as tangles. As risk factors for microinfarcts and other dementing pathologies are likely to differ, identifying these factors is crucial to developing prevention strategies for dementia in the oldest-old.
MeSH term(s)	Aged, 80 and over ; Aging/pathology ; Brain Infarction/etiology ; Cohort Studies ; Dementia/complications ; Dementia/pathology ; Female ; Humans ; Male
Language	English
Publishing date	2016-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1016/j.jalz.2016.04.006
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Article ; Online: MicroRNA-210 regulates the metabolic and inflammatory status of primary human astrocytes.

Kieran, Nicholas W / Suresh, Rahul / Dorion, Marie-France / MacDonald, Adam / Blain, Manon / Wen, Dingke / Fuh, Shih-Chieh / Ryan, Fari / Diaz, Roberto J / Stratton, Jo Anne / Ludwin, Samuel K / Sonnen, Joshua A / Antel, Jack / Healy, Luke M

Journal of neuroinflammation

2022 Volume 19, Issue 1, Page(s) 10

Abstract: Background: Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands ... ...

Abstract	Background: Astrocytes are the most numerous glial cell type with important roles in maintaining homeostasis and responding to diseases in the brain. Astrocyte function is subject to modulation by microRNAs (miRs), which are short nucleotide strands that regulate protein expression in a post-transcriptional manner. Understanding the miR expression profile of astrocytes in disease settings provides insight into the cellular stresses present in the microenvironment and may uncover pathways of therapeutic interest. Methods: Laser-capture microdissection was used to isolate human astrocytes surrounding stroke lesions and those from neurological control tissue. Astrocytic miR expression profiles were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR). Primary human fetal astrocytes were cultured under in vitro stress conditions and transfection of a miR mimic was used to better understand how altered levels of miR-210 affect astrocyte function. The astrocytic response to stress was studied using qPCR, enzyme-linked immunosorbent assays (ELISAs), measurement of released lactate, and Seahorse. Results: Here, we measured miR expression levels in astrocytes around human ischemic stroke lesions and observed differential expression of miR-210 in chronic stroke astrocytes compared to astrocytes from neurological control tissue. We also identified increased expression of miR-210 in mouse white matter tissue around middle cerebral artery occlusion (MCAO) brain lesions. We aimed to understand the role of miR-210 in primary human fetal astrocytes by developing an in vitro assay of hypoxic, metabolic, and inflammatory stresses. A combination of hypoxic and inflammatory stresses was observed to upregulate miR-210 expression. Transfection with miR-210-mimic (210M) increased glycolysis, enhanced lactate export, and promoted an anti-inflammatory transcriptional and translational signature in astrocytes. Additionally, 210M transfection resulted in decreased expression of complement 3 (C3) and semaphorin 5b (Sema5b). Conclusions: We conclude that miR-210 expression in human astrocytes is modulated in response to ischemic stroke disease and under in vitro stress conditions, supporting a role for miR-210 in the astrocytic response to disease conditions. Further, the anti-inflammatory and pro-glycolytic impact of miR-210 on astrocytes makes it a potential candidate for further research as a neuroprotective agent.
MeSH term(s)	Animals ; Astrocytes/metabolism ; HeLa Cells ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Laser Capture Microdissection ; Mice ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Stroke/genetics ; Stroke/metabolism
Chemical Substances	MicroRNAs
Language	English
Publishing date	2022-01-06
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-021-02373-y
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Article ; Online: Association of Antihypertensives That Stimulate vs Inhibit Types 2 and 4 Angiotensin II Receptors With Cognitive Impairment.

Marcum, Zachary A / Cohen, Jordana B / Zhang, Chong / Derington, Catherine G / Greene, Tom H / Ghazi, Lama / Herrick, Jennifer S / King, Jordan B / Cheung, Alfred K / Bryan, Nick / Supiano, Mark A / Sonnen, Joshua A / Weintraub, William S / Williamson, Jeff / Pajewski, Nicholas M / Bress, Adam P

JAMA network open

2022 Volume 5, Issue 1, Page(s) e2145319

Abstract: Importance: Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, this association with cognitive ... ...

Abstract	Importance: Use of antihypertensive medications that stimulate type 2 and 4 angiotensin II receptors, compared with those that do not stimulate these receptors, has been associated with a lower risk of dementia. However, this association with cognitive outcomes in hypertension trials, with blood pressure levels in the range of current guidelines, has not been evaluated. Objective: To examine the association between use of exclusively antihypertensive medication regimens that stimulate vs inhibit type 2 and 4 angiotensin II receptors on mild cognitive impairment (MCI) or dementia. Design, setting, and participants: This cohort study is a secondary analysis (April 2011 to July 2018) of participants in the randomized Systolic Blood Pressure Intervention Trial (SPRINT), which recruited individuals 50 years or older with hypertension and increased cardiovascular risk but without a history of diabetes, stroke, or dementia. Data analysis was conducted from March 16 to July 6, 2021. Exposures: Prevalent use of angiotensin II receptor type 2 and 4-stimulating or -inhibiting antihypertensive medication regimens at the 6-month study visit. Main outcomes and measures: The primary outcome was a composite of adjudicated amnestic MCI or probable dementia. Results: Of the 8685 SPRINT participants who were prevalent users of antihypertensive medication regimens at the 6-month study visit (mean [SD] age, 67.7 [11.2] years; 5586 [64.3%] male; and 935 [10.8%] Hispanic, 2605 [30.0%] non-Hispanic Black, 4983 [57.4%] non-Hispanic White, and 162 [1.9%] who responded as other race or ethnicity), 2644 (30.4%) were users of exclusively stimulating, 1536 (17.7%) inhibiting, and 4505 (51.9%) mixed antihypertensive medication regimens. During a median of 4.8 years of follow-up (95% CI, 4.7-4.8 years), there were 45 vs 59 cases per 1000 person-years of amnestic MCI or probable dementia among prevalent users of regimens that contained exclusively stimulating vs inhibiting antihypertensive medications (hazard ratio [HR], 0.76; 95% CI, 0.66-0.87). When comparing stimulating-only vs inhibiting-only users, amnestic MCI occurred at rates of 40 vs 54 cases per 1000 person-years (HR, 0.74; 95% CI, 0.64-0.87) and probable dementia at rates of 8 vs 10 cases per 1000 person-years (HR, 0.80; 95% CI, 0.57-1.14). Negative control outcome analyses suggested the presence of residual confounding. Conclusions and relevance: In this secondary analysis of SPRINT, prevalent users of regimens that contain exclusively antihypertensive medications that stimulate vs inhibit type 2 and 4 angiotensin II receptors had lower rates of incident cognitive impairment. Residual confounding cannot be ruled out. If these results are replicated in randomized clinical trials, certain antihypertensive medications could be prioritized to prevent cognitive decline.
MeSH term(s)	Aged ; Angiotensin Receptor Antagonists/pharmacology ; Antihypertensive Agents/pharmacology ; Cognitive Dysfunction/chemically induced ; Cognitive Dysfunction/epidemiology ; Dementia/chemically induced ; Dementia/epidemiology ; Female ; Follow-Up Studies ; Heart Disease Risk Factors ; Humans ; Hypertension/drug therapy ; Incidence ; Male ; Middle Aged ; Prevalence ; Proportional Hazards Models ; Randomized Controlled Trials as Topic ; Receptor, Angiotensin, Type 1/drug effects ; Receptor, Angiotensin, Type 2/drug effects
Chemical Substances	Angiotensin Receptor Antagonists ; Antihypertensive Agents ; Receptor, Angiotensin, Type 1 ; Receptor, Angiotensin, Type 2
Language	English
Publishing date	2022-01-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2021.45319
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Article ; Online: Risk of Mild Cognitive Impairment or Probable Dementia in New Users of Angiotensin II Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors: A Secondary Analysis of Data From the Systolic Blood Pressure Intervention Trial (SPRINT).

Cohen, Jordana B / Marcum, Zachary A / Zhang, Chong / Derington, Catherine G / Greene, Tom H / Ghazi, Lama / Herrick, Jennifer S / King, Jordan B / Cheung, Alfred K / Bryan, Nick / Supiano, Mark A / Sonnen, Joshua A / Weintraub, William S / Scharfstein, Daniel / Williamson, Jeff / Pajewski, Nicholas M / Bress, Adam P

JAMA network open

2022 Volume 5, Issue 7, Page(s) e2220680

Abstract: Importance: The cardiovascular and renal outcomes of angiotensin-II receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) treatment are well-known; however, few studies have evaluated initiation of these agents and cognitive ... ...

Abstract	Importance: The cardiovascular and renal outcomes of angiotensin-II receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) treatment are well-known; however, few studies have evaluated initiation of these agents and cognitive impairment. Objective: To emulate a target trial to evaluate the cognitive outcomes of initiating an ARB- vs ACEI-based antihypertensive regimen in individuals at risk for mild cognitive impairment (MCI) and probable dementia (PD). Design, setting, and participants: Active comparator, new-user observational cohort study design using data from the Systolic Blood Pressure Intervention Trial (SPRINT), conducted November 2010 through July 2018. Marginal cause-specific hazard ratios (HRs) and treatment-specific cumulative incidence functions were estimated with inverse probability (IP) weighting to account for confounding. Participants were using neither an ARB nor ACEI at baseline. Data analysis was conducted from April 7, 2021, to April 26, 2022. Exposures: New users of ARB vs ACEI during the first 12 months of trial follow-up. Main outcomes and measures: Composite of adjudicated amnestic MCI or PD. Results: Of 9361 participants, 727 and 1313 new users of an ARB or ACEI, respectively, with well-balanced baseline characteristics between medication exposure groups after inverse probability weighting (mean [SD] age, 67 [9.5] years; 1291 ]63%] male; 240 [33%] Black; 89 [12%] Hispanic; 383 [53%] White; and 15 [2%] other race or ethnicity. In the primary analysis, during a median follow-up of 4.9 years, the inverse probability-weighted rate of amnestic MCI or PD was 4.3 vs 4.6 per 100 person-years among participants initiating ARB vs ACEI (HR, 0.93; 95% CI, 0.76-1.13). In subgroup analyses, new users of an ARB vs ACEI had a lower rate of amnestic MCI or PD among those in the standard systolic blood pressure treatment arm (HR, 0.61; 95% CI, 0.41-0.91) but not in the intensive arm (HR, 1.17; 95% CI, 0.90-1.52) (P = .007 for interaction). Conclusions and relevance: In this observational cohort study of US adults at high cardiovascular disease risk, there was no difference in the rate of amnestic MCI or PD among new users of an ARB compared with ACEI, although 95% CIs were wide.
MeSH term(s)	Adult ; Aged ; Angiotensin Receptor Antagonists/adverse effects ; Angiotensin-Converting Enzyme Inhibitors/adverse effects ; Blood Pressure ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/epidemiology ; Dementia/drug therapy ; Dementia/epidemiology ; Female ; Humans ; Male ; Proportional Hazards Models
Chemical Substances	Angiotensin Receptor Antagonists ; Angiotensin-Converting Enzyme Inhibitors
Language	English
Publishing date	2022-07-01
Publishing country	United States
Document type	Journal Article ; Observational Study ; Research Support, N.I.H., Extramural
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.20680
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Article ; Online: 18F-MK-6240 tau-PET in genetic frontotemporal dementia.

Levy, Jake P / Bezgin, Gleb / Savard, Melissa / Pascoal, Tharick A / Finger, Elizabeth / Laforce, Robert / Sonnen, Joshua A / Soucy, Jean-Paul / Gauthier, Serge / Rosa-Neto, Pedro / Ducharme, Simon

Brain : a journal of neurology

2021 Volume 145, Issue 5, Page(s) 1763–1772

Abstract: Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient's disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this ... ...

Abstract	Tau is one of several proteins associated with frontotemporal dementia. While knowing which protein is causing a patient's disease is crucial, no biomarker currently exists for identifying tau in vivo in frontotemporal dementia. The objective of this study was to investigate the potential for the promising 18F-MK-6240 PET tracer to bind to tau in vivo in genetic frontotemporal dementia. We enrolled subjects with genetic frontotemporal dementia, who constitute an ideal population for testing because their pathology is already known based on their mutation. Ten participants (three with symptomatic P301L and R406W MAPT mutations expected to show tau binding, three with presymptomatic MAPT mutations and four with non-tau mutations who acted as disease controls) underwent clinical characterization, tau-PET scanning with 18F-MK-6240, amyloid-PET imaging with 18F-NAV-4694 to rule out confounding Alzheimer's pathology, and high-resolution structural MRI. Tau-PET scans of all three symptomatic MAPT carriers demonstrated at least mild 18F-MK-6240 binding in expected regions, with particularly strong binding in a subject with an R406W MAPT mutation (known to be associated with Alzheimer's like neurofibrillary tangles). Two asymptomatic MAPT carriers estimated to be 5 years from disease onset both showed modest 18F-MK-6240 binding, while one ∼30 years from disease onset did not exhibit any binding. Additionally, four individuals with symptomatic frontotemporal dementia caused by a non-tau mutation were scanned (two C9orf72; one GRN; one VCP): 18F-MK-6240 scans were negative for three subjects, while one advanced C9orf72 case showed minimal regionally non-specific binding. All 10 amyloid-PET scans were negative. Furthermore, a general linear model contrasting genetic frontotemporal dementia subjects to a set of 83 age-matched controls showed significant binding only in the MAPT carriers in selected frontal, temporal and subcortical regions. In summary, our findings demonstrate mild but significant binding of MK-6240 in amyloid-negative P301L and R406W MAPT mutation subjects, with higher standardized uptake value ratio in the R406W mutation associated with the presence of NFTs, and little non-specific binding. These results highlight that a positive 18F-MK-6240 tau-PET does not necessarily imply a diagnosis of Alzheimer's disease and point towards a potential use for 18F-MK-6240 as a biomarker in certain tauopathies beyond Alzheimer's, although further patient recruitment and autopsy studies will be necessary to determine clinical applicability.
MeSH term(s)	Alzheimer Disease/pathology ; C9orf72 Protein/genetics ; Frontotemporal Dementia/diagnostic imaging ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/metabolism ; Humans ; Isoquinolines ; Mutation ; Neurofibrillary Tangles/pathology ; tau Proteins/genetics ; tau Proteins/metabolism
Chemical Substances	C9orf72 Protein ; Isoquinolines ; MK-6240 ; tau Proteins
Language	English
Publishing date	2021-10-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awab392
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Article ; Online: Theoretical impact of the AT(N) framework on dementia using a community autopsy sample.

Burke, Bridget Teevan / Latimer, Caitlin / Keene, C Dirk / Sonnen, Joshua A / McCormick, Wayne / Bowen, James D / McCurry, Susan M / Larson, Eric B / Crane, Paul K

Alzheimer's & dementia : the journal of the Alzheimer's Association

2021 Volume 17, Issue 12, Page(s) 1879–1891

Abstract: The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) ... ...

Abstract	The AT(N) research framework categorizes eight biomarker profiles using amyloid (A), tauopathy (T), and neurodegeneration (N), regardless of dementia status. We evaluated associations with dementia risk in a community-based cohort by approximating AT(N) profiles using autopsy-based neuropathology correlates, and considered cost implications for clinical trials for secondary prevention of dementia based on AT(N) profiles. We used Consortium to Establish a Registry for Alzheimer's Disease (moderate/frequent) to approximate A+, Braak stage (IV-VI) for T+, and temporal pole lateral ventricular dilation for (N)+. Outcomes included dementia prevalence at death and incidence in the last 5 years of life. A+T+(N)+ was the most common profile (31%). Dementia prevalence ranged from 14% (A-T-[N]-) to 79% (A+T+[N]+). Between 8% (A+T-[N]-) and 68% (A+T+[N]-) of decedents developed incident dementia in the last 5 years of life. Clinical trials would incur substantial expense to characterize AT(N). Many people with biomarker-defined preclinical Alzheimer's disease will never develop clinical dementia during life, highlighting resilience to clinical expression of AD neuropathologic changes and the need for improved tools for prediction beyond current AT(N) biomarkers.
MeSH term(s)	Aged ; Aged, 80 and over ; Autopsy ; Biomarkers ; Brain/pathology ; Cohort Studies ; Dementia/pathology ; Female ; Humans ; Male ; Neurofibrillary Tangles/pathology ; Neuropathology ; Plaque, Amyloid/pathology ; Positron-Emission Tomography ; Secondary Prevention
Chemical Substances	Biomarkers
Language	English
Publishing date	2021-04-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.12348
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 6316: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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