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Article ; Online: Micro-RNA profiles of pathology and resilience in posterior cingulate cortex of cognitively intact elders.

Kelley, Christy M / Maloney, Bryan / Beck, John S / Ginsberg, Stephen D / Liang, Winnie / Lahiri, Debomoy K / Mufson, Elliott J / Counts, Scott E

Brain communications

2024 Volume 6, Issue 2, Page(s) fcae082

Abstract: The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue ...

Abstract	The posterior cingulate cortex (PCC) is a key hub of the default mode network underlying autobiographical memory retrieval, which falters early in the progression of Alzheimer's disease (AD). We recently performed RNA sequencing of post-mortem PCC tissue samples from 26 elderly Rush Religious Orders Study participants who came to autopsy with an ante-mortem diagnosis of no cognitive impairment but who collectively displayed a range of Braak I-IV neurofibrillary tangle stages. Notably, cognitively unimpaired subjects displaying high Braak stages may represent cognitive resilience to AD pathology. Transcriptomic data revealed elevated synaptic and ATP-related gene expression in Braak Stages III/IV compared with Stages I/II, suggesting these pathways may be related to PCC resilience. We also mined expression profiles for small non-coding micro-RNAs (miRNAs), which regulate mRNA stability and may represent an underexplored potential mechanism of resilience through the fine-tuning of gene expression within complex cellular networks. Twelve miRNAs were identified as differentially expressed between Braak Stages I/II and III/IV. However, the extent to which the levels of all identified miRNAs were associated with subject demographics, neuropsychological test performance and/or neuropathological diagnostic criteria within this cohort was not explored. Here, we report that a total of 667 miRNAs are significantly associated (rho > 0.38,
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcae082
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Article ; Online: Frontal Cortex Lipid Alterations During the Onset of Alzheimer's Disease.

Moreno-Rodriguez, Marta / Perez, Sylvia E / Martinez-Gardeazabal, Jonatan / Manuel, Ivan / Malek-Ahmadi, Michael / Rodriguez-Puertas, Rafael / Mufson, Elliott J

Journal of Alzheimer's disease : JAD

2024 Volume 98, Issue 4, Page(s) 1515–1532

Abstract: Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events ... ...

Abstract	Background: Although sporadic Alzheimer's disease (AD) is a neurodegenerative disorder of unknown etiology, familial AD is associated with specific gene mutations. A commonality between these forms of AD is that both display multiple pathogenic events including cholinergic and lipid dysregulation. Objective: We aimed to identify the relevant lipids and the activity of their related receptors in the frontal cortex and correlating them with cognition during the progression of AD. Methods: MALDI-mass spectrometry imaging (MSI) and functional autoradiography was used to evaluate the distribution of phospholipids/sphingolipids and the activity of cannabinoid 1 (CB1), sphingosine 1-phosphate 1 (S1P1), and muscarinic M2/M4 receptors in the frontal cortex (FC) of people that come to autopsy with premortem clinical diagnosis of AD, mild cognitive impairment (MCI), and no cognitive impairment (NCI). Results: MALDI-MSI revealed an increase in myelin-related lipids, such as diacylglycerol (DG) 36:1, DG 38:5, and phosphatidic acid (PA) 40:6 in the white matter (WM) in MCI compared to NCI, and a downregulation of WM phosphatidylinositol (PI) 38:4 and PI 38:5 levels in AD compared to NCI. Elevated levels of phosphatidylcholine (PC) 32:1, PC 34:0, and sphingomyelin 38:1 were observed in discrete lipid accumulations in the FC supragranular layers during disease progression. Muscarinic M2/M4 receptor activation in layers V-VI decreased in AD compared to MCI. CB1 receptor activity was upregulated in layers V-VI, while S1P1 was downregulated within WM in AD relative to NCI. Conclusions: FC WM lipidomic alterations are associated with myelin dyshomeostasis in prodromal AD, suggesting WM lipid maintenance as a potential therapeutic target for dementia.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Cognitive Dysfunction/pathology ; Receptor, Muscarinic M4 ; Frontal Lobe/diagnostic imaging ; Frontal Lobe/pathology ; Cholinergic Agents ; Lipids
Chemical Substances	Receptor, Muscarinic M4 ; Cholinergic Agents ; Lipids
Language	English
Publishing date	2024-04-05
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-231485
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Article ; Online: Oligomeric, phosphorylated, and truncated tau and spliceosome pathology within the entorhinal-hippocampal connectome across stages of Alzheimer's disease.

Mahady, Laura J / Perez, Sylvia E / Malek-Ahmadi, Michael / Mufson, Elliott J

The Journal of comparative neurology

2023 Volume 531, Issue 18, Page(s) 2080–2108

Abstract: Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the ... ...

Abstract	Neurofibrillary tangles (NFTs) contain abnormally phosphorylated tau proteins, which spread within components of the medial temporal lobe (MTL) memory circuit in Alzheimer's disease (AD). Here, we used quantitative immunohistochemistry to determine the density of posttranslational oligomeric (TOC1 and TNT1), phosphorylated (AT8), and late truncated (TauC3) tau epitopes within the MTL subfields including entorhinal cortex (EC) layer II, subiculum, Cornu Ammonis (CA) subfields, and dentate gyrus (DG) in subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD. We also examined whether alterations of the nuclear alternative splicing protein, SRSF2, are associated with tau pathology. Although a significant increase in TOC1, TNT1, and AT8 neuron density occurred in the EC in MCI and AD, subicular, DG granule cell, and CA1 and CA3 densities were only significantly higher in AD. TauC3 counts were not different between connectome regions and clinical groups. SRSF2 intensity in AT8-positive cells decreased significantly in all regions independent of the clinical groups examined. CA1 and subicular AT8, TauC3, and oligomeric densities correlated across clinical groups. EC AT8 counts correlated with CA subfields and subicular and DG values across clinical groups. Oligomeric and AT8 CA1, EC, and subicular density correlated with Braak stage. Decreased nuclear SRSF2 in the presence of cytoplasmic phosphorylated tau suggests a dual-hit process in NFT formation within the entorhinal hippocampal connectome during the onset of AD. Although oligomeric and phosphorylated tau follow a stereotypical pattern, clinical disease stage determined density of tau deposition and not anatomic location within the entorhinal-hippocampal connectome.
MeSH term(s)	Humans ; Alzheimer Disease/pathology ; Connectome ; Spliceosomes/metabolism ; Spliceosomes/pathology ; Hippocampus/metabolism ; tau Proteins/metabolism ; Neurofibrillary Tangles/pathology
Chemical Substances	tau Proteins
Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.25466
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Article: Chronic traumatic encephalopathy and the nucleus basalis of Meynert.

Mufson, Elliott J / Kelley, Christy / Perez, Sylvia E

Handbook of clinical neurology

2021 Volume 182, Page(s) 9–29

Abstract: Due to the growing number of chronic traumatic encephalopathy (CTE) cases in the military and contact sports, defining the cellular and molecular substrate of this disorder is crucial. Most classic neuropathological investigations describe cortical tau ... ...

Abstract	Due to the growing number of chronic traumatic encephalopathy (CTE) cases in the military and contact sports, defining the cellular and molecular substrate of this disorder is crucial. Most classic neuropathological investigations describe cortical tau and, to a lesser extent, amyloid lesions, which may underlie the clinical sequela associated with CTE. The application of modern molecular biologic technology to postmortem human brain tissue has made it possible to evaluate the genetic signature of specific neuronal phenotypes at different stages of CTE pathology. Most recently, molecular pathobiology has been used in the field of CTE, with an emphasis on the cholinergic neurons located within the nucleus basalis of Meynert, which develop tau pathology and are associated with cognitive dysfunction similar to that found in Alzheimer's disease (AD). Quantitative findings derived from single-cell transcript investigations provide clues to our understanding of the selective vulnerability of neurons containing AD-like tau pathology at different stages of CTE. Since human tissue-based studies provide a gold standard for the field of CTE, continued molecular pathological studies are needed to reveal novel drug targets for the treatment of this disorder.
MeSH term(s)	Alzheimer Disease ; Basal Nucleus of Meynert/metabolism ; Chronic Traumatic Encephalopathy ; Humans ; Neurofibrillary Tangles ; tau Proteins/metabolism
Chemical Substances	tau Proteins
Language	English
Publishing date	2021-07-15
Publishing country	Netherlands
Document type	Journal Article ; Review
ISSN	0072-9752
ISSN	0072-9752
DOI	10.1016/B978-0-12-819973-2.00002-2
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Article: Editorial: Down Syndrome, Neurodegeneration and Dementia.

Mufson, Elliott J / Ginsberg, Stephen D / Ma, Tao / Ledreux, Aurélie / Perez, Sylvia E

Frontiers in aging neuroscience

2021 Volume 13, Page(s) 791044

Language	English
Publishing date	2021-12-09
Publishing country	Switzerland
Document type	Editorial
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.791044
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Article: Application of robust regression in translational neuroscience studies with non-Gaussian outcome data.

Malek-Ahmadi, Michael / Ginsberg, Stephen D / Alldred, Melissa J / Counts, Scott E / Ikonomovic, Milos D / Abrahamson, Eric E / Perez, Sylvia E / Mufson, Elliott J

Frontiers in aging neuroscience

2024 Volume 15, Page(s) 1299451

Abstract: Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer's disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables ...

Abstract	Linear regression is one of the most used statistical techniques in neuroscience, including the study of the neuropathology of Alzheimer's disease (AD) dementia. However, the practical utility of this approach is often limited because dependent variables are often highly skewed and fail to meet the assumption of normality. Applying linear regression analyses to highly skewed datasets can generate imprecise results, which lead to erroneous estimates derived from statistical models. Furthermore, the presence of outliers can introduce unwanted bias, which affect estimates derived from linear regression models. Although a variety of data transformations can be utilized to mitigate these problems, these approaches are also associated with various caveats. By contrast, a robust regression approach does not impose distributional assumptions on data allowing for results to be interpreted in a similar manner to that derived using a linear regression analysis. Here, we demonstrate the utility of applying robust regression to the analysis of data derived from studies of human brain neurodegeneration where the error distribution of a dependent variable does not meet the assumption of normality. We show that the application of a robust regression approach to two independent published human clinical neuropathologic data sets provides reliable estimates of associations. We also demonstrate that results from a linear regression analysis can be biased if the dependent variable is significantly skewed, further indicating robust regression as a suitable alternate approach.
Language	English
Publishing date	2024-01-24
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2023.1299451
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Article ; Online: Posterior cingulate cortex reveals an expression profile of resilience in cognitively intact elders.

Kelley, Christy M / Ginsberg, Stephen D / Liang, Winnie S / Counts, Scott E / Mufson, Elliott J

Brain communications

2022 Volume 4, Issue 4, Page(s) fcac162

Abstract: The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical memory retrieval and displays hypometabolic changes early in Alzheimer disease. To obtain an unbiased understanding of the molecular pathobiology of the ... ...

Abstract	The posterior cingulate cortex, a key hub of the default mode network, underlies autobiographical memory retrieval and displays hypometabolic changes early in Alzheimer disease. To obtain an unbiased understanding of the molecular pathobiology of the aged posterior cingulate cortex, we performed RNA sequencing (RNA-seq) on tissue obtained from 26 participants of the Rush Religious Orders Study (11 males/15 females; aged 76-96 years) with a pre-mortem clinical diagnosis of no cognitive impairment and post-mortem neurofibrillary tangle Braak Stages I/II, III, and IV. Transcriptomic data were gathered using next-generation sequencing of RNA extracted from posterior cingulate cortex generating an average of 60 million paired reads per subject. Normalized expression of RNA-seq data was calculated using a global gene annotation and a microRNA profile. Differential expression (DESeq2, edgeR) using Braak staging as the comparison structure isolated genes for dimensional scaling, associative network building and functional clustering. Curated genes were correlated with the Mini-Mental State Examination and semantic, working and episodic memory, visuospatial ability, and a composite Global Cognitive Score. Regulatory mechanisms were determined by co-expression networks with microRNAs and an overlap of transcription factor binding sites. Analysis revealed 750 genes and 12 microRNAs significantly differentially expressed between Braak Stages I/II and III/IV and an associated six groups of transcription factor binding sites. Inputting significantly different gene/network data into a functional annotation clustering model revealed elevated presynaptic, postsynaptic and ATP-related expression in Braak Stages III and IV compared with Stages I/II, suggesting these pathways are integral for cognitive resilience seen in unimpaired elderly subjects. Principal component analysis and Kruskal-Wallis testing did not associate Braak stage with cognitive function. However, Spearman correlations between genes and cognitive test scores followed by network analysis revealed upregulation of classes of synaptic genes positively associated with performance on the visuospatial perceptual orientation domain. Upregulation of key synaptic genes suggests a role for these transcripts and associated synaptic pathways in cognitive resilience seen in elders despite Alzheimer disease pathology and dementia.
Language	English
Publishing date	2022-06-21
Publishing country	England
Document type	Journal Article
ISSN	2632-1297
ISSN (online)	2632-1297
DOI	10.1093/braincomms/fcac162
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Article ; Online: Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study.

Kelley, Christy M / Perez, Sylvia E / Mufson, Elliott J

Acta neuropathologica communications

2019 Volume 7, Issue 1, Page(s) 207

Abstract: Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, ... ...

Abstract	Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Athletes ; Athletic Injuries/epidemiology ; Athletic Injuries/pathology ; Brain Injuries, Traumatic/epidemiology ; Brain Injuries, Traumatic/pathology ; Chronic Traumatic Encephalopathy/epidemiology ; Chronic Traumatic Encephalopathy/pathology ; Humans ; Male ; Middle Aged ; Retrospective Studies ; Temporal Lobe/injuries ; Temporal Lobe/pathology ; tau Proteins/analysis
Chemical Substances	MAPT protein, human ; tau Proteins
Language	English
Publishing date	2019-12-12
Publishing country	England
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.
ZDB-ID	2715589-4
ISSN	2051-5960 ; 2051-5960
ISSN (online)	2051-5960
ISSN	2051-5960
DOI	10.1186/s40478-019-0861-9
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Article: Cerebellar Calcium-Binding Protein and Neurotrophin Receptor Defects in Down Syndrome and Alzheimer's Disease.

Miguel, Jennifer C / Perez, Sylvia E / Malek-Ahmadi, Michael / Mufson, Elliott J

Frontiers in aging neuroscience

2021 Volume 13, Page(s) 645334

Abstract: Cerebellar hypoplasia is a major characteristic of the Down syndrome (DS) brain. However, the consequences of trisomy upon cerebellar Purkinje cells (PC) and interneurons in DS are unclear. The present study performed a quantitative and qualitative ... ...

Abstract	Cerebellar hypoplasia is a major characteristic of the Down syndrome (DS) brain. However, the consequences of trisomy upon cerebellar Purkinje cells (PC) and interneurons in DS are unclear. The present study performed a quantitative and qualitative analysis of cerebellar neurons immunostained with antibodies against calbindin D-28k (Calb), parvalbumin (Parv), and calretinin (Calr), phosphorylated and non-phosphorylated intermediate neurofilaments (SMI-34 and SMI-32), and high (TrkA) and low (p75
Language	English
Publishing date	2021-03-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.645334
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Article ; Online: Telomeric alterations in the default mode network during the progression of Alzheimer's disease: Selective vulnerability of the precuneus.

Mahady, Laura J / He, Bin / Malek-Ahmadi, Michael / Mufson, Elliott J

Neuropathology and applied neurobiology

2020 Volume 47, Issue 3, Page(s) 428–440

Abstract: Aims: Although telomere length (TL) and telomere maintenance proteins (shelterins) are markers of cellular senescence and peripheral blood biomarkers of Alzheimer's disease (AD), little information is available on telomeric alterations during the ... ...

Abstract	Aims: Although telomere length (TL) and telomere maintenance proteins (shelterins) are markers of cellular senescence and peripheral blood biomarkers of Alzheimer's disease (AD), little information is available on telomeric alterations during the prodromal stage (MCI) of AD. We investigated TL in the default mode network (DMN), which underlies episodic memory deficits in AD, as well as shelterin protein and mRNA levels in the precuneus (PreC). Methods: Telomere length was evaluated in DMN hubs and visual cortex using quantitative PCR (qPCR). In the PreC, western blotting and NanoString nCounter expression analyses evaluated shelterin protein and mRNA levels, respectively, in cases with an antemortem clinical diagnosis of no cognitive impairment (NCI), MCI and AD. Results: TL was significantly reduced in the PreC in MCI and AD compared to NCI, but stable in frontal, inferior temporal, posterior cingulate and visual cortex. PreC TL correlated significantly with performance on cognitive tests. NCI cases with high vs low Braak scores displayed significantly shorter TL in posterior cingulate and frontal cortex, which correlated significantly with neuritic and diffuse amyloid-β plaque counts. Shelterin protein levels (TIN2, TRF1, TRF2 and POT1) declined in MCI and AD compared to NCI. The PreC displayed stable expression of shelterins TERF1, TERF2, POT1, RAP1 and TPP1, while TINF2 mRNA significantly increased in AD compared to NCI. Conclusions: These findings indicate a selective vulnerability to telomere attrition within different nodes of the DMN in prodromal AD and in aged NCI individuals with high Braak scores highlighting a putative role in the pathogenesis of AD.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/pathology ; Default Mode Network/pathology ; Disease Progression ; Female ; Humans ; Male ; Parietal Lobe/pathology ; Prodromal Symptoms ; Shelterin Complex ; Telomere/pathology ; Telomere-Binding Proteins/metabolism
Chemical Substances	ACD protein, human ; Shelterin Complex ; Telomere-Binding Proteins
Language	English
Publishing date	2020-12-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12672
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