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Article ; Online: What to do with unusual TDP-43 proteinopathy cases?

Nelson, Peter T

2021 Volume 48, Issue 1, Page(s) e12745

MeSH term(s)	Dementia ; Humans ; TDP-43 Proteinopathies
Language	English
Publishing date	2021-07-13
Publishing country	England
Document type	Letter ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12745
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Article ; Online: Surprising Synergy Between Cerebrovascular and Lewy Body Disease in Parkinsonism.

Nelson, Peter T / Jicha, Gregory A

Neurology

2023 Volume 101, Issue 7, Page(s) 290–292

MeSH term(s)	Humans ; Lewy Body Disease/complications ; Parkinsonian Disorders/complications ; Parkinson Disease
Language	English
Publishing date	2023-06-21
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000207572
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Article ; Online: Response letter: Complexities in pericyte markers.

Nelson, Peter T / Sziraki, Andras / Cao, Junyue

Neuropathology and applied neurobiology

2024 Volume 50, Issue 2, Page(s) e12975

MeSH term(s)	Pericytes ; Endothelial Cells
Language	English
Publishing date	2024-04-02
Publishing country	England
Document type	Letter
ZDB-ID	80371-6
ISSN	1365-2990 ; 0305-1846
ISSN (online)	1365-2990
ISSN	0305-1846
DOI	10.1111/nan.12975
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Article ; Online: LATE Neuropathologic Changes with Little or No Alzheimer Disease is Common and is Associated with Cognitive Impairment but Not Frontotemporal Dementia.

Nelson, Peter T

Journal of neuropathology and experimental neurology

2021 Volume 80, Issue 7, Page(s) 649–651

Abstract: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) often occur in aged brains that also contain appreciable Alzheimer disease neuropathologic changes (ADNC). Question has arisen as to whether LATE-NC can occur ... ...

Abstract	Limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC) often occur in aged brains that also contain appreciable Alzheimer disease neuropathologic changes (ADNC). Question has arisen as to whether LATE-NC can occur independently of ADNC. We evaluated data from the University of Kentucky Alzheimer's Disease Research Center autopsy cohort (383 included subjects) to address 2 questions: (i) Is LATE-NC seen in the absence of ADNC, outside of persons who had the frontotemporal dementia (FTD) clinical syndrome? and (ii) is LATE-NC associated with cognitive impairment across the full spectrum of ADNC severity? In the present study, the pathologic combination of LATE-NC (Stage >1) and low/no ADNC was common: 8.9% (34/383) of all subjects (including demented and non-demented individuals) showed this combination. There were no FTLD-TDP cases to be included from the community-based cohort. Across a broad range of ADNC severity, the presence of LATE-NC was associated with impaired cognition but was never associated with a FTD clinical syndrome.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/epidemiology ; Alzheimer Disease/pathology ; Brain/growth & development ; Brain/pathology ; Cognitive Dysfunction/epidemiology ; Cognitive Dysfunction/pathology ; Female ; Frontotemporal Dementia/epidemiology ; Frontotemporal Dementia/pathology ; Humans ; Male
Language	English
Publishing date	2021-07-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlab050
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Article ; Online: Early Hippocampal Atrophy Is an Important Signal for Clinicians but Not Necessarily a Harbinger of Alzheimer Disease.

Nelson, Peter T / Jicha, Gregory A

Neurology

2023 Volume 101, Issue 24, Page(s) 1087–1088

Abstract: Dementia is one of the most formidable health care challenges we face today. Fortunately, there is new hope for patients and clinicians because we are on the verge of anti-β-amyloid (Aβ) therapies to slow disease progression in Alzheimer disease (AD). ... ...

Abstract	Dementia is one of the most formidable health care challenges we face today. Fortunately, there is new hope for patients and clinicians because we are on the verge of anti-β-amyloid (Aβ) therapies to slow disease progression in Alzheimer disease (AD). But these new therapies are far from curative, and many challenges remain related to confounding pathologic processes and mixed disease states. These challenges are only beginning to be addressed in regard to the use of antemortem biomarkers.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/pathology ; Hippocampus/diagnostic imaging ; Hippocampus/pathology ; Magnetic Resonance Imaging ; Atrophy/pathology
Language	English
Publishing date	2023-11-08
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.0000000000208071
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Article ; Online: Reply: Selected cryptic exons accumulate in hippocampal cell nuclei in Alzheimer's disease with and without associated TDP-43 proteinopathy.

Nelson, Peter T

Brain : a journal of neurology

2020 Volume 143, Issue 3, Page(s) e21

MeSH term(s)	Alzheimer Disease/genetics ; Cell Nucleus ; Consensus ; DNA-Binding Proteins ; Exons ; Hippocampus ; Humans ; TDP-43 Proteinopathies/genetics
Chemical Substances	DNA-Binding Proteins ; TARDBP protein, human
Language	English
Publishing date	2020-02-04
Publishing country	England
Document type	Letter ; Comment
ZDB-ID	80072-7
ISSN	1460-2156 ; 0006-8950
ISSN (online)	1460-2156
ISSN	0006-8950
DOI	10.1093/brain/awaa014
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Article ; Online: In severe ADNC, hippocampi with comorbid LATE-NC and hippocampal sclerosis have substantially more astrocytosis than those with LATE-NC or hippocampal sclerosis alone.

Niedowicz, Dana M / Katsumata, Yuriko / Nelson, Peter T

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 12, Page(s) 987–994

Abstract: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-A) pathologies are found together at autopsy in ∼20% of elderly demented persons. Although astrocytosis is known to occur in ... ...

Abstract	Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and hippocampal sclerosis of aging (HS-A) pathologies are found together at autopsy in ∼20% of elderly demented persons. Although astrocytosis is known to occur in neurodegenerative diseases, it is currently unknown how the severity of astrocytosis is correlated with the common combinations of pathologies in aging brains. To address this knowledge gap, we analyzed a convenience sample of autopsied subjects from the University of Kentucky Alzheimer's Disease Research Center community-based autopsy cohort. The subjects were stratified into 5 groups (n = 51 total): pure ADNC, ADNC + LATE-NC, ADNC + HS-A, ADNC + LATE-NC + HS-A, and low-pathology controls. Following GFAP immunostaining and digital slide scanning with a ScanScope, we measured GFAP-immunoreactive astrocytosis. The severities of GFAP-immunoreactive astrocytosis in hippocampal subfield CA1 and subiculum were compared between groups. The group with ADNC + LATE-NC + HS-A had the most astrocytosis as operationalized by either any GFAP+ or strong GFAP+ immunoreactivity in both CA1 and subiculum. In comparison to that pathologic combination, ADNC + HS or ADNC + LATE-NC alone showed lower astrocytosis. Pure ADNC had only marginally increased astrocytosis in CA1 and subiculum, in comparison to low-pathology controls. We conclude that there appeared to be pathogenetic synergy such that ADNC + LATE-NC + HS-A cases had relatively high levels of astrocytosis in the hippocampal formation.
MeSH term(s)	Aged ; Humans ; Gliosis ; Hippocampal Sclerosis ; Neuropathology ; Hippocampus
Language	English
Publishing date	2023-11-09
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlad085
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Article ; Online: Limbic-predominant age-related TDP-43 encephalopathy (LATE-NC): Co-pathologies and genetic risk factors provide clues about pathogenesis.

Nelson, Peter T / Fardo, David W / Wu, Xian / Aung, Khine Zin / Cykowski, Matthew D / Katsumata, Yuriko

Journal of neuropathology and experimental neurology

2024

Abstract: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE- ... ...

Abstract	Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is detectable at autopsy in more than one-third of people beyond age 85 years and is robustly associated with dementia independent of other pathologies. Although LATE-NC has a large impact on public health, there remain uncertainties about the underlying biologic mechanisms. Here, we review the literature from human studies that may shed light on pathogenetic mechanisms. It is increasingly clear that certain combinations of pathologic changes tend to coexist in aging brains. Although "pure" LATE-NC is not rare, LATE-NC often coexists in the same brains with Alzheimer disease neuropathologic change, brain arteriolosclerosis, hippocampal sclerosis of aging, and/or age-related tau astrogliopathy (ARTAG). The patterns of pathologic comorbidities provide circumstantial evidence of mechanistic interactions ("synergies") between the pathologies, and also suggest common upstream influences. As to primary mediators of vulnerability to neuropathologic changes, genetics may play key roles. Genes associated with LATE-NC include TMEM106B, GRN, APOE, SORL1, ABCC9, and others. Although the anatomic distribution of TDP-43 pathology defines the condition, important cofactors for LATE-NC may include Tau pathology, endolysosomal pathways, and blood-brain barrier dysfunction. A review of the human phenomenology offers insights into disease-driving mechanisms, and may provide clues for diagnostic and therapeutic targets.
Language	English
Publishing date	2024-04-13
Publishing country	England
Document type	Journal Article
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlae032
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Article ; Online: Sex-Biased Expression and Response of microRNAs in Neurological Diseases and Neurotrauma.

Geleta, Urim / Prajapati, Paresh / Bachstetter, Adam / Nelson, Peter T / Wang, Wang-Xia

International journal of molecular sciences

2024 Volume 25, Issue 5

Abstract: Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and ... ...

Abstract	Neurological diseases and neurotrauma manifest significant sex differences in prevalence, progression, outcome, and therapeutic responses. Genetic predisposition, sex hormones, inflammation, and environmental exposures are among many physiological and pathological factors that impact the sex disparity in neurological diseases. MicroRNAs (miRNAs) are a powerful class of gene expression regulator that are extensively involved in mediating biological pathways. Emerging evidence demonstrates that miRNAs play a crucial role in the sex dimorphism observed in various human diseases, including neurological diseases. Understanding the sex differences in miRNA expression and response is believed to have important implications for assessing the risk of neurological disease, defining therapeutic intervention strategies, and advancing both basic research and clinical investigations. However, there is limited research exploring the extent to which miRNAs contribute to the sex disparities observed in various neurological diseases. Here, we review the current state of knowledge related to the sexual dimorphism in miRNAs in neurological diseases and neurotrauma research. We also discuss how sex chromosomes may contribute to the miRNA sexual dimorphism phenomenon. We attempt to emphasize the significance of sexual dimorphism in miRNA biology in human diseases and to advocate a gender/sex-balanced science.
MeSH term(s)	Humans ; Female ; Male ; MicroRNAs/genetics ; Gonadal Steroid Hormones ; Nervous System Diseases
Chemical Substances	MicroRNAs ; Gonadal Steroid Hormones
Language	English
Publishing date	2024-02-24
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25052648
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Article ; Online: LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry.

Katsumata, Yuriko / Fardo, David W / Shade, Lincoln M P / Nelson, Peter T

Journal of neuropathology and experimental neurology

2023 Volume 82, Issue 9, Page(s) 760–768

Abstract: Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE ... ...

Abstract	Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.
MeSH term(s)	Humans ; Alleles ; Aging/pathology ; Polymorphism, Single Nucleotide/genetics ; Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; TDP-43 Proteinopathies/pathology ; Progranulins/genetics ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics ; Sulfonylurea Receptors/genetics
Chemical Substances	GRN protein, human ; Progranulins ; TMEM106B protein, human ; Membrane Proteins ; Nerve Tissue Proteins ; ABCC9 protein, human ; Sulfonylurea Receptors
Language	English
Publishing date	2023-08-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	3088-0
ISSN	1554-6578 ; 0022-3069
ISSN (online)	1554-6578
ISSN	0022-3069
DOI	10.1093/jnen/nlad059
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