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  1. 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 2023-08-01
    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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Genetic associations with dementia-related proteinopathy: Application of item response theory.

    Katsumata, Yuriko / Fardo, David W / Shade, Lincoln M P / Wu, Xian / Karanth, Shama D / Hohman, Timothy J / Schneider, Julie A / Bennett, David A / Farfel, Jose M / Gauthreaux, Kathryn / Mock, Charles / Kukull, Walter A / Abner, Erin L / Nelson, Peter T

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

    2024  Volume 20, Issue 4, Page(s) 2906–2921

    Abstract: Introduction: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.: Methods: We applied multidimensional generalized partial ... ...

    Abstract Introduction: Although dementia-related proteinopathy has a strong negative impact on public health, and is highly heritable, understanding of the related genetic architecture is incomplete.
    Methods: We applied multidimensional generalized partial credit modeling (GPCM) to test genetic associations with dementia-related proteinopathies. Data were analyzed to identify candidate single nucleotide variants for the following proteinopathies: Aβ, tau, α-synuclein, and TDP-43.
    Results: Final included data comprised 966 participants with neuropathologic and WGS data. Three continuous latent outcomes were constructed, corresponding to TDP-43-, Aβ/Tau-, and α-synuclein-related neuropathology endophenotype scores. This approach helped validate known genotype/phenotype associations: for example, TMEM106B and GRN were risk alleles for TDP-43 pathology; and GBA for α-synuclein/Lewy bodies. Novel suggestive proteinopathy-linked alleles were also discovered, including several (SDHAF1, TMEM68, and ARHGEF28) with colocalization analyses and/or high degrees of biologic credibility.
    Discussion: A novel methodology using GPCM enabled insights into gene candidates for driving misfolded proteinopathies.
    Highlights: Latent factor scores for proteinopathies were estimated using a generalized partial credit model. The three latent continuous scores corresponded well with proteinopathy severity. Novel genes associated with proteinopathies were identified. Several genes had high degrees of biologic credibility for dementia risk factors.
    MeSH term(s) Humans ; alpha-Synuclein/genetics ; TDP-43 Proteinopathies/genetics ; TDP-43 Proteinopathies/pathology ; Proteostasis Deficiencies ; Dementia/genetics ; DNA-Binding Proteins ; Biological Products ; Alzheimer Disease/pathology ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics
    Chemical Substances alpha-Synuclein ; DNA-Binding Proteins ; Biological Products ; TMEM106B protein, human ; Membrane Proteins ; Nerve Tissue Proteins
    Language English
    Publishing date 2024-03-09
    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 10.1002/alz.13741
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Analysis of genes (TMEM106B, GRN, ABCC9, KCNMB2, and APOE) implicated in risk for LATE-NC and hippocampal sclerosis provides pathogenetic insights: a retrospective genetic association study.

    Dugan, Adam J / Nelson, Peter T / Katsumata, Yuriko / Shade, Lincoln M P / Boehme, Kevin L / Teylan, Merilee A / Cykowski, Matthew D / Mukherjee, Shubhabrata / Kauwe, John S K / Hohman, Timothy J / Schneider, Julie A / Fardo, David W

    Acta neuropathologica communications

    2021  Volume 9, Issue 1, Page(s) 152

    Abstract: Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is ... ...

    Abstract Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is the most prevalent subtype of TDP-43 proteinopathy, affecting up to 1/3rd of aged persons. LATE-NC often co-occurs with hippocampal sclerosis (HS) pathology. It is currently unknown why some individuals with LATE-NC develop HS while others do not, but genetics may play a role. Previous studies found associations between LATE-NC phenotypes and specific genes: TMEM106B, GRN, ABCC9, KCNMB2, and APOE. Data from research participants with genomic and autopsy measures from the National Alzheimer's Coordinating Center (NACC; n = 631 subjects included) and the Religious Orders Study and Memory and the Rush Aging Project (ROSMAP; n = 780 included) were analyzed in the current study. Our goals were to reevaluate disease-associated genetic variants using newly collected data and to query whether the specific genotype/phenotype associations could provide new insights into disease-driving pathways. Research subjects included in prior LATE/HS genome-wide association studies (GWAS) were excluded. Single nucleotide variants (SNVs) within 10 kb of TMEM106B, GRN, ABCC9, KCNMB2, and APOE were tested for association with HS and LATE-NC, and separately for Alzheimer's pathologies, i.e. amyloid plaques and neurofibrillary tangles. Significantly associated SNVs were identified. When results were meta-analyzed, TMEM106B, GRN, and APOE had significant gene-based associations with both LATE and HS, whereas ABCC9 had significant associations with HS only. In a sensitivity analysis limited to LATE-NC + cases, ABCC9 variants were again associated with HS. By contrast, the associations of TMEM106B, GRN, and APOE with HS were attenuated when adjusting for TDP-43 proteinopathy, indicating that these genes may be associated primarily with TDP-43 proteinopathy. None of these genes except APOE appeared to be associated with Alzheimer's-type pathology. In summary, using data not included in prior studies of LATE or HS genomics, we replicated several previously reported gene-based associations and found novel evidence that specific risk alleles can differentially affect LATE-NC and HS.
    MeSH term(s) Aged, 80 and over ; Apolipoproteins E/genetics ; Cohort Studies ; Female ; Follow-Up Studies ; Genetic Predisposition to Disease/epidemiology ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study/methods ; Hippocampus/pathology ; Humans ; Large-Conductance Calcium-Activated Potassium Channel beta Subunits/genetics ; Male ; Membrane Proteins/genetics ; Nerve Tissue Proteins/genetics ; Progranulins/genetics ; Retrospective Studies ; Sclerosis ; Sulfonylurea Receptors/genetics
    Chemical Substances ABCC9 protein, human ; ApoE protein, human ; Apolipoproteins E ; GRN protein, human ; KCNMB2 protein, human ; Large-Conductance Calcium-Activated Potassium Channel beta Subunits ; Membrane Proteins ; Nerve Tissue Proteins ; Progranulins ; Sulfonylurea Receptors ; TMEM106B protein, human
    Language English
    Publishing date 2021-09-15
    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/s40478-021-01250-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes.

    Dugan, Adam J / Nelson, Peter T / Katsumata, Yuriko / Shade, Lincoln M P / Teylan, Merilee A / Boehme, Kevin L / Mukherjee, Shubhabrata / Kauwe, John S K / Hohman, Timothy J / Schneider, Julie A / Fardo, David W

    Neurobiology of aging

    2021  Volume 111, Page(s) 95–106

    Abstract: The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a ... ...

    Abstract The genetic locus containing the WWOX and MAF genes was implicated as a clinical Alzheimer's disease (AD) risk locus in two recent large meta-analytic genome wide association studies (GWAS). In a prior GWAS, we identified a variant in WWOX as a suggestive risk allele for hippocampal sclerosis. We hypothesized that the WWOX/MAF locus may be preferentially associated with non-plaque- and non-tau-related neuropathological changes (NC). Data from research participants with GWAS and autopsy measures from the National Alzheimer's Coordinating Center and the Religious Orders Study and the Rush Memory and Aging Project were meta-analyzed. Notably, no variants in the locus were significantly associated with ADNC. However, several WWOX/MAF variants had significant adjusted associations with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC), HS, and brain arteriolosclerosis. These associations remained largely unchanged after adjustment for ADNC (operationalized with standard semiquantitative staging), suggesting that these associations are independent of ADNC. Thus, WWOX genetic variants were associated pathologically with LATE-NC, not ADNC.
    MeSH term(s) Aged ; Aged, 80 and over ; Alzheimer Disease/genetics ; Dementia/genetics ; Female ; Genetic Variation/genetics ; Genome-Wide Association Study/methods ; Humans ; Male ; Phenotype ; Proto-Oncogene Proteins c-maf/genetics ; TDP-43 Proteinopathies/genetics ; Tumor Suppressor Proteins/genetics ; WW Domain-Containing Oxidoreductase/genetics
    Chemical Substances MAF protein, human ; Proto-Oncogene Proteins c-maf ; Tumor Suppressor Proteins ; WW Domain-Containing Oxidoreductase (EC 1.1.1.-) ; WWOX protein, human (EC 1.1.1.-)
    Language English
    Publishing date 2021-10-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 604505-4
    ISSN 1558-1497 ; 0197-4580
    ISSN (online) 1558-1497
    ISSN 0197-4580
    DOI 10.1016/j.neurobiolaging.2021.10.011
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Brain arteriolosclerosis.

    Blevins, Brittney L / Vinters, Harry V / Love, Seth / Wilcock, Donna M / Grinberg, Lea T / Schneider, Julie A / Kalaria, Rajesh N / Katsumata, Yuriko / Gold, Brian T / Wang, Danny J J / Ma, Samantha J / Shade, Lincoln M P / Fardo, David W / Hartz, Anika M S / Jicha, Gregory A / Nelson, Karin B / Magaki, Shino D / Schmitt, Frederick A / Teylan, Merilee A /
    Ighodaro, Eseosa T / Phe, Panhavuth / Abner, Erin L / Cykowski, Matthew D / Van Eldik, Linda J / Nelson, Peter T

    Acta neuropathologica

    2020  Volume 141, Issue 1, Page(s) 1–24

    Abstract: Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B- ... ...

    Abstract Brain arteriolosclerosis (B-ASC), characterized by pathologic arteriolar wall thickening, is a common finding at autopsy in aged persons and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC. Recent research indicates other and more complex risk factors and pathogenetic mechanisms. Here, we describe aspects of the unique architecture of brain arterioles, histomorphologic features of B-ASC, relevant neuroimaging findings, epidemiology and association with aging, established genetic risk factors, and the co-occurrence of B-ASC with other neuropathologic conditions such as Alzheimer's disease and limbic-predominant age-related TDP-43 encephalopathy (LATE). There may also be complex physiologic interactions between metabolic syndrome (e.g., hypertension and inflammation) and brain arteriolar pathology. Although there is no universally applied diagnostic methodology, several classification schemes and neuroimaging techniques are used to diagnose and categorize cerebral small vessel disease pathologies that include B-ASC, microinfarcts, microbleeds, lacunar infarcts, and cerebral amyloid angiopathy (CAA). In clinical-pathologic studies that factored in comorbid diseases, B-ASC was independently associated with impairments of global cognition, episodic memory, working memory, and perceptual speed, and has been linked to autonomic dysfunction and motor symptoms including parkinsonism. We conclude by discussing critical knowledge gaps related to B-ASC and suggest that there are probably subcategories of B-ASC that differ in pathogenesis. Observed in over 80% of autopsied individuals beyond 80 years of age, B-ASC is a complex and under-studied contributor to neurologic disability.
    MeSH term(s) Aged ; Aged, 80 and over ; Animals ; Arterioles/pathology ; Brain/pathology ; Cerebral Amyloid Angiopathy ; Cognition Disorders/etiology ; Cognition Disorders/pathology ; Cognition Disorders/psychology ; Humans ; Intracranial Arteriosclerosis/pathology ; Intracranial Arteriosclerosis/psychology ; Neuroimaging
    Language English
    Publishing date 2020-10-24
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-020-02235-6
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