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  1. Article ; Online: Making the diagnosis of frontotemporal lobar degeneration.

    Bigio, Eileen H

    Archives of pathology & laboratory medicine

    2013  Volume 137, Issue 3, Page(s) 314–325

    Abstract: Context: Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the ... ...

    Abstract Context: Autopsy evaluation of the brain of a patient with frontotemporal dementia (FTD) can be daunting to the general pathologist. At some point in their training, most pathologists learn about Pick disease, and can recognize Pick bodies, the morphologic hallmark of Pick disease. Pick disease is a type of frontotemporal lobar degeneration (FTLD), the general category of pathologic process underlying most cases of FTD. The 2 major categories of pathologic FTLD are tauopathies (FTLD-tau) and ubiquitinopathies (FTLD-U). Pick disease is one of the FTLD-tau subtypes and is termed FTLD-tau (PiD).
    Objective: To "demystify" FTLDs, and to demonstrate that subtypes of FTLD-tau and FTLD-U can be easily determined by following a logical, stepwise, histochemical, and immunohistochemical investigation of the FTD autopsy brain.
    Data sources: Previously published peer-reviewed articles.
    Conclusions: The hope is that this article will be a useful reference for the general pathologist faced with performing a brain autopsy on a decedent with frontotemporal dementia.
    MeSH term(s) Frontotemporal Lobar Degeneration/diagnosis ; Humans
    Language English
    Publishing date 2013-03-03
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 194119-7
    ISSN 1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
    ISSN (online) 1543-2165
    ISSN 0363-0153 ; 0096-8528 ; 0003-9985
    DOI 10.5858/arpa.2012-0075-RA
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  2. Article ; Online: Reduced Hippocampal and Anterior Cingulate Expression of Antioxidant Enzymes and Membrane Progesterone Receptors in Alzheimer's Disease with Depression.

    Luo, Wendy / Pryzbyl, Katherine J / Bigio, Eileen H / Weintraub, Sandra / Mesulam, M-Marsel / Redei, Eva E

    Journal of Alzheimer's disease : JAD

    2022  Volume 89, Issue 1, Page(s) 309–321

    Abstract: Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer's disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex ... ...

    Abstract Background: Major depressive disorder (MDD) is a risk factor for dementia including that caused by Alzheimer's disease (AD). Both MDD and AD have a higher prevalence in women than men, and estrogen-related processes have been implicated in this sex difference.
    Objective: To identify if enhanced oxidative stress and decreased expression of the memory enhancer insulin-like growth factor 2 (IGF2), each implicated separately in MDD and AD, are exaggerated in individuals with both AD and MDD compared to those with AD.
    Methods: Expression of target genes are determined by qPCR in postmortem hippocampus (Hip) and anterior cingulate cortex (ACC) of individuals with dementia and autopsy confirmed AD and those of AD+MDD.
    Results: Transcript levels of the antioxidant enzymes catalase (CAT) and superoxide dismutase 1 (SOD1), as well as IGF2 and its receptor (IGF2R) were significantly lower in the Hip and ACC of individuals with both AD and MDD compared to those with AD and no MDD. Expressions of Progestin and AdipoQ Receptor Family Member 7 (PAQR7, alias progesterone receptor alpha, mPRa) and PAQR8 (mPRβ), receptors that bind neurosteroids, were also lower in the Hip and ACC of AD+MDD samples compared to those of AD without MDD. Correlations among these transcripts revealed that estrogen receptor 2 (ESR2) and mPR β are direct or indirect regulators of the expression of the antioxidant enzymes and IGF2R.
    Conclusion: Reduced levels of antioxidant enzymes, decreased IGF2 expression, and diminished estrogen or membrane progesterone receptor-dependent processes might be more pronounced in the subpopulation of individuals with AD and MDD than without MDD.
    MeSH term(s) Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Antioxidants/metabolism ; Depression ; Depressive Disorder, Major/genetics ; Estrogens ; Female ; Gyrus Cinguli/metabolism ; Hippocampus/metabolism ; Humans ; Male ; Progesterone/metabolism ; Receptors, Progesterone/genetics ; Receptors, Progesterone/metabolism
    Chemical Substances Antioxidants ; Estrogens ; PAQR7 protein, human ; Receptors, Progesterone ; Progesterone (4G7DS2Q64Y)
    Language English
    Publishing date 2022-07-20
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1440127-7
    ISSN 1875-8908 ; 1387-2877
    ISSN (online) 1875-8908
    ISSN 1387-2877
    DOI 10.3233/JAD-220574
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  3. Article ; Online: Motor neuron disease: the C9orf72 hexanucleotide repeat expansion in FTD and ALS.

    Bigio, Eileen H

    Nature reviews. Neurology

    2012  Volume 8, Issue 5, Page(s) 249–250

    MeSH term(s) Amyotrophic Lateral Sclerosis/genetics ; C9orf72 Protein ; Frontotemporal Dementia/genetics ; Humans ; Proteins/genetics ; Terminal Repeat Sequences/genetics
    Chemical Substances C9orf72 Protein ; C9orf72 protein, human ; Proteins
    Language English
    Publishing date 2012-04-10
    Publishing country England
    Document type News
    ZDB-ID 2491514-2
    ISSN 1759-4766 ; 1759-4758
    ISSN (online) 1759-4766
    ISSN 1759-4758
    DOI 10.1038/nrneurol.2012.58
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  4. Article ; Online: Speech and Language Presentations of FTLD-TDP Type B Neuropathology.

    Lee, Daniel J / Bigio, Eileen H / Rogalski, Emily J / Mesulam, M-Marsel

    Journal of neuropathology and experimental neurology

    2020  Volume 79, Issue 3, Page(s) 277–283

    Abstract: Four right-handed patients who presented with an isolated impairment of speech or language had transactive response DNA-binding protein of 43 kDa (TDP-43) type B pathology. Comportment and pyramidal motor function were preserved at presentation. Three of ...

    Abstract Four right-handed patients who presented with an isolated impairment of speech or language had transactive response DNA-binding protein of 43 kDa (TDP-43) type B pathology. Comportment and pyramidal motor function were preserved at presentation. Three of the cases developed axial rigidity and oculomotor findings late in their course with no additional pyramidal or lower motor neuron impairments. However, in all 4 cases, postmortem examination disclosed some degree of upper and lower motor neuron disease (MND) pathology in motor cortex, brainstem, and spinal cord. Although TDP-43 type B pathology is commonly associated with MND and behavioral variant frontotemporal dementia, it is less recognized as a pathologic correlate of primary progressive aphasia and/or apraxia of speech as the presenting syndrome. These cases, taken together, contribute to the growing heterogeneity in clinical presentations associated with TDP pathology. Additionally, 2 cases demonstrated left anterior temporal lobe atrophy but without word comprehension impairments, shedding light on the relevance of the left temporal tip for single-word comprehension.
    MeSH term(s) Anomia/complications ; Anomia/pathology ; Aphasia, Broca/complications ; Aphasia, Broca/pathology ; Apraxias/complications ; Apraxias/pathology ; Brain/pathology ; DNA-Binding Proteins/metabolism ; Frontotemporal Lobar Degeneration/complications ; Frontotemporal Lobar Degeneration/pathology ; Frontotemporal Lobar Degeneration/psychology ; Humans ; Inclusion Bodies/metabolism ; Inclusion Bodies/pathology ; Male ; Middle Aged ; TDP-43 Proteinopathies/complications ; TDP-43 Proteinopathies/pathology ; TDP-43 Proteinopathies/psychology
    Chemical Substances DNA-Binding Proteins ; TARDBP protein, human
    Language English
    Publishing date 2020-01-29
    Publishing country England
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1093/jnen/nlz132
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  5. Article ; Online: TDP-43 variants of frontotemporal lobar degeneration.

    Bigio, Eileen H

    Journal of molecular neuroscience : MN

    2011  Volume 45, Issue 3, Page(s) 390–401

    Abstract: It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a "TDP-43" search reveals almost 600 papers. ... ...

    Abstract It has been only 5 years since the identification of TDP-43 as the major protein component of the ubiquitinated inclusions in FTLD-U. At that time, there were approximately a dozen papers about TDP-43; today, a "TDP-43" search reveals almost 600 papers. It is now clear that the majority of FTLD cases containing tau- and alpha-synuclein-negative, ubiquitin-positive inclusions (FTLD-U) are FTLD-TDP. The spectrum of TDP-43 proteinopathies includes FTLD-TDP with or without ALS, with or without mutations in GRN, VCP, or TARDBP, with or without chromosome 9p linkage, and sporadic and non-SOD1 familial ALS with or without FTLD-TDP. There are four sub-types of FTLD-TDP, and these correlate with specific clinical and genetic profiles. Sub-types are determined by the presence, predominance, and distribution of the various TDP-43 immunopositive insoluble aggregates-neuronal cytoplasmic inclusions, neuronal intranuclear inclusions, and dystrophic neurites. In this paper, FTLD-TDP pathologic sub-types will be described, and examples of each sub-type will be shown, and implications for future research will be discussed.
    MeSH term(s) Aged ; Brain/pathology ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Female ; Frontotemporal Lobar Degeneration/classification ; Frontotemporal Lobar Degeneration/genetics ; Frontotemporal Lobar Degeneration/pathology ; Frontotemporal Lobar Degeneration/physiopathology ; Humans ; Inclusion Bodies/pathology ; Male ; Middle Aged
    Chemical Substances DNA-Binding Proteins
    Language English
    Publishing date 2011-05-24
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1043392-2
    ISSN 1559-1166 ; 0895-8696
    ISSN (online) 1559-1166
    ISSN 0895-8696
    DOI 10.1007/s12031-011-9545-z
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  6. Article ; Online: C9ORF72, the new gene on the block, causes C9FTD/ALS: new insights provided by neuropathology.

    Bigio, Eileen H

    Acta neuropathologica

    2011  Volume 122, Issue 6, Page(s) 653–655

    MeSH term(s) Adaptor Proteins, Signal Transducing/metabolism ; Amyotrophic Lateral Sclerosis/genetics ; Amyotrophic Lateral Sclerosis/pathology ; C9orf72 Protein ; Cerebellum/pathology ; DNA Repeat Expansion/genetics ; DNA-Binding Proteins/metabolism ; Female ; Frontotemporal Dementia/genetics ; Frontotemporal Dementia/pathology ; Frontotemporal Lobar Degeneration/pathology ; Hippocampus/pathology ; Humans ; Male ; Neurons/metabolism ; Proteins/genetics ; Sequestosome-1 Protein
    Chemical Substances Adaptor Proteins, Signal Transducing ; C9orf72 Protein ; C9orf72 protein, human ; DNA-Binding Proteins ; Proteins ; SQSTM1 protein, human ; Sequestosome-1 Protein
    Language English
    Publishing date 2011-11-19
    Publishing country Germany
    Document type Editorial ; Comment
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-011-0919-7
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  7. Article ; Online: Phenotypically concordant distribution of pick bodies in aphasic versus behavioral dementias.

    Kawles, Allegra / Keszycki, Rachel / Minogue, Grace / Zouridakis, Antonia / Ayala, Ivan / Gill, Nathan / Macomber, Alyssa / Lubbat, Vivienne / Coventry, Christina / Rogalski, Emily / Weintraub, Sandra / Mao, Qinwen / Flanagan, Margaret E / Zhang, Hui / Castellani, Rudolph / Bigio, Eileen H / Mesulam, M-Marsel / Geula, Changiz / Gefen, Tamar

    Acta neuropathologica communications

    2024  Volume 12, Issue 1, Page(s) 31

    Abstract: Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), ... ...

    Abstract Pick's disease (PiD) is a subtype of the tauopathy form of frontotemporal lobar degeneration (FTLD-tau) characterized by intraneuronal 3R-tau inclusions. PiD can underly various dementia syndromes, including primary progressive aphasia (PPA), characterized by an isolated and progressive impairment of language and left-predominant atrophy, and behavioral variant frontotemporal dementia (bvFTD), characterized by progressive dysfunction in personality and bilateral frontotemporal atrophy. In this study, we investigated the neocortical and hippocampal distributions of Pick bodies in bvFTD and PPA to establish clinicopathologic concordance between PiD and the salience of the aphasic versus behavioral phenotype. Eighteen right-handed cases with PiD as the primary pathologic diagnosis were identified from the Northwestern University Alzheimer's Disease Research Center brain bank (bvFTD, N = 9; PPA, N = 9). Paraffin-embedded sections were stained immunohistochemically with AT8 to visualize Pick bodies, and unbiased stereological analysis was performed in up to six regions bilaterally [middle frontal gyrus (MFG), superior temporal gyrus (STG), inferior parietal lobule (IPL), anterior temporal lobe (ATL), dentate gyrus (DG) and CA1 of the hippocampus], and unilateral occipital cortex (OCC). In bvFTD, peak neocortical densities of Pick bodies were in the MFG, while the ATL was the most affected in PPA. Both the IPL and STG had greater leftward pathology in PPA, with the latter reaching significance (p < 0.01). In bvFTD, Pick body densities were significantly right-asymmetric in the STG (p < 0.05). Hippocampal burden was not clinicopathologically concordant, as both bvFTD and PPA cases demonstrated significant hippocampal pathology compared to neocortical densities (p < 0.0001). Inclusion-to-neuron analyses in a subset of PPA cases confirmed that neurons in the DG are disproportionately burdened with inclusions compared to neocortical areas. Overall, stereological quantitation suggests that the distribution of neocortical Pick body pathology is concordant with salient clinical features unique to PPA vs. bvFTD while raising intriguing questions about the selective vulnerability of the hippocampus to 3R-tauopathies.
    MeSH term(s) Humans ; Pick Disease of the Brain/pathology ; Frontotemporal Dementia/pathology ; Alzheimer Disease/pathology ; Brain/pathology ; Frontotemporal Lobar Degeneration/pathology ; Atrophy/pathology ; Tauopathies/pathology
    Language English
    Publishing date 2024-02-22
    Publishing country England
    Document type Journal Article
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-024-01738-7
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  8. Article: Update on recent molecular and genetic advances in frontotemporal lobar degeneration.

    Bigio, Eileen H

    Journal of neuropathology and experimental neurology

    2008  Volume 67, Issue 7, Page(s) 635–648

    Abstract: Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial ... ...

    Abstract Great strides have been made in the last 2 years in the field of frontotemporal lobar degeneration (FTLD), particularly with respect to the genetics and molecular biology of FTLD with ubiquitinated inclusions. It is now clear that most cases of familial FTLD with ubiquitinated inclusions have mutations in the progranulin gene, located on chromosome 17. It is also clear that most ubiquitinated inclusions in FTLD with ubiquitinated inclusions are composed primarily of TAR DNA-binding protein-43. Thus, FTLDs can be separated into 2 major groups (i.e. tauopathies and ubiquitinopathies), and most of the ubiquitinopathies can now be defined as TAR DNA-binding protein-43 proteinopathies. Many of the familial FTLDs are linked to chromosome 17, including both the familial tauopathies and the familial TAR DNA-binding protein-43 proteinopathies with progranulin mutations. This review highlights the neuropathologic features and the most important discoveries of the last 2 years and places these findings into the historical context of FTLD.
    MeSH term(s) Chromosomes, Human, Pair 17/genetics ; DNA-Binding Proteins/genetics ; Dementia/genetics ; Dementia/pathology ; Humans ; Inclusion Bodies/genetics ; Inclusion Bodies/pathology ; Intercellular Signaling Peptides and Proteins/genetics ; Mutation ; Progranulins ; Tauopathies ; Ubiquitination
    Chemical Substances DNA-Binding Proteins ; GRN protein, human ; Intercellular Signaling Peptides and Proteins ; Progranulins
    Language English
    Publishing date 2008-06-09
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1097/NEN.0b013e31817d751c
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  9. Article: TAR DNA-binding protein-43 in amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and Alzheimer disease.

    Bigio, Eileen H

    Acta neuropathologica

    2008  Volume 116, Issue 2, Page(s) 135–140

    MeSH term(s) Alzheimer Disease/metabolism ; Amyotrophic Lateral Sclerosis/metabolism ; DNA-Binding Proteins/metabolism ; Dementia/metabolism ; Humans
    Chemical Substances DNA-Binding Proteins
    Language English
    Publishing date 2008-06-25
    Publishing country Germany
    Document type Editorial ; Introductory Journal Article
    ZDB-ID 1079-0
    ISSN 1432-0533 ; 0001-6322
    ISSN (online) 1432-0533
    ISSN 0001-6322
    DOI 10.1007/s00401-008-0405-z
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  10. Article ; Online: Differential vulnerability of the dentate gyrus to tauopathies in dementias.

    Kawles, Allegra / Minogue, Grace / Zouridakis, Antonia / Keszycki, Rachel / Gill, Nathan / Nassif, Caren / Coventry, Christina / Zhang, Hui / Rogalski, Emily / Flanagan, Margaret E / Castellani, Rudolph / Bigio, Eileen H / Mesulam, M Marsel / Geula, Changiz / Gefen, Tamar

    Acta neuropathologica communications

    2023  Volume 11, Issue 1, Page(s) 1

    Abstract: The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility ... ...

    Abstract The dentate gyrus (DG), a key hippocampal subregion in memory processing, generally resists phosphorylated tau accumulation in the amnestic dementia of the Alzheimer's type due to Alzheimer's disease (DAT-AD), but less is known about the susceptibility of the DG to other tauopathies. Here, we report stereologic densities of total DG neurons and tau inclusions in thirty-two brains of human participants with autopsy-confirmed tauopathies with distinct isoform profiles-3R Pick's disease (PiD, N = 8), 4R corticobasal degeneration (CBD, N = 8), 4R progressive supranuclear palsy (PSP, N = 8), and 3/4R AD (N = 8). All participants were diagnosed during life with primary progressive aphasia (PPA), an aphasic clinical dementia syndrome characterized by progressive deterioration of language abilities with spared non-language cognitive abilities in early stages, except for five patients with DAT-AD as a comparison group. 51% of total participants were female. All specimens were stained immunohistochemically with AT8 to visualize tau pathology, and PPA cases were stained for Nissl substance to visualize neurons. Unbiased stereological analysis was performed in granule and hilar DG cells, and inclusion-to-neuron ratios were calculated. In the PPA group, PiD had highest mean total (granule + hilar) densities of DG tau pathology (p < 0.001), followed by CBD, AD, then PSP. PPA-AD cases showed more inclusions in hilar cells compared to granule cells, while the opposite was true in PiD and CBD. Inclusion-to-neuron ratios revealed, on average, 33% of all DG neurons in PiD cases contained a tau inclusion, compared to ~ 7% in CBD, 2% in AD, and 0.4% in PSP. There was no significant difference between DAT-AD and PPA-AD pathologic tau burden, suggesting that differences in DG burden are not specific to clinical phenotype. We conclude that the DG is differentially vulnerable to pathologic tau accumulation, raising intriguing questions about the structural integrity and functional significance of hippocampal circuits in neurodegenerative dementias.
    MeSH term(s) Humans ; Female ; Male ; tau Proteins/metabolism ; Tauopathies/pathology ; Alzheimer Disease/pathology ; Supranuclear Palsy, Progressive/pathology ; Corticobasal Degeneration ; Dentate Gyrus/metabolism
    Chemical Substances tau Proteins
    Language English
    Publishing date 2023-01-03
    Publishing country England
    Document type Journal Article ; Research Support, U.S. Gov't, P.H.S. ; Research Support, N.I.H., Extramural
    ZDB-ID 2715589-4
    ISSN 2051-5960 ; 2051-5960
    ISSN (online) 2051-5960
    ISSN 2051-5960
    DOI 10.1186/s40478-022-01485-7
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