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  1. Article ; Online: A History of Senile Plaques: From Alzheimer to Amyloid Imaging.

    Beach, Thomas G

    Journal of neuropathology and experimental neurology

    2022  Volume 81, Issue 6, Page(s) 387–413

    Abstract: Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and pathogenesis of Alzheimer disease (AD), but has also pointed to possible modes of prevention and ... ...

    Abstract Senile plaques have been studied in postmortem brains for more than 120 years and the resultant knowledge has not only helped us understand the etiology and pathogenesis of Alzheimer disease (AD), but has also pointed to possible modes of prevention and treatment. Within the last 15 years, it has become possible to image plaques in living subjects. This is arguably the single greatest advance in AD research since the identification of the Aβ peptide as the major plaque constituent. The limitations and potentialities of amyloid imaging are still not completely clear but are perhaps best glimpsed through the perspective gained from the accumulated postmortem histological studies. The basic morphological classification of plaques into neuritic, cored and diffuse has been supplemented by sophisticated immunohistochemical and biochemical analyses and increasingly detailed mapping of plaque brain distribution. Changes in plaque classification and staging have in turn contributed to changes in the definition and diagnostic criteria for AD. All of this information continues to be tested by clinicopathological correlations and it is through the insights thereby gained that we will best be able to employ the powerful tool of amyloid imaging.
    MeSH term(s) Alzheimer Disease/diagnostic imaging ; Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Amyloidosis/diagnostic imaging ; Amyloidosis/pathology ; Brain/pathology ; Humans ; Plaque, Amyloid/diagnostic imaging ; Plaque, Amyloid/pathology
    Chemical Substances Amyloid beta-Peptides
    Language English
    Publishing date 2022-05-21
    Publishing country England
    Document type 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/nlac030
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  2. Article ; Online: Mechanisms of Swallowing, Speech and Voice Disorders in Parkinson's Disease: Literature Review with Our First Evidence for the Periperal Nervous System Involvement.

    Mu, Liancai / Chen, Jingming / Li, Jing / Nyirenda, Themba / Hegland, Karen Wheeler / Beach, Thomas G

    Dysphagia

    2024  

    Abstract: The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments ... ...

    Abstract The majority of patients with Parkinson's disease (PD) develop swallowing, speech, and voice (SSV) disorders. Importantly, swallowing difficulty or dysphagia and related aspiration are life-threatening conditions for PD patients. Although PD treatments have significant therapeutic effects on limb motor function, their effects on SSV disorders are less impressive. A large gap in our knowledge is that the mechanisms of SSV disorders in PD are poorly understood. PD was long considered to be a central nervous system disorder caused by the death of dopaminergic neurons in the basal ganglia. Aggregates of phosphorylated α-synuclein (PAS) underlie PD pathology. SSV disorders were thought to be caused by the same dopaminergic problem as those causing impaired limb movement; however, there is little evidence to support this. The pharynx, larynx, and tongue play a critical role in performing upper airway (UA) motor tasks and their dysfunction results in disordered SSV. This review aims to provide an overview on the neuromuscular organization patterns, functions of the UA structures, clinical features of SSV disorders, and gaps in knowledge regarding the pathophysiology underlying SSV disorders in PD, and evidence supporting the hypothesis that SSV disorders in PD could be associated, at least in part, with PAS damage to the peripheral nervous system controlling the UA structures. Determining the presence and distribution of PAS lesions in the pharynx, larynx, and tongue will facilitate the identification of peripheral therapeutic targets and set a foundation for the development of new therapies to treat SSV disorders in PD.
    Language English
    Publishing date 2024-03-18
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 632764-3
    ISSN 1432-0460 ; 0179-051X
    ISSN (online) 1432-0460
    ISSN 0179-051X
    DOI 10.1007/s00455-024-10693-3
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  3. Article: A Review of Biomarkers for Neurodegenerative Disease: Will They Swing Us Across the Valley?

    Beach, Thomas G

    Neurology and therapy

    2017  Volume 6, Issue Suppl 1, Page(s) 5–13

    Abstract: Measures of the severity of cognitive impairment or parkinsonism are the usual endpoints in clinical trials for Alzheimer's disease (AD) and Parkinson's disease (PD), but are critically hampered by their lack of disease sensitivity and specificity. Due ... ...

    Abstract Measures of the severity of cognitive impairment or parkinsonism are the usual endpoints in clinical trials for Alzheimer's disease (AD) and Parkinson's disease (PD), but are critically hampered by their lack of disease sensitivity and specificity. Due to the high failure rate of clinical trials, the rate of regulatory approval for efficacious new drugs has stagnated in the past few decades, with the gap between basic science discovery and clinical application metaphorically termed the "Valley of Death". While the causes for this are probably multiple and complex, the usage of biomarkers as surrogate endpoints, particularly when they are molecularly-specific for the disease, has achieved some success in cancer trials, and it is likely that neurodegenerative disease trials would benefit from the same approach. As dementia and parkinsonism are not disease-specific clinical syndromes, both AD and PD trials have been flawed by reliance on clinical diagnosis and clinical endpoints. Clinical improvement has been a requirement for regulatory approval, but molecularly-specific biomarkers should improve both diagnostic accuracy and tracking of disease progression, allowing quicker screening of drug candidates. However, even when a molecularly-specific biomarker is found, such as amyloid imaging for AD, it may not reflect the entire extant molecular disease repertoire and may not serve equally well in the different roles of preclinical detection, diagnostic confirmation and surrogate endpoint, necessitating the usage of two, three or more biomarkers, deployed in series or in parallel.
    Language English
    Publishing date 2017-07-21
    Publishing country New Zealand
    Document type Journal Article ; Review
    ISSN 2193-8253
    ISSN 2193-8253
    DOI 10.1007/s40120-017-0072-x
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  4. Article ; Online: Lack of significant Lewy pathology in 237 essential tremor brains.

    Shill, Holly A / Adler, Charles H / Tremblay, Cécilia / Beach, Thomas G

    Journal of neuropathology and experimental neurology

    2023  Volume 82, Issue 5, Page(s) 452–453

    MeSH term(s) Humans ; Essential Tremor/pathology ; Brain/pathology ; Lewy Body Disease/pathology
    Language English
    Publishing date 2023-03-21
    Publishing country England
    Document type Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Letter ; Comment
    ZDB-ID 3088-0
    ISSN 1554-6578 ; 0022-3069
    ISSN (online) 1554-6578
    ISSN 0022-3069
    DOI 10.1093/jnen/nlad022
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  5. Article ; Online: Isolation of Human Microglia from Neuropathologically Diagnosed Cases in the Single-Cell Era.

    Lue, Lih-Fen / Walker, Douglas G / Beh, Suet Theng / Beach, Thomas G

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

    2022  Volume 2561, Page(s) 43–62

    Abstract: This chapter describes the core procedures that we have developed over the last two decades to isolate routinely the microglia from postmortem human brains. The method is suitable for brain slices consisting of both gray and white matter.The ability to ... ...

    Abstract This chapter describes the core procedures that we have developed over the last two decades to isolate routinely the microglia from postmortem human brains. The method is suitable for brain slices consisting of both gray and white matter.The ability to concomitantly isolate vascular cells with glial cells provides the opportunity to investigate multiple cell types originating from the same donor. This represents a novel approach for -omics research, with the potential for discovering the shared or distinct molecular features among the glia and vascular cells from the same individual.
    MeSH term(s) Humans ; Microglia ; Neuroglia ; White Matter ; Brain
    Language English
    Publishing date 2022-11-18
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-0716-2655-9_3
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  6. Article ; Online: Peripheral tau as a biomarker for neurodegenerative diseases: is life on Earth, life on Mars?

    Dugger, Brittany N / Harvey, Danielle / Beach, Thomas G / Adler, Charles H

    Brain : a journal of neurology

    2022  Volume 145, Issue 8, Page(s) 2629–2631

    MeSH term(s) Biomarkers ; Biopsy ; Humans ; Neurodegenerative Diseases ; Synucleinopathies ; Tauopathies ; tau Proteins
    Chemical Substances Biomarkers ; tau Proteins
    Language English
    Publishing date 2022-09-14
    Publishing country England
    Document type Editorial ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 80072-7
    ISSN 1460-2156 ; 0006-8950
    ISSN (online) 1460-2156
    ISSN 0006-8950
    DOI 10.1093/brain/awac281
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  7. Article ; Online: The Relationship between p-tau217, p-tau231, and p-tau205 in the Human Brain Is Affected by the Cellular Environment and Alzheimer's Disease Pathology.

    Wennström, Malin / Schultz, Nina / Gallardo, Paula Mille / The Netherlands Brain Bank / Serrano, Geidy E / Beach, Thomas G / Bose, Suchira / Hansson, Oskar

    Cells

    2024  Volume 13, Issue 4

    Abstract: The levels of p-tau217 and p-tau231 in cerebrospinal fluid (CSF) are associated with early amyloid beta (Aß) changes in the brain, while the CSF levels of p-tau205 are foremost related to tau pathology in the later stages of the disease. To investigate ... ...

    Abstract The levels of p-tau217 and p-tau231 in cerebrospinal fluid (CSF) are associated with early amyloid beta (Aß) changes in the brain, while the CSF levels of p-tau205 are foremost related to tau pathology in the later stages of the disease. To investigate if the three p-tau variants are found to the same degree in different tau structures and if their co-localization is affected by the diagnosis and presence of Aß plaques, we immunostained sections of the entorhinal cortex (EC) and inferior temporal gyrus (ITG) from non-demented controls (NC), patients with Alzheimer's disease (AD), and primary age-related tauopathy (PART) against p-tau217, p-tau231, and p-tau205 together with Methoxi-X04. An analysis using confocal microscopy showed that the co-localization variable, the Pearson correlation coefficient (PCC), was significantly higher between p-tau231 and p-tau205 in neurofibrillary tangles compared to neuropil threads and dystrophic neurites in plaques. The PCC value between all three p-tau variants in the neuropil threads was significantly lower in the ECs of patients with AD compared to the NC and in the ITGs of patients with AD, with a high Aß load compared to PART. The lowered value was associated with proportionally higher amounts of non-colocalized p-tau231 and p-tau217 compared to p-tau205, and the PCC values were negatively correlated with Aß and the tangle loads in patients with AD, but positively correlated with tangles in PART. These results suggest that the proportion of and co-localization between p-tau217, p-tau231, and p-tau205 are dependent on cellular localization and are altered in response to AD pathology in a spatial-temporal manner.
    MeSH term(s) Humans ; Alzheimer Disease/pathology ; Amyloid beta-Peptides ; tau Proteins/metabolism ; Brain/metabolism ; Tauopathies/pathology
    Chemical Substances Amyloid beta-Peptides ; tau Proteins
    Language English
    Publishing date 2024-02-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2661518-6
    ISSN 2073-4409 ; 2073-4409
    ISSN (online) 2073-4409
    ISSN 2073-4409
    DOI 10.3390/cells13040331
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  8. Article ; Online: Profiling Protein-Protein Interactions in the Human Brain by Refined Cofractionation Mass Spectrometry.

    Shrestha, Him K / Lee, DongGeun / Wu, Zhiping / Wang, Zhen / Fu, Yingxue / Wang, Xusheng / Serrano, Geidy E / Beach, Thomas G / Peng, Junmin

    Journal of proteome research

    2024  Volume 23, Issue 4, Page(s) 1221–1231

    Abstract: Proteins usually execute their biological functions through interactions with other proteins and by forming macromolecular complexes, but global profiling of protein complexes directly from human tissue samples has been limited. In this study, we ... ...

    Abstract Proteins usually execute their biological functions through interactions with other proteins and by forming macromolecular complexes, but global profiling of protein complexes directly from human tissue samples has been limited. In this study, we utilized cofractionation mass spectrometry (CF-MS) to map protein complexes within the postmortem human brain with experimental replicates. First, we used concatenated anion and cation Ion Exchange Chromatography (IEX) to separate native protein complexes in 192 fractions and then proceeded with Data-Independent Acquisition (DIA) mass spectrometry to analyze the proteins in each fraction, quantifying a total of 4,804 proteins with 3,260 overlapping in both replicates. We improved the DIA's quantitative accuracy by implementing a constant amount of bovine serum albumin (BSA) in each fraction as an internal standard. Next, advanced computational pipelines, which integrate both a database-based complex analysis and an unbiased protein-protein interaction (PPI) search, were applied to identify protein complexes and construct protein-protein interaction networks in the human brain. Our study led to the identification of 486 protein complexes and 10054 binary protein-protein interactions, which represents the first global profiling of human brain PPIs using CF-MS. Overall, this study offers a resource and tool for a wide range of human brain research, including the identification of disease-specific protein complexes in the future.
    MeSH term(s) Humans ; Tandem Mass Spectrometry/methods ; Proteins/chemistry ; Chromatography, High Pressure Liquid/methods ; Chromatography, Ion Exchange/methods ; Brain ; Proteome/analysis
    Chemical Substances Proteins ; Proteome
    Language English
    Publishing date 2024-03-20
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2078618-9
    ISSN 1535-3907 ; 1535-3893
    ISSN (online) 1535-3907
    ISSN 1535-3893
    DOI 10.1021/acs.jproteome.3c00685
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  9. Article ; Online: α-synuclein seed amplification in Parkinson's disease.

    Beach, Thomas G / Adler, Charles H / Shill, Holly A / Serrano, Geidy E / Zhang, Nan

    The Lancet. Neurology

    2023  Volume 22, Issue 11, Page(s) 985

    MeSH term(s) Humans ; alpha-Synuclein/genetics ; Parkinson Disease/genetics
    Chemical Substances alpha-Synuclein
    Language English
    Publishing date 2023-10-20
    Publishing country England
    Document type Letter ; Comment
    ZDB-ID 2081241-3
    ISSN 1474-4465 ; 1474-4422
    ISSN (online) 1474-4465
    ISSN 1474-4422
    DOI 10.1016/S1474-4422(23)00373-3
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  10. Article ; Online: Importance of low diagnostic Accuracy for early Parkinson's disease.

    Beach, Thomas G / Adler, Charles H

    Movement disorders : official journal of the Movement Disorder Society

    2018  Volume 33, Issue 10, Page(s) 1551–1554

    MeSH term(s) Autopsy/methods ; Humans ; Neuroimaging ; Parkinson Disease/diagnosis ; Reproducibility of Results
    Language English
    Publishing date 2018-10-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 607633-6
    ISSN 1531-8257 ; 0885-3185
    ISSN (online) 1531-8257
    ISSN 0885-3185
    DOI 10.1002/mds.27485
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