scholarly journals Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study

2021 ◽  
Author(s):  
Johannes Attems ◽  
Jon B. Toledo ◽  
Lauren Walker ◽  
Ellen Gelpi ◽  
Steve Gentleman ◽  
...  
Keyword(s):  
Lewy Body ◽  
Lewy Body Disease ◽  
Staging System ◽  
Considerable Proportion ◽  
Post Mortem ◽  
Lewy Neurites ◽  
Multi Centre Study ◽  
Rater Reliability ◽  
Lewy Pathology ◽  
Staging Systems

AbstractCurrently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.

scholarly journals Fabry Disease With Concomitant Lewy Body Disease

2019 ◽  
Vol 79 (4) ◽  
pp. 378-392 ◽  
Author(s):  
Kelly Del Tredici ◽  
Albert C Ludolph ◽  
Simone Feldengut ◽  
Christian Jacob ◽  
Heinz Reichmann ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Lewy Body ◽  
Neuronal Loss ◽  
Lewy Body Disease ◽  
Therapeutic Interventions ◽  
Substantia Nigra Pars Compacta ◽  
Lysosomal Storage ◽  
Lewy Neurites ◽  
Cerebrovascular Lesions ◽  
Lewy Pathology

Abstract Although Gaucher disease can be accompanied by Lewy pathology (LP) and extrapyramidal symptoms, it is unknown if LP exists in Fabry disease (FD), another progressive multisystem lysosomal storage disorder. We aimed to elucidate the distribution patterns of FD-related inclusions and LP in the brain of a 58-year-old cognitively unimpaired male FD patient suffering from predominant hypokinesia. Immunohistochemistry (CD77, α-synuclein, collagen IV) and neuropathological staging were performed on 100-µm sections. Tissue from the enteric or peripheral nervous system was unavailable. As controls, a second cognitively unimpaired 50-year-old male FD patient without LP or motor symptoms and 3 age-matched individuals were examined. Inclusion body pathology was semiquantitatively evaluated. Although Lewy neurites/bodies were not present in the 50-year-old individual or in controls, severe neuronal loss in the substantia nigra pars compacta and LP corresponding to neuropathological stage 4 of Parkinson disease was seen in the 58-year-old FD patient. Major cerebrovascular lesions and/or additional pathologies were absent in this individual. We conclude that Lewy body disease with parkinsonism can occur within the context of FD. Further studies determining the frequencies of both inclusion pathologies in large autopsy-controlled FD cohorts could help clarify the implications of both lesions for disease pathogenesis, potential spreading mechanisms, and therapeutic interventions.

scholarly journals Generation and Characterization of Novel Monoclonal Antibodies Targeting p62/sequestosome-1 Across Human Neurodegenerative Diseases

2020 ◽  
Vol 79 (4) ◽  
pp. 407-418
Author(s):  
Jorge A Trejo-Lopez ◽  
Zachary A Sorrentino ◽  
Cara J Riffe ◽  
Stefan Prokop ◽  
Dennis W Dickson ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Alzheimer Disease ◽  
Neurodegenerative Diseases ◽  
Progressive Supranuclear Palsy ◽  
Lewy Body ◽  
Lewy Body Disease ◽  
Ubiquitin Proteasome System ◽  
Lewy Neurites ◽  
Sequestosome 1 ◽  
Cellular Autophagy

Abstract Human neurodegenerative diseases can be characterized as disorders of protein aggregation. As a key player in cellular autophagy and the ubiquitin proteasome system, p62 may represent an effective immunohistochemical target, as well as mechanistic operator, across neurodegenerative proteinopathies. In this study, 2 novel mouse-derived monoclonal antibodies 5G3 and 2A5 raised against residues 360–380 of human p62/sequestosome-1 were characterized via immunohistochemical application upon human tissues derived from cases of C9orf72-expansion spectrum diseases, Alzheimer disease, progressive supranuclear palsy, Lewy body disease, and multiple system atrophy. 5G3 and 2A5 reliably highlighted neuronal dipeptide repeat, tau, and α-synuclein inclusions in a distribution similar to a polyclonal antibody to p62, phospho-tau antibodies 7F2 and AT8, and phospho-α-synuclein antibody 81A. However, antibodies 5G3 and 2A5 consistently stained less neuropil structures, such as tau neuropil threads and Lewy neurites, while 2A5 marked fewer glial inclusions in progressive supranuclear palsy. Both 5G3 and 2A5 revealed incidental astrocytic tau immunoreactivity in cases of Alzheimer disease and Lewy body disease with resolution superior to 7F2. Through their unique ability to highlight specific types of pathological deposits in neurodegenerative brain tissue, these novel monoclonal p62 antibodies may provide utility in both research and diagnostic efforts.

scholarly journals Lewy pathology of the esophagus correlates with the progression of Lewy body disease: a Japanese cohort study of autopsy cases

2020 ◽  
Vol 141 (1) ◽  
pp. 25-37
Author(s):  
Zen-ichi Tanei ◽  
Yuko Saito ◽  
Shinji Ito ◽  
Tomoyasu Matsubara ◽  
Atsuko Motoda ◽  
...  
Keyword(s):  
Nervous System ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Wide Distribution ◽  
Esophageal Wall ◽  
Motor Symptoms ◽  
Aging Research ◽  
Lewy Pathology ◽  
Japanese Cohort

AbstractLewy body disease (LBD) is a spectrum of progressive neurodegenerative disorders characterized by the wide distribution of Lewy bodies and neurites in the central and peripheral nervous system (CNS, PNS). Clinical diagnoses include Parkinson’s disease (PD), dementia with Lewy bodies, or pure autonomic failure. All types of LBD are accompanied by non-motor symptoms (NMSs) including gastrointestinal dysfunctions such as constipation. Its relationship to Lewy body-related α-synucleinopathy (Lewy pathology) of the enteric nervous system (ENS) is attracting attention because it can precede the motor symptoms. To clarify the role of ENS Lewy pathology in disease progression, we performed a clinicopathological study using the Brain Bank for Aging Research in Japan. Five-hundred and eighteen cases were enrolled in the study. Lewy pathology of the CNS and PNS, including the lower esophagus as a representative of the ENS, was examined via autopsy findings. Results showed that one-third of older people (178 cases, 34%) exhibited Lewy pathology, of which 78 cases (43.8%) exhibited the pathology in the esophagus. In the esophageal wall, Auerbach’s plexus (41.6%) was most susceptible to the pathology, followed by the adventitia (33.1%) and Meissner’s plexus (14.6%). Lewy pathology of the esophagus was significantly associated with autonomic failures such as constipation (p < 0.0001) and among PNS regions, correlated the most with LBD progression (r = 0.95, p < 0.05). These findings suggest that the propagation of esophageal Lewy pathology is a predictive factor of LBD.

Lewy pathology of the submandibular gland in Lewy body disease: A report of autopsy cases

2021 ◽  
Author(s):  
Yasuhiro Sakashita ◽  
Tomoyasu Matsubara ◽  
Tadayuki Takata ◽  
Zen‐ichi Tanei ◽  
Atsuko Motoda ◽  
...  
Keyword(s):  
Submandibular Gland ◽  
Lewy Body ◽  
Lewy Body Disease ◽  
Lewy Pathology

scholarly journals Neuropathology and molecular diagnosis of Synucleinopathies

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shunsuke Koga ◽  
Hiroaki Sekiya ◽  
Naveen Kondru ◽  
Owen A. Ross ◽  
Dennis W. Dickson
Keyword(s):  
Molecular Diagnosis ◽  
Lewy Body ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Clinical Genetic ◽  
Lewy Neurites ◽  
Cytoplasmic Inclusions ◽  
Glial Cytoplasmic Inclusions

AbstractSynucleinopathies are clinically and pathologically heterogeneous disorders characterized by pathologic aggregates of α-synuclein in neurons and glia, in the form of Lewy bodies, Lewy neurites, neuronal cytoplasmic inclusions, and glial cytoplasmic inclusions. Synucleinopathies can be divided into two major disease entities: Lewy body disease and multiple system atrophy (MSA). Common clinical presentations of Lewy body disease are Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia and MSA with predominant parkinsonism. There are currently no disease-modifying therapies for the synucleinopathies, but information obtained from molecular genetics and models that explore mechanisms of α-synuclein conversion to pathologic oligomers and insoluble fibrils offer hope for eventual therapies. It remains unclear how α-synuclein can be associated with distinct cellular pathologies (e.g., Lewy bodies and glial cytoplasmic inclusions) and what factors determine neuroanatomical and cell type vulnerability. Accumulating evidence from in vitro and in vivo experiments suggests that α-synuclein species derived from Lewy body disease and MSA are distinct “strains” having different seeding properties. Recent advancements in in vitro seeding assays, such as real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), not only demonstrate distinct seeding activity in the synucleinopathies, but also offer exciting opportunities for molecular diagnosis using readily accessible peripheral tissue samples. Cryogenic electron microscopy (cryo-EM) structural studies of α-synuclein derived from recombinant or brain-derived filaments provide new insight into mechanisms of seeding in synucleinopathies. In this review, we describe clinical, genetic and neuropathologic features of synucleinopathies, including a discussion of the evolution of classification and staging of Lewy body disease. We also provide a brief discussion on proposed mechanisms of Lewy body formation, as well as evidence supporting the existence of distinct α-synuclein strains in Lewy body disease and MSA.

Lewy body disease as pure autonomic failure with more than 20 years history: A post mortem study

2016 ◽  
Vol 22 ◽  
pp. e117
Author(s):  
Kotaro Oiwa ◽  
Yasuhiro Hasegawa ◽  
Keizo Yasui ◽  
Yasushi Iwasaki ◽  
Mari Yoshida ◽  
...  
Keyword(s):  
Lewy Body ◽  
Autonomic Failure ◽  
Lewy Body Disease ◽  
Pure Autonomic Failure ◽  
Post Mortem

14-3-3 protein sigma isoform co-localizes with phosphorylated α-synuclein in Lewy bodies and Lewy neurites in patients with Lewy body disease

2018 ◽  
Vol 674 ◽  
pp. 171-175 ◽  
Author(s):  
Kaori Wakabayashi ◽  
Takahiko Umahara ◽  
Katsuiku Hirokawa ◽  
Haruo Hanyu ◽  
Toshiki Uchihara
Keyword(s):  
Lewy Body ◽  
Lewy Bodies ◽  
Lewy Body Disease ◽  
Lewy Neurites
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