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

Attems, Johannes; Toledo, Jon B.; Walker, Lauren; Gelpí, Ellen; Gentleman, Steve; Halliday, Glenda M.; Hortobágyi, Tibor; Jellinger, K. A.; Kovács, Gábor G.; Lee, Edward B.; Love, Seth; McAleese, Kirsty E.; Nelson, Peter T.; Neumann, Manuela; Parkkinen, Laura; Polvikoski, Tuomo; Sikorska, Beata; Smith, Colin; Grinberg, Lea T.; Thal, Dietmar Rudolf; Trojanowski, John Q.; McKeith, Ian

doi:10.1007/s00401-020-02255-2

Cited by 148 publications

(153 citation statements)

References 31 publications

(68 reference statements)

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“…[ 6 ] Furthermore, Lewy pathology (i.e. Lewy bodies and Lewy neurites) was scored using the most recent LP consensus criteria [ 9 ]. For each individual, a tissue block of cortical grey matter from the anterior cingulate was sectioned at 80 µm thickness.…”

Section: Methodsmentioning

confidence: 99%

“…The severity of α-synuclein pathology in the anterior cingulate was graded semi-quantitatively from 0 to 3 based on the validated scoring system from Alafuzoff et al [6] Furthermore, Lewy pathology (i.e. Lewy bodies and Lewy neurites) was scored using the most recent LP consensus criteria [9]. For each individual, a tissue block of cortical grey matter from the anterior cingulate was sectioned at 80 µm thickness.…”

Section: Sample Selectionmentioning

confidence: 99%

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Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

et al. 2021

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Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.

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Section: Methodsmentioning

confidence: 99%

Section: Sample Selectionmentioning

confidence: 99%

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

et al. 2021

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“…In Lewy body diseases, including Parkinson’s disease (PD) and dementia with Lewy bodies (DLB), alpha-synuclein accumulates intraneuronally in the central and peripheral nervous systems [ 1 , 3 , 8 ]. Recent studies [ 3 , 6 ] have suggested that spread of alpha-synuclein positive Lewy-related pathology (LRP) follows two distinct patterns—caudo-rostral progression and an amygdala-based progression, the latter usually seen together with Alzheimer’s disease (AD) pathology [ 6 ].…”

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confidence: 99%

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+ cohort exhibit two divergent patterns: a population-based study

et al. 2021

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“…DLB was defined as dementia occurring either at presentation or within 1 year of the onset of parkinsonism, with a brain distribution of α-synuclein pathology meeting DLB Consortium criteria for “intermediate” or “high” likelihood [ 70 ]. The Unified Staging System and McKeith criteria received good inter-rater reliability scores in a multi-centre comprehensive analysis defining consensus criteria for the evaluation of Lewy body pathology in post mortem brains [ 6 ]. Three out of 10 DLB cases were additionally diagnosed with AD, due to intermediate or high AD neuropathological changes according to [ 21 ].…”

Section: Methodsmentioning

confidence: 99%

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

et al. 2021

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Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is neuropathologically characterized by degeneration of dopaminergic neurons of the substantia nigra (SN) and formation of Lewy bodies and Lewy neurites composed of aggregated α-synuclein. Proteolysis of α-synuclein by matrix metalloproteinases was shown to facilitate its aggregation and to affect cell viability. One of the proteolysed fragments, Gln79-α-synuclein, possesses a glutamine residue at its N-terminus. We argue that glutaminyl cyclase (QC) may catalyze the pyroglutamate (pGlu)79-α-synuclein formation and, thereby, contribute to enhanced aggregation and compromised degradation of α-synuclein in human synucleinopathies. Here, the kinetic characteristics of Gln79-α-synuclein conversion into the pGlu-form by QC are shown using enzymatic assays and mass spectrometry. Thioflavin T assays and electron microscopy demonstrated a decreased potential of pGlu79-α-synuclein to form fibrils. However, size exclusion chromatography and cell viability assays revealed an increased propensity of pGlu79-α-synuclein to form oligomeric aggregates with high neurotoxicity. In brains of wild-type mice, QC and α-synuclein were co-expressed by dopaminergic SN neurons. Using a specific antibody against the pGlu-modified neo-epitope of α-synuclein, pGlu79-α-synuclein aggregates were detected in association with QC in brains of two transgenic mouse lines with human α-synuclein overexpression. In human brain samples of PD and dementia with Lewy body subjects, pGlu79-α-synuclein was shown to be present in SN neurons, in a number of Lewy bodies and in dystrophic neurites. Importantly, there was a spatial co-occurrence of pGlu79-α-synuclein with the enzyme QC in the human SN complex and a defined association of QC with neuropathological structures. We conclude that QC catalyzes the formation of oligomer-prone pGlu79-α-synuclein in human synucleinopathies, which may—in analogy to pGlu-Aβ peptides in Alzheimer’s disease—act as a seed for pathogenic protein aggregation.

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

Cited by 148 publications

References 31 publications

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

Cross-platform transcriptional profiling identifies common and distinct molecular pathologies in Lewy body diseases

Alpha-synuclein pathology of olfactory bulbs/peduncles in the Vantaa85+ cohort exhibit two divergent patterns: a population-based study

A glutaminyl cyclase-catalyzed α-synuclein modification identified in human synucleinopathies

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