Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype

Buciuc, Marina; Whitwell, Jennifer L.; Kasanuki, Koji; Graff‐Radford, Jonathan; Machulda, Mary M.; Duffy, Joseph R.; Strand, Edythe A.; Lowe, Val J.; Graff‐Radford, Neill R.; Rush, Beth; Franczak, Malgorzata; Flanagan, Margaret E.; Baker, Matthew; Rademakers, Rosa; Ross, Owen A.; Ghetti, Bernardino; Parisi, Joseph E.; Raghunathan, Aditya; Reichard, R. Ross; Bigio, Eileen H.; Dickson, Dennis W.; Josephs, Keith A.

doi:10.1002/ana.25979

Cited by 25 publications

(27 citation statements)

References 51 publications

(71 reference statements)

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“…Similar to AD, DLBD is accompanied by significant neuronal degeneration. The dementia of DLBD can be amnestic, visuospatial, dysexecutive, and, rarely, aphasic (Buciuc et al., 2021).…”

Section: Pathologic Hallmarks Of Neurodegenerative Dementiasmentioning

confidence: 99%

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance

Geula

Dunlop

Ayala

et al. 2021

Journal of Neurochemistry

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The basal forebrain cholinergic neurons (BFCN) provide the primary source of cholinergic innervation of the human cerebral cortex. They are involved in the cognitive processes of learning, memory, and attention. These neurons are differentially vulnerable in various neuropathologic entities that cause dementia. This review summarizes the relevance to BFCN of neuropathologic markers associated with dementias, including the plaques and tangles of Alzheimer's disease (AD), the Lewy bodies of diffuse Lewy body disease, the tauopathy of frontotemporal lobar degeneration (FTLD‐TAU) and the TDP‐43 proteinopathy of FTLD‐TDP. Each of these proteinopathies has a different relationship to BFCN and their corticofugal axons. Available evidence points to early and substantial degeneration of the BFCN in AD and diffuse Lewy body disease. In AD, the major neurodegenerative correlate is accumulation of phosphotau in neurofibrillary tangles. However, these neurons are less vulnerable to the tauopathy of FTLD. An intriguing finding is that the intracellular tau of AD causes destruction of the BFCN, whereas that of FTLD does not. This observation has profound implications for exploring the impact of different species of tauopathy on neuronal survival. The proteinopathy of FTLD‐TDP shows virtually no abnormal inclusions within the BFCN. Thus, the BFCN are highly vulnerable to the neurodegenerative effects of tauopathy in AD, resilient to the neurodegenerative effect of tauopathy in FTLD and apparently resistant to the emergence of proteinopathy in FTLD‐TDP and perhaps also in Pick's disease. Investigations are beginning to shed light on the potential mechanisms of this differential vulnerability and their implications for therapeutic intervention.

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“…Similar to AD, DLBD is accompanied by significant neuronal degeneration. The dementia of DLBD can be amnestic, visuospatial, dysexecutive, and, rarely, aphasic (Buciuc et al., 2021).…”

Section: Pathologic Hallmarks Of Neurodegenerative Dementiasmentioning

confidence: 99%

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance

Geula

Dunlop

Ayala

et al. 2021

Journal of Neurochemistry

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“…Patients with DLB developed dementia prior to parkinsonism or within one year after the onset of parkinsonism, while those with PDD develop dementia more than one year after the onset of parkinsonism [28]. In rare cases, patients with LBD present with focal cortical syndromes, such as corticobasal syndrome [30] or progressive aphasia [31,32].…”

Section: Clinical Spectrummentioning

confidence: 99%

Neuropathology, Genetics and Biomarkers of Synucleinopathies

Koga

Sekiya

Kondru

et al. 2021

Preprint

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Synucleinopathies 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 (GCIs). Synucleinopathies can be divided into two major disease entities: Lewy body disease (LBD) and multiple system atrophy (MSA). Common clinical presentations of LBD are Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB), while MSA has two major clinical subtypes, MSA with predominant cerebellar ataxia (MSA-C) and MSA with predominant parkinsonism (MSA-P). There are currently no disease-modifying therapies for the synucleinopathies, but elucidation of genetics and 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 GCI) 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 LBD 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 tissues. 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 review of classification and staging schemes for LBD. We also review evidence supporting the existence of distinct α-synuclein strains in LBD and MSA.

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“…On the other hand, patients who develop dementia, with (or without) parkinsonism after one year of cognitive or psychiatric symptoms are diagnosed with DLB [ 27 ]. In rare cases, patients with Lewy body disease present with focal cortical syndromes [ 29 ], such as corticobasal syndrome [ 30 ], progressive aphasia [ 31 – 33 ], or Capgras syndrome [ 34 ]. Although dysphagia is a common clinical feature of PD and atypical parkinsonian disorders [ 35 – 37 ], there are only a few reports of isolated dysphagia without extrapyramidal syndrome in patients with Lewy body disease, which is referred to as Lewy body dysphagia [ 38 , 39 ].…”

Section: Introductionmentioning

confidence: 99%

Neuropathology and molecular diagnosis of Synucleinopathies

Koga

Sekiya

Kondru

et al. 2021

Mol Neurodegeneration

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165

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Synucleinopathies 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.

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Lewy Body Disease is a Contributor to Logopenic Progressive Aphasia Phenotype

Cited by 25 publications

References 51 publications

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance

Basal forebrain cholinergic system in the dementias: Vulnerability, resilience, and resistance

Neuropathology, Genetics and Biomarkers of Synucleinopathies

Neuropathology and molecular diagnosis of Synucleinopathies

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