Morphological characteristics differentiate dementia with Lewy bodies from Parkinson disease with and without dementia

Ka, Jellinger

doi:10.1007/s00702-023-02660-3

Cited by 6 publications

(6 citation statements)

References 116 publications

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“…The majority of autopsy reports of PDD tried to evaluate the convergence and interactions between basic PD (Lewy) pathology and other cortical proteinopathies (αSyn, tau and Aβ) and their contribution to dementia pathogenesis [ 33 , 34 , 357 , 388 , 389 , 390 , 391 , 392 , 393 , 394 , 395 ] and the role of co-pathologies on cognition [ 203 , 389 , 395 , 396 , 397 ].…”

Section: Neuropathology Of Pddmentioning

confidence: 99%

“…In a recent personal autopsy study of 210 PD cases, 47.6% with dementia, PDD cases were significantly older at death than PD-NC ones (mean 83.9 vs. 77.9 years, p < 0.05) and had a shorter disease duration (mean 9.2 vs. 14.5 years). Their Braak LB score and NFT stage were significantly higher (mean 4.2 vs. 4.1, and 4.4 vs. 2.3, p < 0.01), as were the Aβ phase (mean 3.0 vs. 1.8) and CAA frequency and intensity (50% vs. 24%, and 0.7 vs. 0.3, all p < 0.01) [ 34 ].…”

Section: Neuropathology Of Pddmentioning

confidence: 99%

“…ADNC, severe enough for a pathological diagnosis of AD, was present in about 10% of PD-ND patients, 35% of PD-MCI patients and over 50% of PDD patients [ 28 , 395 , 405 ]. In large autopsy series, around 50% of PD cases showed Braak LB stages 4–6 and NFT stages 4–6 [ 34 , 390 ], while others suggested a significant relationship between cortical LBP and severity of dementia [ 208 , 395 , 414 ]. Four large autopsy studies of PD showed consistent results: while co-morbid ADNC was present in 19–31.5% of total PD cases, the rate of co-morbid ADNC in PDD ranged from 21.5% to 89.4% [ 405 , 413 , 415 ], tau pathology being more severe in the prefrontal than in the temporal cortex [ 416 ].…”

Section: Neuropathology Of Pddmentioning

confidence: 99%

“…CMBs were significantly associated with PDD [ 396 , 443 ], while others associated PDD with amyloid-related CMBs and reduced hippocampal volume [ 446 ]. The association of severe CAA with PDD has been reported repeatedly [ 34 , 398 , 405 ], whereas, according to others, cerebrovascular disease and TDP-43 pathologies had no definite impact on the development of PDD [ 395 ]. Argyrophilic grain disease, an age-related 4-R tauopathy affecting the medial temporal lobe, although a rare co-pathology, may be another important factor inducing dementia in PD [ 447 ], whereas others did not find such a combination [ 25 , 405 ].…”

Section: Impact Of Other Co-pathologies In Cognition In Pdmentioning

confidence: 99%

“…This article, based on literature research in PubMed and Google Scholar until November 2023, will critically review the currently available data about the epidemiology, essential clinical, neuroimaging, connectivity, morphological substrates, and biomarkers of CI in PD. The relations between PDD and dementia with Lewy bodies (DLB), considered as two heterogenic phenotypes of the LB continuum, will not be discussed in this review, since they have been reviewed recently [ 32 , 33 , 34 , 35 , 36 , 37 ], including connectivity studies in DLB [ 38 ].…”

Section: Introductionmentioning

confidence: 99%

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Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Jellinger

2023

IJMS

Self Cite

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Cognitive impairment (CI) is a characteristic non-motor feature of Parkinson disease (PD) that poses a severe burden on the patients and caregivers, yet relatively little is known about its pathobiology. Cognitive deficits are evident throughout the course of PD, with around 25% of subtle cognitive decline and mild CI (MCI) at the time of diagnosis and up to 83% of patients developing dementia after 20 years. The heterogeneity of cognitive phenotypes suggests that a common neuropathological process, characterized by progressive degeneration of the dopaminergic striatonigral system and of many other neuronal systems, results not only in structural deficits but also extensive changes of functional neuronal network activities and neurotransmitter dysfunctions. Modern neuroimaging studies revealed multilocular cortical and subcortical atrophies and alterations in intrinsic neuronal connectivities. The decreased functional connectivity (FC) of the default mode network (DMN) in the bilateral prefrontal cortex is affected already before the development of clinical CI and in the absence of structural changes. Longitudinal cognitive decline is associated with frontostriatal and limbic affections, white matter microlesions and changes between multiple functional neuronal networks, including thalamo-insular, frontoparietal and attention networks, the cholinergic forebrain and the noradrenergic system. Superimposed Alzheimer-related (and other concomitant) pathologies due to interactions between α-synuclein, tau-protein and β-amyloid contribute to dementia pathogenesis in both PD and dementia with Lewy bodies (DLB). To further elucidate the interaction of the pathomechanisms responsible for CI in PD, well-designed longitudinal clinico-pathological studies are warranted that are supported by fluid and sophisticated imaging biomarkers as a basis for better early diagnosis and future disease-modifying therapies.

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Section: Neuropathology Of Pddmentioning

confidence: 99%

Section: Neuropathology Of Pddmentioning

confidence: 99%

Section: Neuropathology Of Pddmentioning

confidence: 99%

Section: Impact Of Other Co-pathologies In Cognition In Pdmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Jellinger

2023

IJMS

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International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions

Kalia,

Berg,

Kordower

et al. 2024

Movement Disorders

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Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson’s Disease Dementia (PDD)

Giraldo-Berrio,

Mendivil-Perez,

Velez-Pardo

et al. 2024

Neurotox Res

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Parkinson’s disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson’s disease (PD) and Alzheimer’s disease (AD). Although it is assumed that alpha-synuclein ($$\mathrm{\alpha }$$ α -Syn), amyloid beta (A$$\upbeta$$ β ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10$$\upmu$$ μ M) for 24 h. ROT provokes loss of $$\Delta \mathrm{\Psi m}$$ Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of $$\mathrm{\alpha }$$ α -synuclein ($$\mathrm{\alpha }$$ α -Syn, Ser129), induces accumulation of intracellular A$$\upbeta$$ β (iA$$\upbeta$$ β ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin-$$\mathrm{ \alpha }$$ α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p-$$\mathrm{ \alpha }$$ α -Syn, iA$$\upbeta$$ β , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

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Morphological characteristics differentiate dementia with Lewy bodies from Parkinson disease with and without dementia

Cited by 6 publications

References 116 publications

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

International Parkinson and Movement Disorder Society Viewpoint on Biological Frameworks of Parkinson's Disease: Current Status and Future Directions

Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson’s Disease Dementia (PDD)

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