Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always

Martin, W. R. Wayne; Younce, John R.; Campbell, Meghan C.; Racette, Brad A.; Norris, Scott A.; Ushe, Mwiza; Criswell, Susan R.; Davis, Albert A.; Alfradique-Dunham, Isabel; Maiti, Baijayanta; Cairns, Nigel J.; Perrin, Richard J.; Kotzbauer, Paul T.; Perlmutter, Joel S.

doi:10.1002/ana.26542

Cited by 21 publications

(15 citation statements)

References 51 publications

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“…Therefore, it is possible that plaque-residing Aβ may have different properties, including immunogenicity, compared to oligomeric species. With regard to LBs whose main component, α-synuclein fibrils, do not appear to have significant immunogenicity [ 29 ] or to correlate neatly with clinical decline, especially in PDD [ 30 ], our finding of a lack of associations between LB scores and cytokine markers suggest that these markers are driven primarily by NFT, and the low levels of cytokines found in PDD and DLB may thus reflect relatively low NFT burden in Lewy body dementias (see Table 1 , [ 3 ]). Importantly, the current data are congruent with the postulated bi-directional links between neuroinflammation and NFT formation.…”

Section: Discussionmentioning

confidence: 99%

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

Chai

Lee

Chong

et al. 2023

J Neuroinflammation

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Background Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer’s disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). Methods Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. Results We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

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Section: Discussionmentioning

confidence: 99%

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

Chai

Lee

Chong

et al. 2023

J Neuroinflammation

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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%

“…The morphological substrate of PDD is heterogenous and includes the following: (1) Lewy body (αSyn) pathology (LBP) in cortical, limbic and subcortical/brainstem structures, (2) AD-related neuropathological changes (ADNC)—diffuse Aβ and neuritic plaques, NFTs and CAA, and (3) a variable combination of these pathologies that has been differently related to the severity of CI [ 357 , 390 , 394 , 395 , 398 ]. Limbic and neocortical LBP were significantly higher in PDD than in MCI, CI often correlating with the severity of LBP in the frontal cortex, hippocampus and periamygdaloid cortex, causing a disruption of the limbic loop similar to that in AD [ 399 ].…”

Section: Neuropathology Of Pddmentioning

confidence: 99%

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Jellinger

2023

IJMS

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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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“…The presence of a widespread synucleinopathy through the cerebral cortex represents the main neuropathological hallmark that typically characterizes Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB; Martin et al, 2023 ). Although PDD and DLB overlap in many features, several distinctive characteristics are also observed ( Jellinger and Korczyn, 2018 ), therefore some concerns still remain dealing with to what extent these disorders can be either categorized as two different clinical entities or merely represents the same disease in different stages of progression ( Jellinger and Korczyn, 2018 ; Jellinger, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

Development and characterization of a non-human primate model of disseminated synucleinopathy

Rico,

Corcho,

Chocarro

et al. 2024

Front. Neuroanat.

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IntroductionThe presence of a widespread cortical synucleinopathy is the main neuropathological hallmark underlying clinical entities such as Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB). There currently is a pressing need for the development of non-human primate (NHPs) models of PDD and DLB to further overcome existing limitations in drug discovery.MethodsHere we took advantage of a retrogradely-spreading adeno-associated viral vector serotype 9 coding for the alpha-synuclein A53T mutated gene (AAV9-SynA53T) to induce a widespread synucleinopathy of cortical and subcortical territories innervating the putamen. Four weeks post-AAV deliveries animals were sacrificed and a comprehensive biodistribution study was conducted, comprising the quantification of neurons expressing alpha-synuclein, rostrocaudal distribution and their specific location.ResultsIntraputaminal deliveries of AAV9-SynA53T lead to a disseminated synucleinopathy throughout ipsi- and contralateral cerebral cortices, together with transduced neurons located in the ipsilateral caudal intralaminar nuclei and in the substantia nigra pars compacta (leading to thalamostriatal and nigrostriatal projections, respectively). Cortical afferent systems were found to be the main contributors to putaminal afferents (superior frontal and precentral gyri in particular).DiscussionObtained data extends current models of synucleinopathies in NHPs, providing a reproducible platform enabling the adequate implementation of end-stage preclinical screening of new drugs targeting alpha-synuclein.

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Neocortical Lewy Body Pathology Parallels Parkinson's Dementia, but Not Always

Abstract: Objective: The objective of this study was to evaluate the relationship between Parkinson's disease (PD) with dementia and cortical proteinopathies in a large population of pathologically confirmed patients with PD.

Cited by 21 publications

References 51 publications

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer’s disease but not Lewy body dementias

Pathobiology of Cognitive Impairment in Parkinson Disease: Challenges and Outlooks

Development and characterization of a non-human primate model of disseminated synucleinopathy

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