Pathologic Accumulation of α-Synuclein and Aβ in Parkinson Disease Patients With Dementia

Kotzbauer, Paul T.; Cairns, Nigel J.; Campbell, Meghan C.; Willis, Allison W.; Racette, Brad A.; Tabbal, Samer D.; Perlmutter, Joel S.

doi:10.1001/archneurol.2012.1608

Cited by 169 publications

(190 citation statements)

References 36 publications

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“…Parkinson's disease dementia cases (n = 12, details in Table I) were consecutive cases meeting the diagnostic criteria for Parkinson's disease (PD) and PDD and were obtained from the Movement Disorders Center at Washington University School of Medicine in St. Louis [11,26]. Initial diagnosis of PD was based on modified United Kingdom Parkinson Disease Society Brain Bank (UKPDSBB) clinical diagnostic criteria [24]: (1) bradykinesia was present in association with at least one of the following, viz.…”

Section: Materials and Methods Casesmentioning

confidence: 99%

Evidence from spatial pattern analysis for the anatomical spread of α-synuclein pathology in Parkinson’s disease dementia

Armstrong

2017

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A b s t r a c t The objective of this study was to determine whether there is evidence from quantitative morphometry and spatial pattern analysis to support the hypothesis of anatomical spread of α-synuclein in Parkinson's disease dementia (PDD). Hence, clustering of α-synuclein-immunoreactive Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) was studied in α-synuclein-immunolabeled sections of cortical and limbic regions in 12 cases of PDD. The data suggested that: (1) LB, LN, and LG occurred in clusters which in 63% of regions were regularly distributed parallel to the tissue boundary, (2) in approximately 30% of cortical regions, the estimated cluster size of LB, LN, and LG was within the size range of cellular columns associated with the cortico-cortical pathways, (3) regularly distributed clusters were present in anatomically connected regions, and (4) the clustering pattern was similar to that of prion protein (PrP sc ) deposits in Creutzfeldt-Jacob disease (CJD). The clustering patterns of LB, LN, andLG were similar to those exhibited by cellular inclusions in other synucleinopathies and by PrP sc deposits in prion disease and therefore, anatomical spread of pathogenic α-synuclein could be involved in the pathogenesis of PDD.

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Section: Materials and Methods Casesmentioning

confidence: 99%

Evidence from spatial pattern analysis for the anatomical spread of α-synuclein pathology in Parkinson’s disease dementia

Armstrong

2017

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“…In the Lewy bodies disease spectrum of disorders, autopsy studies highlighted that co-occurrence of amyloid-b plaques and phosphorylated tau together with -synuclein deposition are associated with greater cognitive decline (Kraybill et al, 2005;Nelson et al, 2009;Ferman et al, 2015;Howlett et al, 2015), and shorter survival (Kotzbauer et al, 2012;Graff-Radford et al, 2015) .…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

Sarro¹,

Senjem

Lundt

et al. 2016

Brain

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Alzheimer's disease pathology frequently coexists with Lewy body disease at autopsy in patients with probable dementia with Lewy bodies. More than half of patients with probable dementia with Lewy bodies have high amyloid-b deposition as measured with 11 C-Pittsburgh compound B binding on positron emission tomography. Biomarkers of amyloid-b deposition precede neurodegeneration on magnetic resonance imaging during the progression of Alzheimer's disease, but little is known about how amyloid-b deposition relates to longitudinal progression of atrophy in patients with probable dementia with Lewy bodies. We investigated the associations between baseline 11 C-Pittsburgh compound B binding on positron emission tomography and the longitudinal rates of grey matter atrophy in a cohort of clinically diagnosed patients with dementia with Lewy bodies (n = 20), who were consecutively recruited to the Mayo Clinic Alzheimer's Disease Research Centre. All patients underwent 11 C-Pittsburgh compound B positron emission tomography and magnetic resonance imaging examinations at baseline. Follow-up magnetic resonance imaging was performed after a mean (standard deviation) interval of 2.5 (1.1) years. Regional grey matter loss was determined on threedimensional T 1 -weighted magnetic resonance imaging with the tensor-based morphometry-symmetric normalization technique. Linear regression was performed between baseline 11 C-Pittsburgh compound B standard unit value ratio and longitudinal change in regional grey matter volumes from an in-house modified atlas. We identified significant associations between greater baseline 11 C-Pittsburgh compound B standard unit value ratio and greater grey matter loss over time in the posterior cingulate gyrus, lateral and medial temporal lobe, and occipital lobe as well as caudate and putamen nuclei, after adjusting for age (P 5 0.05). Greater baseline 11 C-Pittsburgh compound B standard unit value ratio was also associated with greater ventricular expansion rates (P 5 0.01) and greater worsening over time in Clinical Dementia Rating Scale, sum of boxes (P = 0.02). In conclusion, in patients with probable dementia with Lewy bodies, higher amyloid-b deposition at baseline is predictive of faster neurodegeneration in the cortex and also in the striatum. This distribution is suggestive of possible interactions among amyloid-b, tau and a-synuclein aggregates, which needs further investigation. Furthermore, higher amyloid-b deposition at baseline predicts a faster clinical decline over time in patients with probable dementia with Lewy bodies. Keywords: DLB; structural MRI; beta-amyloid; amyloid imaging; brain atrophy Abbreviations: AChEI = acetylcholinesterase inhibitor; CDR-SOB = Clinical Dementia Rating scale, Sum of Boxes; DLB = dementia with Lewy bodies; MMSE = Mini-Mental State Examination; PiB = 11 C-Pittsburgh compound B; SUVR = standardized uptake value ratio; TBM-SyN = tensor-based morphometry using symmetric diffeomorphic image normalization; UPDRS-III =

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“…2(C)]. Approximate size analysis using DLS based on an assumption of a spherical shape for these oligomers showed hydrodynamic diameters of 11.0, 10.3, 7.8, and 4.9 nm for DSO [4][5][6][7][8][9][10][11][12][13] , DSO [3][4][5][6][7][8][9][10] , DSO [3][4][5][6] , and DSO 2-5 , respectively, while monomeric aS showed a hydrodynamic radius of 3.8 nM [ Fig. 2(D)].…”

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confidence: 99%

Dopamine‐induced α‐synuclein oligomers show self‐ and cross‐propagation properties

et al. 2014

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Amyloid aggregates of a-synuclein (aS) protein are the predominant species present within the intracellular inclusions called Lewy bodies in Parkinson's disease (PD) patients. Among various aggregates, the low-molecular weight ones broadly ranging between 2 and 30 mers are known to be the primary neurotoxic agents responsible for the impairment of neuronal function. Recent research has indicated that the neurotransmitter dopamine (DA) is one of the key physiological agents promoting and augmenting aS aggregation, which is thought to be a significant event in PD pathologenesis. Specifically, DA is known to induce the formation of soluble oligomers of aS, which in turn are responsible for inducing several important cellular changes leading to cellular toxicity. In this report, we present the generation, isolation, and biophysical characterization of five different dopamine-derived aS oligomers (DSOs) ranging between 3 and 15 mers, corroborating previously published reports. More importantly, we establish that these DSOs are also capable of replication by self-propagation, which leads to the replication of DSOs upon interaction with aS monomers, a process similar to that observed in mammilian prions. In addition, DSOs are also able to cross-propagate amyloid-b (Ab) aggregates involved in Alzheimer's disease (AD). Interestingly, while self-propagation of DSOs occur with no net gain in protein structure, crosspropagation proceeds with an overall gain in b-sheet conformation. These results implicate the involvement of DSOs in the progression of PD, and, in part, provide a molecular basis for the observed co-existence of AD-like pathology among PD patients.

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Pathologic Accumulation of α-Synuclein and Aβ in Parkinson Disease Patients With Dementia

Cited by 169 publications

References 36 publications

Evidence from spatial pattern analysis for the anatomical spread of α-synuclein pathology in Parkinson’s disease dementia

Evidence from spatial pattern analysis for the anatomical spread of α-synuclein pathology in Parkinson’s disease dementia

Amyloid-β deposition and regional grey matter atrophy rates in dementia with Lewy bodies

Dopamine‐induced α‐synuclein oligomers show self‐ and cross‐propagation properties

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