Patterns of alpha-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Berg, Wilma D. J. van de; Hepp, Dagmar H.; Dijkstra, Anke A.; Rozemuller, J. Annemieke M.; Berendse, H.W.; Foncke, E.M.J.

doi:10.1016/s1353-8020(11)70011-6

Cited by 55 publications

(30 citation statements)

References 19 publications

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“…As in the HC, this increase was present especially in the CA2 and CA3, notably in close proximity to α-synuclein pathology; this suggests that an inflammatory response occurs to these neuropathological alterations, similar to the SN. Strikingly, increases in amoeboid microglia in the SN were observed in iLBD cases too, in which little, if any, DAergic cell loss was present postmortem, nor had any clinical motor symptoms been apparent during these patients’ lives [51]. This is of importance since it contributes to the debate whether microglial activation is merely a reaction to neuronal cell death or whether these cell respond to other (early) pathological events [13] and therefore actively participate in the pathological processes before cell death occurs, as suggested by our observations in the SN and HC.…”

Section: Discussionmentioning

confidence: 99%

“…in ramified, primed/reactive and amoeboid subtypes, and compared the SN to the hippocampus (HC), a brain region that has been implicated in the cognitive deficits and depressive symptoms frequently present in PD [48,49]. We studied tissue of clinically diagnosed and neuropathologically verified PD patients (Braak PD stage 4–6) [50], age- and gender-matched control subjects (Braak PD stage 0) and incidental Lewy body disease (iLBD) cases (Braak PD 1–3), that did not have clinical PD symptoms but displayed α-synuclein deposition at autopsy and can therefore be considered a prodromal state of PD [51]. Moreover, as α-synuclein can stimulate microglia through TLR2, we further investigated whether TLR2 is expressed in the SN and HC of iLBD and PD cases in relation to α-synuclein deposition.…”

Section: Introductionmentioning

confidence: 99%

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Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

Doorn

Moors

Drukarch

et al. 2014

acta neuropathol commun

168

139

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Next to α-synuclein deposition, microglial activation is a prominent pathological feature in the substantia nigra (SN) of Parkinson’s disease (PD) patients. Little is known, however, about the different phenotypes of microglia and how they change during disease progression, in the SN or in another brain region, like the hippocampus (HC), which is implicated in dementia and depression, important non-motor symptoms in PD.We studied phenotypes and activation of microglia in the SN and HC of established PD patients (Braak PD stage 4–6), matched controls (Braak PD stage 0) and of incidental Lewy Body disease (iLBD) cases (Braak PD stage 1–3) that are considered a prodromal state of PD. As recent experimental studies suggested that toll-like receptor 2 (TLR2) mediates α-synuclein triggered microglial activation, we also studied whether TLR2 expression is indeed related to pathology in iLBD and PD patients.A clear α-synuclein pathology-related increase in amoeboid microglia was present in the HC and SN in PD. Also, morphologically primed/reactive microglial cells, and a profound increase in microglial TLR2 expression were apparent in iLBD, but not PD, cases, indicative of an early activational response to PD pathology. Moreover, TLR2 was differentially expressed between the SN and HC, consistent with a region-specific pattern of microglial activation.In conclusion, the regional changes in microglial phenotype and TLR2 expression in primed/reactive microglia in the SN and HC of iLBD cases indicate that TLR2 may play a prominent role in the microglial-mediated responses that could be important for PD progression.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

Doorn

Moors

Drukarch

et al. 2014

acta neuropathol commun

168

139

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“…Multiple pathological studies demonstrate that non-tremor Parkinson disease cases have more severe cortical Lewy pathology, and clinically these cases are more likely to have some cognitive impairment. [34]…”

Section: Discussionmentioning

confidence: 99%

Patterns of Motor and Non-Motor Features in Medication-Naïve Parkinsonism

2015

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Background: Parkinsonism is defined by motor features (tremor, bradykinesia, rigidity, and postural instability). Accompanying non-motor features (e.g. cognitive, autonomic, sleep disturbances) are underrecognized and undertreated. We hypothesized that clinical patterns occurring in early, medication-naïve Parkinsonism are distinguished by features such as tremor, sleep, autonomic, and cognitive dysfunction. Methods: Clinical and neuroimaging data were obtained in the Parkinson's Progression Marker Initiative. Group comparisons of Parkinsonism with dopaminergic deficits (PDD) (n = 388), controls (n = 196), and Parkinsonism with scans without evidence of dopaminergic deficits (n = 64) were done with ANOVA, chi-square, and post-hoc pairwise tests. To examine clinical patterns within the PDD group, k-means clustering was performed with non-motor or motor features, or both. Results: Among PDD, 4 non-motor patterns (% of PDD) (impulsive (14.9%), sleep-autonomic (22.9%), cognitive-olfactory (18.0%), and mild (44.1%)), 4 motor patterns (tremor plus bradykinesia (56.2%), tremor without bradykinesia (16.2%), postural instability (6.7%) and no tremor (20.9%)) and 5 combined motor/non-motor patterns (tremor with bradykinesia (42.3%), tremor without bradykinesia (15.5%), no tremor and mild non-motor features (17.0%), postural instability with sleep-autonomic disturbances (6.7%) and oldest onset cognitive-olfactory (18.6%)) were observed. Conclusions: To our knowledge, this is the first description of non-motor clinical patterns in early, medication-naïve Parkinsonism, suggesting that such features are intrinsic to Parkinsonian disorders.

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“…Although α-syn was first discovered in patients with familial forms of PD and its A53T, E46K and A30P mutations had also been shown to be related to the familial form of PD [4,86], α-syn appeared to be a vital genetic factor of PD pathology both in familial and sporadic cases. Its expression level was positively correlated with the severity of PD [87]. Accumulating evidences proved that the abnormal deposit of α-syn could result in neurotoxicity through a gain-of-function manner [88][89][90].…”

Section: α-Synuclein Aggregation and Parkinson Diseasementioning

confidence: 99%

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

Chen¹,

Lu²,

Duan³

et al. 2017

J Alzheimers Dis Parkinsonism

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Patterns of alpha-synuclein pathology in incidental cases and clinical subtypes of Parkinson's disease

Cited by 55 publications

References 19 publications

Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

Microglial phenotypes and toll-like receptor 2 in the substantia nigra and hippocampus of incidental Lewy body disease cases and Parkinson’s disease patients

Patterns of Motor and Non-Motor Features in Medication-Naïve Parkinsonism

Catechol Tetrahydroisoquinolines Enhance a-Synuclein Aggregation and Specify the Neurotoxicity to Dopaminergic Neurons

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