Parkinson's disease, cortical dysfunction, and alpha‐synuclein

Caviness, John N.; Lue, Lih Fen; Beach, Thomas G.; Hentz, Joseph G.; Adler, Charles H.; Sue, Lucia I.; Sadeghi, Ramin; Driver‐Dunckley, Erika; Evidente, Virgilio Gerald H.; Sabbagh, Marwan N.; Shill, Holly A.; Walker, Douglas G.

doi:10.1002/mds.23697

Cited by 17 publications

(18 citation statements)

References 38 publications

(51 reference statements)

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“…This is consistent with another study from our laboratory that found higher levels of α‐synuclein with the presence of PD motor cortex hyperexcitability, whereas AD pathology biochemistry markers were equal between the groups . Studies show that PD cortical dysfunction and dementia correlate with greater cortical LTS histopathology . The current results from this study go further to show that the building blocks of LTS (i.e., p‐α‐syn) correlate more strongly with physiological cortical dysfunction, as shown by QEEG, than do AD pathology biochemistry markers.…”

Section: Discussionsupporting

confidence: 92%

“…35 Studies show that PD cortical dysfunction and dementia correlate with greater cortical LTS histopathology. 3,4,39 The current results from this study go further to show that the building blocks of LTS (i.e., p-a-syn) correlate more strongly with physiological cortical dysfunction, as shown by QEEG, than do AD pathology biochemistry markers. Our cases had a relatively small proportion of apolipoprotein E4 (apoE4) allele cases, so this may have affected the influence of AD pathology biochemistry markers.…”

Section: Discussionsupporting

confidence: 60%

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Cortical phosphorylated α-Synuclein levels correlate with brain wave spectra in Parkinson's disease

et al. 2016

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Objectives Quantitative EEG features have been identified as surrogates and predictors of cognitive decline/dementia, a common feature of progressive Parkinson's disease. The biochemical correlates for altered quantitative EEG features are unknown. Our primary objective was to test the hypothesis that quantitative EEG measures correlate with cortical levels of phosphorylated α-synuclein, a modified form of the synaptic protein α-synuclein, in Parkinson's disease cases, in contrast to other pathology-associated proteins. A secondary objective was to explore the same correlations among cellular fractions of these proteins. Methods We used posterior cingulate cortex autopsy tissue from 44 Parkinson's disease subjects with various degrees of cognitive decline, who had undergone EEG. In this brain region, which is a major hub of the default mode network, biochemical measurements for levels of phosphorylated α-synuclein, unmodified α-synuclein, Aβ peptide, phosphorylated tau and key synaptic proteins were analyzed, and data correlated with spectral EEG measures. Results Findings revealed significant correlations between background rhythm peak frequency and all bandpower values (highest in delta bandpower) with total phosphorylated α-synuclein, but not any correlation with total α-synuclein, phosphorylated tau protein, Aβ peptide or synaptic proteins. Certain fractions of synaptosomal-associated protein 25 showed correlation with some quantitative EEG measures. Conclusions These data show association between increased phosphorylation of α-synuclein and the abnormal EEG signatures of cognitive decline. Results suggest quantitative EEG may provide an in vivo approximation of phosphorylated α-synuclein in Parkinson's disease cortex. This adds to previous evidence that quantitative EEG measures can be considered valid biomarkers of Parkinson's disease cognitive decline.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 60%

Cortical phosphorylated α-Synuclein levels correlate with brain wave spectra in Parkinson's disease

et al. 2016

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“…In our study, myoclonus was associated with an earlier age of onset of cognitive impairment, raising the possibility that aberrant network excitability may contribute to cognitive dysfunction in DLB. Interestingly, levels of SYN in the sensorimotor cortex were higher in PD patients with myoclonus than in those without 55. Increased cortical SYN pathology may also explain why myoclonus is more frequent, and is thought to be more severe, in DLB patients than in PD patients 39, 45…”

Section: Discussionmentioning

confidence: 99%

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Morris

Sanchez

Verret

et al. 2015

Ann Clin Transl Neurol

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ObjectiveDementia with Lewy bodies (DLB) is associated with the accumulation of wild‐type human α‐synuclein (SYN) in neurons and with prominent slowing of brain oscillations on electroencephalography (EEG). However, it remains uncertain whether the EEG abnormalities are actually caused by SYN.MethodsTo determine whether SYN can cause neural network abnormalities, we performed EEG recordings and analyzed the expression of neuronal activity‐dependent gene products in SYN transgenic mice. We also carried out comparative analyses in humans with DLB.ResultsWe demonstrate that neuronal expression of SYN in transgenic mice causes a left shift in spectral power that closely resembles the EEG slowing observed in DLB patients. Surprisingly, SYN mice also had seizures and showed molecular hippocampal alterations indicative of aberrant network excitability, including calbindin depletion in the dentate gyrus. In postmortem brain tissues from DLB patients, we found reduced levels of calbindin mRNA in the dentate gyrus. Furthermore, nearly one quarter of DLB patients showed myoclonus, a clinical sign of aberrant network excitability that was associated with an earlier age of onset of cognitive impairments. In SYN mice, partial suppression of epileptiform activity did not alter their shift in spectral power. Furthermore, epileptiform activity in human amyloid precursor protein transgenic mice was not associated with a left shift in spectral power.InterpretationWe conclude that neuronal accumulation of SYN slows brain oscillations and, in parallel, causes aberrant network excitability that can escalate into seizure activity. The potential role of aberrant network excitability in DLB merits further investigation.

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“…By analyzing post-mortem tissue from PD patients at various disease stages, Braak et al (2003) determined that frontal cortex Lewy body inclusions are first evident in prefrontal areas; as the disease progresses, Lewy bodies appear in the PMC, then in the SMA and finally in M1. Abnormal aggregation of alpha-synuclein in the motor cortex without classical Lewy bodies has also been observed, suggesting that this may occur during earlier disease stages (Caviness et al, 2011). At this point, how motor cortex Lewy bodies influence cortical function remains unknown.…”

Section: Motor Cortex Pathology In Parkinson’s Diseasementioning

confidence: 99%

Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease

Lindenbach

Bishop

2013

Neuroscience & Biobehavioral Reviews

112

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This review examines the involvement of the motor cortex in Parkinson’s disease (PD), a debilitating movement disorder typified by degeneration of dopamine cells of the substantia nigra. While much of PD research has focused on the caudate/putamen, many aspects of motor cortex function are abnormal in PD patients and in animal models of PD, implicating motor cortex involvement in disease symptoms and their treatment. Herein, we discuss several lines of evidence to support this hypothesis. Dopamine depletion alters regional metabolism in the motor cortex and also reduces interneuron activity, causing a breakdown in intracortical inhibition. This leads to functional reorganization of motor maps and excessive corticostriatal synchrony when movement is initiated. Recent work suggests that electrical stimulation of the motor cortex provides a clinical benefit for PD patients. Based on extant research, we identify a number of unanswered questions regarding the motor cortex in PD and argue that a better understanding of the contribution of the motor cortex to PD symptoms will facilitate the development of novel therapeutic approaches.

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Parkinson's disease, cortical dysfunction, and alpha‐synuclein

Cited by 17 publications

References 38 publications

Cortical phosphorylated α-Synuclein levels correlate with brain wave spectra in Parkinson's disease

Cortical phosphorylated α-Synuclein levels correlate with brain wave spectra in Parkinson's disease

Network dysfunction in α‐synuclein transgenic mice and human Lewy body dementia

Critical involvement of the motor cortex in the pathophysiology and treatment of Parkinson's disease

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