Network dysfunction in <i>α</i>‐synuclein transgenic mice and human Lewy body dementia

Morris, Meaghan; Sanchez, Pascal; Verret, Laure; Beagle, Alexander J.; Guo, Weikun; Dubal, Dena B.; Ranasinghe, Kamalini G.; Koyama, Akihiko; Ho, Kaitlyn; Gui, Yu; Vossel, Keith A.; Mucke, Lennart

doi:10.1002/acn3.257

Cited by 47 publications

(62 citation statements)

References 61 publications

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“…However, both increased seizure susceptibility and aberrant network excitability have been related to the overexpression of both tau protein and ␣-synuclein in animal models of FTD [40] and DLB [41]. Thus, the precise cause of epileptic seizures in patients with neurodegenerative dementias has not been fully elucidated yet, and it is likely underlined by complex mechanism and heterogeneous neuropathology.…”

Section: Discussionmentioning

confidence: 99%

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

Arnaldi

Donniaquio

Mattioli

et al. 2020

JAD

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Background: Seizures are common in patients with dementia but precise epidemiologic data of epilepsy in neurodegenerative dementia is lacking. Objective: The first aim of the study was to investigate prevalence and clinical characteristics of epilepsy in a large cohort of patients with neurodegenerative dementias. Subsequently, we explored clinical, neuropsychological, and quantitative electroencephalogram (qEEG) data of Alzheimer's disease (AD) patients with epilepsy (AD-EPI) as compared to AD patients without epilepsy (AD-CTR). Methods: We retrospectively evaluated consecutive patients with a diagnosis of a neurodegenerative dementia and a clinically diagnosed epilepsy that required antiepileptic drugs (AED). All patients underwent baseline comprehensive neuropsychological assessment. A follow-up of at least one year was requested to confirm the dementia diagnosis. In AD patients, qEEG power band analysis was performed. AD-CTR and AD-EPI patients were matched for age, Mini-Mental State Examination score, and gender. Results: Thirty-eight out of 2,054 neurodegenerative dementia patients had epilepsy requiring AED. The prevalence of epilepsy was 1.82% for AD, 1.28% for the behavioral variant of frontotemporal dementia (bvFTD), 2.47% for dementia with Lewy bodies (DLB), and 12% for primary progressive aphasia. Epilepsy were more drug-responsive in AD than in non-AD dementias. Finally, no significant differences were found in neuropsychological and qEEG data between AD-EPI and AD-CTR patients. Conclusion: In our cohort, AD, FTD, and DLB dementias have similar prevalence of epilepsy, even if AD patients were more responsive to AED. Moreover, AD-EPI patients did not have significant clinical, neuropsychological qEEG differences compared with AD-CTR patients.

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Section: Discussionmentioning

confidence: 99%

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

Arnaldi

Donniaquio

Mattioli

et al. 2020

JAD

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“…Overexpression of APP/Aβ and α-synuclein have each been associated with a reduction in calbindin in the hippocampi of transgenic animal models, and similar changes are observed in postmortem brain samples from patients with AD and DLB [18, 24]. …”

Section: Introductionmentioning

confidence: 94%

“…Additionally, apolipoprotein E4, the most common risk factor for AD, contributes to network hyperexcitability in animal models by causing tau-dependent decrease in GABAergic interneurons in the hippocampus [23]. Finally, overexpression of α-synuclein is sufficient to cause aberrant network excitability in experimental models of DLB, AD, and comorbidity [24]. …”

Section: Introductionmentioning

confidence: 99%

Relative Incidence of Seizures and Myoclonus in Alzheimer’s Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia

Beagle

Darwish

Ranasinghe

et al. 2017

JAD

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Background Patients with Alzheimer’s disease (AD) are more prone to seizures and myoclonus, but relative risk of these symptoms among other dementia types is unknown. Objective To determine incidence of seizures and myoclonus in the three most common neurodegenerative dementias: AD, dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Methods Our institution’s medical records were reviewed for new-onset unprovoked seizures and myoclonus in patients meeting criteria for AD (n=1,320), DLB (n=178), and FTD (n=348). Cumulative probabilities of developing seizures and myoclonus were compared between diagnostic groups, whereas age-stratified incidence rates were determined relative to control populations. Results The cumulative probability of developing seizures after disease onset was 11.5% overall, highest in AD (13.4%) and DLB (14.7%) and lowest in FTD (3.0%). The cumulative probability of developing myoclonus was 42.1% overall, highest in DLB (58.1%). The seizure incidence rates, relative to control populations, were nearly 10 fold in AD and DLB, and 6 fold in FTD. Relative seizure rates increased with earlier age-at-onset in AD (age <50, 127 fold; 50–69, 21 fold; 70+, 2 fold) and FTD (age <50, 53 fold; 50–69, 9 fold), and relative myoclonus rates increased with earlier age-at-onset in all groups. Seizures began an average of 3.9 years after the onset of cognitive or motor decline, and myoclonus began 5.4 years after onset. Conclusions Seizures and myoclonus occur with greater incidence in patients with AD, DLB, and FTD than in the general population, but rates vary with diagnosis, suggesting varied pathomechanisms of network hyperexcitability. Patients often experience these symptoms early in disease, suggesting hyperexcitability could be an important target for interventions.

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“…Cell culture and slice physiology studies demonstrated that pathological α-Syn perturbs normal synaptic function (Volpicelli-Daley et al, 2011;Wu et al, 2019), for instance, by oligomeric α-Syn's actions upon glutamatergic receptors (Durante et al, 2019). Further, brain-surface electroencephalography from transgenic mice overexpressing human α-synuclein, throughout the brain, uncovered aberrant activity, including epileptiform events (Morris et al, 2015). Our in vivo results suggest that elevations in pathological α-Syn, up to a particular level, may be sufficient to entail changes in synaptic coupling or perhaps efficacy which may result in the aberrant LFP activity.…”

Section: Beta Band Activitymentioning

confidence: 99%

“…Prior in situ and ex vivo studies have established that the natively unfolded form of α-Syn can modulate synaptic activity (Burré, 2015;Burré et al, 2010;Chandra et al, 2004). One study used brain surface electroencephalography to uncover changes in network activity of transgenic mice overexpressing human α-Syn (Morris et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Perturbation ofin vivoneural activity following α-Synuclein seeding in the olfactory bulb

Kulkarni

Cortijo

Roberts

et al. 2020

Preprint

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BACKGROUNDParkinson’s disease (PD) neuropathology is characterized by intraneuronal protein aggregates composed of misfolded α-Synuclein (α-Syn), as well as degeneration of substantia nigra dopamine neurons. Deficits in olfactory perception and aggregation of α-Syn in the olfactory bulb (OB) are observed during early stages of PD, and have been associated with the PD prodrome, before onset of the classic motor deficits. α-Syn fibrils injected into the OB of mice cause progressive propagation of α-Syn pathology throughout the olfactory system and are coupled to olfactory perceptual deficits.OBJECTIVEWe hypothesized that accumulation of pathogenic α-Syn in the OB impairs neural activity in the olfactory system.METHODSTo address this, we monitored spontaneous and odor-evoked local field potential dynamics in awake wild type mice simultaneously in the OB and piriform cortex (PCX) one, two, and three months following injection of pathogenic preformed α-Syn fibrils in the OB.RESULTSWe detected α-Syn pathology in both the OB and PCX. We also observed that α-Syn fibril injections influenced odor-evoked activity in the OB. In particular, α-Syn fibril-injected mice displayed aberrantly high odor-evoked power in the beta spectral range. A similar change in activity was not detected in the PCX, despite high levels of α-Syn pathology.CONCLUSIONSTogether, this work provides evidence that synucleinopathy impacts in vivo neural activity in the olfactory system at the network-level.

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

Cited by 47 publications

References 61 publications

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

Epilepsy in Neurodegenerative Dementias: A Clinical, Epidemiological, and EEG Study

Relative Incidence of Seizures and Myoclonus in Alzheimer’s Disease, Dementia with Lewy Bodies, and Frontotemporal Dementia

Perturbation ofin vivoneural activity following α-Synuclein seeding in the olfactory bulb

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