Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically highly related α-synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. Genetic and neuropathological studies directly implicate α-synuclein (αS) abnormalities in PDD and DLB pathogenesis. However, it is currently unknown how αS abnormalities contribute to memory loss, particularly since forebrain neuronal loss in PDD and DLB is less severe than in Alzheimer’s disease. Previously, we found that familial Parkinson’s disease-linked human mutant A53T αS causes aberrant localization of the microtubule-associated protein tau to postsynaptic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the synaptic and memory deficits in a mouse model of α-synucleinopathy (TgA53T) are mediated by tau. TgA53T mice exhibit progressive memory deficits associated with postsynaptic deficits in the absence of obvious neuropathological and neurodegenerative changes in the hippocampus. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau−/−), achieved by mating TgA53T mice to mouse tau-knockout mice, completely ameliorates cognitive dysfunction and concurrent synaptic deficits without affecting αS expression or accumulation of selected toxic αS oligomers. Among the known tau-dependent effects, memory deficits in TgA53T mice were associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau−/− mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results directly implicate tau as a mediator of specific human mutant A53T αS-mediated abnormalities related to deficits in hippocampal neurotransmission and suggest a mechanism for memory impairment that occurs as a consequence of synaptic dysfunction rather than synaptic or neuronal loss. We hypothesize that these initial synaptic deficits contribute to network hyperexcitability which, in turn, exacerbate cognitive dysfunction. Our results indicate that these synaptic changes present potential therapeutic targets for amelioration of memory deficits in α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02032-w) contains supplementary material, which is available to authorized users.

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Introduction: Intravenous Alteplase is currently the only approved medical therapy for treatment of acute ischemic stroke (AIS). Although complications are uncommon, AIS patients receiving IV Alteplase are routinely transferred to higher level stroke centers for monitoring. This resource intensive treatment paradigm is of unclear medical benefit. Methods: We reviewed the stroke thrombolysis database of a single comprehensive stroke center. All presumed AIS patients who received IV Alteplase without thrombectomy from 01/01/2015 to 12/31/2019 were included. Baseline demographics including age, sex, race, ethnicity, comorbidities, and NIHSS were abstracted. Complication rates including angioedema, intracranial and extracranial hemorrhage were recorded. To determine the utility of routine transfer, medical and surgical/neurosurgical interventions to treat complications of Alteplase administration were studied. Complication rates in the transfer and non-transfer cohorts were compared via Fischer’s exact test. Results: Three hundred eighteen patients were reviewed and 222 consecutive AIS patients (median age 67 [IQR 55.5-77], female 48.6%, median NIHSS 5 [IQR 2-10], transfers 54.5%) were eligible for our analysis. Complication rates were not statistically different between transfer and non-transfer patients. Four (1.8%) patients suffered symptomatic intracranial hemorrhage (sICH). All sICH patients received cryoprecipitate and aggressive blood pressure management; none underwent emergent neurosurgical intervention. Conclusion: The overall rate of complications post-Alteplase administration for AIS patients was similarly low between transfer and non-transfer patients. These findings call into question the utility of routine transfer of AIS patients treated with Alteplase. Further study of alternative post-Alteplase monitoring strategies, including remote specialist management via telemedicine, should be considered.