Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4⁺ and CD8⁺ T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD. Graphical Abstract

Deep brain stimulation (DBS) has emerged as a revolutionary technique for accessing and modulating brain circuits. DBS is used to treat dysfunctional neuronal circuits in neurological and psychiatric disorders. Despite over two decades of clinical application, the fundamental mechanisms underlying DBS are still not well understood. One reason is the complexity of in vivo electrical manipulation of the central nervous system, particularly in rodent models. DBS-devices for freely moving rodents are typically custom-designed and not commercially available, thus making it difficult to perform experimental DBS according to common standards. Addressing these challenges, we have developed a novel wireless microstimulation system for deep brain stimulation (wDBS) tailored for rodents. We demonstrate the efficacy of this device for the restoration of behavioral impairments in hemiparkinsonian mice through unilateral wDBS of the subthalamic nucleus. Moreover, we introduce a standardized and innovative pipeline, integrating machine learning techniques to analyze Parkinson’s disease-like and DBS-induced gait changes.

Perfusion impairment is one of the major barriers to using machine perfusion to prepare brain tissue for research and clinical applications. As ischemia progresses, multiple mechanisms, including intravascular obstructions, perivascular cellular edema, mural cell contraction, and vessel wall breakdown, progressively limit the uniform delivery of preservative solutions. This problem is particularly important for connectomics, wherein successful preservation requires both widespread distribution of preservative chemicals and the maintenance of the cellular ultrastructure needed for circuit reconstruction. We conducted a narrative review of interventions used to ameliorate perfusion impairment across multiple fields, including organ transplantation, resuscitation medicine, forensic pathology, embalming, and neuroscience. We evaluated the evidence for these approaches in their original contexts and considered their potential application for brain banking aimed at preserving tissue for connectome reconstruction. We classify interventions into several categories, including anticoagulants, fibrinolytics, vasodilators, washout solutions, surfactants, osmotic agents, colloids, hypothermia, and perfusion pressure optimization. Many of these interventions have the potential to improve perfusion, but each also carries tradeoffs that may adversely affect tissue preservation. As connectomics advances toward profiling larger volumes of human brain tissue, overcoming perfusion impairment is likely to become an increasingly important challenge. This review provides a mechanistic framework for evaluating existing interventions and guiding the development of future perfusion protocols.

Protecting life and restoring health have been at the core of the conception of medical care since antiquity, for health professionals and the public alike. Assisted dying represents a practice that appears to challenge this traditional conception. In jurisdictions where assisted dying is condoned, the question remains as to whether the practice should be medicalized or deferred to non-medical actors. Irrespective of the divisive controversy surrounding assisted dying and its medicalization per se, the practice gives rise to high-stakes ethical, legal and organizational challenges when intersecting with organ transplantation, tissue banking, and Structural Brain Preservation or cryonics. In this narrative account, we describe the contextual framework and outline our experience and operational scope for addressing them at a university hospital in Germany. Based on this description we propose a structured pathway for increasing donation and preservation options for terminal patients while retaining ethical integrity and professional accountability.

We present a case of reversible leukoencephalopathy and parkinsonism associated with type III mixed cryoglobulinemic vasculitis in a patient who initially presented with systemic vasculitic symptoms such as rash and arthralgias. Neither hepatitis C nor monoclonal gammopathy-typical triggers of cryoglobulinemia-was identified. The neurologic syndrome evolved with tremor, rigidity, significant cognitive decline, and extensive white matter abnormalities on MRI, mimicking primary neurodegenerative conditions such as multiple system atrophy. Diagnostic workup ruled out infectious, metabolic, autoimmune, and drug-related etiologies. After immunosuppressive therapy with methotrexate and steroids, the patient experienced marked clinical and radiologic improvement, paralleled by a decline in serum neurofilament levels. This case highlights the importance of recognizing inflammatory CNS involvement as a potentially reversible cause of rapidly progressive parkinsonism and cognitive impairment. Prompt identification and timely immunosuppressive treatment may reverse symptoms and prevent permanent neurologic damage.

Perfusion impairment is one of the major barriers to using machine perfusion to prepare brain tissue for research and clinical applications. As ischemia progresses, multiple mechanisms, including intravascular obstructions, perivascular cellular edema, mural cell contraction, and vessel wall breakdown, progressively limit the uniform delivery of preservative solutions. This problem is particularly important for connectomics, wherein successful preservation requires both widespread distribution of preservative chemicals and the maintenance of the cellular ultrastructure needed for circuit reconstruction. We conducted a narrative review of interventions used to ameliorate perfusion impairment across multiple fields, including organ transplantation, resuscitation medicine, forensic pathology, embalming, and neuroscience. We evaluated the evidence for these approaches in their original contexts and considered their potential application for brain banking aimed at preserving tissue for connectome reconstruction. We classify interventions into several categories, including anticoagulants, fibrinolytics, vasodilators, washout solutions, surfactants, osmotic agents, colloids, hypothermia, and perfusion pressure optimization. Many of these interventions have the potential to improve perfusion, but each also carries tradeoffs that may adversely affect tissue preservation. As connectomics advances toward profiling larger volumes of human brain tissue, overcoming perfusion impairment is likely to become an increasingly important challenge. This review provides a mechanistic framework for evaluating existing interventions and guiding the development of future perfusion protocols.