パーキンソン病

N-methyl-D-aspartate (NMDA) receptor encephalitis stands as the most common form of autoimmune encephalitis in young adults, characterized by a spectrum of distressing symptoms such as seizures, behavioral disruptions, autonomic dysfunction, and memory impairment. We present a noteworthy case involving a young adult male exhibiting seizures and renal failure, initially prompting an evaluation for vasculitis, hyperuricemia-induced acute kidney injury (AKI), and rhabdomyolysis-induced AKI. However, subsequent findings revealed the presence of NMDA receptor antibodies, and a renal biopsy confirmed tubulointerstitial nephritis. This case sheds light on the association between renal failure and NMDA receptor antibody-associated encephalitis, marking a rare instance in our knowledge.

The amygdala is highly vulnerable to protein aggregation and heavily affected in Lewy body diseases (LBDs). However, vulnerability might vary per amygdalar nucleus and it is unclear if the pattern of vulnerability across the nuclei differs between types of protein aggregation and between LBDs. In this study, we aimed to assess the vulnerability of amygdalar nuclei to multiple types of protein aggregation across LBDs. Post-mortem amygdala tissue of donors with incidental LBD (iLBD, n = 6), Parkinson's disease (PD; n = 18), dementia with Lewy bodies (DLB; n = 9) and Alzheimer's disease with Lewy bodies (AD + LB; n = 15) was immunostained with antibodies against alpha-synuclein (aSyn; EP1536Y and 5G4), amyloid beta (Aβ; 4G8), phosphorylated tau (p-tau; AT8) and phosphorylated TDP-43 (p-TDP-43; 11-9), and quantitatively analyzed using QuPath. Neuronal and astrocytic aSyn pathology were most pronounced in the parahippocampal-amygdaloid transition area (PHA) and the basal nucleus, a pattern shared by all disease groups. Vulnerability to Aβ pathology varied per group but was highest in the PHA in AD + LB, whereas diffuse plaques were most common in the accessory basal nucleus. The PHA of DLB and both the basal and accessory basal nucleus of AD + LB cases were most susceptible to p-tau pathology, with fine granular cytoplasmic neuronal tau inclusions being mostly observed in the basal nucleus and neurofibrillary tangles in the accessory basal nucleus. The nuclei in the ventromedial part of the amygdala (PHA, ventral part of the basal nucleus, and cortical nucleus) were found to be hotspots for protein aggregation across LBDs. aSyn pathology in these nuclei predominantly correlated with dementia, hallucinations and anxiety. Our results show that amygdalar nuclei vulnerability differs per protein aggregate and disease entity, although the PHA, basal nucleus and cortical nucleus are generally more vulnerable. Together, our study provides a deeper insight into the selective vulnerability of amygdalar nuclei to protein aggregates and their relation to clinical characteristics in LBDs.

Serotonin 5-HT4 receptors (5-HT4Rs) have emerged as potential therapeutic targets in neuropsychiatric and neurodegenerative disorders by modulating circuits that shape mood, cognition, and motor functions. Ligands for 5-HT4Rs can modify dopamine (DA) and acetylcholine (ACh) transmission, but mechanisms and circuits have not been fully resolved. Some 5-HT4R agonists have been suggested to have effects that include the inhibition of acetylcholinesterase (AChE), raising the speculation that 5-HT4R ligands might modulate ACh and DA through this action. Here, we investigated the impact of RS67333, a partial 5-HT4R agonist, on DA and ACh release dynamics in the striatum detected ex vivo in mouse brain slices using fast-scan cyclic voltammetry (FCV) and genetically encoded ACh sensor GRABACh3.0, respectively. We found that RS67333 significantly modulated electrically evoked DA release in the dorsolateral striatum (DLS) and nucleus accumbens core, effects that were abolished by a nicotinic receptor (nAChR) antagonist. In parallel, RS67333 altered evoked ACh signals by extending extracellular ACh lifetime, and correspondingly, RS67333 was found to inhibit striatal AChE enzymatic activity. By contrast, BIMU8, an alternative 5-HT4R ligand that did not inhibit striatal AChE, had no effect on the evoked striatal ACh or DA release. These findings indicate that RS67333 modulates striatal ACh transmission, which shapes downstream regulation of DA release by nAChRs, not through 5-HT4Rs but through AChE inhibition. These findings emphasize the caution due in attributing functions to 5-HT4Rs but also highlight an alternative pharmacological profile of some purported 5-HT4R ligands as AChE inhibitors of potential utility for treating ACh/DA disorders.

BACKGROUND: In-person assessments face accessibility, scalability, and geographic diversity challenges, especially for rare diseases. Additionally, Cerebellar Ataxia (CA) non-motor symptoms(NMS) are often overlooked. We aimed to address these gaps by leveraging the Internet and machine-learning. METHODS: In a bi-center study, we assessed 100 participants: 30 CA, 45 neurotypically healthy(NH), and 25 Parkinson's disease(PD), recruited from 57 geographical locations across two countries. We evaluated multiple domains-cognition, anxiety, depression, social support, and personality-using accessible online tools. We applied leave-one-out cross-validation and feature importance analysis to examine the machine-learning model's ability to distinguish between groups and identify the most sensitive and specific CA predictors. RESULTS: Machine-learning models trained on these remote non-motor features alone, yield AUCs of 0.74/0.76(CA vs. NH) and 0.78/0.79 (CA vs. PD) using leave-one-out cross-validation, demonstrating classification power exceeding 20%. CONCLUSION: These findings highlight the value of integrating digital-health technologies and machine-learning models for CA NMS evaluation, potentially serving as scalable digital-markers.