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Introduction This study evaluates the impact of Parkinson disease (PD) medication in advanced PD on neuropsychological performance, psychiatric symptoms, impulsivity and the quality of life. In the 4-year period 27 patients with advanced PD, scheduled for deep brain stimulation (DBS) surgery (N=27, mean age: 58.9±7.1, disease duration: 10.0 years±4.2) were examined preoperatively. We hypothesized that a high dosage of PD medication or current use of dopamine agonists affect cognitive functioning and psychiatric wellbeing. Methods We performed two subgroup analyses with low versus high levodopa-equivalent Dosage (LED) medication and without versus with dopaminagonistic medication. Results The neuropsychological testing revealed significant differences in the verbal learn- and memory-test (VLMT) during the learning passage (U=36.500, Z=− 2.475, p=0.012) and in the subtest of the semantic fluency of Regensburg verbal fluency test (RWT) (t(25)=− 2.066, p=0.049) with better results for patients without dopaminagonistic medication. Pearson correlation analyses of LED in correlation with the clinical and cognitive dependent variables showed a significant higher PANSS total score in patients with higher LED medication (r=0.491, p=0.009). In addition, lower LED treatment was associated with significant higher scores in the impulsivity perseverance subtest (r=− 0.509, p=0.008). Discussion In conclusion, we found lower LEDs to be correlated with a better perseverance in the impulsivity test and additional treatment with a dopamine agonist influenced some verbal learning tasks and the PANSS total score in patients with advanced PD. This should be considered prior to DBS surgery. [ABSTRACT FROM AUTHOR]

Background: KBG syndrome is a monogenic disorder caused by heterozygous pathogenic variants in ANKRD11. A recent single-case study suggested that the clinical spectrum of KBG syndrome, classically defined by distinctive craniofacial traits and developmental delay, may include movement disorders. Case report: We report a 24-year-old patient harboring a pathogenic de novo ANKRD11 frameshift variant. The phenotype was dominated by a progressive tremor-dominant movement disorder, characterized by rest, intention and postural tremor of the hands, voice tremor, head and tongue tremor, increased muscle tone and signs of ataxia. Additionally, the patient had a history of mild developmental delay and epilepsy. Discussion: Adding to the recently described individual, our present patient highlights the relevance of movement disorders as a clinically relevant manifestation of KBG syndrome. ANKRD11 pathogenic variants should be considered in the differential diagnosis of combined tremor syndromes. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells,ADcortex, or synthetic peptide) inhibited LTP, and this was prevented by the selectiveNR2Binhibitors ifenprodil andRo25-6981. Soluble Aβ enhanced NR2B-mediatedNMDAcurrents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor DL-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, andLTPimpairment was prevented by inhibitors of p38MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity. [ABSTRACT FROM AUTHOR]

A correction to the article "Identification of a unique TGF-beta-dependent molecular and functional signature in microglia," by Oleg Butovsky et al. that was published in a previous issue of the journal is presented.

Amyloid self-assembly of α-synuclein (αSyn) is linked to the pathogenesis of Parkinson's disease (PD). Type 2 diabetes (T2D) has recently emerged as a risk factor for PD. Cross-interactions between their amyloidogenic proteins may act as molecular links. In fact, fibrils of islet amyloid polypeptide (IAPP) (T2D) can cross-seed αSyn amyloidogenesis and αSyn and IAPP colocalize in PD brains. Inhibition of both self- and IAPP-cross-seeded αSyn amyloidogenesis could thus interfere with PD pathogenesis. Here we show that macrocyclic peptides, designed to mimic IAPP self-/cross-interaction sites and previously found to inhibit amyloidogenesis of IAPP and/or Alzheimer's disease (AD) amyloid-β peptide Aβ40(42), are nanomolar inhibitors of both self- and IAPP-cross-seeded amyloid self-assembly of αSyn. Anti-amyloid function is mediated by nanomolar affinity interactions with αSyn via three αSyn regions which are identified as key sites of both αSyn self-assembly and its cross-interactions with IAPP. We also show that the peptides block Aβ42-mediated cross-seeding of αSyn as well. Based on their broad spectrum anti-amyloid function and additional drug-like features, these peptides are leads for multifunctional anti-amyloid drugs in PD, T2D, AD, and their comorbidities, while the identified αSyn key segments are valuable targets for novel, multi-site targeting amyloid inhibitors in PD and related synucleinopathies., (© 2025 The Author(s). Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objective: Peaks in the beta band of local field potentials (LFPs) may serve as a biological feedback signal for closed-loop deep brain stimulation (DBS) in Parkinson's disease (PD). However, the specific frequency of such peaks and their response to DBS and to different types of movement remains uncertain. In the present study, the authors examined the abundance of discernible peaks in the beta band and the effect of different types of movement and DBS on these peaks., Methods: Subthalamic nucleus LFPs were analyzed from 38 patients with PD in a frequency range between 10 and 35 Hz, as well as the impact of movement (gait, hand movements) and electrical stimulation on these peaks. The position of the electrode segments from which LFPs were recorded was computed., Results: The authors found a bimodal distribution of peaks in the beta band with discernible high- (27 Hz) and low-frequency (15 Hz) peaks. Movement of either hand had no significant effect on these peaks, whereas walking significantly reduced high-frequency beta peaks but not the peaks in the low beta band. Stimulation caused an amplitude-dependent suppression of both peaks., Conclusions: DBS suppresses LFP beta peaks of different frequencies, whereas beta suppression caused by movement is dependent on the type of movement and frequency of the peak. These results will support the investigation of distinct LFP spectra for the application of closed-loop DBS.