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Visual and visual processing deficits are implicated in freezing, falling, and cognitive impairments in Parkinson's disease (PD). In particular, contrast sensitivity deficits are common and may be related to cognitive impairment in PD. While dopaminergic deficits play a role in PD-related visual dysfunction, brain cholinergic systems also modulate many aspects of visual processing. The aim of this study was to explore regional cerebral cholinergic terminal density correlates of contrast sensitivity in PD. Ninety-one PD subjects underwent contrast sensitivity testing, motor testing, cognitive testing, and brain MRI and [ 18 F]-fluoroethoxybenzovesamicol [ 18 F]-FEOBV PET imaging. Whole brain false discovery error-corrected (p < 0.05) correlations revealed significant associations between VAChT deficits in pericentral, limbic, and visual processing regions and contrast sensitivity performance, independent of disease duration and dopaminergic medication doses. These results suggest that brain cholinergic deficits correlate with contrast sensitivity deficits in PD. Additionally, decreased Rabin contrast sensitivity scores were associated with lower total scores in the Parkinson's Disease Cognitive Rating Scale. These findings suggest that diminished cognitive performance correlated with contrast sensitivity partly reflects underlying vulnerabilities of brain cholinergic systems., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prabesh Kanel reports financial support was provided by National Institutes of Health. Nicolaas Bohnen reports a relationship with National Institutes of Health that includes: funding grants. Roger Albin reports a relationship with Parkinson's Disease Foundation that includes: funding grants. No other relationships to declare If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose: The purpose of this systematic review was to examine safety-related outcomes for patients with tracheostomy after flexible endoscopic evaluation of swallowing (FEES) to assess and manage their swallow, when compared to other non-instrumental swallow assessments such as clinical swallowing examination (CSE) and/or a modified Evans blue dye test (MEBDT)., Method: Three databases were searched for articles referring to safety-related outcome data for adults with a tracheostomy, who underwent FEES and CSE and/or MEBDT. Articles were screened using predefined inclusion/exclusion criteria., Result: The search strategy identified 2097 articles; following abstract and full-text screening, seven were included for review. The summary of evidence found low to very low certainty that FEES was associated with improved outcomes across swallow safety, physiological outcomes, tracheostomy cannulation duration, functional outcomes, and detection of upper airway pathologies., Conclusion: This systematic review demonstrated low to very low certainty evidence from seven heterogeneous studies with low sample sizes that incorporating FEES may be associated with improved safety-related outcomes. There is less evidence supporting the accuracy of other swallow assessments conducted at the point of care (i.e. CSE and MEBDT). Future research requires studies with larger sample sizes and routine reporting of safety-related outcomes with use of FEES.

In Huntington's disease (HD), striatal projection neurons (SPNs) degenerate during midlife; the core biological question involves how the disease-causing DNA repeat (CAG) n in the huntingtin (HTT) gene leads to neurodegeneration after decades of biological latency. We developed a single-cell method for measuring this repeat's length alongside genome-wide RNA expression. We found that the HTT CAG repeat expands somatically from 40-45 to 100-500+ CAGs in SPNs. Somatic expansion from 40 to 150 CAGs had no apparent cell-autonomous effect, but SPNs with 150-500+ CAGs lost positive and then negative features of neuronal identity, de-repressed senescence/apoptosis genes, and were lost. Our results suggest that somatic repeat expansion beyond 150 CAGs causes SPNs to degenerate quickly and asynchronously. We conclude that in HD, at any one time, most neurons have an innocuous but unstable HTT gene and that HD pathogenesis is a DNA process for almost all of a neuron's life., Competing Interests: Declaration of interests Patent applications filed by the Broad Institute of MIT and Harvard related to this work include subsets of the authors as inventors. S.A.M. has received compensation for scientific advice to Roche, Pfizer, Biogen, Vertex, and LoQus23 Therapeutics., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Atomic coordinate models are important in the interpretation of 3D maps produced with cryoEM and sub-tomogram averaging in cryoET, or more generically, 3D electron microscopy (3DEM). In addition to visual inspection of such maps and models, quantitative metrics convey the reliability of the atomic coordinates, in particular how well the model is supported by the experimentally determined 3DEM map. A recently introduced metric, Q-score, was shown to correlate well with the reported resolution of the map for well-fitted models. Here we present new statistical analyses of Q-scores based on its application to ∼10,000 maps and models archived in EMDB and PDB. Further we introduce two new metrics based on Q-score: Q-relative-all and Q-relative-resolution to compare a map and model to all entries in the EMDB and those with similar resolution respectively. We also explore through illustrative examples of proteins, nucleic acids, and small molecules how Q-scores can indicate whether the atomic coordinates are well-fitted to 3DEM maps and whether some parts of a map may be poorly resolved due to factors such as molecular flexibility, radiation damage, and/or conformational heterogeneity. Lastly, we show examples of how Q-scores can effectively be converted to atomic B-factors. These analyses provide a basis for how Q-scores can be interpreted effectively to evaluate 3DEM maps and atomic coordinate models prior to publication and archiving., Synopsis: Q-scores are calculated each atom in models fitted to 3DEM (3D electron microscopy) maps. They measure how well the model fits the map, and also reflect the quality of the map as they correlate to resolution. Here we develop a statistical model for Q-scores applied to many maps and models in the EMDB (Electron Microscopy Database) and PDB (Protein Data Bank) respectively, and show how it can be used to assess the reliability of entire models as well as their subcomponents.

The detection of low-molecular-weight biomarkers is essential for diagnosing and managing various diseases, including neurodegenerative conditions such as Alzheimer's disease. A biomarker's low molecular weight is a challenge for label-free optical modalities, as the phase change they detect is directly proportional to the mass bound on the sensor's surface. To address this challenge, we used a resonant Young's slit interferometer geometry and implemented several innovations, such as phase noise matching and optimisation of the fringe spacing, to maximise the signal-to-noise ratio. As a result, we achieved a limit of detection of 2.9 × 10 -6 refractive index units (RIU). We validated our sensor's low molecular weight capability by demonstrating the detection of Aβ-42, a 4.5 kDa peptide indicative of Alzheimer's disease, and reached the clinically relevant pg/mL regime. This system builds on the guided mode resonance modality we previously showed to be compatible with handheld operation using low-cost components. We expect this development will have far-reaching applications beyond Aβ-42 and become a workhorse tool for the label-free detection of low-molecular-weight biomarkers across a range of disease types.

Cerebral venous sinus thrombosis is an uncommon sequela of low intracranial pressure, which may result from a lumbar puncture (LP). We describe a case of a patient in their 40s presenting with 48 hours of persistent headache following intrathecal administration of nusinersen for spinal muscular atrophy (SMA) type 3. There were no focal neurological signs or symptoms apart from baseline symmetrical proximal limb weakness attributed to SMA. Initial investigations revealed radiological evidence of an acute cerebral venous sinus thrombus (CVST). The patient was promptly started on anticoagulation. Partial recanalisation was seen as soon as 48 hours after commencement of anticoagulation, with almost full resolution of the thrombus at follow-up in 2 months. Awareness of CVST as a potential complication of intrathecal therapies and diagnostic LP allows for early identification, management and prevention of serious neurological consequences., Competing Interests: Competing interests: KK received grants from Medical Research Future Fund and Paul Ainsworth Family Foundation. KKumar received honoraria for delivering lectures at the International Parkinson and Movement Disorder Society., (© BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background/objective: Raloxifene, a selective estrogen receptor modulator (SERM), may improve symptoms and cognition in schizophrenia spectrum disorders (SSD). Studies have shown inconsistent efficacy, especially in men with SSD. We assessed whether single nucleotide polymorphisms (SNPs) on genes involved in the pharmacodynamics (ESR1 and COMT) and pharmacokinetics (UGT1A8) of raloxifene can explain the heterogeneous treatment response to raloxifene augmentation in patients with SSD., Methods: We used a subsample of the participants of a previously published randomized controlled trial (RCT) on the effects of 12-week raloxifene augmentation on symptom severity in SSD. The subsample consisted of 83 participants (28 % female), of which 40 were randomized to receive raloxifene 120 mg/day and 43 to placebo. Saliva samples for DNA-analysis were collected at baseline, symptom severity was measured with the Positive and Negative Syndrome Scale (PANSS). Participants were genotyped for two SNPs on ESR1, one on UGT1A8, and four on COMT using the Agena MassArray system. Linear mixed-effect models were used to assess the effect of treatment-by-genotype as the primary analysis and treatment-by-genotype-by-sex as a secondary analysis., Results: We found interactions of treatment-by-genotype for ESR1 rs2234693 (χ 2 = 6.32, p < 0.05), and COMT rs4818 (χ 2 = 4.08, p < 0.05), indicating that for these polymorphisms, the effect of raloxifene differed per genotype. Pairwise comparisons revealed a beneficial effect of raloxifene on general symptom severity in participants with ESR1 rs2234693 TT genotype but not CT and CC genotypes (LSM -3.19 [95 % CI -6.38-0.00]; p = 0.050). Furthermore, mean change in positive symptom severity was greater with raloxifene in participants with COMT rs4818 CG genotype but not CC genotype compared to placebo (LSM -2.18 [-3.93 to -0.43]; p = 0.016). Secondary sex-specific analysis indicated an interaction effect of treatment-by-genotype-by-sex for COMT rs737865 on total (χ 2 = 10.90, p < 0.05) and negative symptom severity (χ 2 = 11.99, p < 0.05). In men, genotype CT but not TT was associated with beneficial effects of raloxifene on total symptoms (LSM -5.46 [-10.43 to -0.48]; p = 0.032), whereas in women, genotype TT but not CT was associated with a beneficial effect of raloxifene on negative symptoms (LSM -7.80 [-12.70 to -2.89]; p = 0.005)., Conclusion: Our results suggest that treatment response to raloxifene may depend on ESR1 and COMT gene variants, while UGT1A8 SNP variation did not affect treatment response. These findings provide evidence that genetic variants may explain the heterogeneous response to raloxifene augmentation in SSD, suggesting that raloxifene may have beneficial effects in genetic subgroups of SSD patients. Our findings warrant further research on the pharmacogenetic effects of raloxifene in SSD., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bodyl A. Brand reports financial support was provided by Stichting De Cock - Hadders Foundation. Bodyl A. Brand reports financial support was provided by University Medical Centre Groningen. Iris Sommer reports financial support was provided by Netherlands Organisation for Health Research and Development. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population. Posture and gait control does not happen automatically, as previously believed, but rather requires continuous involvement of central nervous mechanisms. To effectively exert control over the body, the brain must integrate multiple streams of sensory information, including visual, vestibular, and somatosensory signals. The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work. Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults. Insufficient emphasis, however, has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance. In the present work, we review the contributions of somatosensory, visual, and vestibular modalities, along with their multisensory intersections to gait and balance in older adults and patients with Parkinson's disease. We also review evidence of vestibular contributions to multisensory temporal binding windows, previously shown to be highly pertinent to fall risk in older adults. Lastly, we relate multisensory vestibular mechanisms to potential neural substrates, both at the level of neurobiology (concerning positron emission tomography imaging) and at the level of electrophysiology (concerning electroencephalography). We hope that this integrative review, drawing influence across multiple subdisciplines of neuroscience, paves the way for novel research directions and therapeutic neuromodulatory approaches, to improve the lives of older adults and patients with neurodegenerative diseases., (Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.)

PSD95 is an abundant scaffolding protein that assembles multiprotein complexes controlling synaptic physiology and behavior. Confocal microscopy has previously shown that PSD95 is enriched in the postsynaptic terminals of excitatory synapses and two-dimensional (2D) super-resolution microscopy further revealed that it forms nanoclusters. In this study, we utilized three-dimensional (3D) super-resolution microscopy to examine the nanoarchitecture of PSD95 in the mouse brain, characterizing the spatial arrangement of over 8 million molecules. While we were able to identify molecular arrangements that have been previously reported, imaging in 3D allowed us to classify these with higher accuracy. Furthermore, 3D super-resolution microscopy enabled the quantification of protein levels, revealing that an abundance of PSD95 molecules existed outside of synapses as a diffuse population of supercomplexes, containing multiple copies of PSD95. Further analysis of the supercomplexes containing two units identified two populations: one that had PSD95 molecules separated by 39 ± 2 nm, and a second with a separation of 94 ± 27 nm. The finding that there exists supercomplexes containing two PSD95 units outside of the synapse suggests that supercomplexes containing multiple protein copies assemble outside the synapse and then integrate into the synapse to form a supramolecular nanocluster architecture.