Parkinson's Disease (PD) is a complex, chronic, progressive, and debilitating neurodegenerative disorder. Neither a cure nor effective long-term therapy exist and the lack of knowledge of the molecular mechanisms responsible for PD development is a major impediment to therapeutic advances. The protein \u03b1Synuclein is a central component in PD pathogenesis yet its cellular targets and mechanism of toxicity remains unknown. Mitochondrial dysfunction is also a common theme in PD patients and this review explores the strong possibility that \u03b1Synuclein and mitochondrial dysfunction have an inter-relationship responsible for underlying the disease pathology. Amplifying cycles of mitochondrial dysfunction and \u03b1Synuclein toxicity can be envisaged, with either being the disease-initiating factor yet acting together during disease progression. Multiple potential mechanisms exist in which mitochondrial dysfunction and \u03b1Synuclein could interact to exacerbate their neurodegenerative properties. Candidates discussed within this review include autophagy, mitophagy, mitochondrial dynamics/fusion/fission, oxidative stress and reactive oxygen species, endoplasmic reticulum stress, calcium, nitrosative stress and \u03b1Synuclein Oligomerization.
\n \n\n \n \nAdaptive optics (AO) was shown to improve microscope imaging quality. However, issues like prolonged sample exposures are often associated with sensorless AO implementation. We present an AO solution with embedded intelligence to achieve outstanding performance.
\n \n\n \n \nIn a competitive game involving an animal and an opponent, the outcome is contingent on the choices of both players. To succeed, the animal must continually adapt to competitive pressure, or else risk being exploited and lose out on rewards. In this study, we demonstrate that head-fixed male mice can be trained to play the iterative competitive game \"matching pennies\" against a virtual computer opponent. We find that the animals' performance is well described by a hybrid computational model that includes Q-learning and choice kernels. Comparing between matching pennies and a non-competitive two-armed bandit task, we show that the tasks encourage animals to operate at different regimes of reinforcement learning. To understand the involvement of neuromodulatory mechanisms, we measure fluctuations in pupil size and use multiple linear regression to relate the trial-by-trial transient pupil responses to decision-related variables. The analysis reveals that pupil responses are modulated by observable variables, including choice and outcome, as well as latent variables for value updating, but not action selection. Collectively, these results establish a paradigm for studying competitive decision-making in head-fixed mice and provide insights into the role of arousal-linked neuromodulation in the decision process.
\n \n\n \n \nThe ability to use temporal relationships between cross-modal cues facilitates perception and behavior. Previously we observed that temporally correlated changes in the size of a visual stimulus and the intensity in an auditory stimulus influenced the ability of listeners to perform an auditory selective attention task (Maddox, Atilgan, Bizley, & Lee, 2015). Participants detected timbral changes in a target sound while ignoring those in a simultaneously presented masker. When the visual stimulus was temporally coherent with the target sound, performance was significantly better than when the visual stimulus was temporally coherent with the masker, despite the visual stimulus conveying no task-relevant information. Here, we trained observers to detect audiovisual temporal coherence and asked whether this changed the way in which they were able to exploit visual information in the auditory selective attention task. We observed that after training, participants were able to benefit from temporal coherence between the visual stimulus and both the target and masker streams, relative to the condition in which the visual stimulus was coherent with neither sound. However, we did not observe such changes in a second group that were trained to discriminate modulation rate differences between temporally coherent audiovisual streams, although they did show an improvement in their overall performance. A control group did not change their performance between pretest and post-test and did not change how they exploited visual information. These results provide insights into how crossmodal experience may optimize multisensory integration.
\n \n\n \n \nAging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we confirmed their robustness across measurement modalities using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, \u03bc a g e = 26.9 \u00b1 11.2 years , N = 36). Then, using a multiscale conductance-based neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. As such, the approach facilitates the connection between macroscopic brain activity and cellular-level mechanisms.
\n \n\n \n \nCyclic nucleotide hydrolyzing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g., cAMP and cGMP) signaling. Here, we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF), and the potential of PDEs as therapeutic targets for AF. PDE1-5 and 8 are present and functional in AMs. PDE2-4 are important regulators of AM contraction but their role beyond atrial contractility is unclear. The role of PDE1,5 and 8 in healthy AMs is unknown but of interest because of their roles in ventricular myocytes. We propose that PDE2-5 and PDE8 are potential targets to prevent the triggering of AF considering their effects on Ca2+ handling and/or electrical activity. PDE1-5 are possible targets to treat patients with paroxysmal or persistent AF caused by pulmonary vein automaticity. PDE8B2 is a possible target for patients with persistent AF due to its altered expression. Research should aim to identify the presence, localization, and function of specific PDE isoforms in human atria. Ultimately, the paucity of PDE isoform-specific small molecule modulators and the difficulty of delivering PDE-targeted medications or therapies to particular cell types limit current research and its application.
\n \n\n \n \nBackground: \u03b1-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF \u03b1-synuclein SAA kinetic measures in Parkinson's disease. Methods: In this longitudinal cohort study, we collected and analysed data from participants with Parkinson's disease, progressive supranuclear palsy, and healthy controls enrolled in three cohorts: the UK parkinsonism cohort, the Parkinson's Progression Markers Initiative (PPMI) international observational study, and the T\u00fcbingen Parkinson's disease cohort. Baseline CSF \u03b1-synuclein SAA data and longitudinal clinical data were collected between Jan 1, 2005, and Nov 1, 2023. The following seeding kinetic measures were calculated from the \u03b1-synuclein SAA curve for each SAA-positive sample: time to threshold (TTT) for a positive SAA result; maximum Thioflavin T fluorescence during the reaction time (MaxThT); and area under the fluorescence curve during the reaction time (AUC). We compared seeding kinetic measures between sporadic Parkinson's disease and progressive supranuclear palsy, and between sporadic Parkinson's disease and monogenic Parkinson's disease. We used time-to-event analyses to assess the ability of \u03b1-synuclein SAA kinetic measures to predict an unfavourable outcome in Parkinson's disease, adjusting for sex, age, and disease duration at SAA testing. Findings: We analysed data from 1631 participants: newly generated data from the UK parkinsonism cohort (Parkinson's disease, n=66; progressive supranuclear palsy, n=52; controls, n=9) and previously generated data from the PPMI (Parkinson's disease, n=1036; controls, n=239) and T\u00fcbingen (Parkinson's disease, n=229) cohorts. In the UK parkinsonism cohort, \u03b1-synuclein SAA was positive in 63 (96%) of 66 Parkinson's disease samples and eight (15%) of 52 progressive supranuclear palsy samples, with six (75%) of eight positive progressive supranuclear palsy samples having distinct low and slow seeding kinetics (low MaxThT and high TTT) as a marker of Lewy body co-pathology. TTT was faster in GBA1-associated Parkinson's disease compared with sporadic Parkinson's disease in both the PPMI (p=0\u00b704) and T\u00fcbingen (p=0\u00b701) cohorts. In the PPMI cohort, after excluding individuals who had an unfavourable outcome at the time of baseline SAA testing, an unfavourable outcome was observed in 593 (73%) of 810 participants with \u03b1-synuclein SAA-positive Parkinson's disease during a median follow-up period of 4\u00b75 years (IQR 2\u20139). TTT at baseline predicted only cognitive decline (Montreal Cognitive Assessment score \u226421) as a component of an unfavourable outcome in Parkinson's disease in both the PPMI (n=824, hazard ratio [HR] 2\u00b736 [95% CI 1\u00b760\u20133\u00b746], p=0\u00b7001) and T\u00fcbingen (n=135, 2\u00b717 [1\u00b707\u20134\u00b741], p=0\u00b703) cohorts. TTT also predicted cognitive decline in a subgroup of participants with Parkinson's disease in the PPMI cohort who were Alzheimer's disease biomarker negative (n=355, HR 1\u00b780 [95% CI 1\u00b703\u20133\u00b718], p=0\u00b704). Interpretation: Assessing \u03b1-synuclein SAA kinetic measures might aid in the diagnostic differentiation of Parkinson's disease from progressive supranuclear palsy with Lewy body co-pathology. Furthermore, faster seeding kinetics are found in GBA1-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology. Funding: Medical Research Council, PSP Association. Copyright: \u00a9 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.
\n \n\n \n \nAlzheimer's disease is a multifaceted neurodegenerative disorder, with diverse underlying pathophysiological processes extending beyond amyloid-\u03b2 and tau accumulation. The heterogeneity of Alzheimer's disease necessitates the identification of a broad array of biomarkers that capture the diverse mechanisms contributing to disease onset and progression. In this study, we systematically compiled and analysed cerebrospinal fluid proteomics data from omics studies utilizing mass spectrometry, Olink, or SomaScan platforms. Systematic literature searches for each platform revealed a total of 264 studies. From this, a set of 18 studies were selected based on sample size, number of markers analysed, and open data availability. We found a total of 1,448 differentially expressed proteins between Alzheimer's disease and amyloid negative controls across these datasets, with 635 being found in more than one study. A 'top' set of 61 differentially expressed proteins were consistently reported in at least six studies. Clustering and functional enrichment analysis of the top differentially expressed proteins indicated involvement in metabolic regulation, glutathione metabolism and proteins of the 14-3-3 family, reflecting importance of reactive oxygen species (ROS) response. Synaptic signalling processes were found to generally be downregulated. We further integrated the top differentially expressed proteins with results from a study on familial Alzheimer's disease cerebrospinal fluid to assess at which stage of disease progression these proteins change, highlighting markers shared between sporadic and familial Alzheimer's disease datasets. Lastly, we examine the overlap of the top differentially expressed proteins between cerebrospinal fluid and brain tissue using a publicly available database. This analysis provides a comprehensive overview of the Alzheimer's disease cerebrospinal fluid proteomic landscape, indicating changes in key pathways and cellular processes associated with Alzheimer's disease pathology. By integrating data from different platforms, we highlight reproducible protein changes that may serve as promising candidates for further biomarker research aimed at improving patient stratification, tracking disease progression, and assessing therapeutic interventions.
\n \n\n \n \nThe relationship between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease and neurodegenerative effects is not fully understood. This study investigates neurodegeneration patterns across CSF Alzheimer's disease biomarker groups, the association of brain volumes with CSF amyloid and tau status and sex differences in these relationships in a clinical neurology sample. MRI and CSF Alzheimer's disease biomarkers data were analysed in 306 patients of the Mass General Brigham healthcare system aged 50+ (mean age = 68.4 \u00b1 8.8 years; 43.1% female), who had lumbar punctures within 1 year of clinical MRI scans. We first analysed neurodegeneration patterns across four biomarker groups: 60 controls (A-T-&CU; amyloid negative, tau negative, cognitively unimpaired), 25 A+T- (amyloid positive, tau negative), 121 A+T+ (amyloid positive, tau positive) and 100 other dementia (A-T-&CI; amyloid negative, tau negative, cognitively impaired). Second, we examined volumetric associations with amyloid (amyloid positive, tau negative versus control) and tau in the presence of amyloid (amyloid positive, tau positive versus amyloid positive, tau negative) across 52 brain areas. Third, we examined sex differences in these relationships. Finally, we validated core analyses across three independent datasets-NACC (National Alzheimer's Coordinating Center), ADNI (Alzheimer's Disease Neuroimaging Initiative) and EPAD (European Prevention of Alzheimer's Dementia)-totalling 3137 participants, and performed meta-analyses to obtain more robust estimates. We observed distinct neurodegeneration patterns across biomarker groups, with disrupted connectivity (brain volume covariance networks) in amyloid positive and other dementia groups, while amyloid and tau negative, cognitively unimpaired controls exhibited the most connected network. Amyloid was associated with subcortical, cerebellar and brainstem atrophy, with consistent association observations in the thalamus and amygdala across all four datasets. Tau in the presence of amyloid demonstrated general brain shrinkage through enlargement of extracerebral CSF, alongside unexpected ventricle shrinkages. Sex-based analyses revealed that A+T+ (amyloid positive, tau positive) had lower sex differences in connectivity patterns compared with other groups. Sex differences were also noted in amyloid-related ventricular volume changes. This study reveals how amyloid and tau affect brain connectivity and volume across sex and CSF biomarker groups, emphasizing global brain changes and sex differences. By leveraging automated pipelines and advanced MRI and biomarker analyses, we extracted meaningful and replicable findings from heterogeneous clinical samples from real-world data. The meta-analyses across four datasets enhance the generalizability of our results.
\n \n\n \n \nMRI of hyperpolarized (HP) [1-13C]pyruvate allows in vivo assessment of metabolism and has translated into human studies across diseases at 15 centers worldwide. To determine consensus on best practice for multi-center studies for development of clinical applications. This paper presents the results of a two-round formal consensus building exercise carried out by experts with HP [1-13C]pyruvate human study experience. Twenty-nine participants from 13 sites brought together expertise in pharmacy methods, MR physics, translational imaging, and data analysis with the goal of providing recommendations and best practice statements on conduct of multi-center human studies of HP [1-13C]pyruvate MRI. Overall, the group reached consensus on approximately two-thirds of 246 statements in the questionnaire, covering HP 13C-pyruvate preparation; MRI system setup, calibration, and phantoms; acquisition and reconstruction; and data analysis and quantification. Consensus was present across categories. Examples include: (i) Different HP pyruvate preparation methods could be used in human studies, but the same release criteria have to be followed; (ii) site qualification and quality assurance must be performed with phantoms and the same field strength must be used, but the rest of the system setup and calibration methods could be determined by individual sites; (iii) the same pulse sequence and reconstruction methods were preferable, but the exact choice should be governed by the anatomical target; (iv) normalized metabolite area-under-curve values and metabolite area under curve were the preferred metabolism metrics. The consensus proces revealed that HP[1-13C] pyruvate MRI as a technology has progressed sufficiently to plan multi-center studies. The work confirmed areas of consensus for multi-center study conduct and identified where further research is required to ascertain best practice.
\n \n\n \n \nCongenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene-environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.
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