Longitudinal Network Changes and Phenoconversion Risk in Isolated REM Sleep Behavior Disorder.

Isolated rapid eye movement sleep behavior disorder (iRBD) is a prodromal syndrome for Parkinson's disease (PD) and related α-synucleinopathies. We conducted a longitudinal imaging study of network changes in iRBD and their relationship to phenoconversion. Expression levels for the PD-related motor and cognitive networks (PDRP and PDCP) were measured at baseline, 2 and 4 years, along with dopamine transporter (DAT) binding. PDRP and PDCP expression increased over time, with higher values in the former network. While abnormal functional connections were identified initially within the PDRP, others bridging the two networks appeared later. A model based on the rates of PDRP progression and putamen dopamine loss predicted phenoconversion within 1.2 years in individuals with iRBD. In aggregate, the data suggest that maladaptive reorganization of brain networks takes place in iRBD years before phenoconversion. Network expression and DAT binding measures can be used together to assess phenoconversion risk in these individuals.

Deep brain stimulation of the subthalamic nucleus for Parkinson's disease: A network imaging marker of the treatment response.

Subthalamic nucleus deep brain stimulation (STN-DBS) alleviates motor symptoms of Parkinson's disease (PD), thereby improving quality of life. However, quantitative brain markers to evaluate DBS responses and select suitable patients for surgery are lacking. Here, we used metabolic brain imaging to identify a reproducible STN-DBS network for which individual expression levels increased with stimulation in proportion to motor benefit. Of note, measurements of network expression from metabolic and BOLD imaging obtained preoperatively predicted motor outcomes determined after DBS surgery. Based on these findings, we computed network expression in 175 PD patients, with time from diagnosis ranging from 0 to 21 years, and used the resulting data to predict the outcome of a potential STN-DBS procedure. While minimal benefit was predicted for patients with early disease, the proportion of potential responders increased after 4 years. Clinically meaningful improvement with stimulation was predicted in 18.9 - 27.3% of patients depending on disease duration.

MLT-11 is a transient apical extracellular matrix component required for cuticle patterning and function.

Apical extracellular matrices (aECMs) are associated with all epithelia and form a protective layer against biotic and abiotic threats in the environment. Despite their importance, we lack a deep understanding of their structure and dynamics in development and disease. C. elegans molting offers a powerful entry point to understanding developmentally programmed aECM remodeling. A transient matrix is formed in embryos and at the end of each larval stage, presumably to pattern the new cuticle. Focusing on targets of NHR-23, a key transcription factor which drives molting, we identified the Kunitz family protease inhibitor gene mlt-11 as an NHR-23 target. We identified NHR-23-binding sites that are necessary and sufficient for epithelial expression. mlt-11 is necessary to pattern every layer of the adult cuticle, suggesting a broad patterning role prior to the formation of the mature cuticle. MLT-11::mNeonGreen::3xFLAG transiently localized to the aECM in the cuticle and embryo. It was also detected in lining openings to the exterior (vulva, rectum, mouth). Reduction of mlt-11 function disrupted the barrier function of the cuticle. Tissue-specific RNAi suggested mlt-11 activity is primarily necessary in seam cells and we observed alae and seam cell fusion defects upon mlt-11 inactivation. Predicted mlt-11 null mutations caused fully penetrant embryonic lethality and elongation defects suggesting mlt-11 also plays an important role in patterning the embryonic sheath. Finally, we found that mlt-11 inactivation suppressed the blistered cuticle phenotype of mutants of bli-4 mutants, a subtilisin protease gene but did not affect BLI-4::sfGFP expression. These data could suggest that MLT-11 may be necessary to assure proper levels of BLI-4 activity.

Manifestation and associated factors of systemic and local allergy among patients with allergic fungal rhinosinusitis: An observational study.

Allergic fungal rhinosinusitis (AFRS) is a subtype of chronic rhinosinusitis, characterized by excessive immune responses to environmental molds or fungi. The diagnosis and classification of AFRS into systemic and local types remain clinically challenging due to overlapping characteristics. This study investigated the prevalence of AFRS, its manifestation and associated factors in systemic and local AFRS. A total of 200 patients diagnosed with fungal rhinosinusitis underwent both skin provocation tests (SPT) and nasal provocation tests (NPT) to confirm AFRS and classify systemic and local types. Patients were considered to have AFRS if either the SPT or NPT was positive. Among these, patients with systemic AFRS were those who had a SPT positive. Local AFRS was when patients had a negative SPT and a positive NPT. Medical history, serum total IgE level, nasal endoscopy examinations, and CT scans were also recorded. Most patients were female (65.8%), with a mean age of 55.6 years (SD = 14.4). Based on the SPT and NPT results, 31% of patients (n = 62) were diagnosed with AFRS. Among these, 54.8% (n = 34) had systemic AFRS, while 45.2% (n = 28) had local AFRS. Patients with AFRS exhibited significantly higher levels of total IgE, eosinophils, and more pronounced signs and symptoms compared to those without AFRS. However, no statistically significant differences were observed between patients with systemic AFRS and those with local AFRS. AFRS was prevalent in our study. Among patients with AFRS, both systemic AFRS and local AFRS were also prevalent. While allergic indicators and clinical presentations can aid in AFRS diagnosis, minimal distinctions were observed between systemic and local AFRS. A comprehensive assessment incorporating both local and systemic allergic responses through provocation tests, such as a combination of skin and nasal tests, is imperative for optimizing AFRS diagnosis and management.

Testusterol, a new sterol of the sponge species Xestospongia testudinaria from Phu Quoc island, Vietnam.

A new sterol, named testusterol (1), and five known compounds (2-6) were isolated from the n-hexane and dichloromethane extracts of the sponge species Xestospongia testudinaria. Their chemical structures were elucidated based on extensive spectroscopic analyses (1D, 2D NMR, ESIMS and HRESIMS) and comparison with published data. The results of in vitro test (utilizing brine shrimp Artemia salina LEACH) showed that three extracts ethanol, dichloromethane, and ethanol/water, significantly inhibited Artemia salina with LC50 values ranging from 6.09 to 16.83 µg/mL. Remarkably, the new compound 1 exhibited potent inhibition against both Gram-positive (Staphyloccocus aureus, Bacillus subtilis, Lactobacillus fermentum), and Gram-negative (Escherichia coli, Salmonella enterica, Pseudomonas aeruginosa) bacteria species, with IC50 values of less than 12.0 nM and MIC ranging from 4.70 to 75.23 nM as determined by the broth-microdilution assay.

Orbital infarction syndrome following mechanical thrombectomy in internal carotid artery occlusion: a case report.

BACKGROUND: Orbital ischemic syndrome is a rare entity. The clinical signs typically demonstrate acute loss of visual acuity, chemosis, proptosis, ptosis, and total ophthalmoparesis. We report a case of a man who suffered an acute internal carotid artery occlusion and developed orbital ischemic syndrome after a mechanical thrombectomy. CASE PRESENTATION: A 57-year-old Vietnamese (Kinh ethnicity) man was brought to the emergency room with complaints of a speech disturbance, facial palsy, and severe weakness of the left arm and leg, which had started 4 hours earlier, after waking up. The National Institutes of Health Stroke Scale 12 (NIHSS 12) revealed the neurological score at admission. A head computed tomography scan showed no intracranial bleeding and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 8 on the right brain. Computed tomography angiography showed an occlusion of the right internal carotid artery. After that, a mechanical thrombectomy was performed, and the internal carotid artery was completely reperfused. After 10 hours, he experienced orbital pain, proptosis, ptosis, chemosis, and ophthalmoplegia of the right orbit. He also had acute loss of visual acuity, and fundoscopic examination revealed papilledema, no retinal hemorrhage, and no bruit in orbital auscultation. Intraocular pressure in the right eye was measured at 50.5 mmHg. Computed tomography angiography showed no carotid-cavernous fistula, but slight enlargement of the right medial and lateral rectus muscles. He was treated with steroids and hyperosmolar agents and recovered 7 days later, but had persistent loss of visual acuity in the right eye. CONCLUSION: Orbital ischemic syndrome is a rare complication after mechanical thrombectomy treatment in acute ischemic stroke that can lead to loss of visual acuity.

A spontaneous TIR1 loss-of-function allele in C. elegans.

The auxin-inducible degron (AID) system is a widely-used system for conditional protein depletion. During the course of an experiment, we depleted the nuclear hormone receptor transcription factor NHR-23 to study molting, and we recovered a spontaneous suppressor allele that bypassed the L1 larval arrest caused by NHR-23 depletion. These mutants also failed to deplete a BFP::AID reporter in the strain background, suggesting a broader defect in the AID system. These animals carried an in-frame 18 base pair insertion that produced a 6 amino acid repeat in TIR1. The larval arrest in these animals could be restored by expressing a wild-type TIR1 transgene from an extrachromosomal array. Sister siblings that lost this array developed normally on auxin. Together, these experiments indicate that the TIR1 mutation was causing the loss of developmental arrest in the nhr-23::AID strain. This result highlights the importance of setting up a robust secondary screen to detect such mutants if performing forward genetic screens in conjunction with the AID system.

The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer's Disease.

Psychosis that occurs over the course of Alzheimer's disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human-mutant-tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [11C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment-on both tau and behavior-that may have relevance to AD and other tauopathies.

A Network Imaging Biomarker of X-Linked Dystonia-Parkinsonism.

OBJECTIVE: The purpose of this study was to characterize a metabolic brain network associated with X-linked dystonia-parkinsonism (XDP). METHODS: Thirty right-handed Filipino men with XDP (age = 44.4 ± 8.5 years) and 30 XDP-causing mutation negative healthy men from the same population (age = 37.4 ± 10.5 years) underwent [18 F]-fluorodeoxyglucose positron emission tomography. Scans were analyzed using spatial covariance mapping to identify a significant XDP-related metabolic pattern (XDPRP). Patients were rated clinically at the time of imaging according to the XDP-Movement Disorder Society of the Philippines (MDSP) scale. RESULTS: We identified a significant XDPRP topography from 15 randomly selected subjects with XDP and 15 control subjects. This pattern was characterized by bilateral metabolic reductions in caudate/putamen, frontal operculum, and cingulate cortex, with relative increases in the bilateral somatosensory cortex and cerebellar vermis. Age-corrected expression of XDPRP was significantly elevated (p < 0.0001) in XDP compared to controls in the derivation set and in the remaining 15 patients (testing set). We validated the XDPRP topography by identifying a similar pattern in the original testing set (r = 0.90, p < 0.0001; voxel-wise correlation between both patterns). Significant correlations between XDPRP expression and clinical ratings for parkinsonism-but not dystonia-were observed in both XDP groups. Further network analysis revealed abnormalities of information transfer through the XDPRP space, with loss of normal connectivity and gain of abnormal functional connections linking network nodes with outside brain regions. INTERPRETATION: XDP is associated with a characteristic metabolic network associated with abnormal functional connectivity among the basal ganglia, thalamus, motor regions, and cerebellum. Clinical signs may relate to faulty information transfer through the network to outside brain regions. ANN NEUROL 2023;94:684-695.

NHR-23 activity is necessary for C. elegans developmental progression and apical extracellular matrix structure and function.

Nematode molting is a remarkable process where animals must repeatedly build a new apical extracellular matrix (aECM) beneath a previously built aECM that is subsequently shed. The nuclear hormone receptor NHR-23 (also known as NR1F1) is an important regulator of C. elegans molting. NHR-23 expression oscillates in the epidermal epithelium, and soma-specific NHR-23 depletion causes severe developmental delay and death. Tissue-specific RNAi suggests that nhr-23 acts primarily in seam and hypodermal cells. NHR-23 coordinates the expression of factors involved in molting, lipid transport/metabolism and remodeling of the aECM. NHR-23 depletion causes dampened expression of a nas-37 promoter reporter and a loss of reporter oscillation. The cuticle collagen ROL-6 and zona pellucida protein NOAH-1 display aberrant annular localization and severe disorganization over the seam cells after NHR-23 depletion, while the expression of the adult-specific cuticle collagen BLI-1 is diminished and frequently found in patches. Consistent with these localization defects, the cuticle barrier is severely compromised when NHR-23 is depleted. Together, this work provides insight into how NHR-23 acts in the seam and hypodermal cells to coordinate aECM regeneration during development.

Experimental considerations for study of C. elegans lysosomal proteins.

Lysosomes are an important organelle required for the degradation of a range of cellular components. Lysosome function is critical for development and homeostasis as dysfunction can lead to inherited genetic disorders, cancer, and neurodegenerative and metabolic diseases. The acidic and protease-rich environment of lysosomes poses experimental challenges. Many fluorescent proteins are quenched or degraded, while specific red fluorescent proteins can be cleaved from translational fusion partners and accumulate. While studying MLT-11, a Caenorhabditis elegans molting factor that localizes to lysosomes and the cuticle, we sought to optimize several experimental parameters. We found that, in contrast to mNeonGreen fusions, mScarlet fusions to MLT-11 missed cuticular and rectal epithelial localization. Rapid sample lysis and denaturation were critical for preventing MLT-11 fragmentation while preparing lysates for western blots. Using a model lysosomal substrate (NUC-1), we found that rigid polyproline linkers and truncated mCherry constructs do not prevent cleavage of mCherry from NUC-1. We provide evidence that extended localization in lysosomal environments prevents the detection of FLAG epitopes in western blots. Finally, we optimize an acid-tolerant green fluorescent protein (Gamillus) for use in C. elegans. These experiments provide important experimental considerations and new reagents for the study of C. elegans lysosomal proteins.

Disordered network structure and function in dystonia: pathological connectivity vs. adaptive responses.

Primary dystonia is thought to emerge through abnormal functional relationships between basal ganglia and cerebellar motor circuits. These interactions may differ across disease subtypes and provide a novel biomarker for diagnosis and treatment. Using a network mapping algorithm based on resting-state functional MRI (rs-fMRI), a method that is readily implemented on conventional MRI scanners, we identified similar disease topographies in hereditary dystonia associated with the DYT1 or DYT6 mutations and in sporadic patients lacking these mutations. Both networks were characterized by contributions from the basal ganglia, cerebellum, thalamus, sensorimotor areas, as well as cortical association regions. Expression levels for the two networks were elevated in hereditary and sporadic dystonia, and in non-manifesting carriers of dystonia mutations. Nonetheless, the distribution of abnormal functional connections differed across groups, as did metrics of network organization and efficiency in key modules. Despite these differences, network expression correlated with dystonia motor ratings, significantly improving the accuracy of predictions based on thalamocortical tract integrity obtained with diffusion tensor MRI (DTI). Thus, in addition to providing unique information regarding the anatomy of abnormal brain circuits, rs-fMRI functional networks may provide a widely accessible method to help in the objective evaluation of new treatments for this disorder.

Adaptive and pathological connectivity responses in Parkinson's disease brain networks.

Functional imaging has been used extensively to identify and validate disease-specific networks as biomarkers in neurodegenerative disorders. It is not known, however, whether the connectivity patterns in these networks differ with disease progression compared to the beneficial adaptations that may also occur over time. To distinguish the 2 responses, we focused on assortativity, the tendency for network connections to link nodes with similar properties. High assortativity is associated with unstable, inefficient flow through the network. Low assortativity, by contrast, involves more diverse connections that are also more robust and efficient. We found that in Parkinson's disease (PD), network assortativity increased over time. Assoratitivty was high in clinically aggressive genetic variants but was low for genes associated with slow progression. Dopaminergic treatment increased assortativity despite improving motor symptoms, but subthalamic gene therapy, which remodels PD networks, reduced this measure compared to sham surgery. Stereotyped changes in connectivity patterns underlie disease progression and treatment responses in PD networks.

Sporadic Creutzfeldt-Jakob disease is associated with reorganization of metabolic connectivity in a pathological brain network.

BACKGROUND AND PURPOSE: Although sporadic Creutzfeldt-Jakob disease (sCJD) is a rare cause of dementia, it is critical to understand its functional networks as the prion protein spread throughout the brain may share similar mechanisms with other more common neurodegenerative disorders. In this study, the metabolic brain network associated with sCJD was investigated and its internal network organization was explored. METHODS: We explored 2-[18 F]fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) brain scans of 29 sCJD patients, 56 normal controls (NCs) and 46 other dementia patients from two independent centers. sCJD-related pattern (CJDRP) was identified in a cohort of 16 pathologically proven sCJD patients and 16 age-matched NCs using scaled subprofile modeling/principal component analysis and was prospectively validated in an independent cohort of 13 sCJD patients and 20 NCs. The pattern's specificity was tested on other dementia patients and its clinical relevance by clinical correlations. The pattern's internal organization was further studied using graph theory methods. RESULTS: The CJDRP was characterized by relative hypometabolism in the bilateral caudate, thalami, middle and superior frontal gyri, parietal lobe and posterior cingulum in association with relative hypermetabolism in the hippocampi, parahippocampal gyri and cerebellum. The pattern's expression significantly discriminated sCJD from NCs and other dementia patients (p < 0.005; receiver operating characteristic analysis CJD vs. NCs area under the curve [AUC] 0.90-0.96, sCJD vs. Alzheimer's disease AUC 0.78, sCJD vs. behavioral variant of frontotemporal dementia AUC 0.84). The pattern's expression significantly correlated with cognitive, functional decline and disease duration. The metabolic connectivity analysis revealed inefficient information transfer with specific network reorganization. CONCLUSIONS: The CJDRP is a robust metabolic biomarker of sCJD. Due to its excellent clinical correlations it has the potential to monitor disease in emerging disease-modifying trials.

Disease specific and nonspecific metabolic brain networks in behavioral variant of frontotemporal dementia.

Behavioral variant of frontotemporal dementia (bvFTD) is common among young-onset dementia patients. While bvFTD-specific multivariate metabolic brain pattern (bFDRP) has been identified previously, little is known about its temporal evolution, internal structure, effect of atrophy, and its relationship with nonspecific resting-state networks such as default mode network (DMN). In this multicenter study, we explored FDG-PET brain scans of 111 bvFTD, 26 Alzheimer's disease, 16 Creutzfeldt-Jakob's disease, 24 semantic variant primary progressive aphasia (PPA), 18 nonfluent variant PPA and 77 healthy control subjects (HC) from Slovenia, USA, and Germany. bFDRP was identified in a cohort of 20 bvFTD patients and age-matched HC using scaled subprofile model/principle component analysis and validated in three independent cohorts. It was characterized by hypometabolism in frontal cortex, insula, anterior/middle cingulate, caudate, thalamus, and temporal poles. Its expression in bvFTD patients was significantly higher compared to HC and other dementia syndromes (p < .0004), correlated with cognitive decline (p = .0001), and increased over time in longitudinal cohort (p = .0007). Analysis of internal network organization by graph-theory methods revealed prominent network disruption in bvFTD patients. We have further found a specific atrophy-related pattern grossly corresponding to bFDRP; however, its contribution to the metabolic pattern was minimal. Finally, despite the overlap between bFDRP and FDG-PET-derived DMN, we demonstrated a predominant role of the specific bFDRP. Taken together, we validated the bFDRP network as a diagnostic/prognostic biomarker specific for bvFTD, provided a unique insight into its highly reproducible internal structure, and proved that bFDRP is unaffected by structural atrophy and independent of normal resting state networks loss.

A dual tracer [11C]PBR28 and [18F]FDG microPET evaluation of neuroinflammation and brain energy metabolism in murine endotoxemia.

BACKGROUND: Brain metabolic alterations and neuroinflammation have been reported in several peripheral inflammatory conditions and present significant potential for targeting with new diagnostic approaches and treatments. However, non-invasive evaluation of these alterations remains a challenge. METHODS: Here, we studied the utility of a micro positron emission tomography (microPET) dual tracer ([11C]PBR28 - for microglial activation and [18F]FDG for energy metabolism) approach to assess brain dysfunction, including neuroinflammation in murine endotoxemia. MicroPET imaging data were subjected to advanced conjunction and individual analyses, followed by post-hoc analysis. RESULTS: There were significant increases in [11C]PBR28 and [18F]FDG uptake in the hippocampus of C57BL/6 J mice 6 h following LPS (2 mg/kg) intraperitoneal (i.p.) administration compared with saline administration. These results confirmed previous postmortem observations. In addition, patterns of significant simultaneous activation were demonstrated in the hippocampus, the thalamus, and the hypothalamus in parallel with other tracer-specific and region-specific alterations. These changes were observed in the presence of robust systemic inflammatory responses manifested by significantly increased serum cytokine levels. CONCLUSIONS: Together, these findings demonstrate the applicability of [11C]PBR28 - [18F]FDG dual tracer microPET imaging for assessing neuroinflammation and brain metabolic alterations in conditions "classically" characterized by peripheral inflammatory and metabolic pathogenesis.

Automated differential diagnosis of dementia syndromes using FDG PET and machine learning.

Background: Metabolic brain imaging with 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) is a supportive diagnostic and differential diagnostic tool for neurodegenerative dementias. In the clinic, scans are usually visually interpreted. However, computer-aided approaches can improve diagnostic accuracy. We aimed to build two machine learning classifiers, based on two sets of FDG PET-derived features, for differential diagnosis of common dementia syndromes. Methods: We analyzed FDG PET scans from three dementia cohorts [63 dementia due to Alzheimer's disease (AD), 79 dementia with Lewy bodies (DLB) and 23 frontotemporal dementia (FTD)], and 41 normal controls (NCs). Patients' clinical diagnosis at follow-up (25 ± 20 months after scanning) or cerebrospinal fluid biomarkers for Alzheimer's disease was considered a gold standard. FDG PET scans were first visually evaluated. Scans were pre-processed, and two sets of features extracted: (1) the expressions of previously identified metabolic brain patterns, and (2) the mean uptake value in 95 regions of interest (ROIs). Two multi-class support vector machine (SVM) classifiers were tested and their diagnostic performance assessed and compared to visual reading. Class-specific regional feature importance was assessed with Shapley Additive Explanations. Results: Pattern- and ROI-based classifier achieved higher overall accuracy than expert readers (78% and 80% respectively, vs. 71%). Both SVM classifiers performed similarly to one another and to expert readers in AD (F1 = 0.74, 0.78, and 0.78) and DLB (F1 = 0.81, 0.81, and 0.78). SVM classifiers outperformed expert readers in FTD (F1 = 0.87, 0.83, and 0.63), but not in NC (F1 = 0.71, 0.75, and 0.92). Visualization of the SVM model showed bilateral temporal cortices and cerebellum to be the most important features for AD; occipital cortices, hippocampi and parahippocampi, amygdala, and middle temporal lobes for DLB; bilateral frontal cortices, middle and anterior cingulum for FTD; and bilateral angular gyri, pons, and vermis for NC. Conclusion: Multi-class SVM classifiers based on the expression of characteristic metabolic brain patterns or ROI glucose uptake, performed better than experts in the differential diagnosis of common dementias using FDG PET scans. Experts performed better in the recognition of normal scans and a combined approach may yield optimal results in the clinical setting.

Stereotyped Relationship Between Motor and Cognitive Metabolic Networks in Parkinson's Disease.

BACKGROUND: Idiopathic Parkinson's disease (iPD) is associated with two distinct brain networks, PD-related pattern (PDRP) and PD-related cognitive pattern (PDCP), which correlate respectively with motor and cognitive symptoms. The relationship between the two networks in individual patients is unclear. OBJECTIVE: To determine whether a consistent relationship exists between these networks, we measured the difference between PDRP and PDCP expression, termed delta, on an individual basis in independent populations of patients with iPD (n = 356), patients with idiopathic REM sleep behavioral disorder (iRBD) (n = 21), patients with genotypic PD (gPD) carrying GBA1 variants (n = 12) or the LRRK2-G2019S mutation (n = 14), patients with atypical parkinsonian syndromes (n = 238), and healthy control subjects (n = 95) from the United States, Slovenia, India, and South Korea. METHODS: We used [18 F]-fluorodeoxyglucose positron emission tomography and resting-state fMRI to quantify delta and to compare the measure across samples; changes in delta over time were likewise assessed in longitudinal patient samples. Lastly, we evaluated delta in prodromal individuals with iRBD and subjects with gPD. RESULTS: Delta was abnormally elevated in each of the four iPD samples (P < 0.05), as well as in the at-risk iRBD group (P < 0.05), with increasing values over time (P < 0.001). PDRP predominance was also present in gPD, with higher values in patients with GBA1 variants compared with the less aggressive LRRK2-G2019S mutation (P = 0.005). This trend was not observed in patients with atypical parkinsonian syndromes, who were accurately discriminated from iPD based on PDRP expression and delta (area under the curve = 0.85; P < 0.0001). CONCLUSIONS: PDRP predominance, quantified by delta, assays the spread of dysfunction from motor to cognitive networks in patients with PD. Delta may therefore aid in differential diagnosis and in tracking disease progression in individual patients. © 2022 International Parkinson and Movement Disorder Society.

NHR-23 and SPE-44 regulate distinct sets of genes during Caenorhabditis elegans spermatogenesis.

Spermatogenesis is the process through which mature male gametes are formed and is necessary for the transmission of genetic information. While much work has established how sperm fate is promoted and maintained, less is known about how the sperm morphogenesis program is executed. We previously identified a novel role for the nuclear hormone receptor transcription factor, NHR-23, in promoting Caenorhabditis elegans spermatogenesis. The depletion of NHR-23 along with SPE-44, another transcription factor that promotes spermatogenesis, caused additive phenotypes. Through RNA-seq, we determined that NHR-23 and SPE-44 regulate distinct sets of genes. The depletion of both NHR-23 and SPE-44 produced yet another set of differentially regulated genes. NHR-23-regulated genes are enriched in phosphatases, consistent with the switch from genome quiescence to post-translational regulation in spermatids. In the parasitic nematode Ascaris suum, MFP1 and MFP2 control the polymerization of Major Sperm Protein, the molecule that drives sperm motility and serves as a signal to promote ovulation. NHR-23 and SPE-44 regulate several MFP2 paralogs, and NHR-23 depletion from the male germline caused defective localization of MSD/MFP1 and NSPH-2/MFP2. Although NHR-23 and SPE-44 do not transcriptionally regulate the casein kinase gene spe-6, a key regulator of sperm development, SPE-6 protein is lost following NHR-23+SPE-44 depletion. Together, these experiments provide the first mechanistic insight into how NHR-23 promotes spermatogenesis and an entry point to understanding the synthetic genetic interaction between nhr-23 and spe-44.

The mIAA7 degron improves auxin-mediated degradation in Caenorhabditiselegans.

Auxin-inducible degradation is a powerful tool for the targeted degradation of proteins with spatiotemporal control. One limitation of the auxin-inducible degradation system is that not all proteins are degraded efficiently. Here, we demonstrate that an alternative degron sequence, termed mIAA7, improves the efficiency of degradation in Caenorhabditiselegans, as previously reported in human cells. We tested the depletion of a series of proteins with various subcellular localizations in different tissue types and found that the use of the mIAA7 degron resulted in faster depletion kinetics for 5 out of 6 proteins tested. The exception was the nuclear protein HIS-72, which was depleted with similar efficiency as with the conventional AID* degron sequence. The mIAA7 degron also increased the leaky degradation for 2 of the tested proteins. To overcome this problem, we combined the mIAA7 degron with the C. elegans AID2 system, which resulted in complete protein depletion without detectable leaky degradation. Finally, we show that the degradation of ERM-1, a highly stable protein that is challenging to deplete, could be improved further by using multiple mIAA7 degrons. Taken together, the mIAA7 degron further increases the power and applicability of the auxin-inducible degradation system. To facilitate the generation of mIAA7-tagged proteins using CRISPR/Cas9 genome engineering, we generated a toolkit of plasmids for the generation of dsDNA repair templates by PCR.