Biological characteristics of individuals with REM sleep behavior disorder: A multicenter prospective longitudinal cohort.

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder with heterogeneous subtypes, including cerebellar (MSA-C) and parkinsonian (MSA-P). Dual-tracer PET imaging using 18F FDG and dopamine transporter (DAT) scans provides pathophysiologic insight but poses limitations in cost and resources. Dual-phase 18F FP-CIT PET offers an alternative by capturing perfusion-like and DAT signals in a single scan. To evaluate the diagnostic and phenotypic utility of dual-phase 18F FP-CIT PET in early-stage MSA. We retrospectively studied 39 patients with clinically established MSA who underwent dual-phase 18F FP-CIT PET within 2 years of symptom onset. Early-phase (0-10min) images assessed perfusion-like uptake, and delayed-phase (90min) images measured DAT uptake. PET patterns were visually classified as normal, presynaptic, or trans-synaptic based on DAT and putamen perfusion in the early phase, and compared across clinical subtypes, putaminal 3T MRI findings (DWI and SWI), and clinical severity. In addition, regional SUVR was compared across MSA subtypes and clinical severity. Striatal PET patterns differed by subtype (P<0.001): Trans-synaptic pattern was predominant in MSA-P, while normal and presynaptic patterns were more common in MSA-C. MRI abnormalities in the putamen were present in all patients with abnormal putamen on early PET, but also in 58% of patients with normal PET. Early- and delayed-phase striatal SUVRs correlated inversely with UPDRS part III scores (P<0.001). Asymmetry of cerebellar perfusion on early PET was significantly elevated in MSA-C compared with MSA-P (P<0.001). Levodopa responsiveness was most frequent in patients with trans-synaptic PET patterns. Dual-phase 18F FP-CIT PET provides a single-session approach for capturing both perfusion and DAT status, enabling subtype classification and disease severity assessment in early MSA. Putaminal abnormality on early FP-CIT PET might be less sensitive than MRI, and asymmetric cerebellar perfusion could be a useful marker for differential diagnosis of ataxia.

Seasonal changes, particularly increased daylight exposure, are known to influence dopamine transporter (DAT) availability, potentially affecting mood disorders such as major depressive disorder (MDD). This study aimed to evaluate seasonal variations in the striatum using ¹²³I-FP-CIT SPECT in patients with MDD, and examine associations with specific psychopathological symptoms. In this retrospective study, DAT SPECT scans from 85 patients with MDD were analyzed according to the season of imaging-fall-winter (FW) or spring-summer (SS). Psychometric assessments included the Hamilton Depression Rating Scale (HAMD), Hamilton Anxiety Rating Scale (HAMA), Snaith-Hamilton Pleasure Scale (SHAPS), and Depression Retardation Rating Scale (DRRS). No overall differences in DAT availability were observed between FW and SS. However, anhedonia levels were higher in FW (p = 0.050). Patients with severe depression (HAMD ≥ 25) showed lower DAT availability in the left putamen, especially during SS (p = 0.014). Patients with marked psychomotor retardation (DRRS ≥ 18) exhibited reduced DAT availability in the left putamen (p = 0.002), with further reductions across all striatal regions during SS. Patients with suicidal ideation showed decreased DAT in the right (p = 0.029) and left putamen (p = 0.015). A negative correlation was found between DRRS scores and left putamen DAT availability (p = 0.034). Reduced DAT availability is associated with key depressive symptoms, notably psychomotor retardation and suicidal ideation. Seasonal effects, especially in the SS period, may exacerbate dopaminergic dysregulation. These findings support integrating seasonal and neurobiological factors in the assessment and management of severe MDD.

Synaptic zinc (Zn2+) modulates dopamine and glutamate neurotransmission by binding to the dopamine transporter and glutamate receptors. Among other neurotransmitters, dopamine and glutamate critically regulate physiological processes and behaviors relevant to substance use disorders (SUDs) and addiction. In addition, Zn2+ interacts with inhibitory neurotransmitter systems, including GABA and glycine receptors, further influencing the excitatory-inhibitory balance within circuits relevant to addiction. Nevertheless, the specific involvement of synaptic Zn2+ in such processes is unknown. We propose that synaptic Zn2+ serves as an environmentally derived factor that can influence the vulnerability to and development of SUDs and addiction via its interaction with proteins that regulate dopamine and glutamate neurotransmission in addiction-relevant brain circuits.

The continual emergence of novel synthetic cathinones poses significant public health concerns due to their unpredictable pharmacological profiles and potential for abuse. Among these, 4-F-3-Me-α-PVP-a newly identified analogue of α-PVP-has recently surfaced on the illicit drug market, yet its biological effects remain uncharacterized. To provide the first comprehensive pharmacological evaluation of 4-F-3-Me-α-PVP. In vitro transporter inhibition was assessed using HEK293 cells expressing human dopamine (DA), norepinephrine, and serotonin transporter (DAT, NET, or SERT). In male rodents, locomotor activity was measured after i.p. (mice) or s.c. (rats) administration. In vivo microdialysis in rats quantified extracellular DA in the nucleus accumbens. Rewarding and reinforcing effects were evaluated using conditioned place preference (CPP) in mice and intravenous self-administration (IVSA) in rats under fixed-ratio and progressive-ratio schedules. In vitro assays revealed that 4-F-3-Me-α-PVP acts as a potent DAT and NET inhibitor, with additional, though weaker, activity at SERT. In vivo, 4-F-3-Me-α-PVP significantly increased locomotor activity in male rodents (10 and 30 mg/kg in mice; 3 mg/kg in rats). Importantly, 4-F-3-Me-α-PVP also increased extracellular DA levels in the rat nucleus accumbens (3 mg/kg, s.c.), pointing to its potential for abuse. Behavioral assays further demonstrated rewarding and reinforcing effects in rodents, with significant CPP in mice at all doses tested and dose-dependent IVSA in rats observed under both fixed-ratio and progressive-ratio schedules. Collectively, these findings indicate that 4-F-3-Me-α-PVP possesses substantial psychostimulant and abuse-related effects in rodents, underscoring the need for regulatory vigilance and continued investigation into emerging synthetic cathinones.

To provide a comprehensive description of disease progression in synuclein seeding assay (SAA) positive sporadic Parkinson Disease participants, using Neuronal Synuclein Disease integrated biological and functional impairment staging framework. We analyzed 5-year longitudinal data from 345 participants recruited in the Parkinson's Progression Markers Initiative with the diagnosis of early (less than 2 years of clinical diagnosis at baseline and untreated) sporadic Parkinson's Disease, who were synuclein seeding assay positive. We assessed 5-year progression in a spectrum of clinical and biomarker measures. We used Cox proportional hazards models to assess the association between baseline stage and time to survival, postural instability, cognitive impairment, and other meaningful milestones. Biomarker analysis included dopamine transporter binding measures, CSF-SAA, amyloid-beta, phosphorylated tau and total tau, as well as serum urate, and neurofilament light chain. At baseline there was clear separation of participants by Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). Participants in stage 4 at baseline had a significantly higher rate of reaching disability, postural instability, cognitive decline, and the autonomic dysfunction milestones. There was a stage-dependent increase in dopamine deficit at baseline. There was no difference in fluid biomarkers between the stages at baseline and longitudinally. This study highlights the heterogeneity in the early Parkinson's Disease population defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functional impairment defined inclusion criteria for clinical trials. Biological drivers of stage heterogeneity must be further explored.

Resting-state functional connectivity (rsFC) studies have revealed altered regional homogeneity (ReHo) and degree centrality (DC) in individuals with anorexia nervosa (AN) compared to healthy controls (HC), but the underlying mechanisms remain unclear. Here we explored the spatial alignment with neurotransmitter receptor and transporter densities (i.e., "chemoarchitecture", based on "reference" PET studies) as a potential explanatory factor. We investigated rsFC alterations in acutely underweight patients with AN (n = 87) and age-matched HC (n = 87) cross-sectionally at admission and then again after successful weight-restoration treatment. Global ReHo and DC maps were associated with the spatial distribution of neurotransmitter receptors, transporters and/or metabolic glucose uptake. First, the correlation between rsFC alterations in AN and chemoarchitecture was evaluated at the group/timepoint-level. Second, individual-level correlations of neuroreceptor maps with rsFC alterations were calculated to test for possible associations with early weight restoration. The acute state of AN was characterized by higher DC (but not ReHo) in brain regions with a higher cortical density of vesicular acetylcholine transporter (VAChT), dopamine transporter (DAT) and serotonin transporter (SERT). Conversely, weight restoration was associated with normalization of DC, especially in areas with a higher DAT density. Importantly, individual-level spatial correlations between VAChT, DAT and SERT densities and DC alterations at admission significantly predicted early weight gain over first 90 days of treatment. These results suggest that neurochemical context may underlie functional brain alterations, providing a preliminary step toward identifying biological risk signatures. Replication with individualized PET data will be crucial to validate their potential utility for treatment stratification and personalization.

In vitro inhibition of monoamine transport by amphetamine-like pre-workout supplement ingredients.

BackgroundHigh intensity interval training (HIIT) involves vigorous intensity exercise bouts interspersed with low intensity bouts. Despite growing interest, the optimal dosage and clinical adaptability of HIIT in Parkinson's disease (PD) remain unclear. This scoping review synthesized the literature on systemic adaptations underlying HIIT in PD and developed a clinical framework while considering chronotropic incompetence, orthostatic hypotension, and disease progression.MethodsThree databases were searched for studies that incorporated HIIT interventions in PD. The Template for Intervention Description and Replication checklist was used to characterize the quality of intervention reporting.ResultsA total of 285 studies were screened, of which 10 studies were included. HIIT was administered 2-3 times/week for 30-60 min/session over 8-12 weeks. Seven studies used moderate-volume HIIT and three studies used high-volume HIIT protocols. The quality of intervention reporting was fair to good. HIIT improved cardiorespiratory fitness, motor severity, and functional mobility in PD, however, improvements were comparable to moderate intensity continuous training (MICT). HIIT may facilitate neuroplasticity by increasing brain-derived neurotrophic factor levels and dopamine transporter uptake. We recommend that HIIT programs for individuals with autonomic dysfunction use individualized heart rate targets, and perceived exertion for determining exercise intensity, and incorporate longer duration programs (>12 weeks).ConclusionHIIT is a well-tolerated intervention that may improve cardiorespiratory fitness, disease severity, and certain neurobiological markers in mild-moderate PD, with benefits similar to MICT. Larger trials comparing different HIIT volumes are needed to identify optimal exercise volume to inform individualized exercise prescription.

Noise-induced hearing loss (NIHL) constitutes a growing global health burden, yet effective pharmacological interventions remain elusive. Current therapeutic development is severely constrained by two critical bottlenecks: the lack of rationally identified molecular targets and the absence of dosage forms tailored to the physiological barriers of the inner ear. Addressing these limitations, we propose an integrated precision therapy strategy. First, to overcome the unpredictability of drug selection, we employed a transcriptome-guided network pharmacology approach, which rationally identified GBR-12935 - a dopamine transporter (DAT) inhibitor - as a potent candidate capable of reversing the pathological gene signature of noise injury. However, as a central nervous system (CNS)-active agent, the clinical translation of GBR-12935 is hindered by its rapid clearance from the middle ear and the risk of off-target CNS effects due to the ear's anatomical proximity to the brain. To resolve this delivery dilemma, we engineered an injectable, in situ forming hydrogel specifically designed for sustained intratympanic administration. This biomaterial platform effectively prolongs drug residence time in the round window niche while minimizing systemic leakage, thereby maximizing local cochlear bioavailability and mitigating potential neurotoxicity. In a mouse model of severe acoustic trauma (110 dB SPL), the hydrogel-mediated delivery significantly outperformed free drug administration. Quantitative immunofluorescence revealed that this localized intervention not only prevented the loss of cochlear ribbon synapses but, crucially, inhibited the pathological enlargement and aggregation of surviving ribbons, maintaining their morphological stability against excitotoxic edema. This structural preservation translated into robust functional recovery, evidenced by attenuated Auditory Brainstem Response (ABR) threshold shifts (15 dB rescue at 24 kHz, P < 0.01 vs. noise). Collectively, our study establishes a closed-loop paradigm combining computational prediction with rational biomaterial design, providing a potent and safe non-steroidal auditory protection strategy for addressing cochlear synaptopathy.

Neurofilament light chain protein exposure contributes to protein aggregation, microgliosis, astrogliosis and neuroinflammation via p38/MK2/NF-κB/CREB1/Nrf2/HO-1 signalling leading to Parkinson's disease.

N-acetyl-l-leucine (NALL), a derivative of the branched-chain amino acid leucine, has shown therapeutic potential for neurodegenerative diseases, including in prodromal stages of Parkinson's disease (PD). However, the mechanism of its protective effects has been largely unknown. Using human induced pluripotent stem cell-derived dopaminergic neurons from patients carrying GBA1, LRRK2, or VPS35 mutations, as well as from sporadic PD cases, we found that NALL treatment markedly reduced Ser129 phosphorylated α-synuclein (pS129-syn). Discovery-based proteomic analysis revealed that NALL treatment upregulated lysosomal, mitochondrial, and synaptic proteins without inducing cytotoxicity. The reduction of pS129-syn was dependent on serine protease HTRA1, which was robustly induced by NALL. Moreover, NALL increased the expression of wild-type parkin in mutant dopaminergic neurons, leading to increased glycosylated dopamine transporter, elevated synaptic membrane-associated synaptojanin-1, and accelerated synaptic vesicle endocytosis, suggesting improved synaptic function. Furthermore, in LRRK2R1441C knockin mice, NALL administration decreased pS129-syn, elevated parkin levels, and ameliorated dopamine-dependent motor learning deficits. These findings highlight the therapeutic potential of NALL for PD by its protective effects on α-synuclein pathology and synaptic function in vulnerable dopaminergic neurons.

Automated phenotyping of rodent behavior in the Cylinder Exploration Test using machine learning.

6PPD and its metabolites induce locomotor dysfunction in zebrafish through dopaminergic disruption with brain accumulation.

The dopamine transporter is essential for dopamine homeostasis maintenance. Therefore, single amino acid changes in its gene can be sufficient to induce disease, such as dopamine transporter deficiency syndrome (DTDS). DTDS-associated variants may lead to DAT protein misfolding, retention in the endoplasmic reticulum, and reduced DAT surface expression. In turn, proper dopaminergic regulation is lost. Current treatments for DTDS are largely ineffective, necessitating better options. We developed a novel mouse model of DTDS harboring the A313V knock-in DAT variant, a proxy for the human A314V variant. The A313V mice are hyperactive, have decreased striatal tissue content of dopamine and increases in its metabolite HVA, and impaired dopamine uptake. FDA approved compounds alpha-methyl-para-tyrosine and amphetamine ameliorate the observed hyperactivity. Moreover, alpha-methyl-para-tyrosine may be a disease-modifying treatment by addressing the hyperdopaminergic tone underlying this hyperactivity. Noribogaine, a pharmacological chaperone for DAT, is unable to rescue DAT expression. These findings demonstrate that the A313V knock-in DAT variant mice recapitulate several defining phenotypes seen in patients with DTDS, and provide evidence for two novel treatments for the disease.

In patients with a clinically uncertain parkinsonian syndrome (CUPS), the novel MRI sequence susceptibility map-weighted imaging (SMWI) may be a diagnostic alternative to dopamine transporter (DAT) imaging with the advantage of greater accessibility. This study aimed to assess the diagnostic accuracy of software analyzing SMWI in differentiating dopaminergic neurodegenerative from non-neurodegenerative parkinsonism in CUPS patients. A diagnostic accuracy study was conducted, including patients presenting with CUPS who underwent DAT SPECT imaging. The index test was the result of AI-driven software (Heuron IPD version 1.0.1.9, Heuron Co., Ltd, Seoul, Korea), designed to classify the nigrosome-1 on SMWI acquired at 3T as normal or abnormal. The reference test was the final clinical diagnosis, incorporating findings from DAT SPECT imaging. A total of 176 patients were included in the final analysis; 82 received a final diagnosis of dopaminergic neurodegenerative parkinsonism, and 94 with non-neurodegenerative parkinsonism. The AI-driven SMWI software demonstrated a diagnostic accuracy of 86.9% distinguishing neurodegenerative from non-neurodegenerative parkinsonism, with sensitivity of 92.7% and specificity of 81.9%. This study is the first to evaluate the diagnostic accuracy of software analyzing SMWI in patients presenting with CUPS. The findings highlight the promising diagnostic utility of SMWI in clinical practice for CUPS patients. Future studies are warranted as SMWI might be able to reduce the need for DAT-imaging in the future by offering a more accessible and cost-effective alternative.

Teneurin-4 knockdown disrupts dopamine dynamics and attenuates methamphetamine-induced behaviors.

Addictive drugs, notably opioid drugs, have significant societal implications, yet the cellular and molecular mechanisms underpinning rewarding effects remain largely elusive. Noncoding transcripts, including the microRNAs (miRNAs), are pivotal regulators of diverse biological functions. Notably, the microRNAs miR-132 and miR-212, arising from a shared noncoding transcript, have links to several psychiatric conditions, including cocaine addiction. However, their contribution to opiate rewarding remains speculative. In this study, we discovered that repeated morphine administration decreases the expression of miR-132/212 in the ventral tegmental area (VTA) and induces a concurrent upregulation of the dopamine transporter (DAT). Using a luciferase reporter assay, we found that the DAT coding gene, SLC6A3 mRNA 3'UTR, is a direct target of miR-132/212. These miRNAs negatively regulated both mRNA expression and protein levels of DAT in vitro. This was corroborated by in vivo studies which revealed that behavioral experiments using a morphine-induced conditioned place preference (CPP) paradigm showed that suppression of miR-132/212 in the VTA facilitated the formation of morphine-induced CPP. Conversely, overexpression of miR-132 attenuated morphine preference in male and female adult rats, as well as adolescents. In sum, our findings uncover a regulatory mechanism wherein miR-132/212 modulates morphine induced reward behavior by fine-tuning DAT expression at the posttranscriptional level, providing a potential therapeutic target of rewarding effects.

Muguka, a high-cathinone cultivar of Catha edulis consumed widely in East Africa, presents a growing health risk when co-administered with diazepam. This theoretical study represents one of the first integrated computational investigations focusing on the interaction between Muguka derived cathinone and diazepam, combining molecular docking, ADMET profiling, and physiologically based pharmacokinetic (PBPK) modeling. The in silico analysis identified overlapping CYP2D6 and CYP2C19 pathways, supporting potential mutual metabolic inhibition. The predictive PBPK models suggest moderate CYP2D6/CYP2C19-mediated drug-drug interactions based on a simulated oral dose of 100 mg cathinone and 30 mg diazepam in a human adult population. Co-administration is predicted to increase cathinone systemic exposure by 1.5-fold (AUC ↑50%) and reduce clearance by 33%, while diazepam exposure is projected to rise by 1.3-fold (AUC ↑30%) with 24% clearance reduction. Molecular docking revealed high-affinity binding of cathinone (-6.4 kcal/mol) at the dopamine transporter (DAT) and diazepam (-6.8 kcal/mol) at the γ-aminobutyric acid-A (GABA-A) receptor, indicating distinct yet potentially complementary CNS targets. Collectively, these computational predictions suggest that co-use may prolong CNS exposure and theoretically enhance neurotoxicity, and dependence risk. This integrated computational framework provides a hypothetical mechanistic evidence for stimulant-benzodiazepine interactions and underscores the need for clinical monitoring and validation.

The α-synuclein (α-syn) seed amplification assay (SAA) has shown promising results for diagnosing dementia with Lewy bodies (DLB) using CSF samples. A barrier to implementing α-syn SAA clinically is the use of different protocols for the assay. It is unknown how different protocols perform in comparison with each other. We compared the performance of α-syn SAA across 4 laboratories using CSF samples of patients with DLB. This was a retrospective cross-sectional study that included data from 4 different European laboratories. We included probable patients with DLB with a positive dopamine transporter (DaT)-SCAN and known amyloid-β status who had mild-to-moderate dementia, along with age-matched and sex-matched controls. The α-syn SAA was run across 4 laboratories using different protocols varying α-syn concentration and plate reader settings. CSF samples were provided by a fifth independent laboratory, which also performed statistical and result analyses. We included 20 patients with DLB (mean age 67 ± 6 years, 60% male) and 10 controls (mean age 67 ± 2 years, 70% male). Neuropathologic confirmation was available for 2 patients with DLB. On average, the 4 laboratories achieved 78.8% sensitivity (minimum 55%, maximum 100%), 77.5% specificity (minimum 60%, maximum 100%), and 78.5% accuracy (minimum 57%, maximum 100%) for discriminating DLB from controls, but our findings show that diagnostic performance of SAA varied across laboratories: Lab A achieved 100% sensitivity (CI 84%-100%) and 100% specificity (CI 72%-100%); Lab B achieved 85% sensitivity (CI 64%-95%) and 90% specificity (CI 59%-99%); Lab C achieved 55% sensitivity (CI 34%-74%) and 60% specificity (CI 31%-83%); and Lab D achieved 75% sensitivity (CI 53%-89%) and 60% specificity (CI 31%-83%). In general, SAA results showed numerically lower sensitivity in β-amyloid (Aβ)-positive patients with DLB (70%) compared with Aβ-negative patients with DLB (87.5%) (nonstatistically significant). A fair agreement of SAA results was obtained across the 4 laboratories (average κ = 0.246). This study highlights challenges for the reproducibility of α-syn SAA results across different protocols applied by different laboratories. This finding, together with the methodological variability reported across laboratories, may challenge the clinical implementation of the α-syn SAA. This study provides relevant support for initiating harmonization and standardization of SAA protocols to move the field toward the clinical implementation of SAAs for the biomarker-based diagnosis of DLB. This study provides Class III evidence of variations in the accuracy of CSF α-syn SAA across 4 separate laboratories in distinguishing patients with DLB from healthy controls.