Biology subjects

Mailman, R. B.

Publications and source records attributed to Mailman, R. B..

6 recordsLinked to original sources

bioRxiv2026

Levodopa increases substantia nigra iron: implications for Parkinson's disease

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSBackgroundC_ST_ABSExcessive or unregulated iron in the brain can lead to toxicity via ferroptosis and related mechanisms. Iron accumulation in the substantia nigra (SN) occurs with Parkinsons disease (PD) progression and has been hypothesized to be an etiological mechanism. ObjectiveBased on emerging clinical observations, we tested the hypothesis that iron accumulation in the SN is a consequence of levodopa administration and is treatment-related rather than an intrinsic etiological mechanism. MethodsWe used both unilaterally lesioned 6-OHDA and unlesioned rats. We administered levodopa to rats at doses that were allometrically calculated to be similar to those used in mid-stages of PD. Iron-sensitive MRI (R2*) was used to quantify iron in the brain. Both group and intra-subject analyses were done using paired t-tests and linear mixed models. ResultsExperiment 1 used the unilateral 6-OHDA model to take advantage of the almost complete lack of dopamine neurons on the lesioned side. This permitted testing if levodopa-induced iron accumulation occurred in and/or depended on dopamine neurons. Fifteen days of levodopa treatment caused a marked increase in Fe in both the lesioned (p = 0.042) and unlesioned sides (p = 0.005), showing that iron accumulation does not depend on the presence of dopamine neurons. Based on these data, in experiment 2 unlesioned rats were administered levodopa daily for four months, and iron (R2*) values were assessed at baseline, 1, 2, and 4 months. In these normal rats, the levodopa-treated group had significantly increased Fe (R2*) in the substantia nigra compared to the vehicle group (p = 0.013). Interestingly, these effects were limited to the striatum, with no increases seen in the striatum, ventral tegmental area, or frontal cortex ConclusionLevodopa triggers processes that increase iron deposition in the substantia nigra, but this process may not depend on dopamine neurons. The underlying mechanisms and the effect on PD progression are important to elucidate and may transform how we understand PD and related neurodegenerative disorders

neuroscience↗

bioRxiv2024

Comprehensive mapping of the Interaction of levodopa and iron metabolism in Parkinson's disease

Levodopa remains the primary treatment for Parkinsons disease (PD), yet its long-term use has been associated with iron accumulation in the brain, a phenomenon linked to neurodegeneration. We utilize deep machine learning to determine plausible molecular mechanisms that may underlie the effects of levodopa on iron metabolism. Using the DRIFT platform, we performed a proteome-wide target identification of levodopa and uncovered significant interactions potentially involved in cellular iron transport. Pathway analysis revealed that levodopa may influence critical iron-related pathways, including the response of EIF2AK1 to heme deficiency, heme signaling, and ABC-family protein-mediated transport. These findings suggest that levodopa may contribute to iron dysregulation in PD by interacting with iron transporters and modulating iron-related pathways. Because levodopa is used at relatively high doses in PD, our findings provide new insight into secondary effects unrelated to being a precursor of dopamine. This highlights the need for careful consideration of its effects on iron metabolism as a consequence of use in the long-term management of PD. Further experimental validation is required to confirm these interactions, and also to explore potential strategies to mitigate iron-related side effects while preserving therapeutic efficacy.

bioinformatics↗

bioRxiv2023

Quantifying network behavior in the rat prefrontal cortex: a reproducibility crisis

The question of how consciousness and behavior arise from neural activity is fundamental to understanding the brain, and to improving the diagnosis and treatment of neurological and psychiatric disorders. There is significant murine and primate literature on how behavior is related to the electrophysiological activity of the medial prefrontal cortex and its role in working memory processes such as planning and decision-making. Existing experimental designs, however, have insufficient statistical power to unravel the complex processes of the prefrontal cortex. We therefore examined the theoretical limitations of such experiments, providing concrete guidelines for robust and reproducible science. We piloted the use of dynamic time warping and associated statistical tests to data from neuron spike trains and local field potentials, to quantify neural network synchronicity and correlate neuroelectrophysiology with rat behavior. Our results indicate the statistical limitations of existing data, making meaningful comparison between dynamic time warping with traditional Fourier and wavelet analysis currently impossible until larger and cleaner datasets are available. Significance StatementThe prefrontal cortex is important in decision-making, yet no robust method currently exists to correlate neuron firing in the PFC to behavior. We argue that existing experimental designs are ill-suited to addressing these scientific questions, and we propose a potential method using dynamic time warping to analyze PFC neural electrical activity. We conclude that careful curation of experimental controls is needed to separate true neural signals from noise accurately.

neuroscience↗

bioRxiv2022

Early β-amyloid accumulation and hypoconnectivity in the default mode network are related to its disengagement from global brain activity

AO_SCPLOWBSTRACTC_SCPLOWO_ST_ABSImportanceC_ST_ABSThe specific pattern/trajectory of {beta}-amyloid (A{beta}) pathology spreading in Alzheimers disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood. ObjectiveTo determine if resting-state global brain activity is linked to early A{beta} deposition in the DMN. DesignThis is a retrospect analysis of multi-modal and longitudinal data from the Alzheimers disease Neuroimaging Initiative (ADNI) cohort. SettingThe ADNI was a multicenter project involving 63 research centers. ParticipantsThe study included 144 participants (72.6 {+/-} 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for A{beta}-PET for 112 of the subjects. They were classified into following stages based on the CSF A{beta}42 (CSF+: <192 ng/L) and cortical A{beta} (PET+: >0.872 SUVR) levels: non-A{beta}-accumulators (CSF-/PET-); early-A{beta}-accumulators (CSF+/PET-); and late-A{beta}-accumulators (CSF+/PET+). ExposureResting-state brain activity was assessed by functional magnetic resonance imaging (rsfMRI), whereas glymphatic function was estimated by the coupling between fMRI blood-oxygen-level-dependent (BOLD) signals and CSF movements. Main Outcomes and MeasuresCortical A{beta} accumulation measured by 18F-AV45 amyloid-positron emission tomography (PET), CSF A{beta}42, and total and phosphorylated tau protein levels in all participants. ResultsGlymphatic function assessed by fMRI was strongly ({rho} > 0.43, P < 0.042) associated with various markers of protein aggregation in early A{beta} accumulators in whom A{beta} just begins to accumulate cortically in the DMN. Among these early accumulators, the preferential A{beta} accumulation in the DMN regions in the subsequent two years was correlated with lower gBOLD signal ({rho} = 0.51, P = 0.027) and lower local glymphatic function ({rho} = 0.48, P = 0.041) in the same regions at baseline. Conclusions and RelevanceResting-state global brain activity and related glymphatic function are linked to A{beta} pathology, particularly its preferential deposition in the DMN at the earliest AD stages. This suggests potential novel early therapeutic directions that might provide disease modification. KO_SCPLOWEYC_SCPLOW PO_SCPLOWOINTSC_SCPLOWO_ST_ABSQuestionC_ST_ABSWhy does the {beta}-amyloid (A{beta}) plaque deposit preferentially in the default mode network (DMN) regions at early preclinical stages of Alzheimers disease? FindingsIn this analytic observational cohort study with 144 subjects, we found that the preferential reduction of global resting-state brain activity in the DMN, as well as its coupling with cerebrospinal fluid movement, was significantly correlated with the preferential A{beta} accumulation in these DMN regions among 19 subjects with early A{beta} accumulation. MeaningResting-state global brain activity plays a role in the early A{beta} accumulation in the DMN, presumably due to its involvement in glymphatic clearance.

neuroscience↗

bioRxiv2021

Decoupling of global brain activity and cerebrospinal fluid flow in Parkinson's cognitive decline

BackgroundDeposition and spreading of misfolded proteins (-synuclein and tau) have been linked to Parkinsons cognitive dysfunction. The glymphatic system may play an important role in the clearance of these toxic proteins via cerebrospinal fluid (CSF) flow through perivascular and interstitial spaces. Recent studies discovered that sleep-dependent global brain activity is coupled to CSF flow that may reflect glymphatic function. ObjectiveTo determine if the decoupling of brain activity-CSF flow is linked to Parkinsons cognitive dysfunction. MethodsFunctional and structural MRI data, clinical motor (Unified Parkinson's Disease Rating Scale), and cognitive (Montreal Cognitive Assessment, MoCA) scores were collected from 60 Parkinsons and 58 control subjects. Parkinsons patients were subgrouped into those with (MoCA < 26; N = 29) and without (MoCA [≥] 26; N = 31) mild cognitive impairment (MCI). The coupling strength between the resting-state global blood-oxygen-level-dependent signal (gBOLD) and associated CSF flow was quantified, compared among groups, and associated with clinical and structural measurements. ResultsgBOLD-CSF coupling decreased significantly (p < 0.006) in Parkinsons patients showing MCI, compared to those without MCI and controls. Reduced gBOLD-CSF coupling was associated with decreased MoCA scores that was present in Parkinsons patients (p = 0.005) but not in controls (p = 0.65). Weaker gBOLD-CSF coupling in Parkinsons patients also was associated with a thinner right entorhinal cortex (Spearmans correlation = - 0.36; p = 0.012), an early structural change often seen in Alzheimers. ConclusionsThe decoupling between global brain activity and associated CSF flow is related to Parkinsons cognitive impairment.

neuroscience↗

bioRxiv2020

D1, not D2, dopamine receptor activation dramatically improves MPTP-induced parkinsonism unresponsive to levodopa

AO_SCPLOWBSTRACTC_SCPLOWLevodopa is the Parkinsons disease standard-of-care, but continued loss of dopamine neurons with disease progression decreases its bioconversion to dopamine, leading to increased side effects and decreased efficacy. In theory, dopamine agonists could equal levodopa, but no approved oral "dopamine agonist" matches the efficacy of levodopa. Although there are consistent data in both primate models and in Parkinsons disease showing that selective high intrinsic activity D1 agonists can equal levodopa, there are no data on whether such compounds would be effective in severe disease when levodopa efficacy is lower or even absent. We compared two approved antiparkinson drugs (levodopa and the D2/3 agonist bromocriptine) with the experimental selective D1 full agonist dihydrexidine in two severely parkinsonian MPTP-treated non-human primates. Bromocriptine caused no discernable improvement in parkinsonian signs, whereas levodopa caused a small transient improvement in one of the two subjects. Conversely, the full D1 agonist dihydrexidine caused a dramatic improvement in both subjects, decreasing parkinsonian signs by ca. 75%. No attenuation of dihydrexidine effects was observed when the two subjects were pretreated with the D2 antagonist remoxipride. These data provide evidence that selective D1 agonists may provide profound antiparkinson symptomatic relief even when the degree of nigrostriatal degeneration is so severe that current drugs are ineffective. Until effective disease-modifying therapies are discovered, high intrinsic activity D1 agonists may offer a major therapeutic advance in improving the quality of life, and potentially the longevity, of late stage Parkinsons patients.

neuroscience↗