Abstract
Despite remarkable advances, research into neurodegeneration and Alzheimer Disease (AD) has nonetheless been dominated by inconsistent and conflicting theory. Basic questions regarding how ...and why the brain changes over time remain unanswered. In this work, we lay novel foundations for a consistent, integrated view of the aging brain. We develop neural economics—the study of the brain’s infrastructure, brain capital. Using mathematical modeling, we create ABC (
A
ging
B
rain
C
apital), a simple linear simultaneous-equation model that unites aspects of neuroscience, economics, and thermodynamics to explain the rise and fall of brain capital, and thus function, over the human lifespan. Solving and simulating this model, we show that in each of us, the resource budget constraints of our finite brains cause brain capital to reach an upper limit. The thermodynamics of our working brains cause persistent pathologies to inevitably accumulate. With time, the brain becomes damaged causing brain capital to depreciate and decline. Using derivative models, we suggest that this endogenous aging process underpins the pathogenesis and spectrum of neurodegenerative disease. We develop amyloid–tau interaction theory, a paradigm that bridges the unnecessary conflict between amyloid- and tau-centered hypotheses of AD. Finally, we discuss profound implications for therapeutic strategy and development.
Identifying disease-modifying therapies for neurological diseases remains one of the greatest gaps in modern medicine. Herein, we present the rationale for intranasal (IN) delivery of deferoxamine ...(DFO), a high-affinity iron chelator, as a treatment for neurodegenerative and neurovascular disease with a focus on its novel mechanisms. Brain iron dyshomeostasis with iron accumulation is a known feature of brain aging and is implicated in the pathogenesis of a number of neurological diseases. A substantial body of preclinical evidence and early clinical data has demonstrated that IN DFO and other iron chelators have strong disease-modifying impacts in Alzheimer's disease (AD), Parkinson's disease (PD), ischemic stroke, and intracranial hemorrhage (ICH). Acting by the disease-nonspecific pathway of iron chelation, DFO targets each of these complex diseases via multifactorial mechanisms. Accumulating lines of evidence suggest further mechanisms by which IN DFO may also be beneficial in cognitive aging, multiple sclerosis, traumatic brain injury, other neurodegenerative diseases, and vascular dementia. Considering its known safety profile, targeted delivery method, robust preclinical efficacy, multiple mechanisms, and potential applicability across many neurological diseases, the case for further development of IN DFO is considerable.
•We determined whether intranasal insulin would mitigate the behavioral and neuropathological effects of 6-OHDA in a rat model of PD.•Insulin decreased the turns in a drug induced rotational test and ...walking errors on a ladder test.•Insulin increased dopaminergic cell survival in the brain.•The use of an olfactory delivery device with a low dose of insulin can help with translation to clinical trials.
Emerging evidence continues to demonstrate that disrupted insulin signaling and altered energy metabolism may play a key role underpinning pathology in neurodegenerative conditions. Intranasally administered insulin has already shown promise as a memory-enhancing therapy in patients with Alzheimer’s and animal models of the disease. Intranasal drug delivery allows for direct targeting of insulin to the brain, bypassing the blood brain barrier and minimizing systemic adverse effects. In this study, we sought to expand upon previous results that show intranasal insulin may also have promise as a Parkinson’s therapy. We treated 6-OHDA parkinsonian rats with a low dose (3 IU/day) of insulin and assessed apomorphine induced rotational turns, motor deficits via a horizontal ladder test, and dopaminergic cell survival via stereological counting. We found that insulin therapy substantially reduced motor dysfunction and dopaminergic cell death induced by unilateral injection of 6-OHDA. These results confirm insulin’s efficacy within this model, and do so over a longer period after model induction which more closely resembles Parkinson’s disease. This study also employed a lower dose than previous studies and utilizes a delivery device, which could lead to an easier transition into human clinical trials as a therapeutic for Parkinson’s disease.
Introduction
Intranasal deferoxamine (IN DFO) has been shown to decrease memory loss and have beneficial impacts across several models of neurologic disease and injury, including rodent models of ...Alzheimer's and Parkinson's disease.
Methods
In order to assess the mechanism of DFO, determine its ability to improve memory from baseline in the absence of a diseased state, and assess targeting ability of intranasal delivery, we treated healthy mice with IN DFO (2.4 mg) or intraperitoneal (IP) DFO and compared behavioral and biochemical changes with saline‐treated controls. Mice were treated 5 days/week for 4 weeks and subjected to behavioral tests 30 min after dosing.
Results
We found that IN DFO, but not IP DFO, significantly enhanced working memory in the radial arm water maze, suggesting that IN administration is more efficacious as a targeted delivery route to the brain. Moreover, the ability of DFO to improve memory from baseline in healthy mice suggests a non‐disease‐specific mechanism of memory improvement. IN DFO treatment was accompanied by decreased GSK‐3β activity and increased HIF‐1α activity.
Conclusions
These pathways are suspected in DFO's ability to improve memory and perhaps represent a component of the common mechanism through which DFO enacts beneficial change in models of neurologic disease and injury.
Intranasal deferoxamine (IN DFO) decreases memory loss and has beneficial impacts across several models of neurologic disease and injury. We show that IN DFO improves memory from baseline in normal healthy mice while modifying GSK‐3β and HIF‐1α, suggesting these pathways may be involved in a common mechanism through which DFO enacts beneficial change.
Magnetic resonance-guided focused ultrasound (MRgFUS) has emerged as a precise, incisionless approach to cerebral lesioning and an alternative to neuromodulation in movement disorders. Despite ...rigorous clinical trials, long-term patient-centered outcome data after MRgFUS for tremor-predominant Parkinson's Disease (TPPD) are relatively lacking.
To report long-term data on patient satisfaction and quality of life after MRgFUS thalamotomy for TPPD.
In a retrospective study of patients who underwent MRgFUS thalamotomy for TPPD at our institution between 2015 and 2022, a patient survey was administered to collect self-reported measures of tremor improvement, recurrence, Patients' Global Impression of Change (PGIC), and side effects. Patient demographics, FUS parameters, and lesion characteristics were analyzed.
A total of 29 patients were included with a median follow-up of 16 months. Immediate tremor improvement was achieved in 96% of patients. Sustained improvement was achieved in 63% of patients at last follow-up. Complete tremor recurrence to baseline occurred for 17% of patients. Life quality improvement denoted by a PGIC of 1 to 2 was reported by 69% of patients. Long-term side effects were reported by 38% of patients and were mostly mild. Performing a secondary anteromedial lesion to target the ventralis oralis anterior/posterior nucleus was associated with higher rates of speech-related side effects (56% vs 12%), without significant improvement in tremor outcomes.
Patient satisfaction with FUS thalamotomy for tremor-predominant PD was very high, even at longer term. Extended lesioning to target the motor thalamus did not improve tremor control and may contribute to greater frequency of postoperative motor- and speech-related side effects.
Ectopic variceal bleeding is a potentially under recognized source of gastrointestinal (GI) hemorrhage. While vascular complications following pancreatic transplant are relatively common, the ...development of symptomatic ectopic venous varices has rarely been reported. We report two patients with a remote history of simultaneous kidney pancreas transplant (SPK) presenting two decades after transplant with an occult GI bleed. In both cases, a lengthy diagnostic course was required. The varices were treated with coil embolization via transhepatic approach. Our findings add to the limited literature on this topic and aid in the recognition, diagnosis, and management of this unusual presentation.
Purpose
Outcomes of patients with non-functioning pituitary adenomas categorized using the 2004 and 2017 WHO classification systems are understudied. We report outcomes from the University of ...Virginia of patients with non-functioning pituitary adenomas categorized using both systems.
Methods
We constructed a database from all 239 patients who underwent resection of a non-functioning pituitary adenoma between 2003 and 2015 and had at least 5 years of follow-up. Pathologic diagnosis was determined under both the 2004 and 2017 WHO classification systems. We compared the rates of recurrence and progression between subtypes using univariate and multivariate Cox regression analyses.
Results
Nearly 30% of the tumors in our database were classified as null cell adenomas under the 2004 classification system, whereas only 10% of the tumors were classified as null cell adenomas using the 2017 classification system. Most of these tumors were reclassified as either corticotroph or gonadotroph adenomas. Despite our relatively large cohort and average follow-up of nearly 9 years, we did not detect a significant difference in recurrence and progression between subtypes.
Conclusions
The majority of null cell adenomas diagnosed under the 2004 WHO classification system are reclassified as gonadotroph or corticotroph adenomas under the 2017 WHO classification system. Rates of progression and recurrence between subtypes are not as different as previously believed at our institution and require a larger cohort to further investigate.
Deferoxamine, a metal chelator, has been shown to be neuroprotective in animal models of ischemic stroke, traumatic brain injury and both subarachnoid and intracerebral hemorrhage. Intranasal ...deferoxamine (IN DFO) has also shown promise as a potential treatment for multiple neurodegenerative diseases, including Parkinson’s and Alzheimer’s. However, there have been no attempts to thoroughly understand the dynamics and pharmacokinetics of IN DFO. We developed a new high-performance liquid-chromatography electrospray-tandem mass spectrometry (HPLC/ESI-MS2) method to quantify the combined total levels of DFO, ferrioxamine (FO; DFO bound to iron), and aluminoxamine (AO; aluminum-bound DFO) in brain tissue using a custom-synthesized deuterated analogue (DFO-d 7, Medical Isotopes Inc., Pelham NH) as an internal standard. We applied our method toward understanding the pharmacokinetics of IN DFO delivery to the brain and blood of rats from 15 min to 4 h after delivery. We found that IN delivery successfully targets DFO to the brain to achieve concentrations of 0.5–15 μM in various brain regions within 15 min, and decreasing though still detectable after 4 h. Systemic exposure was minimized as assessed by concentration in blood serum. Serum concentrations were 0.02 μM at 15 min and no more than 0.1 μM at later time points. Compared to blood serum, brain region-specific drug exposure (as measured by area under the curve) ranged from slightly under 10 times exposure in the hippocampus to almost 200 times exposure in the olfactory bulb with IN DFO delivery. These findings represent a major step toward future method development, pharmacokinetic studies, and clinical trials for this promising therapeutic.
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