Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery

Pardridge, William M.

doi:10.3390/ph13110394

Cited by 115 publications

(103 citation statements)

References 139 publications

(248 reference statements)

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“…All of these factors increase the difficulty to properly evaluate the efficacy of any intervention. Drugs targeting Aβ plaques and neurofibrillary tangles have not yet proved their efficacy in treating AD [ 25 ]. We anticipate that a study on a population level with a heterogeneous genetic background and diverse behavioral and lifestyle could potentially neutralize the effects attributed to uncontrolled variables.…”

Section: Introductionmentioning

confidence: 99%

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

et al. 2021

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Bacillus Calmette–Guerin (BCG) is a live attenuated form of Mycobacterium bovis that was developed 100 years ago as a vaccine against tuberculosis (TB) and has been used ever since to vaccinate children globally. It has also been used as the first-line treatment in patients with nonmuscle invasive bladder cancer (NMIBC), through repeated intravesical applications. Numerous studies have shown that BCG induces off-target immune effects in various pathologies. Accumulating data argue for the critical role of the immune system in the course of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). In this study, we tested whether repeated exposure to BCG during the treatment of NMIBC is associated with the risk of developing AD and PD. We presented a multi-center retrospective cohort study with patient data collected between 2000 and 2019 that included 12,185 bladder cancer (BC) patients, of which 2301 BCG-treated patients met all inclusion criteria, with a follow-up of 3.5 to 7 years. We considered the diagnosis date of AD and nonvascular dementia cases for BC patients. The BC patients were partitioned into those who underwent a transurethral resection of the bladder tumor followed by BCG therapy, and a disjoint group that had not received such treatment. By applying Cox proportional hazards (PH) regression and competing for risk analyses, we found that BCG treatment was associated with a significantly reduced risk of developing AD, especially in the population aged 75 years or older. The older population (≥75 years, 1578 BCG treated, and 5147 controls) showed a hazard ratio (HR) of 0.726 (95% CI: 0.529–0.996; p-value = 0.0473). While in a hospital-based cohort, BCG treatment resulted in an HR of 0.416 (95% CI: 0.203–0.853; p-value = 0.017), indicating a 58% lower risk of developing AD. The risk of developing PD showed the same trend with a 28% reduction in BCG-treated patients, while no BCG beneficial effect was observed for other age-related events such as Type 2 diabetes (T2D) and stroke. We attributed BCG’s beneficial effect on neurodegenerative diseases to a possible activation of long-term nonspecific immune effects. We proposed a prospective study in elderly people for testing intradermic BCG inoculation as a potential protective agent against AD and PD.

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Section: Introductionmentioning

confidence: 99%

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

et al. 2021

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“…AD pathogenesis includes the accumulation of insoluble forms of Aβ plaques, tau protein hyperphosphorylation forming neurofibrillary tangles, oxidative stress, and sustained inflammation 5 . Drugs targeting Aβ plaques and neurofibrillary tangles have not yet proved their efficacy in treating AD 6 . Aβ aggregates induce microglial and astrocyte activation that leads to sustained brain inflammation 7-9 .…”

Section: Introductionmentioning

confidence: 99%

Bladder Cancer Immunotherapy by BCG is associated with a significantly reduced risk of Alzheimer‘s disease

Klinger

Hill

Barda

et al. 2021

Preprint

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IMPORTANCE Despite years of investigation and billions of dollars, there is no cure or even a disease-slowing remedy for Alzheimer disease (AD). Most studies thus far have focused on amyloid beta plaques and neurofibrillary tangles as therapeutic targets, and only a few on modulating the associated inflammatory process. OBJECTIVE To determine if exposure to Bacillus Calmette Guerin (BCG) during treatment of non-muscle-invasive bladder cancer (NMIBC) is associated with a lower risk of developing AD. DESIGN, SETTING AND PARTICIPANTS Multicenter retrospective study of 12,185 bladder cancer patients including 2301 BCG treated patients between 2000 and 2019 meeting all inclusion criteria. Data was retrieved from two tertiary hospital systems in Israel and the United States, and the largest Israeli health provider database, with a median follow up of 3.5 to 7 years. MAIN OUTCOMES AND MEASURES The primary outcome was time to the first occurrence of AD/Dementia events following a diagnosis of bladder cancer by trans-urethral resection (TURBT) in BCG treated patients, and in bladder cancer patients not receiving BCG (control group). RESULTS BCG treatment was associated with a significantly reduced risk of developing AD in bladder cancer patients older than 75 years following BCG treatment. A competing risk model using Cox Proportional-Hazard (PH) analysis applied to the largest medical records data showed a Hazard Ratio (HR) of 0.726 (95% CI: 0.529 to 0.996, P = 0.0473). The results were duplicated in analyzing NMIBC patients from a tertiary hospital with a HR of 0.416 (95% CI: 0.203 to 0.853, P = 0.017). A reduction in the risk (by 28%) for developing Parkinson disease (PD) was also shown in bladder cancer patients subjected to BCG immunotherapy. CONCLUSIONS AND RELEVANCE BCG treatment for bladder cancer patients was associated with a significantly reduced risk for developing AD and PD in the elderly population (>75 years), and in NMIBC patients from a tertiary hospital. Prospective studies in elderly inoculated with intradermic BCG should be initiated to evaluate the potential protective effect of BCG against AD and PD.

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“…BMECs express unique tight-junction proteins limiting paracellular diffusion, nutrient transporter regulating the flow of energy and efflux transporter preventing entry of unwanted toxic substances from the brain (Abbott et al, 2010;Pardridge, 2005). While this barrier is essential for preserving healthy brain activity, it has been estimated that only 2 % of small molecule drugs can cross the human BBB and reach a therapeutic target (Pardridge, 2001(Pardridge, , 2020. So far, many devastating brain diseases including neurodegenerative diseases do not have adequate treatments except for some symptomatic therapies (Bright et al, 2019;Dong et al, 2019;Pangalos et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs

Fengler

Kurkowsky

Kaushalya

et al. 2021

Preprint

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Optimizing drug candidates for blood-brain barrier (BBB) penetration in humans remains one of the key challenges and many devastating brain diseases including neurodegenerative diseases still do not have adequate treatments. So far, it has been difficult to establish state-of-the-art human stem cell derived in vitro models that mimic physiological barrier properties including a 3D microvasculature in a format that is scalable enough to screen drugs for BBB penetration in early drug development phases. To address this challenge, we established human induced pluripotent stem cell (iPSC)-derived brain endothelial microvessels in a standardized and scalable multi-well plate format. iPSC-derived brain microvascular endothelial cells (BMECs) were supplemented with primary cell conditioned media and grew to intact microvessels in 10 days of culturing. Produced microvessels show a typical BBB phenotype including endothelial protein expression, tight-junctions and polarized localization of efflux transporter. Microvessels exhibited physiological relevant trans-endothelial electrical resistance (TEER), were leak tight for 10 kDa dextran-Alexa 647 and strongly limited the permeability of sodium fluorescein (NaF). Permeability tests with reference compounds confirmed the suitability of our model as platform to identify potential BBB penetrating anti-inflammatory drugs. In summary, the here presented brain microvessel platform recapitulates physiological properties and allows rapid screening of BBB permeable anti-inflammatory compounds that has been suggested as promising substances to cure so far untreatable neurodegenerative diseases.

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Treatment of Alzheimer’s Disease and Blood–Brain Barrier Drug Delivery

Cited by 115 publications

References 139 publications

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

Bladder Cancer Immunotherapy by BCG Is Associated with a Significantly Reduced Risk of Alzheimer’s Disease and Parkinson’s Disease

Bladder Cancer Immunotherapy by BCG is associated with a significantly reduced risk of Alzheimer‘s disease

Human iPSC-derived brain endothelial microvessels in a multi-well format enable permeability screens of anti-inflammatory drugs

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