A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer’s Disease

Rosenbloom, Michael; Barclay, Terry R.; Kashyap, Bhavani; Hage, Lyndsay M.; O'Keefe, Lauren R; Svitak, Aleta L.; Pyle, Maria; Frey, William H.; Hanson, Leah R.

doi:10.1007/s40266-021-00845-7

Cited by 25 publications

(29 citation statements)

References 18 publications

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“…The sample size ranged from 9 to 240. One study was HIV Dementia (Rubin, 2017 ), one was diagnosed with MDD(major depressive disorder) (Cha et al, 2017 ), and two studies enrolled patients with PDD (Parkinson's disease Dementia) (Novak et al, 2019 ; Yufeng, 2020 ), the others were about AD or MCI (Reger et al, 2006 , 2008a , b ; Rosenbloom, 2011 ; Craft, 2012a , b ; Claxton et al, 2013 , 2015 ; Rosenbloom et al, 2014 , 2021 ; Craft et al, 2017 ; Yufeng, 2020 ). These studies were conducted in the following regions: Canada ( n = 1), China ( n = 1), America ( n = 14).…”

Section: Resultsmentioning

confidence: 99%

Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis

Long

Han

Yang

et al. 2022

Front. Aging Neurosci.

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BackgroundInsulin regulates many aspects of brain function related to mild cognitive impairment (MCI) or dementia, which can be delivered to the brain center via intranasal (IN) devices. Some small, single-site studies indicated that intranasal insulin can enhance memory in patients with MCI or dementia. The pathophysiology of Alzheimer's disease (AD) and diabetes mellitus (DM) overlap, making insulin an attractive therapy for people suffering from MCI or dementia.ObjectiveThe goal of the study is to evaluate the effectiveness of IN insulin on cognition in patients with MCI or dementia.MethodsWe searched the electronic database for randomized controlled trials (RCTs) that verified the effects of insulin on patients with MCI or dementia.16 studies (899 patients) were identified.ResultsThe pooled standard mean difference (SMD) showed no significant difference between IN insulin and placebo groups; however, statistical results suggested a difference between study groups in the effects of ADCS-ADL; AD patients with APOE4 (-) also showed improved performance in verbal memory; other cognitions did not improve significantly.ConclusionIn view of IN insulin's promising potential, more researches should be conducted at a larger dose after proper selection of insulin types and patients.Systematic review registrationhttp://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022353546.

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Section: Resultsmentioning

confidence: 99%

Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis

Long

Han

Yang

et al. 2022

Front. Aging Neurosci.

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“…Another study showed that insulin, but not long-acting analog Detemir, increased memory and preserved volume in several brain regions ( Craft et al, 2017 ). A small trial examining the effect of the rapid acting insulin analog Glulisine in patients with MCI or middle-stage AD failed to show any acute impact in cognition ( Rosenbloom et al, 2021 ). Nasal insulin has also been tested in other neurodegenerative diseases, showing for example improved clinical outcome in PD severity ( Novak et al, 2019 ).…”

Section: Current Therapeutic Strategies To Target Brain Hypometabolismmentioning

confidence: 99%

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

et al. 2022

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Astrocytes play key roles in the regulation of brain energy metabolism, which has a major impact on brain functions, including memory, neuroprotection, resistance to oxidative stress and homeostatic tone. Energy demands of the brain are very large, as they continuously account for 20–25% of the whole body’s energy consumption. Energy supply of the brain is tightly linked to neuronal activity, providing the origin of the signals detected by the widely used functional brain imaging techniques such as functional magnetic resonance imaging and positron emission tomography. In particular, neuroenergetic coupling is regulated by astrocytes through glutamate uptake that triggers astrocytic aerobic glycolysis and leads to glucose uptake and lactate release, a mechanism known as the Astrocyte Neuron Lactate Shuttle. Other neurotransmitters such as noradrenaline and Vasoactive Intestinal Peptide mobilize glycogen, the reserve for glucose exclusively localized in astrocytes, also resulting in lactate release. Lactate is then transferred to neurons where it is used, after conversion to pyruvate, as a rapid energy substrate, and also as a signal that modulates neuronal excitability, homeostasis, and the expression of survival and plasticity genes. Importantly, glycolysis in astrocytes and more generally cerebral glucose metabolism progressively deteriorate in aging and age-associated neurodegenerative diseases such as Alzheimer’s disease. This decreased glycolysis actually represents a common feature of several neurological pathologies. Here, we review the critical role of astrocytes in the regulation of brain energy metabolism, and how dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism. Further, we summarize recent efforts at preclinical and clinical stages to target brain hypometabolism for the development of new therapeutic interventions in age-related neurodegenerative diseases.

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“…The results show, as in previous studies, that glulisine did not affect plasma insulin or glucose levels. There was also no effect of the drug on patients' cognitive function and memory [50].…”

Section: Insulin and Other Antidiabetics As A Potential Therapy For Alzheimer's Diseasementioning

confidence: 87%

Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

Miziak

Błaszczyk²,

Czuczwar

2021

Pharmaceuticals

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Alzheimer’s disease (AD; progressive neurodegenerative disorder) is associated with cognitive and functional impairment with accompanying neuropsychiatric symptoms. The available pharmacological treatment is of a symptomatic nature and, as such, it does not modify the cause of AD. The currently used drugs to enhance cognition include an N-methyl-d-aspartate receptor antagonist (memantine) and cholinesterase inhibitors. The PUBMED, Medical Subject Heading and Clinical Trials databases were used for searching relevant data. Novel treatments are focused on already approved drugs for other conditions and also searching for innovative drugs encompassing investigational compounds. Among the approved drugs, we investigated, are intranasal insulin (and other antidiabetic drugs: liraglitude, pioglitazone and metformin), bexarotene (an anti-cancer drug and a retinoid X receptor agonist) or antidepressant drugs (citalopram, escitalopram, sertraline, mirtazapine). The latter, especially when combined with antipsychotics (for instance quetiapine or risperidone), were shown to reduce neuropsychiatric symptoms in AD patients. The former enhanced cognition. Procognitive effects may be also expected with dietary antioxidative and anti-inflammatory supplements—curcumin, myricetin, and resveratrol. Considering a close relationship between brain ischemia and AD, they may also reduce post-brain ischemia neurodegeneration. An investigational compound, CN-105 (a lipoprotein E agonist), has a very good profile in AD preclinical studies, and its clinical trial for postoperative dementia is starting soon.

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A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer’s Disease

Cited by 25 publications

References 18 publications

Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis

Efficacy of intranasal insulin in improving cognition in mild cognitive impairment or dementia: a systematic review and meta-analysis

Astrocytes as Key Regulators of Brain Energy Metabolism: New Therapeutic Perspectives

Some Candidate Drugs for Pharmacotherapy of Alzheimer’s Disease

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