Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design

Devanand, Devangere P.; Strickler, Jesse G.; Huey, Edward D.; Crocco, Elizabeth; Forester, Brent P.; Husain, Mustafa M.; Vahia, Ipsit V.; Andrews, Howard; Wall, Melanie M.; Pelton, Gregory H.

doi:10.1016/j.cct.2018.05.019

Cited by 48 publications

(9 citation statements)

References 32 publications

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“…Lithium salts are oral drugs approved for treatment of mood disorders including bipolar disorder and major depressive disorder [ 139 ]. Lithium was initially mainly considered for the treatment of agitation and psychosis in AD [ 140 ]. Preclinical studies suggest that lithium is also a direct reversible inhibitor of GSK-3β activity and may be capable of decreasing tau hyperphosphorylation and slowing AD disease progression [ 141 ].…”

Section: Main Textmentioning

confidence: 99%

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Xia

Prokop

Giasson

2021

Mol Neurodegeneration

135

110

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Phosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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Section: Main Textmentioning

confidence: 99%

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Xia

Prokop

Giasson

2021

Mol Neurodegeneration

135

110

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“…The applied search resulted in the identification of several drug candidates being investigated in clinical trials. Table 2 summarizes the data extracted on the investigated drug candidates, which will be discussed in detail below (except for lithium, which has been reviewed comprehensively elsewhere [49,50]).…”

Section: Identification Of Compounds Investigated In Preclinical and mentioning

confidence: 99%

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

et al. 2020

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Along with cognitive decline, 90% of patients with dementia experience behavioral and psychological symptoms of dementia, such as psychosis, aggression, agitation, and depression. Atypical antipsychotics are commonly prescribed off-label to manage certain symptoms, despite warnings from the regulatory agencies regarding the increased risk of mortality associated with their use in elderly patients. Moreover, these compounds display a limited clinical efficacy, mostly owing to the fact that they were developed to treat schizophrenia, a disease characterized by neurobiological deficits. Thus, to improve clinical efficacy, it has been suggested that patients with dementia should be treated with exclusively designed and developed drugs that interact with pharmacologically relevant targets. Within this context, numerous studies have suggested druggable targets that might achieve therapeutically acceptable pharmacological profiles. Based on this, several different drug candidates have been proposed that are being investigated in clinical trials for behavioral and psychological symptoms of dementia. We highlight the recent advances toward the development of therapeutic agents for dementia-related psychosis and agitation/ aggression and discuss the relationship between the relevant biological targets and their etiology. In addition, we review the compounds that are in the early stage of development (discovery or preclinical phase) and those that are currently being investigated in clinical trials for dementia-related psychosis and agitation/aggression. We also discuss the mechanism of action of these compounds and their pharmacological utility in patients with dementia.

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“…It is well recognized that Lithium (Li) has been applied in the treatment of bipolar disorder (BD) for many years in clinical based on its neuroprotective and neurotrophic effects [17], and studies on using Li to treat psychiatric and neurological disorders are still popular, including AD [18][19][20][21]. A metaanalysis of randomized placebo-controlled trials indicated Li treatment may be beneficial for patients with mild cognitive impairment (MCI) and AD dementia [19].…”

Section: Introductionmentioning

confidence: 99%

Preparation and Multitarget Anti-AD Activity Study of Chondroitin Sulfate Lithium in AD Mice Induced by Combination of D-Gal/AlCl3

Gao

Gao³

et al. 2022

Oxidative Medicine and Cellular Longevity

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Previous studies have demonstrated that both CS and LiCl possess anti-Alzheimer’s disease (AD) activities. We prepared chondroitin sulfate-Li (CS-Li) and investigated its effect on AD and explored the possible mechanisms both in vitro and in vivo. We found that CS-Li could inhibit amyloid β (Aβ) aggregation and protect SH-SY5Y cells from Aβ1-42-induced cytotoxicity in vitro. In D-gal and AlCl3-induced AD mouse model, CS-Li improves the spatial learning and memory abilities of AD mice, reverses the nuclear pyknosis and cell edema, and increases the survival rate of neurons in hippocampus of mice. Moreover, CS-Li significantly increased the levels of GSH-Px, Na+/K+-ATPase, and ChAT and decreased the levels of MDA and AchE in AD mice. Western blot results demonstrated that CS-Li could decrease the hyperphosphorylation of tau (Ser396/Ser404) by regulating the expression of p-GSK-3β (Ser9) and PP2A and inhibit the expression of proinflammatory factors through inhibiting NF-κB nuclear translocation by activating the MAPK signaling pathways. In a word, CS-Li can delay AD development through multitarget processes, including Aβ aggregation inhibition, oxidative stress damage, tau hyperphosphorylation, and inflammatory response, thereby improves learning and memory abilities.

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Lithium Treatment for Agitation in Alzheimer's disease (Lit-AD): Clinical rationale and study design

Abstract: ClinicalTrials.gov Identifier NCT02129348.

Cited by 48 publications

References 32 publications

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Management of Dementia-Related Psychosis, Agitation and Aggression: A Review of the Pharmacology and Clinical Effects of Potential Drug Candidates

Preparation and Multitarget Anti-AD Activity Study of Chondroitin Sulfate Lithium in AD Mice Induced by Combination of D-Gal/AlCl3

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