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PIMAVANSERIN: POTENTIAL TREATMENT FOR DEMENTIA-RELATED PSYCHOSIS

 

J. Cummings1, C. Ballard2, P. Tariot3, R. Owen4, E. Foff4, J. Youakim4, J. Norton4, S.Stankovic4

 

1. Cleveland Clinic Lou Ruvo Center for Brain Health, Las Vegas, NV, USA; 2. University of Exeter Medical School, Exeter, UK; 3. Banner Alzheimer’s Institute and University of Arizona College of Medicine, Phoenix, AZ, USA; 4. ACADIA Pharmaceuticals Inc., San Diego, CA, USA

Corresponding Author: Jeffrey Cummings MD, ScD, Cleveland Clinic Lou Ruvo Center for Brain Health, 888 W. Bonneville Ave, Las Vegas, NV, USA, cumminj@ccf.org

J Prev Alz Dis 2018 inpress
Published online August 16, 2018, http://dx.doi.org/10.14283/jpad.2018.29

 


Abstract

Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms – Parkinson’s disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer’s disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS

Key words: Dementia, psychosis, Alzheimer’s disease, Parkinson’s disease, frontotemporal dementia;, dementia with Lewy bodies.


 

Psychosis is a common feature of dementia and becomes more frequent with disease progression (1-3). Psychosis is common in neurodegenerative disorders such as Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) and often occurs concurrently with cognitive decline and other non-motor symptoms and sleep disturbances (4-9). Among patients with PD, psychosis occurs in up to 60% of patients over the course of their disease (10, 11), Similarly, psychosis occurs with varying prevalence across other neurodegenerative diseases including Alzheimer’s disease (AD), Vascular dementia (VaD), and frontotemporal dementia (FTD) (Table 1). In most neurodegenerative dementias, neurobehavioral symptoms such as psychosis are more common among those with cognitive impairment (1-3). The presence of neuropsychiatric signs and symptoms in neurodegenerative diseases is predictive of increased caregiver burden, decreased quality of life, and earlier progression to nursing home care, severe dementia, and death (3, 12). Thus, there is a close relationship between the clinical manifestations of dementia-related psychosis (DRP) and morbidity/mortality in many neurodegenerative diseases (1, 5).

 

Table 1. Prevalence of delusions and hallucinations in patients with dementia, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies

Table 1. Prevalence of delusions and hallucinations in patients with dementia, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies

 

No pharmacological agents are approved for treating patients with DRP, and antipsychotic (AP) drugs are often prescribed off-label for treating psychosis despite safety concerns with use of these medications in this population (13). Meta-analyses of randomized, controlled trials of APs demonstrate limited efficacy for treating DRP (14, 15). The effect size for treatment is modest (effect size=0.2) for psychosis in patients with AD (16-18). Results from the Clinical Antipsychotic Trials on Intervention Effectiveness-Alzheimer’s disease (CATIE-AD) study showed a significant decline in cognitive function with AP use (19), and a meta-analysis of AP in dementia patients found a similar negative effect on cognitive function (20). Further, use of APs for treating patients with dementia and PD is associated with a higher risk of mortality compared with placebo (14, 20-23) as well as an increased risk of morbidity (24). Hence, there is a major unmet need for pharmacological treatment of DRP that effectively manages symptoms of psychosis without compromising cognition and with an acceptable safety and tolerability profile.
Pimavanserin, a selective 5-hydroxytryptamine (HT)2A receptor inverse agonist/antagonist, has minimal affinity for dopaminergic, muscarinic, histaminergic or adrenergic receptors (25). Pimavanserin was developed on the basis of the observation that antagonism of the 5-HT2A receptor is the common feature of most approved and efficacious APs (26).
Pimavanserin is the only drug approved in the United States for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis (PDP) (27). Early supportive evidence of the efficacy of pimavanserin was provided from the results of two placebo-controlled clinical trials in PDP (NCT00477672; NCT00658567; data on file, ACADIA Pharmaceuticals) (28). These studies together with a pivotal Phase 3 study (29) formed the basis of approval of pimavanserin by the US Food and Drug Administration (FDA) in 2016 for the treatment of hallucinations and delusions associated with PDP.
Recently, pimavanserin was shown to improve hallucinations and delusions in patients with AD psychosis (ADP) (30). Analyses from this study also demonstrated that pimavanserin did not negatively impact cognitive function in these patients (Table 2).

Table 2. Completed or ongoing analyses from randomized, placebo-controlled studies with pimavanserin for neuropsychiatric disorders

Table 2. Completed or ongoing analyses from randomized, placebo-controlled studies with pimavanserin for neuropsychiatric disorders

 

The findings of efficacy for pimavanserin in the PDP and ADP populations indicate that pimavanserin may have a favorable treatment effect on psychotic features across many neurodegenerative dementing illnesses. Here we review the pimavanserin clinical development program leading to the approval for PDP along with the data from the study in ADP leading to a proposed trial in DRP across a spectrum of neurodegenerative diseases. The rationale and methodology for DRP development is discussed.

 

A phase 3 study of Pimavanserin for Pakinson’s disease psychosis

The efficacy of pimavanserin in the treatment of hallucinations and delusions associated with PDP was demonstrated in a Phase 3, double-blind, randomized, placebo-controlled study (29).
Patients satisfying diagnostic criteria for PDP were randomized to pimavanserin 34 mg or placebo for a 6-week treatment period. The study included a 2-week screening, baseline (Day 1), 6 weeks of treatment, and a follow up visit 4 weeks after study drug discontinuation. During the 2-week screening period, patients received brief psychosocial therapy (45). The primary efficacy endpoint was mean change from baseline to Week 6 in the SAPS-PD score.
This study demonstrated clinically and statistically significant superiority of pimavanserin 34 mg over placebo in treatment of hallucinations and delusions in patients with PDP. A 5.79 point improvement (least square (LS) mean change) at Week 6 was observed with pimavanserin compared to a 2.73 point improvement for placebo in the SAPS-PD score. This represents a clinically meaningful change with a treatment difference of 3.06 points (p=0.001; effect size 0.50). The effect size of 0.50 indicates a robust effect compared with the 0.2 effect size typically reported with APs (16-18). In addition, pimavanserin was generally well tolerated with no effects on motor function as measured by the Unified Parkinson’s Disease Rating Scale (UPDRS) Parts II+III.

 

Subgroup analysis of outcome by baseline MMSE

Patients with dementia (Mini-Mental State Examination (MMSE) score <20) were excluded in the pivotal clinical trial (30); but some patients exhibited a limited degree of cognitive impairment. A post hoc subgroup analysis conducted from the Phase 3 study, evaluated randomized patients according to the presence or absence of cognitive impairment, defined as a MMSE score of 21 to 24 for cognitive impairment versus ≥25 for non-impaired (46). The cognitively impaired subgroup constituted about 25% of the overall study population (pimavanserin, n=29; placebo, n=21). The primary endpoint of this analysis was mean change from baseline to Week 6 for the SAPS-PD score.
Patients with cognitive impairment (MMSE score 21-24) demonstrated a 6.62 point improvement (LS mean change) in the SAPS-PD score with pimavanserin at Week 6 compared to a 0.91 point improvement with placebo, representing a treatment difference of 5.71 points (p=0.002) (Figure 1). The observed effect size (Cohen’s d) in the subgroup of patients with PDP and dementia was 0.99. This compares to a treatment difference of 3.06 in the overall study population. In the non-cognitively impaired group (MMSE score ≥25) the LS mean change from baseline to Week 6 for the SAPS-PD was -5.50 with pimavanserin vs. -3.23 with placebo with a treatment difference of 2.27 (p=0.046). At Week 6, among the cognitively impaired subgroup for Clinical Global Impressions-Improvement (CGI-I) score, the mean difference from baseline for pimavanserin vs. placebo was 1.0 (p=0.012), and for the non-impaired, the mean difference for pimavanserin vs. placebo was -0.6 (p=0.022).
The results from this subgroup analysis suggest that pimavanserin is efficacious in PDP patients with cognitive impairment and may exhibit a more robust effect in this subgroup of patients. No notable differences were observed for the incidence of adverse events between impaired and non-impaired groups.

Figure 1. LS mean change in the SAPS-PD score to Week 6 for pimavanserin and placebo in the overall population and by baseline MMSE score (46)

Figure 1. LS mean change in the SAPS-PD score to Week 6 for pimavanserin and placebo in the overall population and by baseline MMSE score (46)

 

A Phase 2 study of Pimavanserin for ALzheimer’s disease psychosis

A completed study suggests that pimavanserin is effective in reducing hallucinations and delusions in patients with ADP (30).
This was a Phase 2, 12-week, randomized, double-blind, placebo-controlled, single-center study to assess the safety and efficacy of pimavanserin 34 mg once daily in nursing home residents with ADP (30). The pre-specified primary and secondary endpoints were evaluated at Week 6 of treatment. Eligible patients were required to have a score ≥4 on either the hallucinations or delusions component or a combined hallucinations and delusions score of ≥6 on the Neuropsychiatric Inventory-Nursing Home Version (NPI-NH). During the screening period, patients received brief psychosocial therapy. The primary efficacy endpoint was change from baseline to Week 6 for the NPI-NH psychosis score (delusions + hallucinations domains).
A total of 181 patients were randomized (n=90 pimavanserin and n=91 placebo) with 178 patients were included in the full analysis set (n=87 pimavanserin and n=91 placebo). The mean age of patients was 85.9 years. The mean baseline NPI-NH psychosis score for all patients was 9.8 with comparable mean scores in the pimavanserin (9.5) and placebo (10.0) groups. The mean baseline MMSE score for all patients was 10.1.
For the primary endpoint – drug-placebo difference on change from baseline in NPI-NH psychosis score at Week 6 – pimavanserin demonstrated a significant (p=0.045) treatment effect vs. placebo with a treatment difference of -1.84 and a Cohen’s d effect size of 0.32. Response on the NPI-NH (defined as ≥30% improvement from baseline to Week 6) was observed in 55.2% of subjects in the pimavanserin group and 37.4% of subjects in the placebo group (p=0.016); ≥50% improvement occurred in 50.6% of subjects in the pimavanserin group and 34.1% of subjects in the placebo group (p=0.024). Mean changes from baseline for the MMSE score and UPDRS Part III (motor function) scores were minimal and comparable for pimavanserin and placebo. Patients were followed until week 12. Both pimavanserin and placebo-treated patients continued to improve. The drug-placebo difference at Week 12 – a secondary endpoint – did not reach statistical significance.
This study suggests that pimavanserin may be effective in treating hallucinations and delusions in patients with ADP. Pimavanserin had no adverse effects on motor function (UPDRS) or cognition (MMSE).

 

Subgroup analysis of patients with more severe psychosis at baseline

In the analytic plan of the ADP Phase 2 study data, a pre-specified subgroup analysis was conducted in patients who had more severe psychotic symptoms (hallucinations and delusions) at baseline as measured by NPI-NH psychosis score (30, 47). This pre-specified analysis corroborated the primary endpoint results and showed that patients with more severe psychotic symptoms at baseline (NPI-NH psychosis score ≥12) experienced greater improvement compared to patients with less severe symptoms at baseline (NPI-NH psychosis score <12) (Figure 2). In patients with baseline NPI-NH psychosis score ≥12, LS mean change to Week 6 was -10.15 with pimavanserin vs. -5.72 with placebo (delta= 4.43, Cohen’s d = 0.734, p=0.011), which was a substantively larger treatment effect compared to patients with NPI-NH psychosis score Prespecified responder analyses in residents with more severe baseline symptoms also demonstrated the significant effect of pimavanserin compared with placebo in patients with ADP (Figure 3). A significantly greater proportion of the pimavanserin patients showed ≥30% improvement from baseline and ≥50% improvement from baseline on their NPI-NH psychosis score. Among patients with a NPI-NH psychosis score ≥12, response for pimavanserin and placebo (defined by ≥30% improvement from baseline to Week 6) was observed in 88.9% vs. 43.3% (p<0.001) and, when defined by ≥50% improvement was 77.8% vs. 43.3% (p=0.008), respectively.
Thus, in the subgroup of patients with more severe psychotic symptoms at baseline, significant improvements in mean NPI-NH psychosis score and in NPI-NH responder rates were observed with pimavanserin vs. placebo. These findings were consistent with the observations in the overall population and demonstrate the robust significant treatment effect of pimavanserin vs. placebo in patients with severe symptoms of psychosis at baseline.

Figure 2. LS mean change from baseline to Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 2. LS mean change from baseline to Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 3. Response rate at Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

Figure 3. Response rate at Week 6 for the NPI-NH psychosis score among the overall population from a randomized, placebo-controlled study (30) and in subgroups by severity of psychosis (47)

 

Pimavanserin for the treatment of DRP

The efficacy and safety of pimavanserin for treatment of psychotic symptoms in dementia are being evaluated in an ongoing study: a Double-blind, Placebo-controlled, Relapse Prevention Study of Pimavanserin for the Treatment of Hallucinations and Delusions Associated With Dementia Related Psychosis (Clinicaltrials.gov. NCT03325556). The study is designed to evaluate the efficacy of pimavanserin in preventing relapse of psychotic symptoms in patients with DRP following 12 weeks of open-label treatment with pimavanserin followed by blinded randomized withdrawal of treatment or continued pimavanserin therapy.
Eligible patients will include those who meet criteria for all-cause Dementia according to National Institute on Aging-Alzheimer’s Association (NIA-AA) guidelines (48) as well as satisfying clinical criteria for one of the following disorders (with or without cerebrovascular disease): PDD (49), DLB (50), possible or probable AD, frontotemporal degeneration spectrum disorders (51-53) or vascular dementia (54). In addition, patients will have an MMSE score ≥6 and ≤24, have psychotic symptoms for at least 2 months, SAPS H+D ≥10; CGI-S ≥4 (moderately ill), and have at least one SAPS H+D global item ≥4 (corresponding to moderate or severe psychosis). For those patients taking a cholinesterase inhibitor and/or memantine, the dose of this medication must remain stable for at least 12 weeks prior to baseline. Patients on AP medications at screening will need to be tapered off their medication prior to baseline, if medically appropriate, or they will be excluded. Brief psychosocial therapy will be administered during screening to identify patients who respond to non-pharmacological therapy, and thus who are no longer appropriate for enrollment.
After a 4-week screening period, approximately 360 patients will enter an open-label period with flexible dosing of pimavanserin. At 12 weeks, patients who met specific criteria for sustained response to open-label treatment at both 8 and 12 weeks will be randomized to a daily dose of pimavanserin 20 or 34 mg (based on their open-label dose) or placebo for 26 weeks. The primary outcome is time from randomization to relapse of psychosis in the double-blind period. Relapse is defined as a ≥30% increase from Week 12 on the SAPS-H+D Total Score and a CGI-I score of 6 or 7; treatment with an additional antipsychotic for DRP; patient withdrawing from the study for lack of efficacy; or hospitalization for worsening DRP. A key secondary outcome is time from randomization to “all-cause” discontinuation from the double-blind period.
There are several advantages of the relapse prevention design of this study. First, it maximizes the duration of exposure to a potentially effective treatment (pimavanserin) and minimizes the duration of exposure to placebo (55, 56). A second advantage is the enrichment of the study population with an open-label, run-in phase, which helps to minimize inclusion of non-responders. Also, Brief Psychosocial Therapy will be used at screening to eliminate patients who respond to non-pharmacological therapies, ensuring that most patients in need, receive pharmacological treatment. In addition, the withdrawal design affords the advantage of offering potentially therapeutic medication to all participants at enrollment, making it more feasible to enroll persons with active psychosis who might otherwise be unwilling or unable to consider trial participation. This addresses a major barrier to enrollment in trials when treatment is perceived as most necessary. Similar designs have been used successfully with a number of antipsychotics and antidepressants to demonstrate long-term efficacy and safety in a range of psychiatric indications (57). This design is aligned with 2017 American Psychiatric Association guidelines for use of antipsychotic drugs in dementia patients: if a drug demonstrates no efficacy after 4-6 weeks, therapy should be discontinued. If a drug demonstrates efficacy within 16 weeks, an attempt should be made to taper off medication to determine if ongoing therapy is necessary.
The conceptual basis for using pimavanserin in DRP is based on the observation that a common feature of antipsychotics is antagonism of the 5-HT2A receptor (26) and that this effect is applicable regardless of the associated neuropathology (plaques, tangle, Lewy bodies, TDP-43, vascular lesions). The emergence of psychotic symptoms in many types of dementia suggests that diverse pathologies may give rise to a common symptom complex; this final pathway may be subject to modification from 5-HT2A receptor antagonism.

 

Summary

Clinical evidence is now available that supports potential efficacy of pimavanserin in DRP. This includes results from a Phase 3 study in patients with PDP (29), a secondary analysis of 25% of patients enrolled in this study who also had cognitive impairment (MMSE of 21 to 24) where the observed effect size (Cohen’s d) in the subgroup of patients with PDP and cognitive impairment was 0.99, and a Phase 2 study in patients with ADP (30) indicating a robust effect in patients with more severe psychosis (47).
Across two different models of DRP (PD and AD) pimavanserin has demonstrated meaningful efficacy larger than that reported with current off-label treatments. These clinical data, coupled with a substantial body of research, suggest that psychotic symptoms can manifest independent of the underlying dementia subtype.
In summary, based on the overlap in clinical presentation and pathology, as well as in management of psychotic symptoms in patients with dementia, and importantly, the positive clinical trial results in two neurodegenerative patient populations (PD and ADP), pimavanserin’s effect in patients experiencing hallucinations and delusions associated with DRP across a number of neurodegenerative disorders is being investigated.

 

Acknowmedgement: The authors acknowledge the editorial assistance of Richard S. Perry, PharmD in the preparation of this manuscript, which was supported by ACADIA Pharmaceuticals Inc., San Diego, CA.

Funding: This study was funded by ACADIA Pharmaceuticals Inc., San Diego, California. All authors as well as the sponsor were involved in the design and conduct of the study; the collection, analysis, and interpretation of data; in the preparation of the manuscript; and in the review or approval of the manuscript.

Conflicts of interest: JLC has provided consultation to ACADIA, Accera, Actinogen, ADAMAS, Alkahest, Allergan, Alzheon, Avanir, Axovant, Axsome, BiOasis Technologies, Biogen, Boehinger-Ingelheim, Eisai, Genentech, Grifols, Kyowa, Lilly, Lundbeck, Merck, Nutricia, Otsuka, QR Pharma, Resverlogix, Roche, Samus, Servier, Suven, Takeda, Toyoma, and United Neuroscience companies. Dr. Cummings is supported by Keep Memory Alive (KMA), COBRE grant # P20GM109025; TRC-PAD # R01AG053798; DIAGNOSE CTE # U01NS093334. PT reports the following (pertinent for the last two years): consulting fees from Abbott Laboratories, AbbVie, AC Immune, Acadia Pharmaceuticals, Auspex, Boehringer-Ingelheim, Chase Pharmaceuticals, Eisai, Glia Cure, Insys Therapeutics, and Pfizer; Consulting fees and research support from AstraZeneca, Avanir, Eli Lilly, Lundbeck, and Roche; Research support only from Amgen, Avid, Biogen, Elan, Functional Neuromodulation (f(nm)), GE Healthcare, Genentech, Novartis, Targacept, NIA, and Arizona Department of Health Services; he is a contributor to a patent owned by the University of Rochester, “Biomarkers of Alzheimer’s disease” and owns stock options in Adamas, and he has received research support, consulting fees, and serves on an advisory board for Merck and Co. Dr. Ballard has received grants and personal fees from ACADIA and Lundbeck, personal fees from Heptares, Roche, Lilly, Otsuka, Orion, GlaxoSmithKline, and Pfizer. JY, EF, SS, RO, and JN are employees of and stockholders in ACADIA Pharmaceuticals Inc.

Ethical standard: The study adheres to the Declaration of Helsinki human protection guidelines and was reviewed by ethical standards boards for all participating sites.

Open Access: This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

 

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INTER-SPECIES GLIA DIFFERENCES: IMPLICATIONS FOR SUCCESSFUL TRANSLATION OF TRANSGENIC RODENT ALZHEIMER’S DISEASE MODEL TREATMENT USING BEXAROTENE

G. Bartzokis1,2,3

1. Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; 2. The Brain Research Institute, The David Geffen School of Medicine at UCLA, Los Angeles, CA 90095; 3. Greater Los Angeles VA Healthcare System, West Los Angeles, CA, 90073.

Corresponding Author: George Bartzokis, M.D., 300 UCLA Medical Plaza, Suite 2200, Los Angeles, CA 90095-6968. Telephone # (310) 206-3207; e-mail: gbar@ucla.edu.

J Prev Alz Dis 2014;1(1):46-50

Published online November 19, 2014, http://dx.doi.org/10.14283/jpad.2014.20


 

Abstract

Despite a multitude of efficacious treatments for the cognitive symptoms and pathology in transgenic mouse models of Alzheimer’s disease (AD), success in human trials has been elusive. Rodent-human brain dissimilarities may help explain failures of past human trials and improve outcomes of future ones. This review highlights the essential role of the human brain’s exceptional myelination in achieving and maintaining optimal brain functions, as well as underlying its vulnerability to age-related myelin breakdown and the degenerative brain diseases that process can trigger. This alternative myelin- centered perspective is used herein to help explain key disconnects in the existing treatment literature by focusing on recent reports on brain effects of bexarotene, the only marketed retinoid X receptor (RXR) agonist. The myelin perspective exposes significant yet underexplored opportunities for novel treatment and prevention interventions that have the potential to considerably reduce the tremendous burden of degenerative brain diseases.

Key words: White matter, oligodendrocyte, apolipoprotein E, retinoid X receptor (RXR), liver X receptor (LXR), retinoic acid receptor (RAR), peroxisome proliferator-activated receptor gamma (PPARγ), treatment, dementia, multiple sclerosis, Parkinson’s disease, Lewy body dementia, schizophrenia.


 

Introduction

Deficient retinoic acid (RA) signaling has been proposed to contribute to Alzheimer’s disease (AD) (1) since in humans, retinoid X receptor (RXR) levels decline with age (2) as do brain retinol levels (3). Wild-type mice do not develop brain protein deposits of beta amyloid (Aβ) and tau which help form the neuritic plaques and neurofibrillary tangle lesions that define the pathology of AD, the most prevalent dementia of old age in humans. Nevertheless, hypo functioning of retinoid signaling mechanisms contributes to aging-related declines in rodent hippocampal memory functions while treatment with RA (4, 5) or other signaling activators acting through obligatory heterodimers (see below) (6) can help reverse age-related cognitive decline even in otherwise healthy wild-type mice. Dysfunction of the RXR and retinoic acid receptor (RAR) signaling in forebrain has been shown to impair synaptic long term potentiation (LTP), long-term (hippocampal) social recognition, and episodic memory (5).

High frequency action potential bursts are required to produce LTP and thus help encode memories. Such bursts are better sustained by the over 30-fold shorter refractory times between action potentials made possible by axonal myelination. The breakdown and loss of myelin may thus diminish high frequency bursts and degrade the timing and synchrony of neural network oscillations on which optimal cognitive and behavioral functions depend (7, 8). The age-related breakdown and loss of myelin has been proposed as a fundamental mechanism for age-related cognitive decline which, when accelerated by suboptimal genetics (such as apolipoprotein E4 (ApoE4) or mutations that cause familial AD) and/or environmental/metabolic insults, eventually progresses to AD (reviewed in 9). Augmenting retinoid signaling may be a viable promyelinating intervention that could be developed into treatments for AD and other degenerative brain disorders where age is an important risk factor (9, 10).

Bexarotene (TargretinTM) is a synthetic selective RXR agonist and currently the only such compound marketed for human use as a relatively well tolerated anticancer drug whose toxicities include central hypothyroidism, xeroderma, and elevation of cholesterol and triglycerides (11). RXR forms obligatory heterodimers with a large number of class II nuclear receptors, including RAR, liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPAR). The heterodimer partners of RXR share the same dimerization interface and thus compete with each other for DNA binding. Activation of such heterodimers can accelerate peripheral and central remyelination (12, 13).

In a transgenic rodent model of AD, bexarotene was reported to improve neural network oscillations and cognitive and social functions (14). These improvements were noted both in earlier and advanced stages of AD pathology. The improvements were ascribed to the clearance of insoluble Aβ plaque deposits in the hippocampus and cortex and increased degradation of soluble oligomeric Aβ, which is widely believed to be the toxic cause of AD. Five studies aimed to replicate these results (15-19). None of them replicated Aβ plaque removal and some did not replicate soluble Aβ reductions (15, 19) while others did (17, 18). Nevertheless, all five studies replicated increased lipidation (increased lipid transporters ABCA1 (15-19) and apolipoprotein E (ApoE) (16, 18)) while a sixth study directly demonstrated that ApoE increases in brain interstitial fluid upon treatment with bexarotene (20). Importantly, of the four studies that examined cognition, three showed treatment-related improvements (14, 15, 18) while the fourth one did not (19). Similar improvements in cognitive function have also been observed when AD transgenic mice were treated with more toxic LXR agonists (21-23). Unfortunately none of the above studies examined the impact of bexarotene on myelin, the most lipid-rich structure within the CNS, despite the fact that these treatments target and augment key lipidation molecules (ApoE and ABCA1) that are essential for myelination (9, 13).

The general acceptance of Aβ toxicity as the cause of AD (the “amyloid hypothesis” of AD) has guided the vast majority of treatment research for the past 20 years including the bexarotene studies summarized above. These studies examined the proposition that increased levels of ApoE, its lipidation transporter (ABCA1), and high density lipoprotein (HDL), combine to promote proteolytic degradation of soluble forms of oligomeric Aβ. The mechanism of action of bexarotene seems to require an increase in ApoE since treatment-related changes were not observed in mice lacking the ApoE gene (14). However, a recent study seems to refute the possibility that direct binding of ApoE to Aβ is the mechanism that accelerates Aβ clearance (24). Nevertheless, targeting Aβ through a variety of mechanisms has frequently succeeded in clearing Aβ, removing plaques, and improving cognitive performance in transgenic mouse models of AD. However, these same treatment targets failed to translate into efficacy in human AD trials, even when Aβ plaques were successfully reduced. The failures have been largely attributed to initiation of treatments at a disease stage that was “too late” to change clinical outcome for humans although such treatments seem efficacious in rodents with advanced pathology (14). These and many other inconsistencies have cast doubts on the Aβ-driven pathogenic mechanism at the core of the amyloid hypothesis of AD (reviewed in 9, 25).

The combined human and non-human data have been reconsidered from a systems science perspective that takes into account the evolutionary differences between species such as rodents, primates, and humans and the exceptional susceptibility of humans to develop AD pathology (9, 10, 26). During mammalian brain evolution, hyperscaling of white matter (WM) relative to gray matter (GM) seems to be a consistent feature (27). Amongst primates, the human species has by far the largest brain and, because WM volume hyperscales (while GM scales in direct proportion to the rest of the brain), our brain has proportionately more WM (28, 29). WM makes up approximately 50% of human brain volume which is approximately 20% more than chimpanzees and 500% more than mice (27). Furthermore, approximately 50% of WM is myelin however, in the adult human brain, GM is also exceptionally myelinated compared to other species (30). Thus the inter-species disparity in myelin content (as opposed to WM content) may be considerably greater than the proportions of brain WM listed above.

Normal cognition and behavior depend on the synchronized oscillations of a vast array of neural networks which is made possible by the exquisite timing afforded by optimal brain myelination. To maintain optimal function the adult human brain must maintain and repair/remyelinate over 150,000 km of myelinated fibers (31). This task is especially daunting when one considers that oligodendrocytes and the myelin they produce are exceptionally vulnerable to a variety of insults ranging from traumatic and toxic to metabolic and vascular ones (10). These vulnerabilities together with an age-related decline in the efficiency of remyelination (32), make the maintenance/repair of myelin’s functional integrity of a fully myelinated middle aged human brain increasingly difficult. This results in a generalized age- related decline in myelin integrity in primates and humans (7, 31, 33) that is muted or absent in rodents (34). In humans, the generalized process of age-related myelin breakdown and loss (31, 33) may underline declines in motor and cognitive functions (35, 36). Post mortem and imaging studies confirm that this generalized subcortical myelin loss is more severe in AD (37-40) and reveal that in the cortex, Aβ plaques themselves are associated with focal demyelination (41) and loss of oligodendrocytes (42).

Myelin damage and loss seems to occur prior to the appearance of amyloid and tau lesions in AD transgenic mice (43) and years before clinical symptoms appear in humans predestined to develop the disease due to genetic predispositions (35, 44). An alternative “myelin hypothesis” of AD proposes that production of Aβ, tau, pathologic lesions, and synaptic, axonal, and neuronal losses are byproducts of upstream myelin breakdown and repair processes. These processes involve many of the risk factors, genes, proteins, and lipids associated with AD (age, ApoE, amyloid precursor protein, and gamma and beta secretases, cholesterol, etc.) (9). Thus myelin breakdown and loss is hypothesized to contribute to age-related cognitive declines that can be accelerated by suboptimal genetics and environmental/metabolic factors and result in the more severe deficits associated with AD. The concomitant homeostatic myelin repair/remyelination mechanisms, especially when inefficient, secondarily cause the accumulation of the amyloid and tau proteinaceous brain lesions that have been used to define this disease. The promotion of efficient myelin repair/remyelination may therefore be an essential ingredient needed for clinical improvements to be realized in AD treatment and prevention trials.

In the exceptionally myelinated human brain, ApoE has an especially important role in myelination (13, 35,45) and its deficiency results in age-related degeneration (46) and memory impairment (47). Its role is probably most poignantly exemplified by the striking differences in the risk of developing AD between individuals that carry the ancestral (primate) ApoE4 allele versus the newly evolved ApoE3 and ApoE2 variants present in approximately 85% of humans. Carriers of the ApoE4 allele have fewer ApoE molecules compared to non- carriers (reviewed in 48). A quantitative gradient (ApoE2>ApoE3>ApoE4) is observed in CSF of humans and transgenic mice that had these human ApoE alleles knocked in (49-51). In the face of a generalized and accelerating age-related myelin breakdown process of the middle-aged human brain (31, 33), a reduced capacity to mobilize these lipids and remove/recycle them to aid in remyelination may be a critical disadvantage for ApoE4 carriers.

After aging itself, the presence of an ApoE4 allele is not only the predominant genetic risk factor for late onset AD (increasing risk approximately 10-fold). ApoE4 is also a powerful risk factor for the two other common age- related degenerative diseases: dementia with Lewy bodies (DLB – increasing risk 6-fold) and Parkinson’s disease dementia (PDD – increasing risk 3-fold) (52). The pathology of DLB and PDD differs from that of AD and is characterized by proteinaceous lesions containing alpha- synuclein. It is important to note therefore that the above estimates of increased ApoE-related dementia risk were obtained in selected, pathologically “pure”, samples of each of these three diseases (52). The generalized effects of ApoE on different age-related destructive diseases suggests that in human brain, ApoE’s principal effect may be associated with repair/remyelination (9, 35) as opposed to being limited to an Aβ clearance role (14). Within this wider framework it is not surprising that a recent study of a toxin-induced rodent model of Parkinson’s disease (PD) confirmed that low dose bexarotene was able to increase ApoE, reduce cell loss, as well as mitigate motor and cognitive deficits (53). In healthy humans without cognitive impairment, the lower myelin repair/remyelination associated with ApoE4 alleles seems to mediate an accelerated age-related decline of myelin integrity and cognitive performance (8, 35) that may ultimately manifest as an increased risk and earlier onset of AD as well as other degenerative diseases (52) and worse repair/recovery from traumatic brain injury (54). Not surprisingly, the degraded myelin repair ability associated with ApoE4 alleles may also manifest as worse outcomes for patients with multiple sclerosis, a canonical myelin disease (55).

The existing evidence of bexarotene’s efficacy in mice models may provide the opportunity to compare and test the amyloid- and myelin-centered perspectives and could facilitate the first successful translation of a treatment from transgenic mouse models of AD to the human disease. This assessment is based on the probability that, unlike the many other failed antiamyloid approaches, the underlying mechanism of action of bexarotene is not limited to reducing Aβ , the focus of the prior investigations (14-18). Consideration should be given to the possibility that in the exceptionally myelinated human brain, myelin-related mechanisms upstream of Aβ are etiologically important for AD and other degenerative diseases. These myelin-related mechanisms may contribute to treatment efficacy observed in transgenic mouse models that may fail in humans in part because, unlike humans (who sustain a 45% loss of myelin primarily from late- and thinly-myelinated fibers) (31, 33), mice do not seem to undergo substantial age- related myelin losses (34) and can more easily repair the 5-fold smaller proportion of myelin in their brains (42). In addition to increasing ApoE, RXR activators may act through additional mechanisms. Fantini et al. (56), using SH-SY5Y cells, showed that bexarotene blocks the cholesterol-dependent increase of calcium fluxes induced by β-amyloid peptides, suggesting a direct effect of the drug on potentially damaging amyloid channel formation. It is also important to note that unlike familial AD, on which transgenic models are based, sporadic AD is not associated with the same genetic defects and consequently, transgenic mice might not be the optimal model for sporadic AD.

Vitamin A and its RXR agonist metabolites such as RA are important signaling molecules during development (57) and during myelin repair/remyelination (58). Their deficiency interferes with myelination (59) and can result in Aβ accumulation (60) supporting the suggestion that Aβ is a byproduct of inefficient myelin repair/remyelination (9). Correcting such signaling deficits increases myelin lipids in a dose-dependent manner (59) and can help reverse age-related cognitive decline even in otherwise healthy wild-type mice (4, 5) that do not develop AD- or DLB/PDD/PD-associated brain lesions.

A multi-pronged enhancement of myelin repair/remyelination may be a broader “upstream” explanation for the successes of RXR agonists such as bexarotene in AD and PD models as well as aging wild- type mice. Augmenting myelin repair in the aging brain should be particularly pertinent to the human brain whose much larger size and greater proportion of myelin combine to markedly increase its vulnerability and need for protection and continual repair/remyelination (10).

Multi-pronged treatments such as bexarotene and similar RXR agonists (61), as well as other compounds that act through PPARγ:RXR or LXR:RXR heterodimers and PPARγ activation (12) can potentially improve myelin repair/remyelination efficiency. Such treatments could thus ameliorate the cognitive and behavioral changes associated with aging and AD (9) as well as possibly aiding in the treatment of a variety of other neuropsychiatric disorders involving myelin damage ranging from vascular insufficiency to multiple sclerosis and even schizophrenia (10, 11).

In contradistinction to the amyloid hypothesis of AD, the myelin-centered perspective can help explain many key “disconnects” apparent in the AD literature. These include the weak association between the brain burden Aβ lesions and clinical manifestations of human dementia and the success of antiamyloid and other treatments in curing the “AD” of transgenic mouse models (with robust wild-type myelin (34)) while the same treatments have failed in human AD trials (9, 25, 42). These failures could be due, at least in part, to the remarkably larger myelin repair burden of the more vulnerable aging human brain (31, 33). The myelin repair perspective predicts that a multipronged approach that reduces myelin damage, increases debris clearance, and promotes remyelination should prove most effective in the treatment of AD and other degenerative brain disorders (10). This perspective also suggests that in the context of carefully monitored clinical trials that include sensitive MRI assessments of myelination, bexarotene and similar compounds may hold enough promise of efficacy for patients suffering from impairments caused by myelin-related diseases to counterbalance the risks associated with their considerable side effects.

 

Acknowledgment: Editing by Christina I. Bartzokis is gratefully acknowledged.

Funding: This work was supported in part by NIH grants (MH 0266029; AG027342), the Litwin and RCS Foundations, and the Research and Psychiatry Services of the Department of Veterans Affairs. The sponsors had no role in the design and conduct of the research; in the collection, analysis, and interpretation of data; in the preparation of the manuscript; or in the review or approval of the manuscript.

 

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