Abstract
We present the effects of Targretin® (bexarotene) on cognition and biomarkers in a patient with mild Alzheimer’s disease (AD). Targretin® is a Retinoic X Receptor (RXR) agonist shown to improve synaptic and cognitive functions in animal models of AD by increasing neuronal cholesterol efflux. After 6 months of treatment with Targretin® 300 mg/day, memory improved by about 40% and the tau protein in the cerebrospinal fluid decreased by about 20% . No significant side effects were noticed. This observation in a single patient indicates that Targretin® may improve memory performance and biological markers at an early stage of AD.
INTRODUCTION
Despite the evaluation of numerous potential treatments in clinical trials in the last 30 years, there is still no available therapy able to influence the course of AD [1]. Regardless of this worrying situation, key players in the pharmaceutical industry have recently closed or significantly decreased their R&D spending on AD [2]. Therefore, we clearly need fresh and creative ideas that could provide test tracks for the future. In this communication we will present the effects of Targretin® on cognition and biomarkers in a patient suffering from mild AD.
Targretin® (bexarotene) is a Retinoic X Receptor (RXR) agonist that was approved by the US Food and Drug Administration (FDA) for the treatment of cutaneous T cell lymphoma [3].
Bexarotene was recently demonstrated to decrease brain amyloid burden and to improve cognitive deficits in an AD mouse model [4]. Although this track was not considered as valuable because the effects on the amyloid load were not confirmed in follow-up studies [4–9], the RXR agonist was reported to restore memory in different mouse models of AD with or without reduction of amyloid burden [4–8].
Polymorphisms in genes encoding proteins involved in cholesterol homeostasis are associated with AD [10, 11], and abnormal accumulation of cholesterol has been demonstrated in postmortem AD brain [12], arguing that perturbation of cholesterol homeostasis favors progression of AD.
Neuronal cholesterol homeostasis is known to be essential for basic synaptic function, plasticity, and behavior, and we have recently demonstrated that the amyloid-β protein precursor, producing amyloid-β peptide (Aβ) accumulated in senile plaques of AD, controls cholesterol turnover needed for neuronal activity [13].
The beneficial effects of RXR agonists reported on synaptic and cognitive functions are based on their ability to increase cholesterol efflux [14], further emphasizing the stimulation of neuronal cholesterol turnover as a possible target for the treatment ofdementia.
However, to the best of our knowledge, effects of bexarotene in AD patients were not reported so far, despite the fact that Targretin® is available in many countries, including Belgium, as adjuvant therapy in cases of cutaneous involvement in advanced stages of some types of T-cell lymphoma (http://www.cbip.be/)
MATERIALS AND METHODS
Patient
The patient is a 68-year-old man with university level education. He was diagnosed and followed-up at the Memory Clinic of Saint Luc university Hospital, Brussels. Nineteen months before Targretin® treatment, a slight episodic memory deficit was observed. The Mini-Mental State Exam was 26/30 [15]. He underwent a comprehensive diagnostic assessment including a standard blood sample, ApoE genotyping, a brain MRI scan, and a full neuropsychological examination. On basis of this evaluation, the patient was diagnosed with amnestic mild cognitive impairment (only memory measures showed impairment when compared with matched controls and the patient conserved good everyday functioning). He was found heterozygous for the ApoE4 allele. One year later (7 months before Targretin®), in the context of clinical deterioration, a new cognitive assessment was performed and supplementary examination was carried out. Brain imaging with [18] FDG-PET showed a significant hypometabolism in posterior areas, in particular in the posterior cingulate cortex, as well as a significant amyloid load in the brain on [18] flutemetamol PET [16, 17], both characteristic of AD (Fig. 1). The dramatic impairment in memory performance with impact on daily functioning, the typical hypometabolism pattern on [18] FDG-PET, and the positive amyloid [18] flutemetamol PET scan warranted a diagnosis of AD. The patient was administered an acetylcholinesterase inhibitor (Galantamin 24 mg/day) for seven months with no significant improvement but no further deterioration either. Then, the patient himself and his relatives required testing Targretin® after having read about its potential benefit in AD [4]. As the drug is not registered for this indication, the patient and his prescribing physician decided to use the product off-label. The local ethics committee approved the inclusion of the patient in a follow-up procedure. The patient and his nearest relative gave an informed consent.
Treatment administered, clinical and neuropsychological assessments
Targretin® was taken at the dose of 300 mg/day. The patient also received corrective therapy with thyroid hormones (L-thyroxin 50 micrograms/day) and fenofibrate 200 mg/day. A careful monitoring of blood cholesterol, liver and pancreatic enzymes, blood cell count, and thyroid function was carried out. The time points considered in the study were defined as follows: T-19 corresponds to the first examination and T-7 to the second one, nineteen and seven months before Targretin® respectively. The baseline just before starting the drug was T0 and the evaluation after 6 months of treatment with Targretin® was T+6. At T0 and T+6 a neuropsychological assessment and a spinal tap with cerebrospinal (CSF) biomarkers analysis were performed. The neuropsychological battery evaluated memory (M), language (L), executive functions (E), and visuo-spatial processing (V) with three measures each. The memory test was the Free and Cued Selective Reminding Test (FCSRT)– version in French as RL/RI 16 Test (M1, M2, M3 for the sum of 3 free recalls, the sum of 3 free plus cued recalls and the delayed free recall, with the cut-offs at 26/48, 42/48, and 9/16, respectively). For a full description of the tests used, see [17]. The CSF analysis included a dosage of tau, phospho-tau, and Aβ concentrations in the CSF with enzyme-linked immunosorbent assays (Innogenetics NV, Ghent, Belgium). A [18] flutemetamol PET scan was also obtained at T+6.
RESULTS
Targretin® was well tolerated with no clinical side effects noticed. Cholesterol level in the blood raised but it did not exceed 250 mg/dl for the total and 175 mg/dl for the LDL-cholesterol throughout the study. No other biological side effects were recorded.
During the 6 months period under Targretin® therapy, the patient and his relatives reported an improvement in everyday life although not a normalization of memory functioning. The neuropsychological examination, before and after therapy with Targretin®, is shown in Fig. 2A. Six months after Targretin® treatment (T+6), episodic memory was clearly improved for both the free and cued recall by about 40% compared to baseline (T0) and no deterioration was noticed in other cognitive domains. Tau and phospho-tau concentrations measured in the CSF obtained by lumbar puncture were frankly abnormal whereas the Aβ concentration was borderline at T0 [18]. A 20% decrease in total-tau, a 10% decrease in phospho-tau, and a 10% increases in Aβ concentrations were measured in the CSF after six months of treatment with Targretin® at T+6: see Fig. 2B. Following treatment, a slight 2.08 to 1.94 decrease in [18] flutemetamol standardized uptake value ratio (SUVr) was measured (cut-off 1.6, see [17]).
DISCUSSION
Altogether, these results indicate that a 6 months treatment with Targretin® in an AD patient at an early stage of the disease may improve memory performance and biological markers. The diagnosis of AD in this patient is suggested by the clinical presentation (increasing amnestic syndrome with an impact on everyday life) and strongly supported by biological markers recommended by the NIA and AA [19], showing abnormal deposition of Aβ in the brain on [18] flutemetamol PET, abnormal hypometabolism in typical cortical areas on the [18] FDG-PET and elevated levels of tau and phospho-tau protein in the CSF in an ApoE4 allele carrier. Although the CSF Aβ was above the cut-off used (500 pg/ml), we considered, however, this result as “borderline”. In a recent metanalysis [20], the cut-offs used by 30 centers for the CSF Aβ with the same test were between 380 and 662,65 pg/ml, so according to other normative samples, our results would have been interpreted as pathological. CSF Aβ and amyloid PET imaging measurements are inversely associated in the majority of subjects, so for this matter our case may appear discordant. Nevertheless, PET amyloid+/CSF Aβ– cases have been described and associated with earlier stages of impairment [21]. The changes in cognition and particularly the improvement of all three memory scores on the Free and Cued Selective Reminding Test by about 40% is highly unusual in the natural evolution of patients with a mild form of AD [22] and may suggest a beneficial effect of Targretin®. Although we cannot exclude a placebo effect this explanation seems unlikely as no such effect was observed when the patient was treated with Galantamin. Moreover, the positive effect on the CSF biomarkers with a substantial decrease of about 20% in tau levels at T+6 is intriguing. In a recent study on CSF biomarkers the test-retest mean coefficients of variation were of 12.2% for Aβ and 11.3% for tau [23]. Following treatment, only a slight (about 10% ) variation in the Aβ CSF level and brain deposits measured by PET was recorded, indicating the supposed improvement in memory and tau levels may be amyloid independent. It must be acknowledged that no firm conclusion could be drawn from the study of a single patient. Obviously, much more consolidated data are needed in order to validate the use of bexarotene as a potential drug in neurodegenerative diseases, including results from ongoing clinical trials using bexarotene in AD (Clinical trial NCT01782742). However, in our opinion these findings are noticeable enough and should, hopefully, stir-up further research in this area.
