Use of Eflornithine (DFMO) in the Treatment of Early Alzheimer's Disease: A Compassionate Use, Single-Case Study

Abstract

Background: Recent genome-wide association screening (GWAS) studies have linked Alzheimer's disease (AD) neuropathology to gene networks that regulate immune function. Kan et al. recently reported that Arg1 (an anti-inflammatory gene that codes for arginase-1) is expressed in parts of the brain associated with amyloidosis prior to the onset of neuronal loss, suggesting that chronic brain arginine deprivation promotes AD-related neuropathology. They blocked arginine catabolism in their mouse AD model by administration of eflornithine (DFMO) to juvenile animals, effectively blocking the expression of AD-related amyloid pathology as the mice aged. We report results from a single-case study in which DFMO was administered, for the first time, in an attempt to slow progression of AD in a single woman with multi-domain, amnestic MCI who was unable to tolerate an acetylcholinesterase inhibitor. Methods: Patient C.S. is a 74-year old female with a 5-year history of cognitive decline who was placed on DFMO (500 mg b.i.d.) for 12 months, with amyloid PET scans (baseline and 12-months), APOE genotyping and neuropsychological exams at baseline, 3, 9, and 12 months. Results: C.S. suffered continued cognitive decline over 12 months, including progressive worsening of orientation, social functions and ability to engage in IADL's. She also showed progressive decline on measures of episodic memory and executive function. Florbetapir PET imaging yielded elevated total neocortical SUVr scores at both baseline (SUVr = 1.55) and at 12 months (SUVr = 1.69). Conclusions: We report a first attempt at using DFMO to slow AD progression. This 12-month single-case trial did not halt continued amyloidosis nor cognitive decline. Although this trial was predicated on data reported by Kan et al. (2015) showing that DFMO administered to juvenile AD-prone mice led to diminished amyloid aggregation, this attempt to treat an older mild AD patient may not be a fair test of Kan et al.'s model and results. A future trial might seek to block amyloidosis in young adults who are autosomal gene carriers for early onset AD, or perhaps in adults who are very clearly in the pre-clinical disease stage. Trial Registration: This trial was registered as a Compassionate Use IND #128888 with the United States Food and Drug Administration (FDA).

Keywords: Alzheimer's disease; amyloid pathology; case study; eflornithine (DFMO); mild cognitive impairment.

Figure 1

Results on primary outcome measures for patient CS over 12 months of DFMO therapy. (A) Results on the Mini-Mental Status Exam (MMSE)/30 at baseline, 3, 6, and 12 month exams. CS' MMSE score declined 4 points over the 12 month treatment period, from 26/30 to 22/30, indicating generalized cognitive decline. (B) Results on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) 11—item at baseline, 3, 6, and 12 month exams. Patient CS' ADAS-Cog score increased by 3 points over the 12 month treatment period, from 30/70 to 33/70. Higher scores on this test indicate increased cognitive impairment. (C) Results on the delayed recall portion of the Logical Memory stories at baseline, 3, 6, and 12 month exams. The patient showed impaired verbal learning and episodic memory throughout the 12 month treatment period. Although the patient recalled 6/25 items at the 12 month visit, this was not concurrent with results on other episodic memory tests such as the ADAS-Cog word list learning and recall (0/10 words at delayed recall) and the ISLT (2/12 shopping items at delayed recall). (D) SUVr on Florbetapir PET scan at baseline (1.55) and after 12 month treatment period (1.69).