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ARTICLES: M. A. Reger, G. S. Watson, P. S. Green, C. W. Wilkinson, L. D. Baker, B. Cholerton, M. A. Fishel, S. R. Plymate, J.C.S. Breitner, W. DeGroodt, P. Mehta, and S. Craft Intranasal insulin improves cognition and modulates β-amyloid in early AD Neurology 2008; 70: 440-448 [Abstract] [Full text] [PDF]

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Intranasal insulin improves cognition and modulates â-amyloid in early AD

Mandip S. Dhamoon, MD, MPH, James M. Noble, MD   (8 May 2008)

Reply from the authors

Suzanne Craft, PhD   (8 May 2008)

Intranasal insulin improves cognition and modulates â-amyloid in early AD

Per Gisle Djupesland, MD, PhD   (9 April 2008)

Reply from the authors

Suzanne Craft   (9 April 2008)

Intranasal insulin improves cognition and modulates â-amyloid in early AD 8 May 2008
Mandip S. Dhamoon, MD, MPH, The Neurological Institute, Columbia University 710 W 168th Street, New York, NY 10032, James M. Noble, MD Send Correspondence to journal: Re: Intranasal insulin improves cognition and modulates â-amyloid in early AD mdhamoon{at}neuro.columbia.edu Mandip S. Dhamoon, MD, MPH, et al.	At our department’s recent journal club conference, we discussed Reger et al’s report of intranasal insulin in early Alzheimer’s disease (AD). [1] Given findings of epidemiologic and translational research associating diabetes and dementia, these results are an intriguing extension of their earlier work but raised several questions. [2] First, the sample was somewhat heterogeneous—comprising patients with AD but also mild cognitive impairment with amnestic features (MCI-A). Some baseline differences were evident in cognition and serological markers between treatment and placebo. For example, memory savings scores for baseline placebo and treatment, plus 21-day follow-up placebo arms appeared to be different, but would be expected to be rather similar. Could these differences be related to incomplete randomization, possibly related to small sample size? The proportion of AD and MCI-A patients by treatment and placebo groups would be useful to know. Several patients were unable to perform the Stroop Color-Word task or had missing blood work. From which groups were these data missing? Logical memory percent retention and Stroop performance speed were the neuropsychological tests presented. In the group’s previous work, additional tests included the Buschke Selective Reminding Test (SRT), the Self-Ordered Pointing Task, and a visual search task. [2] That report focused on changes in total delayed logical memory and SRT relative to placebo, with no differences identified on tests of attention or processing speed. If other tests were performed but not reported, it would be helpful if the authors could provide a more comprehensive neuropsychological summary. That report also found a significant interaction with APOE genotype. Was APOE genotyping done for this study? Most analyses compared group means rather than differences in individual performance over test sequence yet the latter might be more informative. Concerning the correlation of Dementia Severity Rating Scale (DSRS) changes with the baseline Mattis Dementia Rating Scale (MDRS) (Figure 3), did these data satisfy an assumption of homoscedasticity prior to fitting the correlation line? Lower MDRS in both groups appeared to be associated with higher variance in DSRS. Also, given a seemingly large fluctuation in DSRS over 21 days within one placebo outlier, was exclusion of this outlier considered? Different DSRS scales between the two groups further complicated interpretation. We appreciate the difficulty of undertaking such a study and satisfying all readers. Perhaps this forum will give the authors an opportunity to present other data. We look forward to the results of their ongoing 120-day trial. [3] References 1. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008;70:440-448. 2. Reger MA, Watson GS, Frey WH 2nd, et al. Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype. Neurobiol Aging. 2006;27:451-458. 3. SNIFF 120: Study of Nasal Insulin to Fight Forgetfulness (120 Days). NCT00438568. From http://www.clinicaltrials.gov accessed March 10, 2008. Disclosure: The authors report no disclosures.
Reply from the authors 8 May 2008
Suzanne Craft, PhD, VAPSHCS/University of Washington 1660 South Columbian Way, Seattle, WA 98108 Send Correspondence to journal: Re: Reply from the authors scraft{at}u.washington.edu Suzanne Craft, PhD	We appreciate the careful consideration of our paper by Drs. Dhamoon and Noble. Our sample included both patients with amnestic mild cognitive impairment (aMCI) and early Alzheimer’s disease (AD), diagnosed by expert consensus. When diagnosed in this manner, the majority of patients with aMCI have prodromal AD. [4] The sample was heterogeneous with respect to severity but likely not type of impairment. Most importantly, the two groups contained comparable numbers of aMCI and AD patients (aMCI comprised 50% of the placebo group and 62% of the insulin-treated group), and the groups had comparable dementia severity as indicated in Table 1 by the Mattis Dementia Rating Scale (DRS). Similarly, there were no significant baseline differences between groups on any cognitive measure, nor were there differences in missing data (two placebo- and one insulin-treated participant unable to complete the Stroop, with an identical pattern observed for amyloid). We agree that randomization is difficult for small pilot trials such as ours, and were fortunate that our groups were comparable on cognitive, demographic, and metabolic variables. Our cognitive battery was tightly focused for this pilot effort. We used the Hopkins Verbal Learning Test rather than the Buschke Test because it is more easily administered. One additional test was included (Self-Ordered Pointing Test), but computer malfunction resulted in uninterpretable data for the majority of participants. We used a repeated measures analysis of covariance analytic approach, which is preferable with small samples, given the variability of difference scores for cognitive measures. Our analysis for the Dementia Severity Rating Scale revealed an interaction with dementia severity as indexed by the Mattis DRS, which was then deconstructed by correlating Mattis scores and the change in Dementia Severity Rating over the 21-day period. We reported Pearson correlations, which as noted may be vulnerable to violation of homoscedasticity or outlier effects, particularly in small samples. However, the correlation pattern remains identical and statistically significant when Spearman rank-order correlations are used which protect against the effects of such violations. Finally, the issue of APOE genotype raises an important point. In two previous studies of the acute effects of intranasal insulin, we observed an APOE-related pattern, such that participants without the APOE-e4 allele benefited from insulin, whereas e4 carriers showed no benefit. [2,5] This APOE-related difference has been observed with other manipulations of insulin. [6,7] The pattern may support a specialized role for insulin abnormalities in the pathophysiology of AD for non-e4 carriers, who comprise about half of patients with AD, but for whom no clear risk factor has been identified. In our pilot study, the insulin-treated group was evenly divided with respect to APOE-e4 carriage (e4-=7, e4+=6). These cell sizes are too small to allow exploration of a differential APOE treatment response, but our ongoing larger clinical trial is powered to determine such an effect. [3] We soon hope to have data to address this important question. References 4. Gauthier S, Reisberg B, Zaudig M, et al. Mild cognitive impairment. Lancet 2006; 67;1262-1270. 5. Reger MA, Watson GS, Green PS, et al. Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-â in memory- impaired older adults. Journal of Alzheimer’s Disease; in press. 6. Craft S, Asthana S, Schellenberg GD, et al. Insulin metabolism in Alzheimer’s disease differs according to apolipoprotein E genotype. Neuroendocrinology 1999;295;2750-2757. 7. Risner ME, Saunders AM, Altman JF, et al. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J 2006;4;246-254. Disclosure on article to which this Correpondence refers: W.D. is a founding member of Kurve Technology, the maker and patent holder of the electronic atomizer used in this study. W.D. holds equity interest in excess of $10,000 in Kurve Technology. The remaining authors have nothing to disclose.
Intranasal insulin improves cognition and modulates â-amyloid in early AD 9 April 2008
Per Gisle Djupesland, MD, PhD, CSO, OptiNose AS Send Correspondence to journal: Re: Intranasal insulin improves cognition and modulates â-amyloid in early AD per.djupesland{at}optinose.no Per Gisle Djupesland, MD, PhD	It has come to my attention that the article by Reger et al. [1] includes a significant error in incorrectly attributing an article published by my colleagues and me (Reference 16 - Djupesland et al, JAM 2004). [2] Page 3 (Procedure, lines 4 to 12) states: "The ViaNase device has been specifically designed to deliver drugs to the olfactory region to maximize drug transport to the CNS. This device releases a metered insulin (20 IU) or saline dose into a chamber covering the subject's nose, which then was inhaled by breathing evenly over a 2-minute period. This method allowed administration of smaller particle sizes to increase drug deposition in the upper nasal cavity without transporting the drug to the lungs. 16". This recitation attributes our published article as disclosing that nasal inhalation of a released drug (here insulin) results in no deposition of the drug in the lungs. This is not the case. Our article specifically states in the abstract that the mean deposition in the lungs for sixteen subjects following nasal inhalation is 22.3 ± 8.1% (range 12.2 - 39.3%). It is only with our patented "Bi-directional" delivery technology, which isolates the nose from the lungs during delivery, that there is no or minimal deposition in the lungs. [2] The reference to our publication in this article is incorrect and misleading. References 1. Reger MA, Watson GS, Green PS, et al. Intranasal insulin improves cognition and modulates -amyloid in early AD. Neurology. 2008;70:440-448. 2. Djupesland PG, Skretting A, Winderen M, Holand T. Bi-directional nasal delivery of aerosols can prevent lung deposition. J Aerosol Med 2004;17:249-259. Disclosure: Dr Djupesland is the CSO, a founder and shareholder of OptiNose AS.
Reply from the authors 9 April 2008
Suzanne Craft, VAPSHCS/University of Washington Send Correspondence to journal: Re: Reply from the authors scraft{at}u.washington.edu Suzanne Craft	We incorrectly cited a study by Dr. Djupesland, the author of this letter, supporting the claim that the ViaNase device did not deposit a significant amount of insulin in the lungs. [2] We apologize for this error. A correction will appear in an upcoming print issue. The study that we cited did not utilize the ViaNase device. [2] Instead, the referenced article refers to a device manufactured by OptiNose. Unpublished data obtained from preliminary testing conducted for our trial by Kurve Technology, Inc., makers of the ViaNase device, indicate that lung and/or nasopharyngeal deposition of intranasally administered insulin would likely range between 2 and 9%. This estimate is based on a mean insulin droplet size of 12.2 microns observed during this preliminary testing (William DeGroodt, personal communication). The amount of deposition may conceivably be affected by variation in breathing patterns. However, regarding the potential import of lung or nasopharyngeal deposition on our results, we observed no changes in peripheral insulin or glucose levels immediately following administration of insulin with the ViaNase device during our trial, and it is unlikely that the positive effects we observed on cognition and plasma amyloid were due to lung or nasopharyngeal deposition of insulin. Disclosures: The following disclosure was published with the article to which this letter corresponds: W.D. is a founding member of Kurve Technology, the maker and patent holder of the electronic atomizer used in this study. W.D. holds equity interest in excess of $10,000 in Kurve Technology. The remaining authors have nothing to disclose.