Frederick K. Goodwin, M.D., citing studies corroborating Dr. Kay's work

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April 17, 1998

Ms. Jane L. Eikleberry, Esq. Waterfall, Economidis, Caidwell, Hanshaw & Villamana Williams Centre - Eighth Floor 5210 East Williams Circle Tucson, Arizona 85711

Dear Ms. Eikleberry:

Re: Marguerite M.B. Kay, M.D.

Enclosed is my response to the University of Arizona hearing panel's request for information on studies corroborating the work of Dr. Kay, plus some additional commentary relating to other aspects of my testimony before the panel. A hard copy of my statement, along with copies of all referenced attachments, is being transmitted to you by Federal Express today.

I would appreciate your ensuring that these materials are disseminated to the hearing panel members. Thank you for your consideration in this matter.

Very truly yours,

Frederick K. Goodwin, M.D. Director, Center on Neuroscience, Medical Progress & Society Director, Psychopharmacology Research Center

April 17,1998

Introduction:

This statement responds to the request of the hearing panel for information on papers that corroborate findings in papers by Marguerite M.B. Kay, MD., that have been questioned by the CAFT panel chaired by Dr. Thomas Cetas ("Cetas panel"). In addition, and indeed of greater importance, in the final part of this statement I elaborate my concerns about the significant procedural defects in the University's investigations of Dr. Kay.

Independent corroboration is clearly important; a number of studies corroborating the questioned papers of Dr. Kay are listed below. However, I need not remind the clinical scientists on the hearing panel that most important clinical findings are followed by both replication and non-replication, due largely to the biological heterogeneity of clinical samples. Thus, the ultimate value and validity of Dr. Kay's work will be tested over many years, as the field advances.

On the other hand, it requires no "wait and see" perspective to conclude that the University's proceedings, and the Cetas panel's work in particular, were rife with serious procedural flaws that should be the primary focus. The hearing panel, with its de novo perspective on these matters, has the opporturnty to effect at Ieast a partial redemption of the University, Dr. Kay, and the culture in which biomedical research is conducted on the campus. With the greatest respect, I urge the hearing panel to give the most careful consideration to these issues.

Corroborating Papers:

With regard to the corroborating papers, I should point out that they do not represent "replications" in the usual, post-publication sense. As the panel knows, the questioned papers were published quite recently; as a consequence, there has hardly been time for traditional replication studies to be conducted and published. Accordingly, the papers described in the following - provided by Dr. Kay but reviewed by me - as papers that in my view report findings that are consistent with those in the questioned Kay papers. Copies of the papers are appended to this staterncnl (Attachments 1 - 7)

Papers reporting findings consistent with papers "A" (Kay & Goodman, Gerontology, 1997) and "B", (Kay et al., Cellular and Molecular Biology, 1996) are as follows:

1. Saitoh et al., "Degradation of proteins in the membrane~cytoskeleton complex in Alzheimer's disease" Annals of the New York Academy of Sciences, 1992, 674, pp. 180-192.

(NOTE: this paper is cited in both papers "A" and "B"; also note Dr. Kay is listed as a coauthor of Saitoh et. al. because she contributed antibodies used in the experiments. All the expermental work was performed in Dr. Saitoh's laboratory in another university and quite independent of Dr. Kay.)

"In Western blot analysis of frontal cortex samples, using several antibodies made against peptides of band-3, we detected decreases in immunoreactivity of intact band-3 in membrane fractions of AD compared to age-matched normal controls... increased antipep-COOH immunoreactivity, which suggests degradation of band-3, correlated well with the expression of AD" (p 182).

"In the normal cortex, staining with anti-pep-COOH antibody showed that the majority of neurons stained weakly... , whereas only a few large neurons were strongly immunoreactive... In AD, the number of anti-pep-COOH-positive neurons increased 260% (p <0.01), and because of a 50% neuronal loss in AD compared to control (... p <0.002), die proportion of remaining neurons that was anti-pep-COOH positive increased 540% ... " (p.183).

2. Bosman et al. "Proteins immunologically related to erythrocyte anion transporter band 3 are altered in brain areas affected by Alzheimer's disease." Acta Neuropathol., 1993, 86, pp. 353-359.

(NOTE: this paper, cited in paper "B," reports experiments using antisera obtained from Dr. Kay, but does not include her as a coauthor. Note also that Giel Bosman, Ph.D., first author of paper 2 and a coauthor of papers 3 - 5, is listed as a coauthor of Dr. Kay's paper "B" because he contributed brain and serum samples for the experiments. Dr. Bosman has written a letter about his role in paper "B" that warrants the hearing panel's attention - Attachment 8.)

"Immunocytochemical studies show increased band 3 immunoreactivity in neurons in the brains of patients with Alzheimer's disease. Immunoblot studies show the presence of band 3-like molecules in brain membrane fractions and suggest changes in expression and/or processing of band 3~ke molecules in Alzhcimer's disease~atfected regions ... these findings indicate changes in expression andlor processing of neuronal band 3-like proteins in AD. it is not clear yet whether the increase in band 3 immunoreaction is the result of, or whether it leads to AD pathology" (pp. 353 - 358; excerpted).

3. Bosman et al., "Involvement of neuronal anion exchange proteins in cell death in Alzheimer's disease." Gerontology, 1997; 43, pp. 67-78.

(NOTE: this paper, cited in paper "B" above, focuses on AE1; AE1 and band 3 [the latter of which was used in Dr. Kay's papers "A" and "B"] are related members of the anion exchange protein family.)

"In Alzheimer's disease-affected brain areas, some anti-AE1 antisera show an increased immunoreactivity... An increased immunoreactivity, both in the number of reactive cells and in the reactivity per cell, is observed especially with antibodies against epitopes of the membrane domain of AE1 ..." p. 70).

"... we conclude that neuronal AE proteins undergo specific structural changes in the membrane of aging and especially degenerating neurons... The strongest reactions are observed with antisera against components of the senescent cell antigen SCA that originates from AE1 in aging erythrocytes. This conclusion indicates that the processes that lead to SCA generation from AE1 in aging erythrocutes may also occur in aging and degenerating neurons in the human brain ... structural changes in the AE membrane domain are the most conspicuous phenomena in AE proteins in the degenerating human neuron" (pp.72-75; excerpted.)

4. Renkawek and Bosman, "Anion exchange proteins are a component of corpora amylacea in Alzheimer disease brain." Clinical Neuroscience and Neuropathology, 1995, 6, pp. 929-932.

"We found abundant CAm [corpora amylacea] in the brains of Alzheimer disease (AD) patients. We show here that proteins of the anion exchanger (AE) gene family, related to erythrocyte band 3, are present in CAm ... Our data support the suggestion that accumulation of altered neuronal membrane proteins may be involved in the pathogenesis of CAm in AD" (p. 929).

5. Bosman et al., "Implications of aging- and degeneration-related changes in anion exchange proteins for the maintenance of neuronal homeostasis." Cellular and Molecular Biology, 1996, 42, pp. 905-918.

(NOTE: this paper is cited in paper "A.")

"Immunohistochemical analysis of human brain tissue shows an increase in neuronal AE protein expression with age and suggests an additional increase in Alzheimer's disease. Biochemical analyses indicate that the latter may be caused by conformational changes in the AE membrane domain that are similar to those observed in AE1 during erythrocyte aging ... Here we present some data from our ongoing studies on expression of AE proteins in neurons in Alzheimer's disease-affected brain ... that indicate that neuronal AE proteins undergo structural changes similar to those occurring in AE1 during the normal erythrocyte aging process" (pp. 905-907; excerpted).

Papers reporting findings consistent with paper "C" (Poulin et al., 1996) are as follows:

1. Sano et al., "A controlled trial of elegiline, alpha-tocopherol [a form of Vitamin E], or both as treatment for Alzheimer's disease" NEJM, 1997, 336, pp. 1216-1222.

"In analyses that included the baseline score on the Mini-Mental State Examination as a covariate, there were significant delays in the time to the primary outcome for the patients treated with selegiline ..., alpha-tocopheroI ..., or combination therapy ..., as compared with the placebo group" (p. 1216). (NOTE: "primary outcome" = death, institutionalization, loss of ability to perform basic activities of daily living, or severe dementia.)

2. McIntosh et al., "Increased susceptibility of Alzheimer's disease temporal cortex to oxygen free radical-mediated processes." Free Radical Biology & Medicine, 1997, 23, pp. 183-190.

"This study indicates that there is increased susceptibility to ROS [reactive oxygen species] in the AD temporal cortex that may contribute to the pathogenesis of the disease. Furthermore, our observations suggest that oral anti-oxidant supplementation may be protective against IPO [liquid peroxidation] in the human brain" (p.183).

The remainder of this letter is very similar to this letter written by Frederick Goodwin.