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Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress.” Evolving neuropathological definitions of Alzheimer’s disease: Where we came from and where we might go
Alzheimer’s & Dementia 1 (2005) 114 –115
Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress.” Evolving neuropathological definitions of Alzheimer’s disease: Where we came from and where we might go Melvyn J. Ball Department of Neuropathology, Oregon Health & Science University, Portland, OR 97239 USA
In 1972, on leave from the University of Western Ontario, I spent a sabbatical year in London, England, at the National Hospital for Nervous Diseases Queen Square, learning the then-innovative techniques of stereology (quantitative morphometery) in the laboratory of Professor Anthony Dayan. Returning to London, Canada, I was certain that the clinico-pathologic approach championed by the Medical Research Council (MRC) of Great Britain would be the most productive way to find an eventual cause and cure for Alzheimer’s disease. With the unstintingly enthusiastic collaborative expertise of Dr. Harold Merskey, Professor of Psychiatry, and Dr. Vladimir Hachinski, Professor of Neurology, we assembled the University of Western Ontario Dementia Study Group, and, in relatively short order, convinced both the MRC of Canada and the National Institutes of Health (NIH) to fund such a longitudinal investigation of patients with Alzheimer’s disease and aged but cognitively intact controls. (By Canadian fiscal standards, our American award, for this team’s first request from the National Institute on Aging (NIA), was regarded as miraculous.) By 1983, 6 neuropathologists at NIA had assembled in a Research Planning Workshop to hammer out a consensus diagnosis for Alzheimer’s disease. We deliberated for several hours, and notes of our viewpoints were eventually published in the (in)famous Khachaturian article in Archives of Neurology in 1985. Although much optimism accompanied this working group’s screed, one still recalls a sense of premature accomplishment, along the lines of “A camel is a horse designed by a committee.” Repeated machinations of a similar nature in later workshops, again while appearing in the best journals, seem, if anything, to have blurred still further the elusive goal of a sharp, universally agreed upon, quantitative, pathologic definition of AD. Through today’s “retrospectiscope,” we are humbled by the complexity of the challenge.
“How many senile plaques, and/or how many neurofibrillary tangles will cause dementia of the Alzheimer type?” The tempting assumption had been that a finite number of the particular causative neuronal lesions will push the patient across some hypothetical boundary from the “benign forgetfulness of senescence” promulgated by Canadian psychiatrist V. Kral, into the frankly demented domain of AD. Moreover, if refined, clinical testing can tease out those prodromal clues identifying a person as “predestined” to have AD, surely the earliest pharmacologic interruption of the biochemical cascade(s) can prevent that individual from amassing sufficient cellular lesions to become demented. But careful reflection now suggests in hindsight that we remain unclear about (a) which specific nerve cell abnormality is the real/main culprit; (b) how many such lesions it takes in one person’s brain to cross the threshold, ie, the concept of markedly variable, interindividual neuronal reserve; (c) what the clinical effect is of concomitant other pathologies (eg, small infarcts, Lewy bodies) on the ADspecific lesion; and (d) how many years/decades before first clinical examination did the critical brain lesion(s) begin to form. Arguably the greatest potential within each of the Alzheimer Disease Centers across this land is the scintillating cross fertilization of ideas from a plethora of clinical and basic science specialists. It therefore behooves the new torch bearers to de-emphasize the notion that national “standardization” will lead instantly to deep pathogenetic revelation and to call more vociferously for new, testable hypotheses of biological causation. Obviously, because a healthy young adult’s brain has no plaques or tangles, whatever etiology triggers their formation can ultimately be forestalled (prevention), or weakened (cure). But much more of the spotlight should focus on triggers of the original pathogenetic pathway. In the absence of a perfect, naturally occurring animal model, brain autopsy on AD victims is still
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2005.09.002
M.J. Ball / Alzheimer’s & Dementia 1 (2005) 114 –115
a treasure trove, but far more crucial are comparative autopsies on cognitively intact persons dying in the first few decades of life. On an optimistic note, my colleague, Professor James Hill at Louisiana State University, New Orleans, has finally secured NIH support to commence a molecular investigation of the role of herpes simplex virus type 1 in dementia Alzheimer type, utilizing autopsy tissue samples garnered during my 15 years directing the Oregon Brain Bank. And Professor Ruth Itzhaki ’s group, University of Manchester, England is likewise enlarging her pursuit of the same theory. If the past decades’ striving leads such thrusts onto finally fertile ground, our many temporary detours along the steep path will fade into the mist with other noble attempts.
115
Should the causative neurobiological phenomenon prove ubiquitous, the day may none too soon approach when all citizens can be protected fully from this neurodegenerative scourge.
Acknowledgment The author thanks the Department of Pathology at Oregon Health & Science University, Portland; the Oregon Health & Science Foundation’s Brain Bank Fund; and the many Oregon and southwest Washington families whose gracious permission for autopsy sustains these investigations.
Commentary on “Diagnosis of Alzheimer’s disease: Two decades of progress.” Evolving neuropathological definitions of Alzheimer’s disease: Where we came from and where we might go Melvyn J. Ball Department of Neuropathology, Oregon Health & Science University, Portland, OR 97239 USA
In 1972, on leave from the University of Western Ontario, I spent a sabbatical year in London, England, at the National Hospital for Nervous Diseases Queen Square, learning the then-innovative techniques of stereology (quantitative morphometery) in the laboratory of Professor Anthony Dayan. Returning to London, Canada, I was certain that the clinico-pathologic approach championed by the Medical Research Council (MRC) of Great Britain would be the most productive way to find an eventual cause and cure for Alzheimer’s disease. With the unstintingly enthusiastic collaborative expertise of Dr. Harold Merskey, Professor of Psychiatry, and Dr. Vladimir Hachinski, Professor of Neurology, we assembled the University of Western Ontario Dementia Study Group, and, in relatively short order, convinced both the MRC of Canada and the National Institutes of Health (NIH) to fund such a longitudinal investigation of patients with Alzheimer’s disease and aged but cognitively intact controls. (By Canadian fiscal standards, our American award, for this team’s first request from the National Institute on Aging (NIA), was regarded as miraculous.) By 1983, 6 neuropathologists at NIA had assembled in a Research Planning Workshop to hammer out a consensus diagnosis for Alzheimer’s disease. We deliberated for several hours, and notes of our viewpoints were eventually published in the (in)famous Khachaturian article in Archives of Neurology in 1985. Although much optimism accompanied this working group’s screed, one still recalls a sense of premature accomplishment, along the lines of “A camel is a horse designed by a committee.” Repeated machinations of a similar nature in later workshops, again while appearing in the best journals, seem, if anything, to have blurred still further the elusive goal of a sharp, universally agreed upon, quantitative, pathologic definition of AD. Through today’s “retrospectiscope,” we are humbled by the complexity of the challenge.
“How many senile plaques, and/or how many neurofibrillary tangles will cause dementia of the Alzheimer type?” The tempting assumption had been that a finite number of the particular causative neuronal lesions will push the patient across some hypothetical boundary from the “benign forgetfulness of senescence” promulgated by Canadian psychiatrist V. Kral, into the frankly demented domain of AD. Moreover, if refined, clinical testing can tease out those prodromal clues identifying a person as “predestined” to have AD, surely the earliest pharmacologic interruption of the biochemical cascade(s) can prevent that individual from amassing sufficient cellular lesions to become demented. But careful reflection now suggests in hindsight that we remain unclear about (a) which specific nerve cell abnormality is the real/main culprit; (b) how many such lesions it takes in one person’s brain to cross the threshold, ie, the concept of markedly variable, interindividual neuronal reserve; (c) what the clinical effect is of concomitant other pathologies (eg, small infarcts, Lewy bodies) on the ADspecific lesion; and (d) how many years/decades before first clinical examination did the critical brain lesion(s) begin to form. Arguably the greatest potential within each of the Alzheimer Disease Centers across this land is the scintillating cross fertilization of ideas from a plethora of clinical and basic science specialists. It therefore behooves the new torch bearers to de-emphasize the notion that national “standardization” will lead instantly to deep pathogenetic revelation and to call more vociferously for new, testable hypotheses of biological causation. Obviously, because a healthy young adult’s brain has no plaques or tangles, whatever etiology triggers their formation can ultimately be forestalled (prevention), or weakened (cure). But much more of the spotlight should focus on triggers of the original pathogenetic pathway. In the absence of a perfect, naturally occurring animal model, brain autopsy on AD victims is still
1552-5260/05/$ – see front matter © 2005 The Alzheimer’s Association. All rights reserved. doi:10.1016/j.jalz.2005.09.002
M.J. Ball / Alzheimer’s & Dementia 1 (2005) 114 –115
a treasure trove, but far more crucial are comparative autopsies on cognitively intact persons dying in the first few decades of life. On an optimistic note, my colleague, Professor James Hill at Louisiana State University, New Orleans, has finally secured NIH support to commence a molecular investigation of the role of herpes simplex virus type 1 in dementia Alzheimer type, utilizing autopsy tissue samples garnered during my 15 years directing the Oregon Brain Bank. And Professor Ruth Itzhaki ’s group, University of Manchester, England is likewise enlarging her pursuit of the same theory. If the past decades’ striving leads such thrusts onto finally fertile ground, our many temporary detours along the steep path will fade into the mist with other noble attempts.
115
Should the causative neurobiological phenomenon prove ubiquitous, the day may none too soon approach when all citizens can be protected fully from this neurodegenerative scourge.
Acknowledgment The author thanks the Department of Pathology at Oregon Health & Science University, Portland; the Oregon Health & Science Foundation’s Brain Bank Fund; and the many Oregon and southwest Washington families whose gracious permission for autopsy sustains these investigations.