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20 January 2010. Gary Reiswig has variously been a young farmer, preacher, Ph.D., city planner, innkeeper, real estate agent, and author. He will always be a member of the “Volga Germans.” Through their research participation, this extended family made possible the identification of presenilin 2 on chromosome 1 (Levy-Lahad et al., 1995; Rogaev et al., 1995; Levy-Lahad et al., 1995) as the third gene known to cause autosomal-dominant Alzheimer disease, and the term Volga Germans became a fixture in AD genetics. Reiswig tells a harrowing tale, interweaving chronological chapters of his family’s and personal life story with snapshots of how the field of U.S. Alzheimer’s science evolved in those same years. This book offers something for everyone among the diverse Alzforum audience of researchers and related professionals, caregivers, and early-stage patients themselves. Scientists will find a compassionate inside story of what goes on in families stricken with eFAD, and the story features some of their familiar colleagues, including Thomas Bird, Gerry Schellenberg, Rudy Tanzi, and Bill Klunk. To families and AD activists, the book validates their own experience. It offers an account of what they have achieved to date in the way of bringing their issue before Congress and to the national media. These readers may recognize Chuck Jackson (statement to Congress), a cousin of Reiswig’s who lives with AD and works to raise public awareness.
The book creates moments of dread when Reiswig realizes that AD is beginning to claim members of the next, younger generation. Some of these moments echo past tragedies. For example, while driving across the wide open prairie of the Oklahoma panhandle, Reiswig’s grandfather, a farmer, overlooked an oncoming train. The train killed his wife, a mother of 14 children. Reiswig attributed this accident to a mental lapse during his grandfather’s early-stage AD. Four decades later, Reiswig asks his father to drive across several states to help his own young family move house. His father gets utterly lost, returning home to the family farm days late and plunging Reiswig into guilt over having denied his father’s condition. And three decades later still, after Reiswig’s siblings and cousins have been decimated by AD, his nephew, who has taken over the family farm, causes a car accident amid subtle symptoms of forgetting and confusion. This nephew is about to become a young grandfather, extending a line of life at risk for early-onset AD.
This family is hit hard. Of Reiswig’s 13 aunts and uncles, only three escaped the mutation. His brother and sister both died young from AD. Going back in history, Reiswig cites speculation by Tom Bird of the University of Washington, Seattle, that Alois Alzheimer’s famous patient Auguste Deter herself might have been a distant relative of the Reiswigs, as his ancestors emigrated to Russia from a region near Frankfurt, Germany, where Deter lived.
The author touches on themes that frequently come up in conversation with families living with eFAD. While the disease prompts some relatives to pull close, its taboos and the burden it imposes also tear families apart. Reiswig notes how he left home as early as he could, having watched his grandfather’s final years as a young child and seeing as a teenager how his own dad was starting down the same road. Others fled, causing a tight family that had settled in the rural heartland to scatter to both U.S. coasts and Australia, as if trying to outrun a fate that was sealed at conception. Reiswig also describes vivid vignettes of how early symptoms—loss of skills, lapses in judgment—manifest in able farmers and craftsmen who were increasingly stumped trying to repair their machinery, or made ill-advised purchases. The book’s title evokes a sign that relatives and dementia clinicians know well—that long, forlorn stare into the distance, that glance where the person behind the eyes is strangely missing. Incidentally, a new study out this week formally characterizes staring and mental lapses as an early sign of Alzheimer disease (Escandon et al., 2010).
Many readers will find food for thought in Reiswig’s description of how the family tried to move past denial toward a more proactive stance, and the attendant effort to become engaged in research. As is often the case, one relative—strong-willed aunt Esther May—drove this move toward openness in the Reiswig family. She drew the scorn of some relatives but managed to address Congress in testimony that contributed in the 1970s to the initiation of the country’s system of federally funded Alzheimer’s Disease Research Centers.
At several points in the book, Reiswig describes the Dominantly Inherited Alzheimer Network (DIAN) study, a much more recent research initiative that is currently enrolling participants. DIAN invites relatives of families with autosomal-dominant AD to join an international registry of longitudinal research to understand and treat the presymtomatic decade of AD, where pathology builds up in the brain. That is the time before people develop mental lapses and the thousand-mile stare. (For more information on DIAN, see ARF related news story; Dominantly Inherited Alzheimer Network (DIAN).) But also, as Reiswig recounts how for decades he lived in fear of developing AD himself, he mentions that he found out he had escaped the mutation only by seeing his family’s pedigree printed in Science magazine, which he, a Long Island innkeeper at the time, obtained after reading about the presenilin 2 discovery in The New York Times. His research participation apparently had not triggered information back that the family’s gene had been found and his family tree was about to be published with this pertinent information in it. This was in 1995. Since then, scientists have wrestled with the issue of information sharing with research participants, and a consensus is growing that ways must be found to communicate with research volunteers more fully.
Published by Nicholas Brealey and widely available online, this short book would have benefitted from rigorous editing to iron out some weaknesses in the scientific sections, but it remains well worth a read. For a special section of Alzforum dedicated to this form of Alzheimer disease and the families who live with it, see Early-Onset Familial AD.—Gabrielle Strobel.
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Related News: Research Brief: Auguste D.'s Mutation Identified?
Comment by: Gary Reiswig
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Submitted 20 May 2010
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Posted 20 May 2010
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In The Thousand Mile Stare, I describe a frightening scene in which my sister threatened to kill my brother-in-law because she thought he was a stranger who broke into the house. This is only one of a number of incidents in which paranoid behavior has been exhibited by members of my family while in the throes of living with Alzheimer's. I also described how one of my uncles, who was institutionalized as was Frau D., lay curled up in the fetal position, incontinent and unresponsive in the final stage of his disease. This also happened to more than one of my family members. These descriptions are quite similar to Dr. Alzheimer's observations of his patient, who did not trust, and was at times, afraid of her family, and reacted in a paranoid fashion to her caregivers. And, she was described in the final stage of her disease as lying in her bed, curled in the fetal position, incontinent and unresponsive. I find the similarity of the descriptions of Frau D.'s suffering uncannily similar to the suffering of my family, and the age of onset of her symptoms and death are precisely...
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In The Thousand Mile Stare, I describe a frightening scene in which my sister threatened to kill my brother-in-law because she thought he was a stranger who broke into the house. This is only one of a number of incidents in which paranoid behavior has been exhibited by members of my family while in the throes of living with Alzheimer's. I also described how one of my uncles, who was institutionalized as was Frau D., lay curled up in the fetal position, incontinent and unresponsive in the final stage of his disease. This also happened to more than one of my family members. These descriptions are quite similar to Dr. Alzheimer's observations of his patient, who did not trust, and was at times, afraid of her family, and reacted in a paranoid fashion to her caregivers. And, she was described in the final stage of her disease as lying in her bed, curled in the fetal position, incontinent and unresponsive. I find the similarity of the descriptions of Frau D.'s suffering uncannily similar to the suffering of my family, and the age of onset of her symptoms and death are precisely that of my father and of many other members of my family.
And one more personal observation, even more subjective. The first time I saw a picture of Frau D., I thought I was looking at the picture of a relative. The cheekbones and eyes appear very similar to the facial construction of my father's generation that was 100 percent ethnic German.
 View all comments by Gary Reiswig |
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Related News: DIAN Dispatch from Hawaii: Glimpse at Data, Push for Trials
Comment by: Vincent Marchesi, ARF Advisor
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Submitted 20 July 2010
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Posted 23 July 2010
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One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.
But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?
Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease....
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One can only applaud the courage and commitment of the investigators involved in this study. It is surely a wise move to follow people with dominant mutations who are clearly at risk for clinical AD, and the markers to be studied are probably the best available.
But I'd still like to ask two questions: How sure are we that the accumulation of amyloid seen by scanning and the CSF levels of Aβ and tau that are being measured do indeed reflect the earliest pathogenic mechanisms that lead to symptomatic AD?
Secondly, is this the best time to couple this study with a battery of untested experimental therapies? No one is more aware than I of the desperate need for effective treatments, and the pressure on the investigators to add them to the study must surely be suffocating. My concerns are these: Although the evidence linking amyloid Aβ to AD is overwhelming, we still don’t know how or when it becomes toxic, and, equally important, whether other factors, such as inflammation, oxidative damage, and vascular injury are just as critical to the development of clinical disease. Does this overwhelming focus on amyloid as the primary culprit divert attention and resources away from the study of these other factors? If we continue to ignore them, the best designed therapies for the control of amyloid may be rendered ineffective.
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Related News: London: What Regulators Say About Trials in Familial AD
Comment by: René Spiegel
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Submitted 9 December 2010
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Posted 9 December 2010
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Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.
My colleagues and I take the view that long-term use of placebo...
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Placebo or Historical Controls: Mathematical Model Offers a Better Choice
I read this informative series about the expert conference organized by EMA with interest. Among the issues discussed, this meeting touched on the question of whether studies with potential therapeutic agents in carriers of autosomal-dominant AD mutations could serve as a model for simplified clinical testing of new medications against pre-symptomatic stages of the more common sporadic forms of AD. My comment pertains to Part 3 of this series, which addresses the topic of placebo-controlled studies as part of clinical trials of new medications. I notice that this discussion, which comprised primarily questions by participants and answers by regulators, failed to distinguish between early and late clinical development phases of new medications. However, this differentiation is essential, because Phases 1, 2, and 3 of clinical development tackle different questions based on quite different knowledge bases about the therapy at hand.
My colleagues and I take the view that long-term use of placebo in studies of new compounds that are in advanced development, typically Phase 3, is highly ethically problematic. The Declaration of Helsinki (Seoul, 2008, paragraph 32) allows use of placebo instead of the best current proven intervention in situations “where no current proven intervention exists; or where for compelling and scientifically sound methodological reasons the use of placebo is necessary to determine the efficacy or safety of an intervention and the patients who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. Extreme care must be taken to avoid abuse of this option.“
With regard to long-term treatment of pre-symptomatic stages of all forms of AD, the first condition (i.e., lack of current proven treatments) is met; however, this is not true for the second condition. Without doubt, patients with autosomal-dominant AD face a high risk of serious or irreversible harm if treated with placebo for extended periods of time (18 months or longer, depending on the mechanism of action of the intervention studied). The same applies to patients with amnestic MCI who show specific neuropsychological, neurochemical, or brain imaging markers of pre-symptomatic AD. In the spirit of the Declaration, it is therefore unacceptable to knowingly expose such trial participants for extended periods of time to an ineffective intervention (placebo) when studying a treatment that in prior clinical trials has shown clear potential for clinically relevant efficacy and acceptable tolerability. These latter elements are customarily established in Phase 1 and early Phase 2 trials, which are shorter in duration and do require placebo control. For pre-registration trials, so-called pivotal studies, however, the scientific community and regulatory authorities would be well advised to consider novel study designs. Such designs should combine maximal protection of patients against ineffective treatments with the ability to foster scientifically valid testing of new candidate drugs.
In an attempt to realize an alternative to placebo-based study designs that is both ethically and scientifically sound, our group has developed mathematical models to reliably forecast clinically relevant endpoints and disease trajectories of AD patients in pre-symptomatic stages (MCI subjects). Our models make use of medical history, biological, and neuropsychological measures that are routinely established at baseline of every therapeutic study. Model-based forecasted endpoints and trajectories of decline constitute the background—the “simulated placebo group”—against which potential drug effects can be contrasted. We call this alternative study design the Placebo Group Simulation Approach (PGSA). Our ideas about it were presented at the recent CTAD congress in Toulouse (Poster 25, Abstract in J Nutrition Health & Aging 14: S16, 2010; we will gladly send a PDF file of the poster to colleagues interested in our concept).
First results using data from the ADNI database clearly demonstrate that empirically established and mathematically modelled endpoints and disease trajectories show high concordance in large samples of pre-symptomatic AD patients. We are currently attempting to validate our models using several independent datasets. Based on the first encouraging findings, we hope that the PGSA will replace placebo-controlled long-term studies in advanced stages of development of new anti-AD drugs. Needless to say, trials offering treatment with active drug to all participants are also easier to perform and less costly.
(Previously at Novartis, the author was a project leader in the development of the cholinesterase inhibitor drug rivastigmine; see, e.g., Spiegel, 2002 and Almqvist et al., 2004.)
View all comments by René Spiegel
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Related News: DIAN Forms Pharma Consortium, Submits Treatment Trial Grant
Comment by: Luis Salguero
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Submitted 26 December 2011
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Posted 4 January 2012
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