A roadmap for the prevention of dementia: The inaugural Leon Thal Symposium

Khachaturian, Zaven S.; Petersen, Ronald C.; Gauthier, Serge; Buckholtz, Neil S.; Corey-Bloom, J.; Evans, Bill; Fillit, Howard; Foster, Norman L.; Greenberg, Barry D.; Grundman, Michael; Sano, Mary; Simpkins, James W.; Schneider, Lon S.; Weiner, Michael W.; Galasko, Doug; Hyman, Bradley T.; Kuller, Lew; Schenk, Dale; Snyder, S. M.; Thomas, Ronald G.; Tuszynski, Mark H.; Vellas, Bruno; Wurtman, Richard J.; Snyder, Peter J.; Frank, Richard A.; Albert, Marilyn; Doody, Rachelle S.; Ferris, Steven; Kaye, Jeffrey; Koo, Edward H.; Morrison‐Bogorad, Marcelle; Reisberg, Barry; Salmon, David P.; Gilman, Sid; Mohs, Richard C.; Aisen, Paul S.; Breitner, John C.S.; Cummings, Jeffrey L.; Kawas, Claudia H.; Phelps, Creighton H.; Poirier, Judes; Sabbagh, Marwan; Touchon, Jacques; Khachaturian, Ara S.; Bain, Lisa J.

doi:10.1016/j.jalz.2008.03.005

Cited by 45 publications

(24 citation statements)

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“…Information is accruing that will facilitate such studies. As Khachaturian et.al [50] have recently noted in their consensus report entitled “A roadmap for the prevention of dementia,” “additional targets that need to be explored particularly for the prodromal stages of AD, include … disrupted synaptic function … Other targets that should be explored for the relevance to AD … include those related to cerebrovascular disease, plasticity, and neurogenesis. Investigations of these and other targets could lead to more clarity in the question of how and when intervention should or could begin”.…”

Section: Discussionmentioning

confidence: 99%

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Reisberg

Shulman

Torossian

et al. 2010

Alzheimer's & Dementia

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Background Subjective cognitive impairment (SCI) in older persons without manifest symptomatology is a common condition with a largely unclear prognosis. We hypothesized that (1) examining outcome for a sufficient period by using conversion to mild cognitive impairment (MCI) or dementia would clarify SCI prognosis, and (2) with the aforementioned procedures, the prognosis of SCI subjects would differ significantly from that of demographically matched healthy subjects, free of SCI, termed no cognitive impairment (NCI) subjects. Methods A consecutive series of healthy subjects, aged ≥40 years, presenting with NCI or SCI to a brain aging and dementia research center during a 14-year interval, were studied and followed up during an 18-year observation window. The study population (60 NCI, 200 SCI, 60% female) had a mean age of 67.2 ± 9.1 years, was well-educated (mean, 15.5 ± 2.7 years), and cognitively normal (Mini-Mental State Examination, 29.1 ± 1.2). Results A total of 213 subjects (81.9% of the study population) were followed up. Follow-up occurred during a mean period of 6.8 ± 3.4 years, and subjects had a mean of 2.9 ± 1.6 follow-up visits. Seven NCI (14.9%) and 90 SCI (54.2%) subjects declined (P < .0001). Of NCI decliners, five declined to MCI and two to probable Alzheimer’s disease. Of SCI decliners, 71 declined to MCI and 19 to dementia diagnoses. Controlling for baseline demographic variables and follow-up time, Weibull proportional hazards model revealed increased decline in SCI subjects (hazard ratio, 4.5; 95% confidence interval, 1.9–10.3), whereas the accelerated failure time model analysis with an underlying Weibull survival function showed that SCI subjects declined more rapidly, at 60% of the rate of NCI subjects (95% confidence interval, 0.45–0.80). Furthermore, mean time to decline was 3.5 years longer for NCI than for SCI subjects (P = .0003). Conclusions These results indicate that SCI in subjects with normal cognition is a harbinger of further decline in most subjects during a 7-year mean follow-up interval. Relevance for community populations should be investigated, and prevention studies in this at-risk population should be explored.

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Section: Discussionmentioning

confidence: 99%

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Reisberg

Shulman

Torossian

et al. 2010

Alzheimer's & Dementia

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491

404

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“…1 A series of cholinergic interventions that proved unable to arrest the disease led Zaven Kachaturian to call for a five-years delay in symptom expression or disease onset. 2 His goal was a broadly based public health approach to disease prevention and modification. This policy and the time-limited efficacy of cholinesterase inhibitors shifted over 200 subsequent drug developments to pursue a new goal in AD, disease course modification.…”

Section: Introductionmentioning

confidence: 99%

(-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer’s Disease

Becker

Greig

Lahiri

et al. 2018

CAR

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Background: Concussion (mild) and other moderate traumatic brain injury (TBI) and Alzheimer's disease (AD) share overlapping neuropathologies, including neuronal pre-programmed cell death (PPCD), and clinical impairments and disabilities. Multiple clinical trials targeting mechanisms based on the Amyloid Hypothesis of AD have so far failed, indicating that it is prudent for new drug developments to also pursue mechanisms independent of the Amyloid Hypothesis. To address these issues, we have proposed the use of an animal model of concussion/TBI as a supplement to AD transgenic mice to provide an indication of an AD drug candidate’s potential for preventing PPCD and resulting progression towards dementia in AD. Methods: We searched PubMed/Medline and the references of identified articles for background on the neuropathological progression of AD and its implications for drug target identification, for AD clinical trial criteria used to assess disease modification outcomes, for plasma biomarkers associated with AD and concussion/TBI, neuropathologies and especially PPCD, and for methodological critiques of AD and other neuropsychiatric clinical trial methods. Results: We identified and address seven issues and highlight the Thal-Sano AD ‘Time to Onset of Impairment' Design for possible applications in our clinical trials. Diverse and significant pathological cascades and indications of self-induced neuronal PPCD were found in concussion/TBI, anoxia, and AD animal models. To address the dearth of peripheral markers of AD and concussion/TBI brain pathologies and PPCD we evaluated Extracellular Vesicles (EVs) enriched for neuronal origin, including exosomes. In our concussion/TBI, anoxia and AD animal models we found evidence consistent with the presence of time-dependent PPCD and (-)-phenserine suppression of neuronal self-induced PPCD. We hence developed an extended controlled release formulation of (-)-phenserine to provide individualized dosing and stable therapeutic brain concentrations, to pharmacologically interrogate PPCD as a drug development target. To address the identified problems potentially putting any clinical trial at risk of failure, we developed exploratory AD and concussion/TBI clinical trial designs. Conclusions: Our findings inform the biomarker indication of progression of pathological targets in neurodegenerations and propose a novel approach to these conditions through neuronal protection against self-induced PPCD.

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“…The specific topics under consideration were previously considered at the inaugural Leon Thal Symposium in 2007 4 , and discussed in a webinar held on October 27, 2008. These subjects centered on recommendations concerning the National Institutes of Health (NIH), the Centers for Disease Control (CDC), the Food and Drug Administration (FDA), the Centers for Medicare and Medicaid Services (CMS), and the Department of Commerce (DoC).…”

Section: Public Policy Initiatives – Thinking Bigmentioning

confidence: 99%

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008

Khachaturian

Snyder²,

Doody³

et al. 2009

Alzheimer's & Dementia

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Executive Summary This document proposes an array of recommendations for a National Plan of Action to accelerate the discovery and development of therapies to delay or prevent the onset of disabling symptoms of Alzheimer's disease. A number of the key scientific and public policy needs identified in this document will be incorporated by the Alzheimer Study Group (ASG) into a broader National Alzheimer's Strategic Plan (NASP), which will be presented to the 111th Congress and the Obama administration in March 2009. The NASP is expected to include additional recommendations for governance, family support, healthcare and social services delivery.

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A roadmap for the prevention of dementia: The inaugural Leon Thal Symposium

Cited by 45 publications

References 0 publications

Outcome over seven years of healthy adults with and without subjective cognitive impairment

Outcome over seven years of healthy adults with and without subjective cognitive impairment

(-)-Phenserine and Inhibiting Pre-Programmed Cell Death: In Pursuit of a Novel Intervention for Alzheimer’s Disease

A roadmap for the prevention of dementia II: Leon Thal Symposium 2008

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