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Articles
by
Constantine G. Lyketsos |
Total Records (
6 ) for
Constantine G. Lyketsos |
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Constantine G. Lyketsos
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The publication in Alzheimers & Dementia of new criteria for preclinical Alzheimers disease (AD) [1], mild cognitive impairment (MCI) [2] due to AD, and dementia due to AD [3] represents the dawning of a new era in our field. Coupled with the groundbreaking recommendation of an advisory panel to the Food and Drug Administration regarding marketing approval for florbetapir in the diagnosis of AD [4], we move into a period during which attention is shifted from the diagnosis of a single syndrome to the staging of a complex disease and its clinical manifestations. |
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John C. Breitner
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Laura D. Baker
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Thomas J. Montine
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Curtis L. Meinert
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Constantine G. Lyketsos
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Karen H. Ashe
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Jason Brandt
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Suzanne Craft
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Denis E. Evans
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Robert C. Green
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M. Saleem Ismail
,
Barbara K. Martin
,
Michael J. Mullan
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Marwan Sabbagh
and
Pierre N. Tariot
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Background
Epidemiologic evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) delay onset of Alzheimers dementia (AD), but randomized trials show no benefit from NSAIDs in patients with symptomatic AD. The Alzheimers Disease Anti-inflammatory Prevention Trial (ADAPT) randomized 2528 elderly persons to naproxen or celecoxib versus placebo for 2 years (standard deviation = 11 months) before treatments were terminated. During the treatment interval, 32 cases of AD revealed increased rates in both NSAID-assigned groups.
Methods
We continued the double-masked ADAPT protocol for 2 additional years to investigate incidence of AD (primary outcome). We then collected cerebrospinal fluid (CSF) from 117 volunteer participants to assess their ratio of CSF tau to Aβ1-42.
Results
Including 40 new events observed during follow-up of 2071 randomized individuals (92% of participants at treatment cessation), there were 72 AD cases. Overall, NSAID-related harm was no longer evident, but secondary analyses showed that increased risk remained notable in the first 2.5 years of observations, especially in 54 persons enrolled with cognitive impairmentno dementia (CIND). These same analyses showed later reduction in AD incidence among asymptomatic enrollees who were given naproxen. CSF biomarker assays suggested that the latter result reflected reduced Alzheimer-type neurodegeneration.
Conclusions
These data suggest a revision of the original ADAPT hypothesis that NSAIDs reduce AD risk, as follows: NSAIDs have an adverse effect in later stages of AD pathogenesis, whereas asymptomatic individuals treated with conventional NSAIDs such as naproxen experience reduced AD incidence, but only after 2 to 3 years. Thus, treatment effects differ at various stages of disease. This hypothesis is consistent with data from both trials and epidemiological studies. |
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Constantine G. Lyketsos
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Maria C. Carrillo
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J. Michael Ryan
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Ara S. Khachaturian
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Paula Trzepacz
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Joan Amatniek
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Jesse Cedarbaum
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Robert Brashear
and
David S. Miller
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Neuropsychiatric symptoms (NPS) are core features of Alzheimers disease and related dementias. Once thought to emerge primarily in people with late-stage disease, these symptoms are currently known to manifest commonly in very early disease and in prodromal phases, such as mild cognitive impairment. Despite decades of research, reliable treatments for dementia-associated NPS have not been found, and those that are in widespread use present notable risks for people using these medications. An Alzheimers Association Research Roundtable was convened in the spring of 2010 to review what is known about NPS in Alzheimers disease, to discuss classification and underlying neuropathogenesis and vulnerabilities, and to formulate recommendations for new approaches to tailored therapeutics. |
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Michelle M. Mielke
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Ozioma C. Okonkwo
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Kenichi Oishi
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Susumu Mori
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Sarah Tighe
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Michael I. Miller
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Can Ceritoglu
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Timothy Brown
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Marilyn Albert
and
Constantine G. Lyketsos
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Background
The fornix is the predominant outflow tract of the hippocampus, a brain region known to be affected early in the course of Alzheimers disease (AD). The aims of the present study were to: (1) examine the cross-sectional relationship between fornix diffusion tensor imaging (DTI) measurements (fractional anisotropy [FA], mean diffusivity [MD], axial diffusivity, and radial diffusivity), hippocampal volume, and memory performance, and (2) compare fornix DTI measures with hippocampal volumes as predictors of progression and transition from amnestic mild cognitive impairment to AD dementia.
Methods
Twenty-three mild cognitive impairment participants for whom hippocampal volumetry and DTI were conducted at baseline received detailed evaluations at baseline; 3, 6, and 12 months; and 2.5 years. Six participants converted to AD over the follow-up period. Fornix and posterior cingulum DTI measurements and hippocampal volumes were ascertained using manual measures. Random effects models assessed each of the neuroimaging measures as predictors of decline on the Mini-Mental State Examination, Clinical Dementia Rating-sum of boxes, and memory z scores; receiver operating characteristic analyses examined the predictive value for conversion to AD.
Results
There was a significant correlation between fornix FA and hippocampal volumes. However, only the fornix measurements (FA, MD, radial diffusivity, and axial diffusivity) were cross-sectionally correlated with memory z scores. Both fornix FA and hippocampal volumes were predictive of memory decline. Individually, fornix FA and MD and hippocampal volumes were very good predictors of progression, with likelihood ratios >83, and better than 90% accuracy.
Conclusion
Fornix FA both cross-sectionally correlated with and longitudinally predicted memory decline and progression to AD. Manually drawn region of interest within the fornix shows promise comparable with hippocampal volume as a predictive biomarker of progression, and this finding warrants replication in a larger study. |
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Lea T. Drye
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Zahinoor Ismail
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Anton P. Porsteinsson
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Paul B. Rosenberg
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Daniel Weintraub
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Daniel Weintraub
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Daniel Weintraub
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Constantine Frangakis
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Peter V. Rabins
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Cynthia A. Munro
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Curtis L. Meinert
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D.P. Devanand
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Jerome Yesavage
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Jacobo E. Mintzer
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Lon S. Schneider
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Bruce G. Pollock
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Constantine G. Lyketsos
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Background
Agitation is one of the most common neuropsychiatric symptoms of Alzheimers disease (AD), and is associated with serious adverse consequences for patients and caregivers. Evidence-supported treatment options for agitation are limited. The citalopram for agitation in Alzheimers disease (CitAD) study was designed to evaluate the potential of citalopram to ameliorate these symptoms.
Methods
CitAD is a randomized, double-masked, placebo-controlled multicenter clinical trial, with two parallel treatment groups assigned in a 1:1 ratio and randomization stratified by clinical center. The study included eight recruiting clinical centers, a chairs office, and a coordinating center located in university settings in the United States and Canada. A total of 200 individuals having probable AD with clinically significant agitation and without major depression were recruited for this study. Patients were randomized to receive citalopram (target dose of 30 mg/d) or matching placebo. Caregivers of patients in both treatment groups received a structured psychosocial therapy. Agitation was compared between treatment groups using the NeuroBehavioral Rating Scale and the AD Cooperative Study- Clinical Global Impression of Change, which are the primary outcomes. Functional performance, cognition, caregiver distress, and rates of adverse and serious adverse events were also measured.
Conclusion
The authors believe the design elements in CitAD are important features to be included in trials assessing the safety and efficacy of psychotropic medications for clinically significant agitation in AD. |
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Michelle M. Mielke
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Jeannie-Marie Leoutsakos
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Chris D. Corcoran
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Robert C. Green
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Maria C. Norton
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Kathleen A. Welsh- Bohmer
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JoAnn T. Tschanz
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Constantine G. Lyketsos
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Background
Observational studies suggest that cholinesterase inhibitors and/or memantine may delay clinical progression of Alzheimers disease (AD) in 40% of individuals taking the medications. Given this response and existence of side effects, we sought to quantify medication use and benefits in a population-based study of incident AD cases.
Methods
The Cache County Dementia Progression Study enrolled and followed a cohort of 327 incident AD cases for a maximum of 9 years. Drug exposure was expressed using a persistency index (PI), calculated as total years of drug use divided by total years of observation. Linear mixed-effects models examined PI, and interactions with sex and apolipoprotein E (APOE) as predictors of clinical progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes.
Results
A total of 69 participants (21.1%) reported having ever used cholinesterase inhibitors or memantine. There was a strong three-way interaction between PI, sex, and time. Among women, a higher PI (i.e., greater duration of use) of cholinesterase inhibitors was associated with slower progression on the Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes, particularly among those with an APOE ɛ4 allele. In contrast, higher PI was associated with faster progression in males.
Conclusion
A low percentage of individuals with AD in the community are taking cholinesterase inhibitors or memantine. This study suggests that women, particularly those with an APOE ɛ4 allele, may benefit the most from these medications. With the newly approved increased dose of donepezil, it will be imperative to determine whether a higher dose is needed in men or whether other factors warrant consideration. |
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