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Search Results: 1 - 10 of 198394 matches for " Marwan N. Sabbagh "
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Investigational drugs for the treatment of AD: what can we learn from negative trials?
Sandra A Jacobson, Marwan N Sabbagh
Alzheimer's Research & Therapy , 2011, DOI: 10.1186/alzrt73
Abstract: In the two decades since the amyloid hypothesis was first proposed [1], a great deal of evidence has accrued in support of this mechanism in the pathogenesis of Alzheimer's disease (AD), mostly from preclinical studies of transgenic mice, autosomal dominant presenilin cases, and in vitro data supporting the neurotoxic effects of amyloid-beta (Aβ). The theoretical promise of this model, however, has yet to be realized in the world of AD therapeutics. Robust treatments still seem elusive, even with an identified therapeutic target. Others have addressed the question of why this may be the case [2,3], and this review builds on that literature.The process of drug development, from preclinical investigation through phase III study, is shown in Figure 1. Considering each phase separately helps to identify confounders that might be driving a type II error, if such an error exists in reference to new drug development for AD.Zahs and Ashe [2] reviewed mouse models of AD and made several observations in regard to translational research. These authors identified more than 300 reports of effective AD interventions based on these models. They noted, however, that none of the models is actually a complete replication of AD. In fact, what the models do simulate is a presymptomatic phase of AD, which might correspond to a time many years before a patient would present to a memory clinic or a subject would present to a clinical trial.Becker and Greig [3] identified approximately 100 candidate drugs for AD with more than 40 different mechanisms of action, and 20 of those 100 drugs showed early promise through phase II studies. Table 1 of the authors' report shows a representative sample of 16 drugs trialed within the last decade, and most of them failed because of lack of efficacy in phase III study. Trials of these drugs are reviewed in more detail below.This was the first trial in humans of an active immunotherapy approach, in which Aβ42 was introduced as an antigen to stimulate an
KIF6 719Arg Carrier Status Association with Homocysteine and C-Reactive Protein in Amnestic Mild Cognitive Impairment and Alzheimer’s Disease Patients
Michael Malek-Ahmadi,Amar Patel,Marwan N. Sabbagh
International Journal of Alzheimer's Disease , 2013, DOI: 10.1155/2013/242303
Abstract: Recent research has demonstrated associations between statin use, KIF6 719Arg carrier status, and cholesterol levels and amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) patients. The association between 719Arg carrier status with homocysteine (tHcy) and c-reactive protein (CRP) levels in aMCI and AD has not been previously investigated. Data from 175 aMCI and AD patients were used for the analysis. 719Arg carriers had significantly lower levels of tHcy than noncarriers ( ). No significant difference in CRP levels between 719Arg carriers and noncarriers was present ( ). Logistic regression yielded no significant effect for 719Arg status on CRP [OR = 1.79 (0.85, 3.83), ] but did demonstrate a significant effect for tHcy [OR = 0.44 (0.23, 0.83), ] after adjusting for ApoE carrier status, age, gender, and statin use. This study is the first to explore the relationship between KIF6 719Arg carrier status with tHcy and CRP levels. 719Arg carriers were more likely to have normal tHcy levels after adjusting for ApoE status, age, gender, and statin use. These results suggest that the KIF6 gene might influence cardiovascular pathways associated with AD. 1. Introduction The KIF6 gene is one of several molecular components involved in the intracellular transport of protein complexes, membrane organelles, and messenger ribonucleic acid along microtubules [1]. There are three polymorphisms of the KIF6 gene which include Arg/Arg, Trp/Arg, and Trp/Trp. Individuals carrying the Arg/Arg or Trp/Arg polymorphisms are classified as 719Arg carriers and have been linked to an increased risk for cardiovascular disease [1–6] relative to 719Arg noncarriers (Trp/Trp). Some of these studies also demonstrated a greater lipid lowering response from statin therapy among 719Arg carriers when compared to noncarriers [1–4]. Others have found no association between 719Arg carrier status and cardiovascular outcomes [7, 8]. A recent study by Sabbagh et al. [9] found that positive 719Arg carrier status combined with statin use was associated with lower total cholesterol (TC) and lower low density lipoprotein (LDL) levels in a sample of amnestic mild cognitive impairment (aMCI) and Alzheimer’s disease (AD) patients. In terms of disease risk, cholesterol levels and statin use have garnered significant attention from aMCI/AD researchers [10–13]; however, homocysteine (tHcy) [14, 15] and c-reactive protein (CRP) [16–18] have also been implicated as risk factors for aMCI and AD. Troen and Rosenberg [19] describe several studies that established elevated tHcy as a risk
Informant-reported cognitive symptoms that predict amnestic mild cognitive impairment
Michael Malek-Ahmadi, Kathryn Davis, Christine M Belden, Sandra Jacobson, Marwan N Sabbagh
BMC Geriatrics , 2012, DOI: 10.1186/1471-2318-12-3
Abstract: The current study utilized a case-control design using data from an ongoing validation study of the Alzheimer's Questionnaire (AQ), an informant-based dementia assessment. Data from 51 cognitively normal (CN) individuals participating in a brain donation program and 47 aMCI individuals seen in a neurology practice at the same institute were analyzed to determine which AQ items differentiated aMCI from CN individuals.Forward stepwise multiple logistic regression analysis which controlled for age and education showed that 4 AQ items were strong indicators of aMCI which included: repetition of statements and/or questions [OR 13.20 (3.02, 57.66)]; trouble knowing the day, date, month, year, and time [OR 17.97 (2.63, 122.77)]; difficulty managing finances [OR 11.60 (2.10, 63.99)]; and decreased sense of direction [OR 5.84 (1.09, 31.30)].Overall, these data indicate that certain informant-reported cognitive symptoms may help clinicians differentiate individuals with aMCI from those with normal cognition. Items pertaining to repetition of statements, orientation, ability to manage finances, and visuospatial disorientation had high discriminatory power.The process of differentiating age-associated memory decline from those who might have a clinically significant disorder of memory and cognition is difficult. In particular, distinguishing individuals with amnestic mild cognitive impairment (aMCI) from those who are cognitively normal (CN) is challenging, as memory and cognitive complaints are often reported in both groups from both the patient and informants [1]. Given that the current diagnostic criteria for aMCI include subjective (patient and/or family report of decline) and objective (neuropsychological testing) evidence of memory decline, a clinician's initial impression from a relatively short office visit may not allow for an accurate assessment [2].Amnestic MCI was first characterized as a syndrome consisting of memory performance at or below 1.5 standard deviations
Broader Considerations of Higher Doses of Donepezil in the Treatment of Mild, Moderate, and Severe Alzheimer's Disease
Camryn Berk,Marwan Sabbagh
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/707468
Abstract: Donepezil, a highly selective acetylcholinesterase inhibitor (AChEI), is approved as a symptomatic treatment mild, moderate, and severe Alzheimer's disease (AD). Donepezil exerts its treatment effect through multiple mechanisms of action including nicotinic receptor stimulation, mitigation of excitotoxicity, and influencing APP processing. The use of donepezil at higher doses is justified given the worsening cholinergic deficit as the disease advances. Donepezil has been investigated in several clinical trials of subjects with moderate-to-severe AD. While the side effects are class specific (cholinergically driven), demonstrable benefit has been shown at the 10 mg dose and the 23 mg doses. Here, we review the clinical justification, efficacy, safety, and tolerability of use of donepezil in the treatment of moderate-to-severe AD.
Progressive cholinergic decline in Alzheimer's Disease: consideration for treatment with donepezil 23 mg in patients with moderate to severe symptomatology
Marwan Sabbagh, Jeffrey Cummings
BMC Neurology , 2011, DOI: 10.1186/1471-2377-11-21
Abstract: Alzheimer's disease (AD) is a progressive disorder that advances from a period of mild cognitive impairment through moderate and severe stages. There are currently an estimated 5.3 million people with AD in the United States [1], and more than half of these individuals will likely be categorized as having moderate or severe disease [2]. These advanced stages of AD extend over a period of several years and are often the most difficult for both patients and caregivers [1].As AD progresses toward the more advanced stages, symptoms worsen, and the need for effective treatments grows more critical; yet, clinicians have few options. Only 2 agents are currently approved in the United Stated for treatment beyond the mild to moderate stage--donepezil, an acetylcholinesterase inhibitor (AChEI), and memantine, a glutamate receptor antagonist that can be used alone or in combination with an AChEI [3,4]. Progression of AD is inevitable, however, and cannot be halted by these therapy options, which address primarily the disease symptoms. Given the limited choices for therapy and the often devastating and prolonged impact of further decline in cognitive and functional abilities, additional options for treatment are urgently needed for this segment of the AD population.In the development of AChEIs, determination of appropriate dosing was typically based on decisions regarding a balance of efficacy versus tolerability. For the past decade, the immediate-release formulation of donepezil has been used at an approved dose of 5-10 mg/d [3]. However, a higher-dose (23 mg/d) donepezil formulation was recently approved in the United States that provides more gradual systemic absorption, a longer time to maximum concentration (8 hours) compared with the immediate-release formulation (3 hours), and higher concentrations. In this article we provide information on the effects of donepezil on the cholinergic system and review the scientific and clinical evidence supporting the use of higher-dos
Morphological and Pathological Evolution of the Brain Microcirculation in Aging and Alzheimer’s Disease
Jesse M. Hunter, Jason Kwan, Michael Malek-Ahmadi, Chera L. Maarouf, Tyler A. Kokjohn, Christine Belden, Marwan N. Sabbagh, Thomas G. Beach, Alex E. Roher
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036893
Abstract: Key pathological hallmarks of Alzheimer’s disease (AD), including amyloid plaques, cerebral amyloid angiopathy (CAA) and neurofibrillary tangles do not completely account for cognitive impairment, therefore other factors such as cardiovascular and cerebrovascular pathologies, may contribute to AD. In order to elucidate the microvascular changes that contribute to aging and disease, direct neuropathological staining and immunohistochemistry, were used to quantify the structural integrity of the microvasculature and its innervation in three oldest-old cohorts: 1) nonagenarians with AD and a high amyloid plaque load; 2) nonagenarians with no dementia and a high amyloid plaque load; 3) nonagenarians without dementia or amyloid plaques. In addition, a non-demented (ND) group (average age 71 years) with no amyloid plaques was included for comparison. While gray matter thickness and overall brain mass were reduced in AD compared to ND control groups, overall capillary density was not different. However, degenerated string capillaries were elevated in AD, potentially suggesting greater microvascular “dysfunction” compared to ND groups. Intriguingly, apolipoprotein ε4 carriers had significantly higher string vessel counts relative to non-ε4 carriers. Taken together, these data suggest a concomitant loss of functional capillaries and brain volume in AD subjects. We also demonstrated a trend of decreasing vesicular acetylcholine transporter staining, a marker of cortical cholinergic afferents that contribute to arteriolar vasoregulation, in AD compared to ND control groups, suggesting impaired control of vasodilation in AD subjects. In addition, tyrosine hydroxylase, a marker of noradrenergic vascular innervation, was reduced which may also contribute to a loss of control of vasoconstriction. The data highlight the importance of the brain microcirculation in the pathogenesis and evolution of AD.
Reduced clinical and postmortem measures of cardiac pathology in subjects with advanced Alzheimer's Disease
Thomas G Beach, Chera L Maarouf, Reed G Brooks, Scophil Shirohi, Ian D Daugs, Lucia I Sue, Marwan N Sabbagh, Douglas G Walker, LihFen Lue, Alex E Roher
BMC Geriatrics , 2011, DOI: 10.1186/1471-2318-11-3
Abstract: Clinically documented cardiovascular conditions from AD (n = 35) and elderly non-demented control subjects (n = 22) were obtained by review of medical records. Coronary artery stenosis and other gross anatomical measures, including heart weight, ventricular wall thickness, valvular circumferences, valvular calcifications and myocardial infarct number and volume were determined at autopsy.Compared to non-demented age-similar control subjects, those with AD had significantly fewer total diagnosed clinical conditions (2.91 vs 4.18), decreased coronary artery stenosis (70.8 vs 74.8%), heart weight (402 vs 489 g for males; 319 vs 412 g for females) and valvular circumferences. Carriage of the Apolipoprotein E-ε4 allele did not influence the degree of coronary stenosis. Group differences in heart weight remained significant after adjustment for age, gender, body mass index and apolipoprotein E genotype while differences in coronary artery stenosis were significantly associated with body mass index alone.The results are in agreement with an emerging understanding that, while midlife risk factors for ATH increase the risk for the later development of AD, once dementia begins, both risk factors and manifest disease diminish, possibly due to progressive weight loss with increasing dementia as well as disease involvement of the brain's vasomotor centers.Alzheimer's disease (AD) is the most common neurodegenerative brain disease and the most common cause of dementia in the elderly. The disease has a progressive course over several years that often leaves the victim uncommunicative and bedridden. Five million Americans have AD and the cost of the disease to the US is estimated at $100 billion annually. Finding a cure or prevention for AD is an important national goal. Over the last decade considerable evidence has accumulated supporting a statistical linkage between atherosclerotic vascular disease (ATH) and AD. Several established risk factors for atherosclerosis, including hyp
Essential Tremor in the Elderly and Risk for Dementia
Holly A. Shill,Joseph G. Hentz,Sandra A. Jacobson,Christine Belden,Marwan N. Sabbagh,Thomas G. Beach,Erika Driver-Dunckley,Charles H. Adler
Journal of Neurodegenerative Diseases , 2014, DOI: 10.1155/2014/328765
Abstract: The objective is to examine the risk of dementia in subjects with essential tremor (ET) involved in the Arizona Study of Aging and Neurodegenerative Disorders. All subjects were free of a neurodegenerative diagnosis at baseline and had annual motor, general neurological, and neuropsychological assessments. Subjects with ET were compared with controls for the risk of dementia. There were 83 subjects with ET and 424 subjects without tremor. Mean age at study entry was for ET and for controls. Median tremor duration was 5.2 years at study entry. Followup was a median of 5.4 years (range 0.9 to 12.1). The hazard ratio for the association between ET and dementia was 0.79 (95% CI 0.33 to 1.85). The hazard ratio for the association between tremor onset at age 65 or over, versus onset before age 65, was 2.1 (95% CI 0.24 to 18) and the hazard ratio for the association between tremor duration greater than 5 years, versus less than 5 years, was 0.46 (95% CI 0.08 to 2.6). We conclude that all elderly ET was not associated with an increased risk of dementia but that a subset of subjects with older age onset/shorter duration tremor may be at higher risk. 1. Introduction Essential tremor (ET) is a common neurological condition which increases with the age of the population and contributes to significant disability in most affected patients. Previous cross-sectional studies have shown that patients with ET may have minor cognitive deficits on formal testing although most of these older studies have been done with advanced ET patients being assessed for deep brain stimulation as treatment for tremor [1, 2]. More recently, a population study of ET demonstrated that more mildly affected, largely untreated ET individuals may be more likely to complain of memory problems and have deficits at testing [3]. This same population was more likely to have prevalent dementia, largely driven by elderly onset ET [4]. In those nondemented at baseline, incident dementia was greater in ET [5]. This study seeks to compare the risk of developing dementia in subjects with ET versus controls without tremor in a large, well-categorized cohort of individuals involved in a longitudinal aging study, the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). 2. Methods Participants without dementia or another neurodegenerative disorder at study entry and who had at least one follow-up visit were selected from the 23 May 2013 version of the AZSAND database which included 3300 subjects. All participants, both cases and controls, were initially recruited into the study largely as a result
New Acetylcholinesterase Inhibitors for Alzheimer's Disease
Mona Mehta,Abdu Adem,Marwan Sabbagh
International Journal of Alzheimer's Disease , 2012, DOI: 10.1155/2012/728983
Abstract: Acetylcholinesterase (AChE) remains a highly viable target for the symptomatic improvement in Alzheimer's disease (AD) because cholinergic deficit is a consistent and early finding in AD. The treatment approach of inhibiting peripheral AchE for myasthenia gravis had effectively proven that AchE inhibition was a reachable therapeutic target. Subsequently tacrine, donepezil, rivastigmine, and galantamine were developed and approved for the symptomatic treatment of AD. Since then, multiple cholinesterase inhibitors (ChEI) continue to be developed. These include newer ChEIs, naturally derived ChEIs, hybrids, and synthetic analogues. In this paper, we summarize the different types of ChEIs in development and their respective mechanisms of actions. This pharmacological approach continues to be active with many promising compounds.
Quantitative Appraisal of Ventricular Cerebrospinal Fluid Biomarkers in Neuropathologically Diagnosed Parkinson's Disease Cases Lacking Alzheimer's Disease Pathology
Chera L. Maarouf, Thomas G. Beach, Charles H. Adler, Michael Malek-Ahmadi, Tyler A. Kokjohn, Brittany N. Dugger, Douglas G. Walker, Holly A. Shill, Sandra A. Jacobson, Marwan N. Sabbagh, Alex E. Roher and Arizona Parkinson’s Disease Consortium
Biomarker Insights , 2012, DOI: 10.4137/BMI.S11422
Abstract: Identifying biomarkers that distinguish Parkinson’s disease (PD) from normal control (NC) individuals has the potential to increase diagnostic sensitivity for the detection of early-stage PD. A previous proteomic study identified potential biomarkers in postmortem ventricular cerebrospinal fluid (V-CSF) from neuropathologically diagnosed PD subjects lacking Alzheimer’s disease (AD) neuropathology. In the present study, we assessed these biomarkers as well as p-tau181, Aβ42, and S100B by ELISA in PD (n = 43) and NC (n = 49) cases. The p-tau181/A 42 ratio and ApoA-1 showed statistically significant differences between groups. Multiple regression analysis demonstrated that p-tau181/Aβ42 had a significant odds ratio: OR = 1.42 (95% confidence interval [CI], 1.12–1.84), P = 0.006. Among the molecules investigated, intriguing correlations were observed that require further investigation. Our results suggest co-existent AD CSF biomarkers within the PD group notwithstanding that it was selected to minimize AD neuropathological lesions.
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