Jeffrey L Cummings

University of Nevada, Las Vegas, Las Vegas, Nevada, United States

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Publications (524)3124.76 Total impact

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    ABSTRACT: Most Alzheimer's disease (AD) clinical trials enroll participants multinationally. Yet, few data exist to guide investigators and sponsors regarding the types of patients enrolled in these studies and whether participant characteristics vary by region. We used data derived from four multinational phase III trials in mild to moderate AD to examine whether regional differences exist with regard to participant demographics, safety reporting, and baseline scores on the Mini Mental State Examination (MMSE), the 11-item Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-cog11), the Clinical Dementia Rating scale Sum of Boxes (CDR-SB), the Alzheimer's Disease Cooperative Study-Activities of Daily Living Inventory (ADCS-ADL), and the Neuropsychiatric Inventory (NPI). We assigned 31 participating nations to 7 geographic regions: North America, South America/Mexico, Western Europe/Israel, Eastern Europe/Russia, Australia/South Africa, Asia, and Japan. North America, Western Europe/Israel, and Australia/South Africa enrolled similar proportions of men, apolipoprotein E ε4 carriers, and participants with spouse study partners, whereas Asia, Eastern Europe/Russia, and South America/Mexico had lower proportions for these variables. North America and South America/Mexico enrolled older subjects, whereas Asia and South America/Mexico enrolled less-educated participants than the remaining regions. Approved AD therapy use differed among regions (range: 73% to 92%) and was highest in North America, Western Europe/Israel, and Japan. Dual therapy was most frequent in North America (48%). On the MMSE, North America, Western Europe/Israel, Japan, and Australia/South Africa had higher (better) scores, and Asia, South America/Mexico, and Eastern Europe/Russia had lower scores. Eastern Europe/Russia had more impaired ADAS-cog11 scores than all other regions. Eastern Europe/Russia and South America/Mexico had more impaired scores for the ADCS-ADL and the CDR-SB. Mean scores for the CDR-SB in Asia were milder than all regions except Japan. NPI scores were lower in Asia and Japan than in all other regions. Participants in North America and Western Europe/Israel reported more adverse events than those in Eastern Europe/Russia and Japan. These findings suggest that trial populations differ across geographic regions on most baseline characteristics and that multinational enrollment is associated with sample heterogeneity. The data provide initial guidance with regard to the regional differences that contribute to this heterogeneity and are important to consider when planning global trials.
    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0122-5 · 3.98 Impact Factor
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    ABSTRACT: OPtimizing Transdermal Exelon In Mild-to-moderate Alzheimer's disease (OPTIMA) was a randomized, double-blind comparison of 13.3 mg/24 h versus 9.5 mg/24 h rivastigmine patch in patients with mild-to-moderate Alzheimer's disease who declined despite open-label treatment with 9.5 mg/24 h patch. Over 48 weeks of double-blind treatment, high-dose patch produced greater functional and cognitive benefits compared with 9.5 mg/24 h patch. Using OPTIMA data, a post-hoc responder analysis was performed to firstly, compare the proportion of patients demonstrating improvement or absence of decline with 13.3 mg/24 h versus 9.5 mg/24 h patch; and secondly, identify predictors of improvement or absence of decline. 'Improvers' were patients who improved on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) by ≥4 points from baseline, and did not decline on the instrumental domain of the Alzheimer's Disease Cooperative Study-Activities of Daily Living scale (ADCS-IADL). 'Non-decliners' were patients who did not decline on either scale. Overall, 265 patients randomized to 13.3 mg/24 h and 271 to 9.5 mg/24 h patch met the criteria for inclusion in the intention-to-treat population and were included in the analyses. Significantly more patients were 'improvers' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Weeks 24 (44 (16.6%) versus 19 (7.0%); P < 0.001) and 48 (21 (7.9%) versus 10 (3.7%); P = 0.023). A significantly greater proportion of patients were 'non-decliners' with 13.3 mg/24 h compared with 9.5 mg/24 h patch at Week 24 (71 (26.8%) versus 44 (16.2%); P = 0.002). At Week 48, there was a trend in favor of 13.3 mg/24 h patch. Functional and cognitive assessment scores at double-blind baseline did not consistently predict effects at Weeks 24 or 48. More patients with mild-to-moderate Alzheimer's disease who are titrated to 13.3 mg/24 h rivastigmine patch at time of decline are 'improvers' or 'non-decliners' i.e. show responses on cognition and activities of daily living compared with patients remaining on 9.5 mg/24 h patch. identifier: NCT00506415; registered July 20, 2007.
    Alzheimer's Research and Therapy 12/2015; 7(1):9. DOI:10.1186/s13195-014-0088-8 · 3.98 Impact Factor
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    ABSTRACT: To facilitate enrollment and meet local registration requirements, sponsors have increasingly implemented multi-national Alzheimer's disease (AD) studies. Geographic regions vary on many dimensions that may affect disease progression or its measurement. To aid researchers designing and implementing Phase 3 AD trials, we assessed disease progression across geographic regions using placebo data from four large, multi-national clinical trials of investigational compounds developed to target AD pathophysiology. Four similarly-designed 76 to 80 week, randomized, double-blind placebo-controlled trials with nearly identical entry criteria enrolled patients aged ≥55 years with mild or moderate NINCDS/ADRDA probable AD. Descriptive analyses were performed for observed mean score and observed mean change in score from baseline at each scheduled visit. Data included in the analyses were pooled from the intent-to-treat placebo-assigned overall (mild and moderate) AD dementia populations from all four studies. Disease progression was assessed as change from baseline for each of 5 scales - the AD Assessment Scale-cognitive subscale (ADAS-cog11), the AD Cooperative Study- Activities of Daily Living Scale (ADCS-ADL), Mini-Mental State Examination (MMSE), the Clinical Dementia Rating scored by the sum of boxes method (CDR-SB), and the Neuropsychiatric Inventory (NPI). Regions were heterogeneous at baseline. At baseline, disease severity as measured by ADAS-cog11, ADCS-ADL, and CDR-SB was numerically worse for Eastern Europe/Russia compared with other regions. Of all regional populations, Eastern Europe/Russia showed the greatest cognitive and functional decline from baseline; Japan, Asia and/or S. America/Mexico showed the least cognitive and functional decline. These data suggest that in multi-national clinical trials, AD progression or its measurement may differ across geographic regions; this may be in part due to heterogeneity across populations at baseline. The observed differences in AD progression between outcome measures across geographic regions may generalize to 'real-world' clinic populations, where heterogeneity is the norm. NCT00594568 - IDENTITY. Registered 11 January 2008. NCT00762411 - IDENTITY2. Registered 26 September 2008 NCT00905372 - EXPEDITION. Registered 18 May 2009 NCT00904683 - EXPEDITION2. Registered 18 May 2009.
    Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0127-0 · 3.98 Impact Factor

  • 10/2015; DOI:10.1038/nrdp.2015.56
  • Joel Raskin · Jeffrey Cummings · John Hardy · Kory Schuh · Robert A. Dean ·
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    ABSTRACT: Background: Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder with interrelated molecular, physiological, anatomical, biomarker, and cognitive dimensions. Methods: This article reviews the biological changes (genetic, molecular, and cellular) underlying AD and their correlation with the clinical syndrome. Results: Dementia associated with AD is related to the aberrant production, processing, and clearance of beta-amyloid and tau. Beta-amyloid deposition in brain follows a distinct spatial progression starting in the basal neocortex, spreading throughout the hippocampus, and eventually spreading to the rest of the cortex. The spread of tau pathology through neural networks leads to a distinct and consistent spatial progression of neurofibrillary tangles, beginning in the transentorhinal and hippocampal region and spreading superolaterally to the primary areas of the neocortex. Synaptic dysfunction and cell death is shown by progressive loss of cerebral metabolic rate for glucose and progressive brain atrophy. Decreases in synapse number in the dentate gyrus of the hippocampus correlate with declining cognitive function. Amyloid changes are detectable in cerebrospinal fluid and with amyloid imaging up to 20 years prior to the onset of symptoms. Structural atrophy may be detectable via magnetic resonance imaging up to 10 years before clinical signs appear. Conclusion: This review highlights the progression of biological changes underlying AD and their association with the clinical syndrome. Many changes occur before overt symptoms are evident and biomarkers provide a means to detect AD pathology even in patients without symptoms.
    Current Alzheimer Research 10/2015; 12(8). DOI:10.2174/1567205012666150701103107 · 3.89 Impact Factor
  • M Soto · S Abushakra · J Cummings · J Siffert · P Robert · B Vellas · C G Lyketsos ·
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    ABSTRACT: The management of neuropsychiatric symptoms (NPS) such as agitation and aggression is a major priority in caring for people with Alzheimer's disease (AD). Agitation and aggression (A/A) are among the most disruptive symptoms, and given their impact, they are increasingly an important target for development of effective treatments. Considerable progress has been made in the last years with a growing number of randomized controlled trials (RCTs) of drugs for NPS. The limited benefits reported in some RCTs may be accounted for by the absence of a biological link of the tested molecule to NPS and also by key methodological issues. In recent RCTs of A/A, a great heterogeneity design was found. Designing trials for dementia populations with NPS presents many challenges, including identification of appropriate participants for such trials, engagement and compliance of patients and caregivers in the trials and the choice of optimal outcome measures to demonstrate treatment effectiveness. The EU/US -CTAD Task Force, an international collaboration of investigators from academia, industry, non-profit foundations, and regulatory agencies met in Philadelphia on November 19, 2014 to address some of these challenges. Despite potential heterogeneity in clinical manifestations and neurobiology, agitation and aggression seems to be accepted as an entity for drug development. The field appears to be reaching a consensus in using both agitation and aggression (or other NPS)-specific quantitative measures plus a global rating of change for agitation outcomes based on clinician judgment as the main outcomes.
    09/2015; 2(3):184-188. DOI:10.14283/jpad.2015.77
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    ABSTRACT: IMPORTANCE Agitation is common among patients with Alzheimer disease; safe, effective treatments are lacking. OBJECTIVE To assess the efficacy, safety, and tolerability of dextromethorphan hydrobromide-quinidine sulfate for Alzheimer disease-related agitation. DESIGN, SETTING, AND PARTICIPANTS Phase 2 randomized, multicenter, double-blind, placebo-controlled trial using a sequential parallel comparison design with 2 consecutive 5-week treatment stages conducted August 2012-August 2014. Patients with probable Alzheimer disease, clinically significant agitation (Clinical Global Impressions-Severity agitation score≥4), and a Mini-Mental State Examination score of 8 to 28 participated at 42 US study sites. Stable dosages of antidepressants, antipsychotics, hypnotics, and antidementia medications were allowed. INTERVENTIONS In stage 1, 220 patients were randomized in a 3:4 ratio to receive dextromethorphan-quinidine (n = 93) or placebo (n = 127). In stage 2, patients receiving dextromethorphan-quinidine continued; those receiving placebo were stratified by response and rerandomized in a 1:1 ratio to dextromethorphan-quinidine (n = 59) or placebo (n = 60). MAIN OUTCOMES AND MEASURES The primary end pointwas change from baseline on the Neuropsychiatric Inventory (NPI) Agitation/Aggression domain (scale range, 0 [absence of symptoms] to 12 [symptoms occur daily and with marked severity]). RESULTS Atotal of 194 patients (88.2%) completed the study. With the sequential parallel comparison design, 152 patients received dextromethorphan-quinidine and 127 received placebo during the study. Analysis combining stages 1 (all patients) and 2 (rerandomized placebo nonresponders)showedsignificantlyreducedNPIAgitation/Aggressionscoresfordextromethorphanquinidinevsplacebo( ordinaryleastsquareszstatistic,-3.95;P < .001).Instage1,meanNPIAgitation/ Aggression scoreswere reduced from 7.1 to 3.8 with dextromethorphan-quinidine and from 7.0to 5.3withplacebo.Between-grouptreatmentdifferencesweresignificantinstage1(leastsquaresmean, -1.5; 95%CI, -2.3 to -0.7; P<.001). In stage 2, NPI Agitation/Aggression scoreswere reduced from 5.8 to 3.8 with dextromethorphan-quinidine and from 6.7 to 5.8 with placebo. Between-group treatmentdifferenceswere also significant in stage2(leastsquaresmean,-1.6;95%CI,-2.9to-0.3; P=.02).Adverseevents included falls (8.6%fordextromethorphan-quinidine vs3.9%for placebo), diarrhea (5.9%vs 3.1%respectively), and urinary tract infection (5.3%vs 3.9%respectively). Serious adverse events occurred in 7.9%with dextromethorphan-quinidine vs 4.7%with placebo. Dextromethorphan-quinidinewas not associated with cognitiveimpairment, sedation, or clinically significantQTc prolongation. CONCLUSIONS AND RELEVANCE In this preliminary 10-week phase 2 randomized clinical trial of patients with probable Alzheimer disease, combination dextromethorphan-quinidine demonstrated clinically relevant efficacy for agitation and was generally well tolerated. TRIAL REGISTRATION Identifier: NCT01584440
    JAMA The Journal of the American Medical Association 09/2015; 314(12):1242-1254. DOI:10.1001/jama.2015.10214 · 35.29 Impact Factor
  • Jeffrey Cummings · Kate Zhong ·
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    ABSTRACT: Neuropsychiatric symptoms are common in Alzheimer's disease (AD) and other neurodegenerative disorders. Recent progress has been made with clinical trials, advancing new therapies for psychosis in Parkinson's disease (PD), agitation in AD, and apathy in AD. Definitions have emerged for agitation and apathy in patients with cognitive impairment, facilitating recruitment of clinical trial populations. Progress in clinical trial design and the agents being assessed promise to advance therapies for disabling symptoms and improve quality of life for patients and caregivers.
    Clinical Pharmacology &#38 Therapeutics 07/2015; 98. DOI:10.1002/cpt.190 · 7.90 Impact Factor
  • Hui-Fen Mao · Chun-An Kuo · Wen-Ni Huang · Jeffrey L Cummings · Tzung-Jeng Hwang ·
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    ABSTRACT: To estimate the minimal clinically important difference (MCID) for the Neuropsychiatric Inventory Questionnaire (NPI-Q), a widely used measure of behavioral and psychological symptoms of dementia (BPSDs) and associated caregiver stress. Ten registered nurses rated the severity of BPSDs and caregiver distress using the NPI-Q during six monthly assessments and an external reference, a 7-point Likert-type global rating of BPSDs change during five monthly assessments from the second to the sixth month. An anchor-based (global ratings of change) approach and a distribution-based (standard error of measurement) approach were used to determine the MCID for the NPI-Q severity and distress subscales. Long-term care facility. Nonbedridden residents with dementia (n = 45) and registered nurses (n = 10). NPI-Q (severity and caregiver distress subscales) and global ratings of changes in BPSDs on a 7-point Likert-type scale. The NPI-Q MCID ranges were 2.77 to 3.18 for severity and 3.10 to 3.95 for distress. Residents in the highest NPI-Q tertile at baseline had higher MCID severity (3.62) and distress (5.08) scores than those in the lowest tertile (severity (2.40), distress (3.10)). This study provides an estimate of the MCID for severity and distress subscales of the NPI-Q, which can help clinicians and researchers determine whether NPI-Q change scores within a group of individuals with dementia are beyond measurement error and are clinically important. © 2015, Copyright the Authors Journal compilation © 2015, The American Geriatrics Society.
    Journal of the American Geriatrics Society 06/2015; 63(7). DOI:10.1111/jgs.13473 · 4.57 Impact Factor
  • Sally J. Vogel · Sarah J. Banks · Jeffrey L. Cummings · Justin B. Miller ·
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    ABSTRACT: Introduction: The concordance of the Montreal cognitive assessment (MoCA) with more comprehensive neuropsychological measures remains unclear. This study examined the individual MoCA domains with more comprehensive and commonly used neuropsychological measures to determine the degree of overlap. Methods: Data included individuals seen in an outpatient neurology clinic specializing in neurodegenerative disease who were administered the MoCA and also underwent neuropsychological assessment (n=471). A principal component analysis with varimax rotation was completed using the MoCA domain scores and comprehensive neuropsychological evaluation measures. Results: Four factors emerged accounting for 55.6% of the variance: (1) visuospatial/executive functioning; (2) memory; (3) attention; and (4) language. The individual MoCA domain scores demonstrated high factor loadings with standard neuropsychological measures purported to measure similar cognitive constructs. Discussion: These findings provide empirical validation for the MoCA domain classifications, lending further support for the use of the MoCA as a cognitive screen that reflects similar constructs as those measured by a comprehensive battery.
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    ABSTRACT: Apathy is a common feature of neurodegenerative disorders but is difficult to study in a clinical trial setting due to practical and conceptual barriers. Principal challenges include a paucity of data regarding apathy in these disorders, an absence of established diagnostic criteria, the presence of confounding factors (eg, coexisting depression), use of concomitant medications, and an absence of a gold-standard apathy assessment scale. Based on a literature search and ongoing collaboration among the authors, we present recommendations for the design of future clinical trials of apathy, suggesting Alzheimer disease and Parkinson disease as models with relevance across a wider array of neuropsychiatric disorders. Recommendations address clarification of the targeted study population (apathy diagnosis and severity at baseline), confounding factors (mood/cognition, behavior, and treatment), outcome measures, study duration, use of comparators and considerations around environment, and the role of the caregiver and patient assent. This review contributes to the search for an optimal approach to study treatment of apathy in neuropsychiatric disorders. © The Author(s) 2015.
    Journal of Geriatric Psychiatry and Neurology 03/2015; 28(3). DOI:10.1177/0891988715573534 · 2.24 Impact Factor

  • American Journal of Geriatric Psychiatry 03/2015; 23(3):S164-S165. DOI:10.1016/j.jagp.2014.12.171 · 4.24 Impact Factor
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    Jeffrey L. Cummings · Richard S. Isaacson · Frederick A. Schmitt · Drew M. Velting ·
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    ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia and its prevalence is increasing. Recent developments in AD management provide improved ways of supporting patients and their caregivers throughout the disease continuum. Managing cardiovascular risk factors, maintaining an active lifestyle (with regular physical, mental and social activity) and following a Mediterranean diet appear to reduce AD risk and may slow cognitive decline. Pharmacologic therapy for AD should be initiated upon diagnosis. All of the currently available cholinesterase inhibitors (ChEIs; donepezil, galantamine, and rivastigmine) are indicated for mild-to-moderate AD. Donepezil (10 and 23 mg/day) and rivastigmine transdermal patch (13.3 mg/24 h) are indicated for moderate-to-severe AD. Memantine, an N-methyl-d-aspartate receptor antagonist, is approved for moderate-to-severe AD. ChEIs have been shown to improve cognitive function, global clinical status and patients' ability to perform activities of daily living. There is also evidence for reduction in emergence of behavioral symptoms with ChEI therapy. Treatment choice (e.g., oral vs. transdermal) should be based on patient or caregiver preference, ease of use, tolerability, and cost. Treatment should be individualized; patients can be switched from one ChEI to another if the initial agent is poorly tolerated or ineffective. Memantine may be introduced in moderate-to-severe disease stages. Clinicians will regularly monitor symptoms and behaviors, manage comorbidities, assess function, educate and help caregivers access information and support, evaluate patients' fitness to drive or own firearms, and provide advice about the need for legal and financial planning. Review of caregiver well-being and prompt referral for support is vital.
    03/2015; 2(3). DOI:10.1002/acn3.166
  • G Alva · J L Cummings · J E Galvin · X Meng · D M Velting ·
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    ABSTRACT: Rivastigmine patch is approved for the treatment of all stages of Alzheimer's disease (AD). Application site reactions may be a concern to clinicians and we used two large clinical trial databases to investigate the incidence of skin reactions in patients receiving rivastigmine patch. Data from a 24-week, randomised, double-blind (DB) evaluation of 13.3 vs. 4.6 mg/24 h rivastigmine patch in severe AD (ACTION) and a 72- to 96-week study comprising an initial open-label (IOL) phase followed by a 48-week randomised, DB phase (13.3 vs. 9.5 mg/24 h rivastigmine patch) in declining patients with mild-to-moderate AD (OPTIMA) were analyzed. The incidence, frequency, severity, management and predictors of application site reactions were assessed. Application site reactions were mostly mild or moderate in severity and reported by similar proportions in each treatment group (ACTION: 13.3 mg/24 h, 24.5% and 4.6 mg/24 h, 24.2%; OPTIMA: IOL 9.5 mg/24 h, 22.9%; DB 13.3 mg/24 h, 11.4% and 9.5 mg/24 h, 12.0%); none were rated serious. In both studies, < 9% of patients required treatment for application site reactions. Application site reactions led to discontinuation of 1.7% and 2.5% of the 13.3 mg/24 h and 4.6 mg/24 h groups, respectively, in ACTION, 8.7% in OPTIMA IOL and 1.8% and 3.5% of the 13.3 mg/24 h and 9.5 mg/24 h groups, respectively, in OPTIMA DB. Application site reactions were experienced by < 25% of patients in both studies, with no notable effect of dose. No reactions qualified as serious and skin reactions were uncommon as a reason for study discontinuation. © 2015 John Wiley & Sons Ltd.
    International Journal of Clinical Practice 02/2015; 69(5). DOI:10.1111/ijcp.12621 · 2.57 Impact Factor
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    ABSTRACT: Prior studies indicate psychiatric symptoms such as depression, apathy and anxiety are risk factors for or prodromal symptoms of incipient Alzheimer's disease. The study of persons at 50% risk for inheriting autosomal dominant Alzheimer's disease mutations allows characterization of these symptoms before progressive decline in a population destined to develop illness. We sought to characterize early behavioural features in carriers of autosomal dominant Alzheimer's disease mutations. Two hundred and sixty-one persons unaware of their mutation status enrolled in the Dominantly Inherited Alzheimer Network, a study of persons with or at-risk for autosomal dominant Alzheimer's disease, were evaluated with the Neuropsychiatric Inventory-Questionnaire, the 15-item Geriatric Depression Scale and the Clinical Dementia Rating Scale (CDR). Ninety-seven asymptomatic (CDR = 0), 25 mildly symptomatic (CDR = 0.5), and 33 overtly affected (CDR > 0.5) autosomal dominant Alzheimer's disease mutation carriers were compared to 106 non-carriers with regard to frequency of behavioural symptoms on the Neuropsychiatric Inventory-Questionnaire and severity of depressive symptoms on the Geriatric Depression Scale using generalized linear regression models with appropriate distributions and link functions. Results from the adjusted analyses indicated that depressive symptoms on the Neuropsychiatric Inventory-Questionnaire were less common in cognitively asymptomatic mutation carriers than in non-carriers (5% versus 17%, P = 0.014) and the odds of experiencing at least one behavioural sign in cognitively asymptomatic mutation carriers was lower than in non-carriers (odds ratio = 0.50, 95% confidence interval: 0.26-0.98, P = 0.042). Depression (56% versus 17%, P = 0.0003), apathy (40% versus 4%, P < 0.0001), disinhibition (16% versus 2%, P = 0.009), irritability (48% versus 9%, P = 0.0001), sleep changes (28% versus 7%, P = 0.003), and agitation (24% versus 6%, P = 0.008) were more common and the degree of self-rated depression more severe (mean Geriatric Depression Scale score of 2.8 versus 1.4, P = 0.006) in mildly symptomatic mutation carriers relative to non-carriers. Anxiety, appetite changes, delusions, and repetitive motor activity were additionally more common in overtly impaired mutation carriers. Similar to studies of late-onset Alzheimer's disease, we demonstrated increased rates of depression, apathy, and other behavioural symptoms in the mildly symptomatic, prodromal phase of autosomal dominant Alzheimer's disease that increased with disease severity. We did not identify any increased psychopathology in mutation carriers over non-carriers during the presymptomatic stage, suggesting these symptoms result when a threshold of neurodegeneration is reached rather than as life-long qualities. Unexpectedly, we found lower rates of depressive symptoms in cognitively asymptomatic mutation carriers. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 02/2015; 138(4). DOI:10.1093/brain/awv004 · 9.20 Impact Factor
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    ABSTRACT: Alzheimer's disease (AD) is a slowly progressing non-linear dynamic brain disease in which pathophysiological abnormalities, detectable in vivo by biological markers, precede overt clinical symptoms by many years to decades. Use of these biomarkers for the detection of early and preclinical AD has become of central importance following publication of two international expert working group's revised criteria for the diagnosis of AD dementia, mild cognitive impairment (MCI) due to AD, prodromal AD and preclinical AD. As a consequence of matured research evidence six AD biomarkers are sufficiently validated and partly qualified to be incorporated into operationalized clinical diagnostic criteria and use in primary and secondary prevention trials. These biomarkers fall into two molecular categories: biomarkers of amyloid-beta (Aβ) deposition and plaque formation as well as of tau-protein related hyperphosphorylation and neurodegeneration. Three of the six gold-standard ("core feasible) biomarkers are neuroimaging measures and three are cerebrospinal fluid (CSF) analytes. CSF Aβ1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven diagnostic accuracy and risk enhancement in prodromal MCI and AD dementia. Conversely, having all three biomarkers in the normal range rules out AD. Intermediate conditions require further patient follow-up. Magnetic resonance imaging (MRI) at increasing field strength and resolution allows detecting the evolution of distinct types of structural and functional abnormality pattern throughout early to late AD stages. Anatomical or volumetric MRI is the most widely used technique and provides local and global measures of atrophy. The revised diagnostic criteria for "prodromal AD" and "mild cognitive impairment due to AD" include hippocampal atrophy (as the fourth validated biomarker), which is considered an indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both in regions of interest, such as the hippocampus and in an exploratory fashion, observer and hypothesis-indedendent, throughout the entire brain. Evolving modalities such as diffusion-tensor imaging (DTI) and advanced tractography as well as resting-state functional MRI provide useful additionally useful measures indicating the degree of fiber tract and neural network disintegration (structural, effective and functional connectivity) that may substantially contribute to early detection and the mapping of progression. These modalities require further standardization and validation. The use of molecular in vivo amyloid imaging agents (the fifth validated biomarker), such as the Pittsburgh Compound-B and markers of neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as the sixth validated biomarker) support the detection of early AD pathological processes and associated neurodegeneration. How to use, interpret, and disclose biomarker results drives the need for optimized standardization. Multimodal AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping fashion. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. AD biomarkers can be combined to increase accuracy or risk. A list of genetic risk factors is increasingly included in secondary prevention trials to stratify and select individuals at genetic risk of AD. Although most of these biomarker candidates are not yet qualified and approved by regulatory authorities for their intended use in drug trials, they are nonetheless applied in ongoing clinical studies for the following functions: (i) inclusion/exclusion criteria, (ii) patient stratification, (iii) evaluation of treatment effect, (iv) drug target engagement, and (v) safety. Moreover, novel promising hypothesis-driven, as well as exploratory biochemical, genetic, electrophysiological, and neuroimaging markers for use in clinical trials are being developed. The current state-of-the-art and future perspectives on both biological and neuroimaging derived biomarker discovery and development as well as the intended application in prevention trials is outlined in the present publication.
    12/2014; DOI:10.14283/jpad.2014.32
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    ABSTRACT: Background: Agitation is common across neuropsychiatric disorders and contributes to disability, institutionalization, and diminished quality of life for patients and their caregivers. There is no consensus definition of agitation and no widespread agreement on what elements should be included in the syndrome. The International Psychogeriatric Association formed an Agitation Definition Work Group (ADWG) to develop a provisional consensus definition of agitation in patients with cognitive disorders that can be applied in epidemiologic, non-interventional clinical, pharmacologic, non-pharmacologic interventional, and neurobiological studies. A consensus definition will facilitate communication and cross-study comparison and may have regulatory applications in drug development programs. Methods: The ADWG developed a transparent process using a combination of electronic, face-to-face, and survey-based strategies to develop a consensus based on agreement of a majority of participants. Nine-hundred twenty-eight respondents participated in the different phases of the process. Results: Agitation was defined broadly as: (1) occurring in patients with a cognitive impairment or dementia syndrome; (2) exhibiting behavior consistent with emotional distress; (3) manifesting excessive motor activity, verbal aggression, or physical aggression; and (4) evidencing behaviors that cause excess disability and are not solely attributable to another disorder (psychiatric, medical, or substance-related). A majority of the respondents rated all surveyed elements of the definition as "strongly agree" or "somewhat agree" (68-88% across elements). A majority of the respondents agreed that the definition is appropriate for clinical and research applications. Conclusions: A provisional consensus definition of agitation has been developed. This definition can be used to advance interventional and non-interventional research of agitation in patients with cognitive impairment.
    International Psychogeriatrics 10/2014; 27(1):1-11. DOI:10.1017/S1041610214001963 · 1.93 Impact Factor
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    ABSTRACT: The Alzheimer's Disease Cooperative Study Prevention Instrument Project is a longitudinal study that recruited 644 cognitively healthy older subjects (aged between 75 and 93 years, 58% women) at baseline and evaluated their cognitive change over 4 years. The study was structured like a clinical trial to anticipate a prevention trial and to determine the performance of novel trial instruments in a longitudinal non-interventional trial framework. Behavioral symptoms were assessed at baseline. The existence of participant-reported behavioral symptoms at baseline predicted conversion to Clinical Dementia Rating scale score ≥0.5 over the 4-year period. The results imply that early anxiety and depression may be harbingers of future cognitive decline, and that patients exhibiting such symptoms, even in the absence of co-occurring cognitive symptoms, should be closely followed over time.
    09/2014; 4(3):509-16. DOI:10.1159/000357775
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    ABSTRACT: Background: In patients with Alzheimer's disease (AD), the relationship between cognitive and functional progression is not fully understood; however, functional decline has been postulated to follow cognitive decline. Objective: To assess the relationship between cognitive and functional treatment effects in mild AD dementia patients. Methods: Data of patients with mild AD were pooled from two multicenter, double-blind, Phase 3 studies. Patients were randomized to infusions of 400-mg solanezumab (n = 654), or placebo (n = 660) every 4 weeks for 18 months. Cognitive and functional outcome measures were assessed using the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study-Activities of Daily Living (ADCS-ADL), respectively. Analyses included comparisons among normalized scales, correlations between outcome measures, and path analyses to model the relationship of treatment effect on cognition and function. Results: Normalized ADAS-Cog and ADCS-ADL scales showed cognitive impairment was more evident than functional impairment in mild AD. The correlation between cognition and function increased over time. Path analyses demonstrated that 87% of the treatment effect on function was driven by the treatment effect on cognition, with the remaining 13% due to direct treatment effect. Conclusion: Findings from this study are consistent with the hypothesis that functional impairment is primarily driven by and follows cognitive decline in mild AD dementia. The cognitive treatment effect appeared to explain the majority of the functional treatment effect. It is possible that a cognitive treatment effect may be considered as a leading indicator for functional outcomes in an 18-month clinical trial for milder stages of AD.
    Journal of Alzheimer's disease: JAD 08/2014; 43(3). DOI:10.3233/JAD-140792 · 4.15 Impact Factor
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Publication Stats

30k Citations
3,124.76 Total Impact Points


  • 2012-2015
    • University of Nevada, Las Vegas
      • Department of Psychology
      Las Vegas, Nevada, United States
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
  • 2014
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
  • 2012-2014
    • Cleveland Clinic
      Cleveland, Ohio, United States
  • 1986-2013
    • University of California, Los Angeles
      • • Department of Neurology
      • • Department of Psychiatry and Biobehavioural Sciences
      • • Division of Adult Psychiatry
      • • School of Dentistry
      • • Department of Medicine
      Los Angeles, California, United States
    • Spokane VA Medical Center
      Spokane, Washington, United States
  • 1991-2010
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
  • 2008
    • CSU Mentor
      Long Beach, California, United States
  • 2007-2008
    • Medical University of Graz
      Gratz, Styria, Austria
    • Stavanger University Hospital
      Stavenger, Rogaland, Norway
  • 2006
    • University of California, San Francisco
      San Francisco, California, United States
    • University of Rochester
      • Department of Psychiatry
      Rochester, New York, United States
  • 2005
    • Mahidol University
      Krung Thep, Bangkok, Thailand
  • 2004-2005
    • University of California, San Diego
      San Diego, California, United States
    • California State University
      • Department of Neurology
      Long Beach, California, United States
  • 2003
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2002
    • National Institute of Mental Health (NIMH)
      • Adult Treatment and Preventive Intervention Research Branch
      Maryland, United States
  • 2001
    • Università di Pisa
      Pisa, Tuscany, Italy
    • National Yang Ming University
      T’ai-pei, Taipei, Taiwan
  • 1989-2000
    • Harbor-UCLA Medical Center
      Torrance, California, United States
    • The Ohio State University
      Columbus, Ohio, United States
  • 1999
    • University of Arkansas for Medical Sciences
      • Department of Psychiatry
      Little Rock, AR, United States
    • Cornell University
      Итак, New York, United States
  • 1998
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
    • National Institutes of Health
      Maryland, United States
    • IRCCS Centro San Giovanni di Dio, Fatebenefratelli, Brescia
      • Cognitive Neuroscience Section
      Brescia, Lombardy, Italy