Jeffrey L Cummings

Mayo Clinic - Scottsdale, Scottsdale, Arizona, United States

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Publications (613)3874.97 Total impact

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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 · 3.50 Impact Factor
  • Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0127-0 · 3.50 Impact Factor
  • Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0122-5 · 3.50 Impact Factor
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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; DOI:10.1177/0891988715573534 · 1.63 Impact Factor
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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
  • American Journal of Geriatric Psychiatry 03/2015; 23(3):S164-S165. DOI:10.1016/j.jagp.2014.12.171 · 3.52 Impact Factor
  • 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 · 2.54 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 · 10.23 Impact Factor
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    ABSTRACT: 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 · 1.89 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.
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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; DOI:10.3233/JAD-140792 · 3.61 Impact Factor
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  • J. Cummings, S. Isaacson, R. Mills
    The Lancet 07/2014; 384(9937):28-28. · 45.22 Impact Factor
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    Jeffrey L Cummings, Travis Morstorf, Kate Zhong
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    ABSTRACT: Alzheimer's disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD.
    Alzheimer's Research and Therapy 07/2014; 6(4):37. DOI:10.1186/alzrt269 · 3.50 Impact Factor
  • Alzheimer's and Dementia 07/2014; 10(4):P275. DOI:10.1016/j.jalz.2014.04.450 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P821. DOI:10.1016/j.jalz.2014.05.1617 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P203. DOI:10.1016/j.jalz.2014.04.256 · 17.47 Impact Factor
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    Alzheimer's and Dementia 07/2014; 10(4):P856-P857. DOI:10.1016/j.jalz.2014.05.1702 · 17.47 Impact Factor
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    ABSTRACT: Repurposing Food and Drug Administration (FDA)-approved drugs for a new indication may offer an accelerated pathway for new treatments to patients but is also fraught with significant commercial, regulatory, and reimbursement challenges. The Alzheimer's Drug Discovery Foundation (ADDF) and the Michael J. Fox Foundation for Parkinson's Research (MJFF) convened an advisory panel in October 2013 to understand stakeholder perspectives related to repurposing FDA-approved drugs for neurodegenerative diseases. Here, we present opportunities on how philanthropy, industry, and government can begin to address these challenges, promote policy changes, and develop targeted funding strategies to accelerate the potential of FDA-approved repurposed drugs.
    07/2014; 1(7). DOI:10.1002/acn3.76
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    ABSTRACT: Progress has been made in understanding the genetics and molecular biology of frontotemporal dementia (FTD). Targets for intervention have been identified, therapies are being developed, and clinical trials are advancing. A major challenge for FTD research is that multiple underlying pathologies can be associated with heterogeneous phenotypes. The neuropsychological profiles associated with FTD spectrum disorders often include executive dysfunction, language impairments and behavioral disturbance. Behavioral variant FTD is characterized by an initial presentation of changes in personality, behavior and/or emotion, which are often difficult to objectively capture using traditional neuropsychological measures. The two principal language variants of FTD are Progressive Nonfluent Aphasia (PNFA) with predominant agrammatic/non-fluent impairments and Semantic Dementia (SD) with semantic impairments and visual agnosia. Selection of appropriate endpoints for clinical trials is critical to ensure that the measures are adequately sensitive to detect change, yet specific enough to isolate signal from noise, and acceptable to regulatory agencies. Given the anticipated potential for small effect sizes, measures must be able to identify small incremental changes over time. It is also imperative that the measures provide adequate coverage of the constructs or behaviors of interest. Selected outcome measures should be suitable for repeat administration, yet relatively robust to practice effects to ensure that observed changes reflect true signal variance and not residual effects due to repeated measurement or poor reliability. To facilitate widespread adoption as an endpoint, measures should be readily accessible. We provide several examples of potential global, composite, and individual cognitive measures, as well as behavioral measures promising for FTD trials. Development and application of appropriate trial outcomes is critically important to success in advancing new treatments for FTD patients.
    06/2014; 3:12. DOI:10.1186/2047-9158-3-12

Publication Stats

41k Citations
3,874.97 Total Impact Points


  • 2014
    • Mayo Clinic - Scottsdale
      Scottsdale, Arizona, United States
  • 2012–2014
    • University of Nevada, Las Vegas
      • Department of Psychology
      Las Vegas, Nevada, United States
    • Barrow Neurological Institute
      Phoenix, Arizona, United States
    • 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
  • 2006–2012
    • University of California, San Francisco
      • Department of Neurology
      San Francisco, California, United States
    • Icahn School of Medicine at Mount Sinai
      Manhattan, New York, United States
    • New York University
      • Alzheimer’s Disease Center
      New York City, NY, United States
  • 1996–2010
    • Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center
      • Department of Medicine
      Torrance, California, United States
    • Dokuz Eylul University
      • Faculty of Medicine
      İzmir, Izmir, Turkey
  • 2007–2008
    • Medical University of Graz
      Gratz, Styria, Austria
    • Stavanger University Hospital
      Stavenger, Rogaland, Norway
  • 2004–2008
    • CSU Mentor
      • Department of Neurology
      Long Beach, California, United States
  • 2004–2006
    • University of Rochester
      • Department of Psychiatry
      Rochester, New York, United States
  • 2001–2006
    • Taipei Veterans General Hospital
      • Neurological Institute
      Taipei, Taipei, Taiwan
    • Università di Pisa
      Pisa, Tuscany, Italy
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
    • University of Iowa
      • Department of Psychiatry
      Iowa City, IA, United States
    • Baylor College of Medicine
      • Department of Neurology
      Houston, TX, United States
  • 2000–2006
    • Washington University in St. Louis
      • Department of Neurology
      San Luis, Missouri, United States
    • Pacific Neuropsychiatric Institute
      Seattle, Washington, United States
  • 2005
    • National Yang Ming University
      T’ai-pei, Taipei, Taiwan
    • Providence Health and Services
      Renton, Washington, United States
  • 2004–2005
    • University of California, San Diego
      San Diego, California, United States
  • 2002–2005
    • Mahidol University
      • Faculty of Medicine Siriraj Hospital
      Krung Thep, Bangkok, Thailand
    • Rancho Los Amigos Rehabilitation Center
      Downey, California, United States
    • National Institute of Mental Health (NIMH)
      • Adult Treatment and Preventive Intervention Research Branch
      Maryland, United States
  • 2003
    • University of Alabama at Birmingham
      Birmingham, Alabama, United States
  • 2000–2003
    • University of Arkansas at Little Rock
      Little Rock, Arkansas, United States
  • 1999
    • University of Arkansas for Medical Sciences
      • Department of Psychiatry
      Little Rock, AR, United States
    • Harvard University
      Cambridge, Massachusetts, United States
    • Central Arkansas Veterans Healthcare System
      Washington, Washington, D.C., United States
    • Cornell University
      Итак, New York, United States
  • 1996–1999
    • Harbor-UCLA Medical Center
      • Department of Pediatrics
      Torrance, California, United States
  • 1998
    • Istituto di Cura e Cura a Carattere Scientifico Basilicata
      Rionero in Vulture, Basilicate, Italy
  • 1997
    • London Research Institute
      Londinium, England, United Kingdom
    • University of Washington Seattle
      • Department of Neurology
      Seattle, Washington, United States
    • Butler Hospital
      Providence, Rhode Island, United States
  • 1995
    • University of Oklahoma Health Sciences Center
      Oklahoma City, Oklahoma, United States
    • Emory University
      • Department of Neurology
      Atlanta, GA, United States
  • 1989
    • The Ottawa Hospital
      • Department of Psychiatry
      Ottawa, Ontario, Canada
  • 1987
    • University of Ottawa
      • Department of Psychiatry
      Ottawa, Ontario, Canada