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04/2018 journal articles

Editorials

WHAT WE LEARN FROM THE CTAD 2018 (CLINICAL TRIALS ALZHEIMER’S DISEASE)

B. Vellas, P. Aisen, M. Weiner, J. Touchon

J Prev Alz Dis 2018;5(4):214-215

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CITATION:
B. Vellas ; P. Aisen ; M. Weiner ; J. Touchon (2018): What We Learn from the CTAD 2018 (Clinical Trials Alzheimer’s Disease). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.38

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Original Research

ASSESSMENT OF INSTRUMENTAL ACTIVITIES OF DAILY LIVING IN OLDER ADULTS WITH SUBJECTIVE COGNITIVE DECLINE USING THE VIRTUAL REALITY FUNCTIONAL CAPACITY ASSESSMENT TOOL (VRFCAT)

A.S. Atkins, A. Khan, D. Ulshen, A. Vaughan, D. Balentin, H. Dickerson, L.E. Liharska, B. Plassman, K. Welsh-Bohmer, R. S.E. Keefe

J Prev Alz Dis 2018;5(4):216-224

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Background: Continuing advances in the understanding of Alzheimer’s disease progression have inspired development of disease-modifying therapeutics intended for use in preclinical populations. However, identification of clinically meaningful cognitive and functional outcomes for individuals who are, by definition, asymptomatic remains a significant challenge. Clinical trials for prevention and early intervention require measures with increased sensitivity to subtle deficits in instrumental activities of daily living (IADL) that comprise the first functional declines in prodromal disease. Validation of potential endpoints is required to ensure measure sensitivity and reliability in the populations of interest. Objectives: The present research validates use of the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) for performance-based assessment of IADL functioning in older adults (age 55+) with subjective cognitive decline. Design: Cross-sectional validation study. Setting: All participants were evaluated on-site at NeuroCog Trials, Durham, NC, USA. Participants: Participants included 245 healthy younger adults ages 20-54 (131 female), 247 healthy older adults ages 55-91 (151 female) and 61 older adults with subjective cognitive decline (SCD) ages 56-97 (45 female). Measures: Virtual Reality Functional Capacity Assessment Tool; Brief Assessment of Cognition App; Alzheimer’s Disease Cooperative Study Prevention Instrument Project – Mail-In Cognitive Function Screening Instrument; Alzheimer’s Disease Cooperative Study Instrumental Activities of Daily Living – Prevention Instrument, University of California, San Diego Performance-Based Skills Assessment – Validation of Intermediate Measures; Montreal Cognitive Assessment; Trail Making Test- Part B. Results: Participants with SCD performed significantly worse than age-matched normative controls on all VRFCAT endpoints, including total completion time, errors and forced progressions (p≤0001 for all, after Bonferonni correction). Consistent with prior findings, both groups performed significantly worse than healthy younger adults (age 20-54). Participants with SCD also performed significantly worse than controls on objective cognitive measures. VRFCAT performance was strongly correlated with cognitive performance. In the SCD group, VRFCAT performance was strongly correlated with cognitive performance across nearly all tests with significant correlation coefficients ranging from 0.3 to 0.7; VRFCAT summary measures all had correlations greater than r=0.5 with MoCA performance and BAC App Verbal Memory (p<0.01 for all). Conclusions: Findings suggest the VRFCAT provides a sensitive tool for evaluation of IADL functioning in individuals with subjective cognitive decline. Strong correlations with cognition across groups suggest the VRFCAT may be uniquely suited for clinical trials in preclinical AD, as well as longitudinal investigations of the relationship between cognition and function.

CITATION:
A.S. Atkins ; A. Khan ; D. Ulshen ; A. Vaughan ; D. Balentin ; H. Dickerson ; L.E. Liharska ; B. Plassman ; K. Welsh-Bohmer ; R. S.E. Keefe (2018): Assessment of Instrumental Activities of Daily Living in Older Adults with Subjective Cognitive Decline Using the Virtual Reality Functional Capacity Assessment Tool (VRFCAT). The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.28

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FEMALE SEX AND ALZHEIMER’S RISK: THE MENOPAUSE CONNECTION

O. Scheyer, A. Rahman, H. Hristov, C. Berkowitz, R.S. Isaacson, R. Diaz Brinton, L. Mosconi

J Prev Alz Dis 2018;5(4):225-230

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Along with advanced age and apolipoprotein E (APOE)-4 genotype, female sex is a major risk factor for developing late-onset Alzheimer’s disease (AD). Considering that AD pathology begins decades prior to clinical symptoms, the higher risk in women cannot simply be accounted for by their greater longevity as compared to men. Recent investigation into sex-specific pathophysiological mechanisms behind AD risk has implicated the menopause transition (MT), a midlife neuroendocrine transition state unique to females. Commonly characterized as ending in reproductive senescence, many symptoms of MT are neurological, including disruption of estrogen-regulated systems such as thermoregulation, sleep, and circadian rhythms, as well as depression and impairment in multiple cognitive domains. Preclinical studies have shown that, during MT, the estrogen network uncouples from the brain bioenergetic system. The resulting hypometabolic state could serve as the substrate for neurological dysfunction. Indeed, translational brain imaging studies demonstrate that 40-60 year-old perimenopausal and postmenopausal women exhibit an AD-endophenotype characterized by decreased metabolic activity and increased brain amyloid-beta deposition as compared to premenopausal women and to age-matched men. This review discusses the MT as a window of opportunity for therapeutic interventions to compensate for brain bioenergetic crisis and combat the subsequent increased risk for AD in women.

CITATION:
O. Scheyer ; A. Rahman ; H. Hristov ; C. Berkowitz ; R.S. Isaacson ; R. Diaz Brinton ; L. Mosconi (2018): Female Sex and Alzheimer’s Risk: The Menopause Connection. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.34

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GEOGRAPHIC CLUSTERS OF ALZHEIMER’S DISEASE MORTALITY RATES IN THE USA: 2008-2012

R.W. Amin, E.M. Yacko, R.P. Guttmann

J Prev Alz Dis 2018;5(4):231-235

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Importance: The results identified geographic clusters of high and low Alzheimer’s disease (AD)-related mortality across the contiguous United States. These clusters identify specific geographic groupings of counties that allow researchers to narrow the focus to identify some of the biopsychosocial variables contributing to increased or decreased AD mortality. Objectives: To determine the extent to which geographic clusters exist where AD mortality significantly differs from the national average. Such knowledge could further future research in a more focused study of variables that are contributing to these differences. Design: Age adjusted AD mortality rates were analyzed with a spatial cluster analysis using the disease surveillance software SatScanTM. Results: Three large clusters had elevated age-adjusted AD mortality of at least 60% above the national average. These clusters were in Washington State, Iowa, and North and South Dakota. Below average AD mortality was observed in several areas including New York City, and parts of Arizona, California, Arkansas and Texas. Conclusion and Relevance: This study demonstrates the use of disease surveillance methodology in identifying geographic patterns of unusually high or low AD mortality rates in the USA. Such results provide supporting evidence of appropriate locations to test interventions with the goal to reduce AD mortality.

CITATION:
R.W. Amin ; E.M. Yacko ; R.P. Guttmann (2018): Geographic Clusters of Alzheimer’s Disease Mortality Rates in the USA: 2008-2012. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.36

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PSYCHOMETRIC EVALUATION OF THE NEUROPSYCHOLOGICAL TEST BATTERY IN INDIVIDUALS WITH NORMAL COGNITION, MILD COGNITIVE IMPAIRMENT, OR MILD TO MODERATE ALZHEIMER’S DISEASE: RESULTS FROM A LONGITUDINAL STUDY

J.E. Harrison, D.M. Rentz, H.R. Brashear, H.M. Arrighi, M.T. Ropacki, E. Liu

J Prev Alz Dis 2018;5(4):236-244

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Background: The Neuropsychological Test Battery (NTB) is a combination of widely used clinical neuropsychological tests measuring memory and executive function and was designed to overcome some of the limitations of the traditionally used Alzheimer’s disease Assessment Scale – Cognitive subscale (ADAS-Cog). A previously reported account indicated high levels of NTB reliability in patients with mild-to-moderate Alzheimer’s disease (AD) and mild cognitive impairment (MCI). Objectives: We examined capacity of the Neuropsychological Test Battery (NTB) and its component subtests to measure cognitive change over time. Correlations with other cognitive and functional assessments were also determined. Design, Settings, Participants: This was a multicentre, prospective, non-interventional, longitudinal cohort study involving patients with mild-to-moderate AD (n=196), MCI (n=70), or cognitively normal control participants (NC, n=75). Intervention: The NTB, as well as other Clinical Outcome Assessments including, ADAS-Cog, other cognitive measures, functional/behavioral questionnaires, health outcome questionnaires, and resource utilization tools were administered. Results: Mean change from baseline for the NTB composite score and the six individual NTB subtests showed greater reductions in performance over time in the AD and MCI groups, compared with NC group. The ADAS-Cog was found to be more sensitive to change than the NTB in all three populations. Conclusions: The NTB showed high correlation with the ADAS-Cog and appears to be a sensitive and reliable assessment tool for measuring cognitive decline in patients with mild-to-moderate AD. However, the ADAS-Cog was found to be more sensitive to change over time in both the AD and MCI populations.

CITATION:
J.E. Harrison ; D.M. Rentz ; H.R. Brashear ; H.M. Arrighi ; M.T. Ropacki ; E. Liu (2018): Psychometric Evaluation of the Neuropsychological Test Battery in Individuals with Normal Cognition, Mild Cognitive Impairment, or Mild to Moderate Alzheimer’s Disease: Results from a Longitudinal Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.31

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Review Articles

CLINICAL APPLICATION OF APOE IN ALZHEIMER’S PREVENTION: A PRECISION MEDICINE APPROACH

C.L. Berkowitz, L. Mosconi, A. Rahman, O. Scheyer, H. Hristov, R.S. Isaacson

J Prev Alz Dis 2018;5(4):245-252

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Population-attributable risk models estimate that up to one-third of Alzheimer’s disease (AD) cases may be preventable through risk factor modification. The field of AD prevention has largely focused on addressing these factors through universal risk reduction strategies for the general population. However, targeting these strategies in a clinical precision medicine fashion, including the use of genetic risk factors, allows for potentially greater impact on AD risk reduction. Apolipoprotein E (APOE), and specifically the APOE ε4 variant, is one of the most well-established genetic influencers on late-onset AD risk. In this review, we evaluate the impact of APOE ε4 carrier status on AD prevention interventions, including lifestyle, nutrigenomic, pharmacogenomic, AD comorbidities, and other biological and behavioral considerations. Using a clinical precision medicine strategy that incorporates APOE ε4 carrier status may provide a highly targeted and distinct approach to AD prevention with greater potential for success.

CITATION:
C.L. Berkowitz ; L. Mosconi ; A. Rahman ; O. Scheyer ; H. Hristov ; R.S. Isaacson (2018): Clinical Application of APOE in Alzheimer’s Prevention: A Precision Medicine Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.35

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PIMAVANSERIN: POTENTIAL TREATMENT FOR DEMENTIA-RELATED PSYCHOSIS

J. Cummings, C. Ballard, P. Tariot, R. Owen, E. Foff, J. Youakim, J. Norton, S.Stankovic

J Prev Alz Dis 2018;5(4):253-258

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Psychosis is common across dementia types with a prevalence of 20% to 70%. Currently, no pharmacologic treatment is approved for dementia-related psychosis. Atypical antipsychotics are frequently used to treat these disorders, despite significant safety concerns. Pimavanserin, a selective 5-HT2A inverse agonist/antagonist, was approved in the U.S. for treating hallucinations and delusions associated with Parkinson’s disease psychosis (PDP). Patients in the pimavanserin group experienced a significant (p=0.001) improvement in Scale for the Assessment of Positive Symptoms - Parkinson’s disease (SAPS-PD) scores vs. placebo. In a subgroup analysis of patients with cognitive impairment (MMSE score ≥21 but ≤24), the observed improvement on the SAPS-PD with pimavanserin (N=50) was also significant (p=0.002) and larger than in the overall study population without an adverse effect on cognition. In a Phase 2 study with pimavanserin in Alzheimer’s disease psychosis, pimavanserin significantly (p=0.045) improved psychosis at Week 6 vs. placebo on the NPI-NH Psychosis Score (PS). In a prespecified subgroup of patients with a baseline NPI-NH PS ≥12, a substantively larger treatment effect (p=0.011) was observed vs. participants with NPI-NH PS <12. The results of these studies in cognitively impaired patients with PDP provided the scientific foundation for an ongoing study of pimavanserin for treating patients with dementia-related psychosis associated with the most common neurodegenerative disorders. The study uses a relapse-prevention design with the endpoint of time-to-relapse of psychosis to evaluate the long-term efficacy and safety of pimavanserin as a potential treatment for hallucinations and delusions of dementia-related psychosis.

CITATION:
J. Cummings ; C. Ballard ; P. Tariot ; R. Owen ; E. Foff ; J. Youakim ; J. Norton ; S. Stankovic (2018): Pimavanserin: Potential Treatment For Dementia-Related Psychosis. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.29

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Letter to the Editor

LETTER TO THE EDITOR: PREVENTING DEMENTIA THROUGH COMMUNITY INVOLVEMENT AND ALTRUISTIC BEHAVIORS

Y. Maki

J Prev Alz Dis 2018;5(4):259-260

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CITATION:
Y. Maki (2018): Preventing Dementia through Community Involvement and Altruistic Behaviors. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.37

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Clinical Trials and Aging: 11th Conference Clinical Trials on Alzheimer’s Disease, October 24-27, 2018, Barcelona, Spain

CTAD: SYMPOSIA, ORAL COMMUNICATIONS, POSTERS

Abstracts

J Prev Alz Dis 2018;5(S1):S1-S196

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