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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

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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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PIMAVANSERIN: POTENTIAL TREATMENT FOR DEMENTIA-RELATED PSYCHOSIS

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

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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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PIMAVANSERIN IN ALZHEIMER’S DISEASE PSYCHOSIS: EFFICACY IN PATIENTS WITH MORE PRONOUNCED PSYCHOTIC SYMPTOMS

C. Ballard, J.M. Youakim, B. Coate, S. Stankovic

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Background: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Objective: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer’s disease (AD). Design: Randomized, double-blind, placebo-controlled trial Setting: Nursing home residents Participants: Patients with AD psychosis Interventions: Pimavanserin 34 mg or placebo daily for 12 weeks Measurements: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. Results: Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen’s d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks. Conclusions: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

CITATION:
C. Ballard ; J.M. Youakim ; B. Coate ; S. Stankovic (2018): Pimavanserin in Alzheimer’s Disease Psychosis: Efficacy in Patients with More Pronounced Psychotic Symptoms. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.30

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PIMAVANSERIN IN ALZHEIMER’S DISEASE PSYCHOSIS: EFFICACY IN PATIENTS WITH MORE PRONOUNCED PSYCHOTIC SYMPTOMS

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Background: Pimavanserin is a 5-HT2A receptor inverse agonist/antagonist and is approved in the United States for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis. Objective: Evaluate the efficacy of pimavanserin on symptoms of psychosis in patients with Alzheimer’s disease (AD). Design: Randomized, double-blind, placebo-controlled trial Setting: Nursing home residents Participants: Patients with AD psychosis Interventions: Pimavanserin 34 mg or placebo daily for 12 weeks Measurements: The primary endpoint was mean change from baseline at Week 6 on the Neuropsychiatric Inventory-Nursing Home Version psychosis score (NPI-NH-PS). In the prespecified subgroup analysis, the mean change in NPI-NH-PS and the responder rates among those with baseline NPI-NH-PS ≥12 were evaluated. Results: Of 181 patients randomized (n=90 pimavanserin; n=91 placebo), 57 had baseline NPI-NH-PS ≥12 (n=27 pimavanserin; n=30 placebo). In this severe subgroup, large treatment effects were observed (delta=-4.43, Cohen’s d=-0.73, p=0.011), and ≥30% improvement was 88.9% vs. 43.3% (p<0.001) and ≥50% improvement was 77.8% vs. 43.3% (p=0.008) for pimavanserin and placebo, respectively. The rate of adverse events (AEs) in the severe subgroup was similar between treatment groups, and urinary tract infection, fall, and agitation were most frequent. Serious AEs was similar with pimavanserin (17.9%) and placebo (16.7%) with fewer discontinuations due to AEs with pimavanserin (7.1%) compared to placebo (10.0%). Minimal change from baseline occurred for the mean MMSE score over 12 weeks. Conclusions: Pimavanserin demonstrated significant efficacy in AD psychosis in patients with higher baseline severity of psychotic symptoms (NPI-NH-PS ≥12). Treatment with pimavanserin showed an acceptable tolerability profile.

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BIFIDOBACTERIUM BREVE A1 SUPPLEMENTATION IMPROVED COGNITIVE DECLINE IN OLDER ADULTS WITH MILD COGNITIVE IMPAIRMENT: AN OPEN-LABEL, SINGLE-ARM STUDY

Y. Kobayashi, T. Kinoshita, A. Matsumoto, K. Yoshino, I. Saito, J.-Z. Xiao

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Objectives: We previously reported the therapeutic potential of Bifidobacterium breve A1 (B. breve A1) for preventing cognitive impairment in Alzheimer’s disease model mice, which suggested that supplementation of the probiotics could be an effective therapeutic strategy for managing cognitive function in mild cognitive impairment (MCI). Design and settings: We conducted an open-label, single-arm study to examine the effects of 24-week supplementation of B. breve A1 on elderly with MCI in Aki Orthopedics Rehabilitation Clinic in Japan. Participants: 27 participants were screened by their Mini Mental State Examination (MMSE) scores. Measurements: Cognitive function was assessed using MMSE and Digit Symbol Substitution Test (DSST) at baseline and every 8 weeks. Mental condition and quality of life for gastrointestinal symptoms were measured using the Profile of Mood States 2nd Edition (POMS2), and the Gastrointestinal Symptom Rating Scale (GSRS). Results: Of the 27 participants enrolled, 19 completed the study. MMSE scores were significantly increased during the intervention by mixed model Dunnett’s test and Wilcoxon signed-rank tests (+1.7, P < 0.01). POMS2 and GSRS scores were significantly improved during intervention when analyzed by Wilcoxon signed-rank tests. Conclusion: The present study showed that oral supplementation of B. breve A1 in participants with MCI improved cognitive function, thus suggesting the potential of B. breve A1 for improving cognitive function and maintaining quality of life of the elderly. Further randomized, double-blind placebo-controlled studies are worth conducting to examine the beneficial effect of B. breve A1.

CITATION:
Y. Kobayashi ; T. Kinoshita ; A. Matsumoto ; K. Yoshino ; I. Saito ; J.-Z. Xiao (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.2018.32

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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

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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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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

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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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INCREASED FUNCTIONAL CONNECTIVITY AFTER LISTENING TO FAVORED MUSIC IN ADULTS WITH ALZHEIMER DEMENTIA

J.B. King, K.G. Jones, E. Goldberg, M. Rollins, K. MacNamee, C. Moffit, S.R. Naidu, M.A. Ferguson, E. Garcia-Leavitt, J. Amaro, K.R. Breitenbach, J.M. Watson, R.K. Gurge, J.S. Anderson, N.L. Foster

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Background: Personalized music programs have been proposed as an adjunct therapy for patients with Alzheimer disease related dementia, and multicenter trials have now demonstrated improvements in agitation, anxiety, and behavioral symptoms. Underlying neurophysiological mechanisms for these effects remain unclear. Methods: We examined 17 individuals with a clinical diagnosis of Alzheimer disease related dementia using functional MRI following a training period in a personalized music listening program. Results: We find that participants listening to preferred music show specific activation of the supplementary motor area, a region that has been associated with memory for familiar music that is typically spared in early Alzheimer disease. We also find widespread increases in functional connectivity in corticocortical and corticocerebellar networks following presentation of preferred musical stimuli, suggesting a transient effect on brain function. Conclusions: Findings support a mechanism whereby attentional network activation in the brain’s salience network may lead to improvements in brain network synchronization.

CITATION:
J.B. King ; K.G. Jones ; E. Goldberg ; M. Rollins ; K. MacNamee ; C. Moffit ; S.R. Naidu ; M.A. Ferguson ; E. Garcia-Leavitt ; J. Amaro ; K.R. Breitenbach ; J.M. Watson ; R.K. Gurgel ; J.S. Anderson1 ; N.L. Foster (2018): Increased Functional Connectivity After Listening to Favored Music in Adults With Alzheimer Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.19

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JPAD Volume 5, N°03 - 2018

 

Editorials

PLASMA BIOMARKER FOR ALZHEIMER’S DISEASE: ARE WE READY NOW FOR CLINICAL PRACTICE AND DRUG TRIALS?

A. Nakamura

J Prev Alz Dis 2018;5(3):158-159

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CITATION:
A. Nakamura (2018): Plasma Biomarker for Alzheimer’s Disease: Are We Ready Now for Clinical Practice and Drug Trials?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.24

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TURNING POINT TOWARDS BLOOD BIOMARKER-GUIDED TARGETED THERAPY FOR PRECISION MEDICINE IN ALZHEIMER’S DISEASE

H. Hampel, A. Vergallo, U. Bonuccelli, S. Lista, for the Alzheimer Precision Medicine Initiative (APMI)

J Prev Alz Dis 2018;5(3):160-164

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CITATION:
H. Hampel ; A. Vergallo ; U. Bonuccelli ; S. Lista ; for the Alzheimer Precision Medicine Initiative (APMI) ; (2018): Turning Point towards Blood Biomarker-Guided Targeted Therapy for Precision Medicine in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.25

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WHO GUIDELINES ON COMMUNITY-LEVEL INTERVENTIONS TO MANAGE DECLINES IN INTRINSIC CAPACITY: THE ROAD TO PREVENTION COGNITIVE DECLINE IN OLDER AGE?

B. Vellas, R. Scrase, G.A. Rosenberg, S. Andrieu, I. Araujo de Carvalho, L.T. Middleton

J Prev Alz Dis 2018;5(3):165-167

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CITATION:
B. Vellas ; R. Scrase ; G.A. Rosenberg ; S. Andrieu ; I. Araujo de Carvalho ; L.T. Middleton (2018): WHO Guidelines on Community-Level Interventions to Manage Declines in Intrinsic Capacity: The Road to Prevention Cognitive Decline in Older Age?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.26

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Commentary

FATTY ACIDS AND ALZHEIMER’S DISEASE: EVIDENCE ON COGNITION AND CORTICAL ?-AMYLOID FROM SECONDARY ANALYSES OF THE MULTIDOMAIN ALZHEIMER PREVENTIVE TRIAL

C. Hooper, B. Vellas

J Prev Alz Dis 2018;5(3):168-170

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CITATION:
C. Hooper ; B. Vellas (2018): Fatty acids and Alzheimer’s disease: evidence on cognition and cortical β-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.7

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CTAD Task Force

WHAT HAVE WE LEARNED FROM EXPEDITION III AND EPOCH TRIALS? PERSPECTIVE OF THE CTAD TASK FORCE

P.S. Aisen, E. Siemers, D. Michelson, S. Salloway, C. Sampaio, M.C. Carrillo, R. Sperling, R. Doody, P. Scheltens, R. Bateman, M. Weiner, B. Vellas, and the EU/US/CTAD Task Force members

J Prev Alz Dis 2018;5(3):171-170

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Although the results were disappointing from two recent clinical trials of amyloid-targeting drugs in mild-to-moderate AD, the trials provided information that will be important for future studies, according to the EU-US CTAD Task Force, which met in November 2017 to discuss the EXPEDITION3 and EPOCH trials. These trials tested two of the predominant drug development strategies for AD: amyloid immunotherapy and BACE inhibition in populations largely composed of mild AD dementia patients. The results of these trials support the emerging consensus that effective amyloid-targeted treatment will require intervention in early, even pre-symptomatic stages of the disease. Further, the Task Force suggested that a refinement of the amyloid hypothesis may be needed and that other hypotheses should be more fully explored. In addition, they called for improved biomarkers and other outcome assessments to detect the earliest changes in the development of AD.

CITATION:
P.S. Aisen ; E. Siemers ; D. Michelson ; S. Salloway ; C. Sampaio ; M.C. Carrillo ; R. Sperling ; R. Doody ; P. Scheltens ; R. Bateman ; M. Weiner ; B. Vellas ; and the EU/US/CTAD Task Force members* (2018): What Have We Learned from Expedition III and EPOCH Trials? Perspective of the CTAD Task Force. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.23

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Brief Report

EFFECTS OF A SIX-MONTH MULTI-INGREDIENT NUTRITION SUPPLEMENT INTERVENTION OF OMEGA-3 POLYUNSATURATED FATTY ACIDS, VITAMIN D, RESVERATROL, AND WHEY PROTEIN ON COGNITIVE FUNCTION IN OLDER ADULTS: A RANDOMISED, DOUBLE-BLIND, CONTROLLED TRIAL

C. Moran, A. Scotto di Palumbo, J. Bramham, A. Moran, B. Rooney, G. De Vito, B. Egan

J Prev Alz Dis 2018;5(3):175-183

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Objectives: To investigate the impact of a six-month multi-ingredient nutrition supplement intervention (Smartfish®), containing omega-3 polyunsaturated fatty acids (PUFAs), vitamin D, resveratrol, and whey protein, on cognitive function in Irish older adults. Design: Double-blind, randomised controlled trial (ClinicalTrials.gov: NCT02001831). A quantitative, mixed-model design was employed in which the dependent variable (cognitive function) was analysed with a between-subjects factor of group (placebo, intervention) and within-subjects factor of testing occasion (baseline, three-months, six-months). Setting: Community-based intervention including assessments conducted at University College Dublin, Ireland. Participants: Thirty-seven community-dwelling older adults (68-83 years; mean (x̄)= 75.14 years; standard deviation (SD)= 3.64; 18 males) with normal cognitive function (>24 on the Mini Mental State Examination) were assigned to the placebo (n= 17) or intervention (n= 20) via a block randomisation procedure. Intervention: Daily consumption for six-months of a 200mL liquid juice intervention comprising 3000mg omega-3 PUFAs [1500mg docosahexaenoic acid (DHA) and 1500mg eicosapentaenoic acid (EPA)], 10μg vitamin D3, 150mg resveratrol and 8g whey protein isolate. The placebo contained 200mL juice only. Measurements: A standardised cognitive assessment battery was conducted at baseline and follow-ups. Individual test scores were z-transformed to generate composite scores grouped into cognitive domains: executive function, memory, attention and sensorimotor speed. Motor imagery accuracy and subjective awareness of cognitive failures variables were computed from raw scores. Results: A hierarchical statistical approach was used to analyse the data; first, by examining overall cognitive function, then by domain, and then by individual test scores. Using mixed between-within subjects, analyses of variance (ANOVAs), no significant differences in overall cognitive function or composite cognitive domains were observed between groups over time. The only significant interaction was for Stroop Color-Word Time (p< 0.05). The intervention group demonstrated reduced task completion time at three- and six-month follow-ups, indicating enhanced performance. Conclusion: The present nutrition intervention encompassed a multi-ingredient approach targeted towards improving cognitive function, but overall had only a limited beneficial impact in the older adult sample investigated. Future investigations should seek to establish any potential clinical applications of such targeted interventions with longer durations of supplementation, or in populations with defined cognitive deficits.

CITATION:
C. Moran ; A. Scotto di Palumbo ; J. Bramham ; A. Moran ; B. Rooney ; G. De Vito ; B. Egan (2018): Effects of a Six-Month Multi-Ingredient Nutrition Supplement Intervention of Omega-3 Polyunsaturated Fatty Acids, vitamin D, Resveratrol, and Whey Protein on Cognitive Function in Older Adults: A Randomised, Double-Blind, Controlled Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.11

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Original Research

ANALYSIS OF THE RELATIONSHIP OF COGNITIVE IMPAIRMENT AND FUNCTIONAL IMPAIRMENT IN MILD ALZHEIMER’S DISEASE IN EXPEDITION 3

H. Liu-Seifert, E. Siemers, K. Sundell, M. Mynderse, J. Cummings, R. Mohs, P. Aisen

J Prev Alz Dis 2018;5(3):184-187

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BACKGROUND: Clinical progression of Alzheimer’s disease is characterized by impairment in cognition and function. OBJECTIVE: To assess the relationship between cognitive and functional impairment in mild Alzheimer’s disease. DESIGN: Spearman’s rank correlations between cognitive and functional measures were calculated. Autoregressive cross-lagged panel analyses were used to determine the temporal relationship between cognitive and functional decline. SETTING: Post-hoc analysis of clinical trial data. PARTICIPANTS: Placebo-treated patients with mild Alzheimer’s disease from the Phase 3 solanezumab study EXPEDITION 3. INTERVENTION: Placebo MEASUREMENTS: Cognitive and functional measures were assessed at baseline and at six post-baseline time points through Week 80. RESULTS: Correlation between cognitive and functional measures was 0.41 at baseline and 0.65 at Week 80. Autoregressive cross-lagged panel analysis demonstrated that cognitive impairment preceded and predicted subsequent functional decline, but functional scores did not predict cognitive outcomes. CONCLUSIONS: This study supports the hypothesis that functional impairment predictably follows cognitive decline in mild Alzheimer’s disease dementia.

CITATION:
H. Liu-Seifert ; E. Siemers ; K. Sundell ; M. Mynderse ; J. Cummings ; R. Mohs ; P. Aisen (2018): Analysis of the Relationship of Cognitive Impairment and Functional Impairment in Mild Alzheimer’s Disease in EXPEDITION 3. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.22

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DETECTION OF RATER ERRORS ON COGNITIVE INSTRUMENTS IN A CLINICAL TRIAL SETTING

D.J. Connor, C.W. Jenkins, D. Carpenter, R. Crean, P. Perera

J Prev Alz Dis 2018;5(3):188-196

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OBJECTIVES: This study examines errors committed by raters in a clinical trial of a memory enhancement compound. BACKGROUND: Findings of clinical trials are directly dependent on the quality of the data obtained but there is little literature on rates or nature of rater errors on cognitive instruments in a multi-site setting. DESIGN: Double-blind placebo-controlled study. SETTING: 21 clinical sites in North America. PARTICIPANTS: Two hundred seventy-five participants. MEASUREMENTS: MMSE, WMS-R Logical Memory I & II, WMS-R Verbal Paired Associates I, WASi Vocabulary, WASi Matrix Reasoning, GDS and MAC-Q. RESULTS: The WMS-R Logical Memory I & II and WASi Vocabulary tests were found to have the greatest number of scoring errors. Few substantive errors were detected on source document review of the MMSE, GDS, MAC-Q and WMS-R Verbal Paired Associates I. Some additional administration and scoring issues were identified during feedback sessions with the raters. CONCLUSIONS: Cognitive measures used in clinical trials are prone to errors which can be detected with proper monitoring. Some instruments are particularly prone to inter-rater variably and should therefore be targets for focused training and ongoing monitoring. Areas in need of further investigation to help inform and optimize quality of clinical trial data are discussed.

CITATION:
D.J. Connor ; C.W. Jenkins ; D. Carpenter ; R. Crean ; P. Perera (2018): Detection of Rater Errors on Cognitive Instruments in a Clinical Trial Setting. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.20

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AURAPTENE IN THE PEELS OF CITRUS KAWACHIENSIS (KAWACHIBANKAN) CONTRIBUTES TO THE PRESERVATION OF COGNITIVE FUNCTION: A RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY IN HEALTHY VOLUNTEERS

M. Igase, Y. Okada, M. Ochi, K. Igase, H. Ochi, S. Okuyama, Y. Furukawa, Y. Ohyagi

J Prev Alz Dis 2018;5(3):197-201

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OBJECTIVES: Dementia, which is characterized by a progressive decline in cognitive function, is a major concern in aging societies. Although a number of treatments have been approved, an effective therapy to prevent the disorder is lacking. A supplement that improves cognitive function would benefit patients. The aim of this study was to assess whether auraptene, a citrus coumarin, has a protective effect on cognitive decline. DESIGN: A randomized, placebo-controlled, double-blind study SETTING: Outpatient medical check-up program for cognitive disorders PARTICIPANTS: 84 adult volunteers (they are cognitively normal) met inclusion and exclusion criteria to participate. INTERVENTION: 42 participants received auraptene enriched (containing 6.0 mg/day of auraptene) test juice, and another participants received placebo juice. MEASUREMENTS: 1) Mild Cognitive Impairment (MCI) Screen using the 10-word immediate recall test. 2) The Mini-Mental State Examination (MMSE). Cognitive assessment ware carried out baseline and at 24 weeks. RESULTS: Auraptene enriched test juice did not improve cognitive function after 24 weeks compared with baseline data. However, there was a significant difference in the percentage change in cognitive function between the test and placebo orange juice groups (6.3 ± 18.9 vs. −2.4 ± 14.8, P < 0.05). Multiple regression analysis demonstrated a significant independent relationship between the percentage change in the 10-word immediate recall test score and test juice consumption including baseline 10-word immediate recall test score in all subjects. CONCLUSION: This is the first study to assess the effectiveness of auraptene in the prevention of cognitive decline. Our results suggest that auraptene is a safe supplement for the prevention of cognitive decline.

CITATION:
M. Igase ; Y. Okada ; M. Ochi ; K. Igase ; H. Ochi ; S. Okuyama ; Y. Furukawa ; Y. Ohyagi (2017): Auraptene in the Peels of Citrus Kawachiensis (Kawachibankan) Contributes to the Preservation of Cognitive Function: A Randomized, Placebo-Controlled, Double-Blind Study in Healthy Volunteers. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.47

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CORRELATION OF CSF- AND MRI-BIOMARKERS AND PROGRESSION OF COGNITIVE DECLINE IN AN OPEN LABEL MCI TRIAL

L.K. Joachim, L. Frölich, E. Rüther, J. Wiltfang, W. Maier, J. Kornhuber, C. Bauer, I. Heuser, O. Peters

J Prev Alz Dis 2018;5(3):202-206

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Background: In several randomized controlled trials (RCT) acetylcholinesterase-inhibitors (AChE-I) were tested in patients with mild cognitive impairment (MCI) but were ineffective in delaying disease progression as determined by neuropsychological testing only. Here we present data from an open label observational extension of a multicenter RCT in order to assess if biomarkers are providing useful additional information about a drug’s efficacy. We followed 83 amnestic MCI patients and performed correlational analyses of Aβ 1-42 and total-Tau in the cerebrospinal fluid (CSF), hippocampal and amygdala volume at baseline, the total duration of blinded and open label AChE-I treatment and the outcome 24 months after inclusion into the RCT. Twelve out of 83 amnestic MCI (14%) had progressed to Alzheimer’s disease (AD). Overall, worsening and disease progression as measured by the Alzheimer’s Disease Assessment Scale - cognitive subscale (ADAS-cog), Alzheimer’s Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) and Clinical Dementia Rating (CDR) did not correlate with the duration of AChE-I treatment. However, a specific multidimensional biomarker profile at baseline indicated more reliably than cognitive testing alone progression to AD. We conclude that pharmacological RCTs testing symptomatic treatment effects in MCI should include biomarker assessment.

CITATION:
L.K. Joachim ; L. Frölich ; E. Rüther ; J. Wiltfang ; W. Maier ; J. Kornhuber ; C. Bauer ; I. Heuser ; O. Peters (2018): Correlation of CSF- and MRI-Biomarkers and Progression of Cognitive Decline in an Open Label MCI Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.5

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Position Paper

AN ACTION PLAN TO FACE THE CHALLENGE OF DEMENTIA: INTERNATIONAL STATEMENT ON DEMENTIA FROM IAP FOR HEALTH

H. Chertkow

J Prev Alz Dis 2018;5(3):207-212

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An international committee set up through the IAP for Health met to develop an action plan for dementia. Comprehensive international and national initiatives should move forward with calls for action that include increased public awareness regarding brain health and dementia, support for a broad range of dementia research objectives, and investment in national health care systems to ensure timely competent person-centred care for individuals with dementia. The elements of such action plans should include: 1) Development of national plans including assessment of relevant lifecourse risk and protective factors; 2) Increased investments in national research programs on dementia with approximately 1% of the national annual cost of the disease invested; 3) Allocating funds to support a broad range of biomedical, clinical, and health service and systems research; 4) Institution of risk reduction strategies; 5) Building the required trained workforce (health care workers, teachers, and others) to deal with the dementia crisis; 6) Ensuring that it is possible to live well with dementia; and 7) Ensuring that all have access to prevention programs, care, and supportive living environments.

CITATION:
H. Chertkow, (2018): An Action Plan to Face the Challenge of Dementia: INTERNATIONAL STATEMENT ON DEMENTIA from IAP for Health. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2018.27

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