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03/2018 journal articles

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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