A Combined Measure of Cognition and Function for Clinical Trials: The Integrated Alzheimer’s Disease Rating Scale (iADRS)

A.M. Wessels, E.R. Siemers, P. Yu, S.W. Andersen, K.C. Holdridge, J.R. Sims, K. Sundell, Y. Stern, D.M. Rentz, B. Dubois, R.W. Jones, J. Cummings & P.S. Aisen
It is generally recognized that more sensitive instruments for the earliest stages of Alzheimer’s disease (AD) are needed. The integrated Alzheimer’s Disease Rating Scale (iADRS) combines scores from 2 widely accepted measures, the Alzheimer’s Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and the Alzheimer’s Disease Cooperative Study – instrumental Activities of Daily Living (ADCS-iADL). Disease progression and treatment differences as measured by the iADRS were analyzed using data from solanezumab EXPEDITION, EXPEDITION2, and EXPEDITION-EXT Studies; semagacestat IDENTITY...

193 Related Works

Effects on Cognition of Berry, Pomegranate, Grape and Biophenols: A General Review

L. Al Damen, A. Stockton & E.A.S. Al-Dujaili
Decline in cognitive function can be observed in normal aging, MCI, neurodegenerative disorders, cerebral hypoperfusion and post-surgery. Cognitive impairment presents with limited therapeutic options. Berries, pomegranates and grapes are polyphenol-rich fruits that have both antioxidant and anti-inflammatory effects. This review aims to explore the effects of these fruits and their biophenols on cognitive function in healthy subjects and their protective effects on cognitive deficits in normal aging, mild cognitive impairment, Alzheimer’s disease (AD), cerebral hypoperfusion...

Detection of Rater Errors on Cognitive Instruments in a Clinical Trial Setting

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

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. Gurgel, J.S. Anderson1 & N.L. Foster
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...

Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer’s Disease

A.H. Burstein, M. Sabbagh, R. Andrews, C. Valcarce, I. Dunn & L. Altstiel
Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer’s disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Aβ plaque deposition; reduce total Aβ brain concentration while increasing plasma Aβ levels; decreases sAPPβ while...

A Literature Review of Methodologies Used in Randomized Clinical Trials of Agitation in Alzheimer’s Disease

S. Dubé, J.T. Megerian & R. Malamut
Agitation is a common and burdensome symptom associated with Alzheimer’s disease (AD). This is a narrative literature review of the designs and methods used in randomized clinical trials of agitation in patients with AD; sources range from published, to completed but not published, to ongoing studies in the past 10 years. Selection for review included blinded, randomized trials conducted to assess the effect of a pharmacological intervention for which agitation in patients with AD was...

Minimizing the Sample Sizes of Clinical Trials on Preclinical and Early Symptomatic Stage of Alzheimer Disease

J. Luo, H. Weng, J.C. Morris & C. Xiong
Background: Clinical trials of investigational drugs for Alzheimer disease (AD) increasingly focus on the prodromal (symptomatic) stage of the illness and now its preclinical (asymptomatic) stage. Sensitive and specific cognitive and functional endpoints are needed to track subtle cognitive and functional changes in the early and preclinical stages to minimize sample sizes in these trials. Objectives: To identify informative items in a standard clinical assessment protocol and a psychometric battery that are predictive of onset...

Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: A Report from the EU/US/CTAD Task Force

M. Sano, M. Soto, M. Carrillo, J. Cummings, S. Hendrix, J. Mintzer, A. Porsteinsson, P. Rosenberg, L. Schneider, J. Touchon, P. Aisen, B. Vellas, C. Lyketsos & And The EU/US/CTAD Task Force Members
For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 – Operationalizing agitation criteria established by the IPA; 2 – Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 – Using global ratings to...

Prevention of Alzheimer’s Disease in Chinese: Status, Challenges and Directions

L. Feng, J. Li, J.-T. Yu, C. Zhang, B. Yang, B. Vellas & C. Li
In January 2018, the investigators from Eli Lily’s EXPEDITION3 trial published their negative findings of a large phase 3 trial on the antibody Solanezumab (1). The lacking of statistically significant between-group difference on primary endpoint dampened enthusiasm again, and added the study to a long and growing list of failed trials (including EXPEDITION 1 and EXPEDITION2 from the same company) in the field of AD therapeutics. Without promising disease modifying agents, more and more clinicians...

Biomarker and Clinical Trial Design Support for Disease-Modifying Therapies: Report of a Survey of the EU/US: Alzheimer’s Disease Task Force

J. Cummings, N. Fox, B. Vellas, P. Aisen, G. Shan & For The EU/US Alzheimer’ Disease Task Force
BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer’s disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs....

Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women’s Healthy Ageing Project

E. Hill, C. Szoeke, L. Dennerstein, S. Campbell & P. Clifton
Background: Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer’s disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. Objectives: To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. Design: This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically...

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
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...

The Integrated Alzheimer’s Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial

A.M. Wessels, S.W. Andersen, S.A. Dowsett & E.R. Siemers
The Integrated Alzheimer’s Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS-iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD...

Diabetes Mellitus and Cognitive Decline – Prevention Should Not Be Delayed!

A.J. Sinclair & B. Vellas
The recent addition of the Diabetes and Cognitive Decline section to JPAD marks a milestone in the history of this progressive journal as it recognises the important contribution that Diabetes makes to the aetiology of both vascular and neurodegenerative dementia syndromes (1-3). It has been observed that diabetes in the presence of hypertension leads to a more pronounced cognitive decline (4) and that at an early stage of cognitive decline (mild cognitive impairment (MCI)), diabetes...

The Role of Advanced Practice Nurses in Alzheimer’s Disease Prevention

B. Fougère
To the editor, Worldwide, the population of older adults is increasing. The global population aged 60 years or over numbered 962 million in 2017, more than twice as large as in 1980 when there were 382 million older persons worldwide. The number of older persons is expected to double again by 2050, when it is projected to reach nearly 2.1 billion (1). The United Nations reports that by the year 2045, the number of individuals...

Fatty acids and Alzheimer’s disease: evidence on cognition and cortical β-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial

C. Hooper & B. Vellas
Fatty acids are long-chain hydrocarbons that can be separated into four groups: saturated, monounsaturated, polyunsaturated, and trans fats (1). The brain is highly enriched in fatty acids particularly polyunsaturated fatty acids (PUFAs) with docosahexaenoic acid (an omega 3: n-3 PUFA) and arachidonic acid (an omega 6: n-6 PUFA) being the most abundant (2,3). Fats control the structure and function of cell membranes and therefore impact upon signal transduction and neurotransmission and PUFAs play a role...

Nanorobots the Future of Neurology: A Perspective on Alzheimer’s Disease

C. Hooper & S. Layé
Nanorobots are complex machines measured in nanometers that operate at the molecular level inside patients. In the future these small nanoscale machines could potentially be used as biosensors to screen for disease, to combat pathological cellular or molecular processes or to deliver medication to precise locations. Nanorobots are akin to manipulatable electronic white blood cells that patrol the body. A nanorobot in the form of a micro-rocket has already been shown to bind and transport...

Delayed-Start Analyses in the Phase 3 Solanezumab EXPEDITION3 Study in Mild Alzheimer’s Disease

H. Liu-Seifert, M.G. Case, S.W. Andersen, K.C. Holdridge, P.S. Aisen, S. Kollack-Walker & E. Siemers
OBJECTIVE: A delayed-start design has been proposed to assess a potential disease-modifying effect in investigational drugs for Alzheimer’s disease that target the underlying disease process. We extended this methodology to recently obtained data from the EXPEDITION3. METHODS: EXPEDITION3 was a Phase 3, double-blind study with participants randomized to solanezumab (400 mg) or placebo every 4 weeks for 80 weeks, with an optional extension of active treatment. The delayed-start analysis was designed to determine if a...

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
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...

Responses: Long-Term Tea Consumption and Depressive and Anxiety Symptoms in Elderly

L. Feng
Responses: We thank Dr Joob and Dr Wiwanitkit for their interest in our research work and the valuable comments and suggestions they have provided. I fully agree with them that some uncontrolled factors, such as the intake of other foods, beverages or activities, may help protect against depressive and anxiety symptoms, and hence residual confounding cannot be completely ruled out. Further investigation is needed for a definitive conclusion. Indeed, motivated by growing evidence on neuroprotective...

Long-Term Tea Consumption and Depressive and Anxiety Symptoms in Elderly

B. Joob & V. Wiwanitkit
To the editor, the publication on “Associations of Long-Term Tea Consumption with Depressive and Anxiety Symptoms in Community-Living Elderly” is very interesting (1). Chan et al. concluded that “There was evidence suggesting that long-term tea consumption was associated with reduced depressive and anxiety symptoms among community-living elderly (1).” In fact, tea drinking is a rooted behavior among Chinese Asian population. The health usefulness of tea is approved. Neuroprotective system due to tea drinking is believed...

Detecting Treatment Group Differences in Alzheimer’s Disease Clinical Trials: A Comparison of Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog) and the Clinical Dementia Rating - Sum of Boxes (CDR-SB)

A.M. Wessels, S.A. Dowsett & J.R. Sims
The Alzheimer’s Disease Assessment Scale’s cognitive subscale (ADAS-Cog) has been widely used as an outcome measure in Alzheimer’s Disease (AD) clinical trials. In its original form (ADAS-Cog11), the scale has been used successfully in mild-to-moderate AD dementia populations, but its use is more limited in the study of earlier disease (mild cognitive impairment [MCI] or mild dementia due to AD) owing to lack of appropriate sensitivity of some items. With recent focus on earlier treatment,...

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
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...

Strong Relationship between Malnutrition and Cognitive Frailty in the Singapore Longitudinal Ageing Studies (SLAS-1 and SLAS-2)

L. Chye, K. Wei, M.S.Z. Nyunt, Q. Gao, S.L. Wee & T.P. Ng
Background: Physical frailty is well known to be strongly associated with malnutrition, but the combined impact of physical frailty and cognitive impairment among non-demented older persons (cognitive frailty) on malnutrition prevalence is not well documented. Design: Cross-sectional cohort study. Setting and Participants: Community-dwelling older Singaporeans aged ≥55y (n=5414) without dementia in the Singapore Longitudinal Ageing Study (SLAS-1 and SLAS-2). Measurements: The Mini Nutritional Assessment – short form (MNA-SF) and Nutrition Screening Initiative (NSI) Determine Checklist...

Neuroprotective Effects of Guarana (Paullinia cupana Mart.) against Vincristine in Vitro Exposure

F. Veloso, A.K. Machado, F.C. Cadoná, V.F. Azzolin, I.B.M. Cruz & A.F. Silveira
Background: Vincristine (VCR) is not a specific chemotherapeutic drug, responsible for cause several side effects. In this sense, many natural products have been studied to reduce this problem. Objetives: To examine the guarana neuroprotective effect in mice brain and cerebellum cells against vincristine (VCR) exposition. Design: An in vitro study was performed using mice brain and cerebellum mice in monolayer culture. First, cells were exposed to VCR (0.009 µM for 24 hours and 0.0007 µM...

The Value of Pre-screening in the Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Trial

S. Rios-Romenets, M. Giraldo-Chica, H. López, F. Piedrahita, C. Ramos, N. Acosta-Baena, C. Muñoz, P. Ospina, C. Tobón, W. Cho, M. Ward, J.B. Langbaum, P.N. Tariot, E.M. Reiman & F. Lopera
The Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease (ADAD) trial evaluates the anti-amyloid-β antibody crenezumab in cognitively unimpaired persons who, based on genetic background and age, are at high imminent risk of clinical progression, and provides a powerful test of the amyloid hypothesis. The Neurosciences Group of Antioquia implemented a pre-screening process with the goals of decreasing screen failures and identifying participants most likely to adhere to trial requirements of the API ADAD trial...

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