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01/2016 journal articles

Editorials

JPAD IS MOVING FAST

J Prev Alz Dis 2016;3(1):3-4

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CITATION:
JPAD Is Moving Fast. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.87

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MRI FOR PRE-DEMENTIA TRIALS

G.B. Frisoni, M. Boccardi

J Prev Alz Dis 2016;3(1):5-7

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Structural magnetic resonance imaging (MRI) provides valid markers of whole brain and regional areas of atrophy in Alzheimer’s disease (AD), which are sensitive to change and correlate with clinical progression. Recent efforts to develop standardized and harmonized protocols for MRI indicate high measurement stability and good reproducibility, supporting the use of these measures in clinical trials. Newer MRI measures of microstructural and connectivity changes are also showing promise as early stage biomarkers of neurodegeneration and potentially as measures of treatment effects. Further work is needed to validate these markers for use in clinical trials.

CITATION:
G.B. Frisoni ; M. Boccardi (2015): MRI for Pre-Dementia Trials . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.69

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Original Research

THE FEASIBILITY OF AT-HOME IPAD COGNITIVE TESTING FOR USE IN CLINICAL TRIALS

D.M. Rentz, M. Dekhtyar, J. Sherman, S. Burnham, D. Blacker, S.L. Aghjayan, K.V. Papp, R.E. Amariglio, A. Schembri, T. Chenhall, P. Maruff, P. Aisen, B.T. Hyman, R.A. Sperling

J Prev Alz Dis 2016;3(1):8-12

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Background: Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. Objectives: We used a Computerized Cognitive Composite for Preclinical Alzheimer’s Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. Design, Setting, Participants: Forty-nine cognitively normal older individuals (mean age, 71.46±7.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women’s Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at-home measuring episodic memory, reaction time and working memory. Measurements: A reliability analysis explored equivalence of the six alternate C3-PAD test versions. A feasibility assessment calculated the percentage of individuals who completed all at-home tests correctly, in contrast to incomplete assessments. Correlational analyses examined the association between C3-PAD-clinic compared to C3-PAD-home assessments and between C3-PAD performance and standardized paper and pencil tests. Results: Excellent reliability was observed among the 6 C3-PAD alternate versions (Cronbach alpha coefficient=0.93). A total of 28 of 49 participants completed all at-home sessions correctly and 48 of 49 completed four out of five correctly. There were no significant differences in participant age, sex or education between complete and incomplete at-home assessments. A single in-clinic C3-PAD assessment and the at-home C3-PAD assessments were highly associated with each other (r2=0.508, p<0.0001), suggesting that at-home tests provide reliable data as in-clinic assessments. There was also a moderate association between the at-home C3-PAD assessments and the in-clinic standardized paper and pencil tests covering similar cognitive domains (r2= 0.168, p< 0.003). Conclusions: Reliable and valid cognitive data can be obtained from the C3-PAD assessments in the home environment. With initial in-clinic training, a high percentage of older individuals completed at-home assessments correctly. At-home cognitive testing shows promise for inclusion into clinical trial designs.

CITATION:
D.M. Rentz ; M. Dekhtyar ; J. Sherman ; S. Burnham ; D. Blacker ; S.L. Aghjayan ; K.V. Papp ; R.E. Amariglio ; A. Schembri ; T. Chenhall ; P. Maruff ; P. Aisen ; B.T. Hyman ; R.A. Sperling (2015): The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.78

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SELF-REPORTED MEMORY COMPLAINTS: A COMPARISON OF DEMENTED AND UNIMPAIRED OUTCOMES

R.J. Kryscio, E.L. Abner, G.A. Jicha, P.T. Nelson, C.D. Smith, L.J. Van Eldik, W. Lou, D.W. Fardo, G.E. Cooper, F.A. Schmitt

J Prev Alz Dis 2016;3(1):13-19

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Background: Subjective memory complaints are common in aged persons, indicating an increased, but incompletely understood, risk for dementia. Objective: To compare cognitive trajectories and autopsy results of individuals with subjective complaints after stratifying by whether a subsequent clinical dementia occurred. Design: Observational study. Setting: University of Kentucky cohort with yearly longitudinal assessments and eventual autopsies Participants: Among 516 patients who were cognitively intact and depression-free at enrollment, 296 declared a memory complaint during follow-up. Among those who came to autopsy, 118 died but never developed dementia, while 36 died following dementia diagnosis. Measurements: Cognitive domain trajectories were compared using linear mixed models adjusted for age, gender, years of education and APOE status. Neuropathological findings were compared cross-sectionally after adjustment for age at death. Results: While the groups had comparable cognitive test scores at enrollment and the time of the first declaration of a complaint, the group with subsequent dementia development had steeper slopes of decline in episodic memory and naming but not fluency or sequencing. Autopsies showed the dementia group had more severe Alzheimer pathology and a higher proportion of subjects with hippocampal sclerosis of aging and arteriolosclerosis, whereas the non-demented group had a higher proportion expressing primary age related tauopathy (PART). Conclusions: While memory complaints are common among the elderly, not all individuals progress to dementia. This study indicates that biomarkers are needed to predict whether a complaint will lead to dementia if this is used as enrollment criteria in future clinical trials.

CITATION:
R.J. Kryscio ; E.L. Abner ; G.A. Jicha ; P.T. Nelson ; C.D. Smith ; L.J. Van Eldik ; W. Lou ; D.W. Fardo ; G.E. Cooper ; F.A. Schmitt (2015): Self-Reported Memory Complaints: A Comparison of Demented and Unimpaired Outcomes. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.74

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WEB-BASED SOFTWARE FOR REAL-TIME SIMULATION-ASSISTED TRIAL DESIGN IN ALZHEIMER’S DISEASE

D. Polhamus, J. Kang, J. Rogers, M. Gastonguay, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2016;3(1):20-23

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Clinical trials for Alzheimer’s Disease (AD) are necessarily designed in the presence of substantial quantitative uncertainty. Certain important aspects of this uncertainty can be mitigated by developing longitudinal models for AD progression and by using these models to simulate virtual trials and estimate operating characteristics (such as statistical power, the probability of stopping at an interim analysis, the probability of identifying the correct dose, etc.) as a function of candidate design features, such as inclusion / exclusion criteria. In this brief report we describe the development and deployment of a customized software solution that allows such simulation-based results to be generated “on the fly” in the context of a drug development team meeting. This solution leverages a number of recent practical advances in statistical and scientific computing that could be much more broadly leveraged to assure more quantitatively grounded trial designs in Alzheimer’s Disease.

CITATION:
D. Polhamus ; J. Kang ; J. Rogers ; M. Gastonguay ; for the Alzheimer’s Disease Neuroimaging Initiative (2015): Web-based Software for Real-time Simulation-Assisted Trial Design in Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.54

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GINKGETIN AMELIORATES NEUROPATHOLOGICAL CHANGES IN APP/PS1 TRANSGENICAL MICE MODEL

Y.-Q. Zeng, Y.-J. Wang, X.-F. Zhou

J Prev Alz Dis 2016;3(1):24-29

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The extracellular accumulation of amyloid beta protein (Aβ), reactive gliosis and cerebral amyloid angiopathy (CAA) play critical roles in the pathogenesis of Alzheimer’s disease (AD). Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported to exhibit strong neuroprotection against cytotoxic insults induced by oxidative stress and amyloid beta, but it remains unclear whether ginkgetin has therapeutic effect on Alzheimer’s disease (AD) in vivo. In the present study, we investigated 9 months treatment effects of ginkgetin diet in APP/PS1 mice. Our results show that ginkgetin can significantly reduce plasma Aβ levels 59% and Aβ plaque 51% in the brain of APP/PS1 transgenic mice (P<0.05), effectively inhibits cerebral microhemorrhage 69% (P<0.05), significantly decreases astrogliosis 50% and ameliorate inflammation (P<0.05), exhibits several biological properties for AD.

CITATION:
Y.-Q. Zeng ; Y.-J. Wang ; X.-F. Zhou (2015): Ginkgetin Ameliorates Neuropathological Changes in APP/PS1 Transgenical Mice Model. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.84

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Review Articles

BRIDGING THE GAP BETWEEN RESEARCH AND CLINICAL PRACTICE IN ASYMPTOMATIC ALZHEIMER’S DISEASE

A.M. Downing, R. Yaari, D.E. Ball, K.J. Selzler, M.D. Devous, Sr

J Prev Alz Dis 2016;3(1):30-42

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Due to the growing global health impact of Alzheimer’s disease (AD), there is a greater need for interventions that prevent or delay the onset of clinical symptoms of this debilitating disease. Clinical trials for disease-modifying compounds in AD have shifted towards earlier stages in the spectrum of illness, including the stage prior to cognitive symptoms. A population of specific interest for clinical research includes individuals with evidence of Alzheimer’s disease pathology who are asymptomatic (ADPa). The challenges and barriers regarding medical treatment of ADPa must be identified and addressed prior to the completion of a positive clinical trial in order to accelerate the translation of research findings to clinical practice. This report applies an existing public health impact model from Spencer and colleagues (2013) to evaluate the readiness of the clinical practice environment to treat ADPa individuals if a disease-modifying agent achieves approval. We contrast the current clinical practice environment with a potential future state through investigating the effectiveness, reach, feasibility, sustainability, and transferability of the practice of treating ADPa individuals.

CITATION:
A.M. Downing ; R. Yaari ; D.E. Ball ; K.J. Selzler ; M.D. Devous, Sr (2015): Bridging the Gap between Research and Clinical Practice in Asymptomatic Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.86

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VITAMIN D AND DEMENTIA

T.J. Littlejohns, K. Kos, W.E. Henley, E. Ku?ma, D.J. Llewellyn

J Prev Alz Dis 2016;3(1):43-52

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Emerging evidence suggests that low vitamin D concentrations are potentially involved in the pathogenesis of dementia. This is of particular interest when considering the high prevalence of vitamin D deficiency in elderly adults and the urgent need to identify modifiable risk factors for dementia. Studies have found that vitamin D is implicated in procognitive and neuroprotective functions, including the reduction of Alzheimer’s disease hallmarks such as amyloid beta and phosphorylated tau. Cross-sectional studies have consistently found that vitamin D concentrations are significantly lower in individuals with Alzheimer’s disease and cognitive impairment compared to healthy controls. Longitudinal studies support an association between low vitamin D concentrations and an increased risk of dementia and cognitive decline. Neuroimaging studies are beginning to uncover the potential neurodegenerative and cerebrovascular mechanisms that underlie these associations such as white matter hyperintensities and enlarged ventricular volume, although there is currently a lack of longitudinal studies. In contrast to observational studies, findings from interventional studies have produced mixed results on the benefits of vitamin D supplementation on dementia and cognitive outcomes. Interpretation of the findings from these studies is hampered by several major methodological limitations, such as small sample sizes, inadequate doses and inclusion of participants unlikely to benefit from vitamin D supplementation. There is a need for large double-blind randomised-control trials investigating whether vitamin D supplementation can halt or delay the risk of dementia-related outcomes in individuals with low vitamin D concentrations.

CITATION:
T.J. Littlejohns ; K. Kos ; W.E. Henley ; E. Kuźma ; D.J. Llewellyn (2015): Vitamin D and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.68

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DIETARY FACTORS AND COGNITIVE DECLINE

P.J. Smith, J.A. Blumenthal

J Prev Alz Dis 2016;3(1):53-64

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Cognitive decline is an increasingly important public health problem, with more than 100 million adults worldwide projected to develop dementia by 2050. Accordingly, there has been an increased interest in preventive strategies that diminish this risk. It has been recognized that lifestyle factors including dietary patterns, may be important in the prevention of cognitive decline and dementia in later life. Several dietary components have been examined, including antioxidants, fatty acids, and B vitamins. In addition, whole dietary eating plans, including the Mediterranean diet (MeDi), and the Dietary Approaches to Stop Hypertension (DASH) diet, with and without weight loss, have become areas of increasing interest. Although prospective epidemiological studies have observed that antioxidants, fatty acids, and B vitamins are associated with better cognitive functioning, randomized clinical trials have generally failed to confirm the value of any specific dietary component in improving neurocognition. Several randomized trials have examined the impact of changing ‘whole’ diets on cognitive outcomes. The MeDi and DASH diets offer promising preliminary results, but data are limited and more research in this area is needed.

CITATION:
P.J. Smith ; J.A. Blumenthal (2015): Dietary Factors and Cognitive Decline. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.71

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