03/2014 journal articles
BLOOD-BRAIN BARRIER PERMEABILITY IN AGING AND ALZHEIMER’S DISEASE
J Prev Alz Dis 2014;1(3):138-140Show summaryHide summary
G.A. Rosenberg (2014): BLOOD-BRAIN BARRIER PERMEABILITY IN AGING AND ALZHEIMER’S DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.25
ALZHEIMER’S DISEASE PREVENTION: REALITY OR UTOPIA?
E. Cavedo, G.B. Frisoni
J Prev Alz Dis 2014;1(3):141-142Show summaryHide summary
E. Cavedo ; G.B. Frisoni (2014): ALZHEIMER’S DISEASE PREVENTION: REALITY OR UTOPIA?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.26
A PATIENT-CENTERED ANALYSIS OF ENROLLMENT AND RETENTION IN A RANDOMIZED BEHAVIORAL TRIAL OF TWO COGNITIVE REHABILITATION INTERVENTIONS FOR MILD COGNITIVE IMPAIRMENT
D.E.C. Locke, M. Chandler Greenaway, N. Duncan, J.A. Fields, A.V. Cuc, C. Hoffman Snyder, S. Hanna, A. Lunde, G.E. Smith
J Prev Alz Dis 2014;1(3):143-150Show summaryHide summary
BACKGROUND: A major potential barrier for studying
behavioral interventions for patients with Mild Cognitive
Impairment (MCI) is the willingness and ability of people to
enroll in and adhere to behavioral interventions, especially
when the intervention involves dyads of patients with MCI and
support partners. Details regarding recruitment strategies and
processes (such as number of dyads screened) are often missing
from reports of behavioral trials. In addition, reports do not
detail the reasons a potentially eligible candidate opts out of
participation in a research study.
OBJECTIVES: To describe the challenges and successes of enrollment and retention in a behavioral trial for persons with MCI and their care partners, and to better understand barriers to participation from the patient’s point of view.
DESIGN: Multi-site, randomized trial.
SETTING: Major medical centers.
PARTICIPANTS: Our accrual target for the study was 60 participants. Potential candidates were patients presenting to memory evaluation clinics whose resulting clinical diagnosis was MCI. A total of 200 consecutive potential candidates were approached about participating in the study across the three sites.
INTERVENTION: Detailed recruitment and retention data of a randomized trial comparing two behavioral interventions (memory notebook training versus computer training) provided in two separate training time frames (10 days versus 6 weeks).
MEASUREMENTS: Structured interview with those declining to participate in the trial.
RESULTS: Overall recruitment 37% with a range of 13%-72% across sites. Overall retention 86% with a range of 74%-94% across sites.
CONCLUSIONS: The primary barriers to enrollment from the patient’s perspective were distance to the treatment center and competing comprehensive behavioral programming. However, retention data suggest that those dyads who enroll in behavioral programs are highly committed.
D.E.C. Locke ; M. Chandler Greenaway ; N. Duncan ; J.A. Fields ; A.V. Cuc ; C. Hoffman Snyder ; S. Hanna ; A. Lunde ; G.E. Smith (2014): A PATIENT-CENTERED ANALYSIS OF ENROLLMENT AND RETENTION IN A RANDOMIZED BEHAVIORAL TRIAL OF TWO COGNITIVE REHABILITATION INTERVENTIONS FOR MILD COGNITIVE IMPAIRMENT. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.27
BRAIN DONATION BY PROXY: ARE THERE PREDICTORS IN NEURODEGENERATIVE DEMENTIA?
J. Olazarán, J. López-Álvarez, L. Agu?era-Ortiz, M. Valentí, M.A. Zea-Sevilla, B. González, B. León-Salas, J.L. Dobato, A. Rábano
J Prev Alz Dis 2014;1(3):151-159Show summaryHide summary
OBJECTIVES: To describe the frequency and predictors of brain
donation by relatives in patients with neurodegenerative
DESIGN: Database review and quantitative analysis.
SETTING: The Alzheimer Center Reina Sofia Foundation (ACRSF), a center devoted to the care and research of patients with neurodegenerative dementia.
PARTICIPANTS: Patients with signed consent for participation in the ACRSF research program.
MEASUREMENTS: A set of 38 demographic, clinical, and social variables related to patient and closest relative, which were collected by the ACRSF multidisciplinary team upon patient admission.
RESULTS: Admission data were available for 198 patients who entered the ACRSF research program; 85 of them (42.9%) died during follow-up. Mean age (SD) at admission was 82.3 (6.8) years and 80.8% of the patients were female. Family link between patient and closest relative was spouse or partner (12.0%), son or daughter (74.9%), or other link (13.1%). Brain was obtained from 56 patients (65.9%). Consent by legal representative and patient’s depressive symptoms were more frequent in the donors (p<0.05, corrected) and trend was observed for more aberrant motor symptoms in the donors (p<0.05, uncorrected).
CONCLUSION: A high rate of brain donation was achieved, probably due to the unique characteristics of the ACRSF and consent for research policy. Wish of alleviating suffering, as well as general interest in dementia research, possibly exerted an influence in brain donation. More research is needed to ascertain the values, motivations, and circumstances that may lead to brain donation by proxy in neurodegenerative dementia.
J. Olazarán ; J. López-Álvarez ; L. Agüera-Ortiz ; M. Valentí ; M.A. Zea-Sevilla ; B. González ; B. León-Salas ; J.L. Dobato ; A. Rábano (2014): BRAIN DONATION BY PROXY: ARE THERE PREDICTORS IN NEURODEGENERATIVE DEMENTIA?. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.28
CEREAL INTAKE INCREASES AND DAIRY PRODUCTS DECREASE RISK OF COGNITIVE DECLINE AMONG ELDERLY FEMALE JAPANESE
R. Otsuka, Y. Kato, Y. Nishita, C. Tange, M. Nakamoto, M. Tomida, T. Imai, F. Ando, H. Shimokata
J Prev Alz Dis 2014;1(3):160-167Show summaryHide summary
BACKGROUND: If cognitive decline can be prevented through
changes in daily diet with no medical intervention, it will be
highly significant for dementia prevention.
OBJECTIVES: This longitudinal study examined the associations of different food intakes on cognitive decline among Japanese subjects.
DESIGN: Prospective cohort study.
SETTING: The National Institute for Longevity Sciences - Longitudinal Study of Aging, a community-based study.
PARTICIPANTS: Participants included 298 males and 272 females aged 60 to 81 years at baseline who participated in the follow-up study (third to seventh wave) at least one time.
MEASUREMENTS: Cognitive function was assessed with the Mini-Mental State Examination (MMSE) in all study waves. Nutritional intake was assessed using a 3-day dietary record in the second wave. Cumulative data among participants with an MMSE >27 in the second wave were analyzed using a generalized estimating equation. Multivariate adjusted odds ratios (OR) and 95% confidence intervals (CI) for an MMSE score ≤27 in each study wave according to a 1 standard deviation (SD) increase of each food intake at baseline were estimated, after adjusting for age, follow-up time, MMSE score at baseline, education, body mass index, annual household income, current smoking status, energy intake, and history of diseases.
RESULTS: In men, after adjusting for age, and follow-up period, MMSE score at baseline, the adjusted OR for a decline in MMSE score was 1.20 (95% CI, 1.02-1.42; p=0.032) with a 1-SD increase in cereal intake. After adjusting for education and other confounding variables, the OR for a decrease in MMSE score did not reach statistical significance for this variable. In women, multivariate adjusted OR for MMSE decline was 1.43 (95% CI, 1.15-1.77; p=0.001) with a 1-SD increase in cereal intake and 0.80 (95% CI, 0.65-0.98; p=0.034) with a 1-SD increase in milk and dairy product intake.
CONCLUSIONS: This study indicates that a 1-SD (108 g/day) decrease in cereal intake and a 1-SD (128 g/day) increase in milk and dairy product intake may have an influence of cognitive decline in community-dwelling Japanese women aged 60 years and older. Further studies are needed in order to explore the potential causal relationship.
R. Otsuka ; Y. Kato ; Y. Nishita ; C. Tange ; M. Nakamoto ; M. Tomida ; T. Imai ; F. Ando ; H. Shimokata (2014): CEREAL INTAKE INCREASES AND DAIRY PRODUCTS DECREASE RISK OF COGNITIVE DECLINE AMONG ELDERLY FEMALE JAPANESE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.29
UPDATE ON PREVENTION TRIALS IN ALZHEIMER’S DISEASE
J Prev Alz Dis 2014;1(3):168-175Show summaryHide summary
An evolving consensus about the need to treat AD in the
presymptomatic phase has emerged following the
disappointing results of several trials that enrolled subjects with
mild to moderate disease, as well as accumulating research
demonstrating that AD pathologic process begins decades
before the appearance of symptoms. Several lessons can be
learned from past prevention trials. The targeted populations
were too diverse, the interventions probably not strong enough,
and the time of exposure was most likely too short. We have
learned from these trials that future prevention trials must be
targeted, use strong interventions with known biological
activity, and must be sustained with a long-term intervention.
In this paper, we focus on three prevention trial approaches:
A. Targeted therapy: Preventing AD by targeting a specific
population with a specific intervention. Such preventive
approaches and trials must be based on biomarkers and
imaging to select a study population in accordance with the
mechanism of the specific intervention;
B. Multi-domain interventions targeting a larger, more diverse
population over a longer time period with long-term exposure
to non-specific, multi-domain intervention. The rationale for
this approach stems from studies showing that several
environmental factors are associated with the risk of developing
dementia. These factors may include educational level, vascular
and metabolic risk factors, physical activity, cognitive
stimulation, and nutritional status. It may also be possible to
identify healthy adults at high risk of AD and likely to benefit
from intervention based on subjective memory complaint,
ApoEε4 carriage, family history of AD, or the presence of
frailty; and use multidomain interventions to compensate for
C. What will be probably the future of clinical practice: A
preventive approach, integrated into primary care settings that
begins with longitudinal monitoring of memory function in a
general population to identify decliners, followed by a specific
intervention based on biomarkers and imaging discussed case
by case. Finally, preventing AD will require new and improved
B. Vellas (2014): UPDATE ON PREVENTION TRIALS IN ALZHEIMER’S DISEASE. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.30
THREE CARDINAL LESSONS FROM ADAPT – 10 YEARS ON
J.C.S. Breitner, C.G. Lyketsos
J Prev Alz Dis 2014;1(3):176-180Show summaryHide summary
The Alzheimer’s Disease Anti-inflammatory Prevention Trial
was a placebo-controlled three-arm pharmaco-prevention trial
of the non-steroidal anti-inflammatory drugs naproxen sodium
and celecoxib for prevention of incident Alzheimer’s disease
(AD) dementia in older (aged 70 and over) adults. Although
subjects were at increased risk of symptoms because of a firstdegree
family history, they were meant to be cognitively
healthy at enrollment. ADAPT encountered several problems
that resulted in the termination of its treatments after only two
years on average. Interim results were complex but potentially
interesting. In the end, however, the results were null. We
describe the complications that prevented ADAPT from
achieving conclusive results, and suggest that these could have
been avoided if the trial design and execution had been better
guided by preliminary data. We believe such data should be
available before beginning further ambitious phase III trials of
this sort, and we suggest a broad method by which such data
can be accumulated with reasonable economy.
J.C.S. Breitner ; C.G. Lyketsos (2014): THREE CARDINAL LESSONS FROM ADAPT – 10 YEARS ON. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.31
THE ROAD AHEAD TO CURE ALZHEIMER\'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS
E. Cavedo , S. Lista, Z. Khachaturian, P. Aisen, P. Amouyel, K. Herholz, C.R. Jack Jr, R. Sperling, J. Cummings, K. Blennow, S. O’Bryant, G.B. Frisoni, A. Khachaturian , M. Kivipelto, W. Klunk, K. Broich, S. Andrieu, M. Thiebaut de Schotten, J.-F. Mangin, A.A. Lammertsma, K. Johnson, S. Teipel , A. Drzezga , A. Bokde , O. Colliot , H. Bakardjian , H. Zetterberg , B. Dubois , B. Vellas, L.S. Schneider, H. Hampel
J Prev Alz Dis 2014;1(3):181-202Show summaryHide summary
Alzheimer's disease (AD) is a slowly progressing non-linear
dynamic brain disease in which pathophysiological
abnormalities, detectable in vivo by biological markers, precede
overt clinical symptoms by many years to decades. Use of these
biomarkers for the detection of early and preclinical AD has
become of central importance following publication of two
international expert working group's revised criteria for the
diagnosis of AD dementia, mild cognitive impairment (MCI)
due to AD, prodromal AD and preclinical AD. As a
consequence of matured research evidence six AD biomarkers
are sufficiently validated and partly qualified to be incorporated
into operationalized clinical diagnostic criteria and use in
primary and secondary prevention trials. These biomarkers fall
into two molecular categories: biomarkers of amyloid-beta (Aβ)
deposition and plaque formation as well as of tau-protein
related hyperphosphorylation and neurodegeneration. Three of
the six gold-standard ("core feasible) biomarkers are
neuroimaging measures and three are cerebrospinal fluid (CSF)
analytes. CSF Aβ 1-42 (Aβ1-42), also expressed as Aβ1-42 : Aβ1-
40 ratio, T-tau, and P-tau Thr181 & Thr231 proteins have proven
diagnostic accuracy and risk enhancement in prodromal MCI
and AD dementia. Conversely, having all three biomarkers in
the normal range rules out AD. Intermediate conditions require
further patient follow-up. Magnetic resonance imaging (MRI) at
increasing field strength and resolution allows detecting the
evolution of distinct types of structural and functional
abnormality pattern throughout early to late AD stages.
Anatomical or volumetric MRI is the most widely used
technique and provides local and global measures of atrophy.
The revised diagnostic criteria for “prodromal AD” and "mild
cognitive impairment due to AD" include hippocampal atrophy
(as the fourth validated biomarker), which is considered an
indicator of regional neuronal injury. Advanced image analysis techniques generate automatic and reproducible measures both
in regions of interest, such as the hippocampus and in an
exploratory fashion, observer and hypothesis-indedendent,
throughout the entire brain. Evolving modalities such as
diffusion-tensor imaging (DTI) and advanced tractography as
well as resting-state functional MRI provide useful additionally
useful measures indicating the degree of fiber tract and neural
network disintegration (structural, effective and functional
connectivity) that may substantially contribute to early
detection and the mapping of progression. These modalities
require further standardization and validation. The use of
molecular in vivo amyloid imaging agents (the fifth validated
biomarker), such as the Pittsburgh Compound-B and markers of
neurodegeneration, such as fluoro-2-deoxy-D-glucose (FDG) (as
the sixth validated biomarker) support the detection of early AD
pathological processes and associated neurodegeneration. How
to use, interpret, and disclose biomarker results drives the need
for optimized standardization. Multimodal AD biomarkers do
not evolve in an identical manner but rather in a sequential but
temporally overlapping fashion. Models of the temporal
evolution of AD biomarkers can take the form of plots of
biomarker severity (degree of abnormality) versus time. AD
biomarkers can be combined to increase accuracy or risk. A list
of genetic risk factors is increasingly included in secondary
prevention trials to stratify and select individuals at genetic risk
of AD. Although most of these biomarker candidates are not yet
qualified and approved by regulatory authorities for their
intended use in drug trials, they are nonetheless applied in
ongoing clinical studies for the following functions: (i)
inclusion/exclusion criteria, (ii) patient stratification, (iii)
evaluation of treatment effect, (iv) drug target engagement, and
(v) safety. Moreover, novel promising hypothesis-driven, as
well as exploratory biochemical, genetic, electrophysiological,
and neuroimaging markers for use in clinical trials are being
developed. The current state-of-the-art and future perspectives
on both biological and neuroimaging derived biomarker
discovery and development as well as the intended application
in prevention trials is outlined in the present publication.
E. Cavedo ; S. Lista ; Z. Khachaturian ; P. Aisen ; P. Amouyel ; K. Herholz ; C.R. Jack Jr ; R. Sperling ; J. Cummings ; K. Blennow ; S. O’Bryant ; G.B. Frisoni ; A. Khachaturian ; M. Kivipelto ; W. Klunk ; K. Broich ; S. Andrieu ; M. Thiebaut de Schotten ; J.-F. Mangin ; A.A. Lammertsma ; K. Johnson ; S. Teipel ; A. Drzezga ; A. Bokde ; O. Colliot ; H. Bakardjian ; H. Zetterberg ; B. Dubois ; B. Vellas ; L.S. Schneider ; H. Hampel (2014): THE ROAD AHEAD TO CURE ALZHEIMER'S DISEASE: DEVELOPMENT OF BIOLOGICAL MARKERS AND NEUROIMAGING METHODS FOR PREVENTION TRIALS ACROSS ALL STAGES AND TARGET POPULATIONS. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.32
Clinical Trials and Aging: 7th Conference Clinical Trials on Alzheimer’s Disease, November 20-22, 2014, Philadelphia, USA
FOREWORD: AD DRUG DEVELOPMENT IS NOT BROKEN: CLINICAL TRIALS IN ALZHEIMER’S DISEASE 2014 CONFERENCE, PHILADELPHIA
J Prev Alz Dis 2014;1(3):212-213Show summaryHide summary
J. Touchon (2014): FOREWORD: AD DRUG DEVELOPMENT IS NOT BROKEN: CLINICAL TRIALS IN ALZHEIMER’S DISEASE 2014 CONFERENCE, PHILADELPHIA. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2014.33
CTAD: SYMPOSIA, ORAL COMMUNICATIONS, POSTERS
J Prev Alz Dis 2014;1(3):214-296Show summaryHide summary
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