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03/2016 journal articles

Editorials

HEALTHYBRAINS.ORG: FROM REGISTRY TO RANDOMIZATION

K. Zhong, J. Cummings

J Prev Alz Dis 2016;3(3):123-126

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Healthbrains.org is an interactive digital platform designed to establish an online community-based registry with a well characterized population who are willing and ready to participate in clinical trials. It challenges the community to get involved in a brain-healthy life style to reduce the risk of brain disorders. Users can choose to browse the site anonymously, sign up for updates and news, or register to get a “brain checkup” by completing questionnaires on their health and family history, demographic data, and other relevant life style information. In return, the registrants will receive their individualized Brain Health Index (BHI), and a personalized brain health report with customized recommendations. The site strives to empower registrants and enhance the user experiences through an interactive dashboard which acts as an engagement and motivation tool. The information provided by the registrants allows the site to identify individuals that are interested in and may be appropriate for trials. Of 7,142 users with data available for review, 71 % are women, 58 % are 55 years old or older, 31 % have a family history of dementia, and 42 % are concerned about their memory. Among 4,150 who completed the BHI, 1,389 finished the Cognitive Function Instrument (CFI) (33%). As of April 2016, 3,869 have opted in for clinical trials, out of that 931 resided in the Las Vegas area, where 38 individuals were prescreened and 4 were randomized for A4 clinical trials to the Lou Ruvo Center for Brain Health in Las Vegas. The site will contribute to the evolving understanding of using web-based approaches to information capture and clinical trial recruitment.

CITATION:
K. Zhong ; J. Cummings (2016): Healthybrains.org: From Registry to Randomization. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.100

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Case Report

INTEGRATING INFORMATION FROM FDG - AND AMYLOID PET FOR DETECTING DIFFERENT TYPES OF DEMENTIA IN OLDER PERSONS. A CASE-SERIES STUDY

L. Ruffini, F. Lauretani, M. Scarlattei, A. Ticinesi, T. Meschi, C. Ghetti, G. Serreli, M. Maggio, P. Caffarra

J Prev Alz Dis 2016;3(3):127-132

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A significant progress has been made in the understanding of the neurobiology of Alzheimer’s disease. The post-mortem studies are the gold standard for a correct histopathological diagnosis, contributing to clarify the correlation with cognitive, behavioral and extra-cognitive domains. However, the relationship between pathological staging and clinical involvement remains challenging. Neuroimaging, including positron emission tomography (PET) and magnetic resonance, could help to bridge the gap by providing in vivo information about disease staging. In the last decade, advances in the sensitivity of neuroimaging techniques have been described, in order to accurately distinguish AD from other causes of dementia. Fluorodeoxyglucose-traced PET (FDG-PET) is able to measure cerebral metabolic rates of glucose, a proxy for neuronal activity, theoretically allowing detection of AD. Many studies have shown that this technique could be used in early AD, where reduced metabolic activity correlates with disease progression and predicts histopathological diagnosis. More recently, molecular imaging has made possible to detect brain deposition of histopathology-confirmed neuritic β-amyloid plaques (Aβ) using PET. Although Aβ plaques are one of the defining pathological features of AD, elevated levels of Aβ can be detected with this technique also in older individuals without dementia. This raises doubts on the utility of Aβ PET to identify persons at high risk of developing AD. In the present case-series, we sought to combine metabolic information (from FDG-PET) and amyloid plaque load (from Aβ PET) in order to correctly distinguish AD from other forms of dementia. By selecting patients with Aβ PET + / FDG-PET + and Aβ PET – / FDG-PET +, we propose an integrated algorithm of clinical and molecular imaging information to better define type of dementia in older persons.

CITATION:
L. Ruffini ; F. Lauretani ; M. Scarlattei ; A. Ticinesi ; T. Meschi ; C. Ghetti ; G. Serreli ; M. Maggio ; P. Caffarra (2016): Integrating Information from FDG - and Amyloid PET for Detecting Different Types of Dementia in Older Persons. A Case-Series Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.101

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Original Research

A PERSONALIZED 12-WEEK “BRAIN FITNESS PROGRAM” FOR IMPROVING COGNITIVE FUNCTION AND INCREASING THE VOLUME OF HIPPOCAMPUS IN ELDERLY WITH MILD COGNITIVE IMPAIRMENT

M. Fotuhi, B. Lubinski, N. Hausterman, T. Riloff, M. Hadadi, C.A. Raji, M. Trullinger

J Prev Alz Dis 2016;3(3):133-137

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Reducing cognitive decline in patients with Mild Cognitive Impairment (MCI) may slow their progression to develop dementia. In this 12-week single-arm intervention trial, elderly patients (n = 127, age 70.69 +/-10.53, 63% female) with a diagnosis of MCI were enrolled in a multi-disciplinary Brain Fitness Program. The main outcome measure was changes in a battery of 10 cognitive domains. Each patient received weekly personalized cognitive stimulation, neurofeedback training, and brain coaching/counseling for eating a Mediterranean diet, taking omega-3 supplements, increasing fitness, and practicing mindfulness meditation. The post-program testing showed 84% of the patients experienced statistically significant improvements in their cognitive function (p< 0.05). Among the random sample of 17 patients who had a post-program quantitative MRI, 12 patients had either no atrophy or an actual growth above the baseline volume of their hippocampus. These preliminary findings support the concept that a personalized Brain Fitness Program can improve cognitive function and either reverse or grow the volume of hippocampus in elderly with MCI.

CITATION:
M. Fotuhi ; B. Lubinski ; M. Trullinger ; N. Hausterman ; T. Riloff ; M. Hadadi ; C.A. Raji (2016): A Personalized 12-week “Brain Fitness Program” for Improving Cognitive Function and Increasing the Volume of Hippocampus in Elderly with Mild Cognitive Impairment . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.92

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CORRELATION BETWEEN COGNITION AND FUNCTION ACROSS THE SPECTRUM OF ALZHEIMER’S DISEASE

H. Liu-Seifert, E. Siemers, K. Selzler, K. Sundell, P. Aisen, J. Cummings, J. Raskin, R. Mohs, for the Alzheimer’s Disease Neuroimaging Initiative

J Prev Alz Dis 2016;3(3):138-144

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Background: Both cognitive and functional deterioration are characteristic of the clinical progression of Alzheimer’s disease (AD). Objectives: To systematically assess correlations between widely used measures of cognition and function across the spectrum of AD. Design: Spearman rank correlations were calculated for cognitive and functional measures across datasets from various AD patient populations. Setting: Post-hoc analysis from existing databases. Participants: Pooled data from placebo-treated patients with mild (MMSE score ≥20 and ≤26) and moderate (MMSE score ≥16 and ≤19) AD dementia from two Phase 3 solanezumab (EXPEDITION/2) and two semagecesatat (IDENTITY/2) studies and normal, late mild cognitive impairment (LMCI) and mild AD patients from the Alzheimer’s Disease Neuroimaging Initiative 2-Grand Opportunity (ADNI-2/GO). Intervention (if any): Placebo (EXPEDITION/2 and IDENTITY/2 subjects) Measurements: Cognitive and functional abilities were measured in all datasets. Data were collected at baseline and every three months for 18 months in EXPEDITION and IDENTITY studies; and at baseline, 6, 12, and 24 months in the ADNI dataset. Results: The relationship of cognition and function became stronger over time as AD patients progressed from preclinical to moderate dementia disease stages, with the magnitude of correlations dependent on disease stage and the complexity of functional task. The correlations were minimal in the normal control population, but became stronger with disease progression. Conclusions: This analysis found that measures of cognition and function become more strongly correlated with disease progression from preclinical to moderate dementia across multiple datasets. These findings improve the understanding of the relationship between cognitive and functional clinical measures during the course of AD progression and how cognition and function measures relate to each other in AD clinical trials.

CITATION:
H. Liu-Seifert ; E. Siemers ; K. Selzler ; K. Sundell ; P. Aisen ; J. Cummings ; J. Raskin ; R. Mohs ; for the Alzheimer’s Disease Neuroimaging Initiative ; (2016): Correlation between Cognition and Function across the Spectrum of Alzheimer’s Disease. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.99

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EFFECTS OF COMPUTERIZED COGNITIVE TRAINING ON GAIT SPEED IN COMMUNITY DWELLING OLDER ADULTS, A PILOT STUDY

J. Blackwood, T. Houston

J Prev Alz Dis 2016;3(3):145-150

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Background: In older adults declines in gait speed have been identified as predictors of functional decline and have been found in those with cognitive dysfunction. Cognitive training interventions that emphasize addressing executive function (EF) have resulted in a transfer effect from training cognitive processes into improved function. However research examining the effects of an EF specific computerized cognitive training (CCT) program on gait speed (GS) is limited. Objectives: To compare the effects of a six week EF specific CCT program on GS in community dwelling older adults using a pretest/posttest experimental design with subgroup comparisons based on a cutoff GS of 1.0m/s. Setting: Home based Participants: Forty independent living older adults (>65 years) without diagnosed cognitive impairment participated in either the intervention or control groups. Intervention: A six week long progressively challenging EF focused CCT program was performed at home. Measurements: Demographic variables, cognitive function (Trail-Making Test Part B) and GS were measured at baseline at week 7. Between group comparisons were completed for the whole sample initially with subgroup comparisons performed based on participants’ initial GS (Slow walkers: GS<1.0m/s; Fast Walkers: GS>1.0m/s). Results: No differences in GS were found for the whole population, but subgroup analyses restricted to slow walkers demonstrated a statistically significant improvement in GS after 6 weeks of CCT (µ =0.33 m/s, p = 0.03). Other outcomes measures were not statistically different at posttest. Conclusions: Older adults who walk at speeds <1.0m/s may benefit from a progressively challenging CCT program when self-administered in the home.

CITATION:
J. Blackwood ; T. Houston (2016): Effects of Computerized Cognitive Training on Gait Speed in Community Dwelling Older Adults, A Pilot Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.102

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NEUROPSYCHOLOGICAL PROFILE OF “COGNITIVE FRAILTY” SUBJECTS IN MAPT STUDY

J. Delrieu, S. Andrieu, M. Pahor, C. Cantet, M. Cesari, P.J. Ousset, T. Voisin, B. Fougère, S. Gillette, I. Carrié, B. Vellas

J Prev Alz Dis 2016;3(3):151-159

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Objectives: An international group proposed the existence of “cognitive frailty”, a condition defined by simultaneous presence of physical frailty and cognitive impairment in the absence of dementia. The objective was to compare the neuropsychological profiles in subgroups of elders differentiated across their physical frailty (Fried phenotype) and cognitive status (Clinical Dementia Rating score) to characterize the “cognitive frailty” entity. Method: We studied baseline characteristics of 1,617 subjects enrolled in Multidomain Alzheimer Disease Preventive Trial (MAPT). Included subjects were aged 70 years or older and presented at least 1 of the 3 following clinical criteria: (1) Memory complaint spontaneously reported to a general practitioner, (2) limitation in one instrumental activity of daily living, (3) slow gait speed. Subjects with dementia were not included in the trial. Results: “Cognitive frailty individuals” significantly differed from “individuals with cognitive impairment and without physical frailty”, scoring worse at executive, and attention tests. They presented subcortico-frontal cognitive pattern different of Alzheimer Disease. Cognitive performance of subjects with 3 criteria or more of the frailty phenotype are cognitively more impaired than subjects with only one. Discusion: The characterization of “cognitive frailty” must be done in frail subjects to set up specific preventive clinical trials for this population.

CITATION:
J. Delrieu ; S. Andrieu ; M. Pahor ; C. Cantet ; M. Cesari ; P.J. Ousset ; T. Voisin ; B. Fougère ; S. Gillette ; I. Carrie ; B. Vellas (2016): Neuropsychological Profile of “Cognitive Frailty” Subjects in MAPT Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.94

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Review Articles

PRIMARY PREVENTION OF DEMENTIA: AN EPIDEMIOLOGICAL POINT OF VIEW

C. Berr

J Prev Alz Dis 2016;3(3):160-163

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From an epidemiological perspective, in order to increase the level of evidence, it is necessary to refer to data from longitudinal studies to validate the temporal relationship between exposure (e.g. the behavior or modifying factor) and the disease. Findings from such studies are useful for defining risk factors and laying the groundwork for proposing interventions for prevention. This step is crucial in order to define the periods (life-course approach) and groups at risk, which will then become the targets of interventions designed to modify behaviors or lifestyle. Specifying the underlying mechanisms of these risk factors is one of the objectives of etiological epidemiology which focuses on the origin of diseases but is not essential for a more pragmatic interventional approach. These questions are essential for dementia prevention and are discussed in this paper. Furthermore, timing interventions is a major problem even if we identify primary prevention pathways in dementia. Another important concern for epidemiologists is the need to make projections to estimate the number of dementia cases in the next decades considering different intervention scenarios. These models require adequate descriptive indicators of dementia, demography and mortality and precise estimations of the impact of potential interventions in terms of delaying disease onset for instance.

CITATION:
C. Berr (2016): Primary Prevention of Dementia: An Epidemiological Point of View. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.103

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COMBINATION THERAPY OF ANTI-TAU AND ANTI-AMYLOID DRUGS FOR DISEASE MODIFICATION IN EARLY-STAGE ALZHEIMER’S DISEASE: SOCIO-ECONOMIC CONSIDERATIONS MODELED ON TREATMENTS FOR TUBERCULOSIS, HIV/AIDS AND BREAST CANCER

S. Tomaszewski, S. Gauthier, A. Wimo, P. Rosa-Neto

J Prev Alz Dis 2016;3(3):164-172

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Current drugs for treatment of mild to severe dementia of the Alzheimer’s type include cholinesterase inhibitors and the NMDA non-competitive receptor antagonist memantine. There is controversy as to the additive benefit of these symptomatic drugs, and their effects are clinically modest. Patients with Alzheimer’s disease (AD) are known to have characteristic pathology, including senile plaques with amyloid beta-protein aggregates and neurofibrillary tangles with assembled tau proteins, which start in the hippocampus and spread to neighboring areas. Amyloid and tau modifying drugs are under clinical testing. Based on this pathophysiology, it is crucial to investigate whether anti-amyloid and anti-tau combined therapy would show efficacy in early stage of AD, beyond what could be achieved with anti-amyloid or anti-tau monotherapy. It is equally important to consider the socio-economic implications of such a combination therapy, if effective. We hypothesize that the high costs of combination therapy for early-stage AD patients will require societal and public health initiatives to ensure universal access to AD treatment. In order to better predict these socio-economic implications, we summarize the management of other combination therapies used for tuberculosis, HIV/AIDS, and breast cancer, based on a database search of PubMed and other relevant sources. We put forward a framework for testing a potential anti-amyloid and anti-tau disease modifying combination therapy for early-stage AD patients and present an analysis of the socio-economic implications of such a combination therapy.

CITATION:
S. Tomaszewski1 ; S. Gauthier ; A. Wimo ; P. Rosa-Neto (2015): Combination Therapy of Anti-Tau and Anti-Amyloid Drugs for Disease Modification in Early-Stage Alzheimer’s Disease: Socio-Economic Considerations Modeled on Treatments for Tuberculosis, HIV/AIDS and Breast Cancer. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2015.85

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THE CASE FOR USING ACTIGRAPHY GENERATED SLEEP AND ACTIVITY ENDPOINTS IN ALZHEIMER’S DISEASE CLINICAL TRIALS

M. Mc Carthy, W. Muehlhausen, P. Schüler

J Prev Alz Dis 2016;3(3):173-176

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More and more people in the industrialised world use wearables and smartphones to monitor their health and fitness. These devices are often used in combination with special apps to monitor and document daily activities and sleep. It would appear to be a logical step to assess the relevance of these devices in drug development trials. In contrast to the consumer devices, the technology used in clinical trials needs to be validated and compliant with the relevant regulations. Even under these complex requirements, wearables offer a number of new opportunities to objectively capture clinically relevant outcome measures –potentially with lower burden for patients and site staff. As an example, we describe the use in Alzheimer’s disease drug development studies. This is an indication where there have been a number of failures, in part due to the difficulties this patient population has in reliably completing existing tools. In addition rater scales add complexity due to inter- and intra-rater variability.

CITATION:
M. Mc Carthy ; W. Muehlhausen ; P. Schüler (2016): The Case for Using Actigraphy Generated Sleep and Activity Endpoints in Alzheimer’s Disease Clinical Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2016.98

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