03/2017 journal articles
SWINGS AND ROUNDABOUTS IN CNS DRUG BIOMARKERS
M.B. Isaac, S. Vamvakas
J Prev Alz Dis 2017;4(3):134-135Show summaryHide summary
Despite substantial advances in the understanding of central nervous system (CNS) disorders, healthcare systems worldwide face an unprecedented challenge in dealing with the unmet needs in this area (1). Meanwhile, the CNS drug pipeline looks worryingly dry. There are several reasons for this, including the obvious complexity of the CNS, a lack of interdisciplinary collaborations, increased drug development costs and the higher risk of clinical failure of CNS drugs, compared with those in other areas of drug development. The year 2016 was also disappointing in terms of failed trials of Alzheimer’ Dementia (AD) drugs.
M.B. Isaac ; S. Vamvakas (2017): Swings and Roundabouts in CNS Drug Biomarkers. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.18
CLINICAL EFFECTS OF ORAL TRAMIPROSATE IN APOE4/4 HOMOZYGOUS PATIENTS WITH MILD ALZHEIMER’S DISEASE SUGGEST DISEASE MODIFICATION
J Prev Alz Dis 2017;4(3):136-137Show summaryHide summary
M.N. Sabbagh (2017): Clinical Effects of Oral Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.24
DEMENTIA PREVENTION BY DISEASE-MODIFICATION THROUGH NUTRITION
A.D. Smith, H. Refsum
J Prev Alz Dis 2017;4(3):138-139Show summaryHide summary
It is agreed that disease-modification is the most desirable approach to tackling dementia (1), but we are often told that it is not yet feasible and that “no disease modifying therapy has proven effective in clinical trials” (2). The purpose of our Editorial is to show that disease-modification is not only feasible but that there is good evidence that it has already been achieved in subjects with Mild Cognitive Impairment (MCI).
A.D. Smith ; H. Refsum (2017): Dementia Prevention by Disease-Modification through Nutrition. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.16
POTENTIAL UTILITY OF PRACTICE EFFECTS IN PREVENTIVE TRIALS
J Prev Alz Dis 2017;4(3):140-142Show summaryHide summary
S. Villeneuve (2017): Potential Utility of Practice Effects in Preventive Trials. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.25
DIABETES MITIGATES THE ROLE OF MEMORY COMPLAINT IN PREDICTING DEMENTIA RISK: RESULTS FROM THE PREVENTION OF ALZHEIMER’S DISEASE WITH VITAMIN E AND SELENIUM STUDY
X. Zhang, F.A. Schmitt, A.M. Caban-Holt, X. Ding, R.J. Kryscio, E. Abner
J Prev Alz Dis 2017;4(3):143-148Show summaryHide summary
Background: Subjective memory complaints (SMCs) are associated with increased risk of dementia in older adults, but the role of comorbidities in modifying this risk is unknown.
Objectives: To assess whether comorbidities modify estimated dementia risk based on SMCs.
Design: The Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study (PREADVISE) was designed as an ancillary study to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, multi-center prostate cancer prevention trial with sites in the Unites States, Puerto Rico, and Canada. In 2009, PREADVISE and SELECT were changed into cohort studies.
Setting: Secondary analysis of PREADVISE data.
Participants: PREADVISE recruited 7,540 non-demented male volunteers from participating SELECT sites from 2002 to 2009. SMCs, demographics, and comorbidities including hypertension, diabetes, coronary artery bypass graft (CABG), stroke, sleep apnea, and head injury were ascertained by participant interview.
Measurements: Cox models were used to investigate whether baseline comorbidities modified hazard ratios (HR) for SMC-associated dementia risk using two methods: (1) we included one interaction term between SMC and a comorbidity in the model at a time, and (2) we included all two-way interactions between SMC and covariates of interest and reduced the model by “backward” selection. SMC was operationalized as any complaint vs. no complaint.
Results: Baseline SMCs were common (23.6%). In the first analyses, with the exception of stroke, presence of self-reported comorbidities was associated with lower estimated HR for dementia based on SMC status (complaint vs. no complaint), but this difference was only significant for diabetes. In the second analysis, the two-way interactions between SMC and race as well as SMC and diabetes were significant. Here, black men without diabetes who reported SMC had the highest estimated dementia risk (HR=5.05, 95% CI 2.55-10.00), while non-black men with diabetes who reported SMC had the lowest estimated risk (HR=0.71, 95% CI 0.35-1.41).
Conclusions: SMCs were more common among men with comorbidities, but these complaints appeared to be less predictive of dementia risk than those originating from men without comorbidities, suggesting that medical conditions such as diabetes may explain SMCs that are unrelated to an underlying neurodegenerative process.
X. Zhang ; F.A. Schmitt ; A.M. Caban-Holt ; X. Ding ; R.J. Kryscio ; E. Abner (2017): Diabetes Mitigates the Role of Memory Complaint in Predicting Dementia Risk: Results from the Prevention of Alzheimer’s Disease with Vitamin E and Selenium Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.7
CLINICAL EFFECTS OF TRAMIPROSATE IN APOE4/4 HOMOZYGOUS PATIENTS WITH MILD ALZHEIMER’S DISEASE SUGGEST DISEASE MODIFICATION POTENTIAL
S. Abushakra, A. Porsteinsson, P. Scheltens, C. Sadowsky, B. Vellas, J. Cummings, S. Gauthier, J.A. Hey, A. Power, P. Wang, L. Shen, M. Tolar
J Prev Alz Dis 2017;4(3):149-156Show summaryHide summary
Background: Alzheimer’s Disease (AD) patients homozygous for the APOE4 allele (APOE4/4) have a distinct clinical and biological phenotype with high levels of beta amyloid (Aβ) pathology and toxic Aβ oligomers. Tramiprosate, an oral agent that inhibits Aβ monomer aggregation into toxic oligomers, was evaluated in two Phase 3 Mild to Moderate AD studies which did not show efficacy in the overall population. Re-analyses of these trials showed the most consistent clinical benefits in APOE4/4 patients. We analyzed efficacy in the APOE4/4 patients with Mild disease.
Objectives: To determine the optimal stage of AD for future trials in APOE4/4 homozygotes.
Design: Two randomized, double-blind, placebo-controlled parallel-arm multi-center studies of 78-weeks duration.
Setting: Academic Alzheimer’s disease centers, community-based memory clinics, and neuropsychiatric research sites.
Participants: Participants included 2,025 AD patients with MMSE 16-26. Approximately 13-15% had APOE4/4 genotype (N= 147 and 110 per study), mean age 71.1 years, 56% females. Almost all were on stable symptomatic drugs.
Intervention: Randomized subjects received oral placebo, 100mg BID, or 150mg BID of tramiprosate.
Measurements: Co-primary outcomes were change from baseline in the ADAS-cog11 and CDR-SB. Disability assessment for dementia (DAD) was a secondary outcome.
Results: In APOE4/4 homozygotes receiving 150mg BID tramiprosate, efficacy in the traditional Mild AD patients (MMSE 20-26) was higher than the overall group (MMSE 16-26) and efficacy in the Mild patients (MMSE 22-26) was highest. Tramiprosate benefits compared to placebo on ADAS-cog, CDR-SB, and DAD were 125%, 81% and 71%, respectively (p<0.02). The Mild subgroup (MMSE 22-26) showed cognitive stabilization with no decline over 78 weeks, both ADAS-cog and DAD effects increased over time. Tramiprosate safety in APOE4/4 patients was favorable. Most common adverse events were nausea, vomiting, depression and decreased weight.
Conclusions: The Mild subgroup of APOE4/4 AD patients (MMSE 22-26) showed larger benefits on the high dose of tramiprosate than the overall Mild and Moderate group. Consistent with its preclinical effects on Aβ oligomers, tramiprosate seemed to stabilize cognitive performance, supporting its disease modification potential. Confirmatory studies using ALZ-801, an improved pro-drug formulation of tramiprosate, will target APOE4/4 patients with Mild AD.
S. Abushakra ; A. Porsteinsson ; P. Scheltens ; C. Sadowsky ; B. Vellas ; J. Cummings ; S. Gauthier ; J.A. Hey ; A. Power ; P. Wang ; L. Shen ; M. Tolar (2017): Clinical Effects of Tramiprosate in APOE4/4 Homozygous Patients with Mild Alzheimer’s Disease Suggest Disease Modification Potential . The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.26
FROM BRAIN DISEASE TO BRAIN HEALTH: PRIMARY PREVENTION OF ALZHEIMER’S DISEASE AND RELATED DISORDERS IN A HEALTH SYSTEM USING AN ELECTRONIC MEDICAL RECORD-BASED APPROACH
A.M. Fosnacht, S. Patel, C. Yucus, A. Pham, E. Rasmussen, R. Frigerio, S. Walters, D. Maraganore
J Prev Alz Dis 2017;4(3):157-164Show summaryHide summary
Background: Alzheimer’s disease and aging brain disorders are progressive, often fatal neurodegenerative diseases. Successful aging, modern lifestyles and behaviors have combined to result in an expected epidemic. Risks for these diseases include genetic, medical, and lifestyle factors; over 20 modifiable risks have been reported.
Objectives: We aim to primarily prevent Alzheimer’s disease and related disorders through electronic medical record (EMR)-based screening, risk assessments, interventions, and surveillance.
Design: We identified modifiable risks; developed human, systems and infrastructural resources; developed interventions; and targeted at-risk groups for the intervention.
Setting: A Community Based Health System.
Participants: In year one (June 2015 to May 2016), 133 at-risk patients received brain health services with the goal of delaying or preventing Alzheimer’s disease and related disorders.
Measurements: We created mechanisms to identify patients at high risk of neurodegenerative disease; EMR-based structured clinical documentation support tools to evaluate risk factors and history; evidence-based interventions to modify risk; and the capacity for annual surveillance, pragmatic trials, and practice-based and genomic research using the EMR.
Results: This paper describes our Center for Brain Health, our EMR tools, and our first year of healthy but at-risk patients.
Conclusion: We are translating research into primary prevention of Alzheimer’s disease and related disorders in our health system and aim to shift the paradigm in Neurology from brain disease to brain health.
A.M. Fosnacht ; S. Patel ; C. Yucus ; A. Pham ; E. Rasmussen ; R. Frigerio ; S. Walters ; D. Maraganore (2017): From Brain Disease to Brain Health: Primary Prevention of Alzheimer’s Disease and Related Disorders in a Health System Using an Electronic Medical Record-Based Approach. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.3
SEX AND AGE DIFFERENCES IN THE ASSOCIATION OF BLOOD PRESSURE AND HYPERTENSION WITH COGNITIVE FUNCTION IN THE ELDERLY: THE RANCHO BERNARDO STUDY
D. Kritz-Silverstein, G.A. Laughlin, L.K. McEvoy, E. Barrett-Connor
J Prev Alz Dis 2017;4(3):165-173Show summaryHide summary
Objectives: This study examines sex and age differences in associations of systolic and diastolic blood pressure (SBP, DBP), pulse pressure and hypertension with cognitive function in a community-dwelling population.
Design: Cross-sectional study.
Setting: Research clinic visit in 1988-91.
Participants: Participants were 693 men and 1022 women aged 50-97
Measurements: Blood pressure was measured and 12 cognitive function tests were administered.
Results: Average age was 73.8±9.9 in men and 73.2±9.3 in women; 62.6% of men and 63.4% of women were hypertensive (SBP≥140 mmHg, DBP≥90 mmHg, or antihypertensive medication use). Each 5-unit increment in SBP, DBP, or pulse pressure and categorical hypertension was associated with significantly increased odds of poor verbal fluency performance in men and poor Trails B performance in women, with strongest associations for hypertension (OR=1.97, CI:1.01,3.85 in men; OR=1.51, CI:1.01,2.26 in women). After age stratification, associations remained statistically significant in younger (<80 years ) but not older (≥80 years) participants.
Conclusion: Blood pressure as a continuous or categorical variable was associated with poor performance on cognitive function tests, but domains varied by sex and associations were found only in those younger than 80 years. The absent associations in those aged 80 years and older could support the hypothesis that increased blood flow is required to maintain cerebral perfusion with advancing age, or could reflect a survivor effect.
D. Kritz-Silverstein ; G.A. Laughlin ; L.K. McEvoy ; E. Barrett-Connor (2017): Sex and Age Differences in the Association of Blood Pressure and Hypertension with Cognitive Function in the Elderly: The Rancho Bernardo Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.6
B-VITAMIN THERAPY FOR KIDNEY TRANSPLANT RECIPIENTS LOWERS HOMOCYSTEINE AND IMPROVES SELECTIVE COGNITIVE OUTCOMES IN THE RANDOMIZED FAVORIT ANCILLARY COGNITIVE TRIAL
T.M. Scott, G. Rogers, D.E. Weiner, K. Livingston, J. Selhub, P.F. Jacques, I.H. Rosenberg, A.M. Troen, for the FACT Study Investigators
J Prev Alz Dis 2017;4(3):174-182Show summaryHide summary
Background: Objectives: Elevated plasma total homocysteine (tHcy) is associated with increased risk of cardiovascular disease, stroke and dementia. Results of clinical trials using B-vitamins to reduce the cognitive risks attributed to tHcy have been inconsistent. The high prevalence of both hyperhomocysteinemia and cognitive impairment among kidney transplant recipients makes them an important population in which to evaluate the effect of lowering homocysteine on cognitive function. We therefore evaluated whether B-vitamin therapy to lower tHcy would prevent cognitive-decline in a cohort of stable kidney transplant recipients.
Design: The study was a longitudinal ancillary of the FAVORIT trial, a randomized, placebo-controlled multi-site trial of high-dose B vitamins to reduce cardiovascular and cerebrovascular events in clinically stable kidney transplant recipients with elevated tHcy.
Participants: 584 participants from 18 sites across North America.
Intervention: The intervention consisted of a daily multivitamin containing high-doses of folate (5.0 mg), vitamin B12 (1.0 mg) and vitamin B6 (50 mg). The placebo consisted of a daily multi-vitamin containing no folate and recommended daily allowances of vitamins B12 and B6 (0 mg folate; 2.0 µg vitamin B12; 1.4 mg vitamin B6).
Measurements: Annual neuropsychological assessment for up to 5 years (mean 3.3 years) using a standardized test battery. Efficacy was analyzed on an intention-to-treat basis using end-of-trial data. Subgroup analyses included stratification for baseline plasma B-vitamin and tHcy concentrations.
Results: At baseline, cognitive impairment was common with 61% of participants falling more than one standard deviation below published norms for at least one cognitive test. Fewer than 1% of participants had insufficient plasma folate < 5 ng/ml or vitamin B12 < 148 pmol/L. However, 44.6% had plasma B6 concentrations < 30 nmol/L. At follow-up, processing speed and memory scores were modestly but significantly better in the B-vitamin supplement group than in controls (p≤0.05). There was no interaction between baseline tHcy, B-vitamin status and treatment on the cognitive outcomes.
Conclusions: High-dose B-vitamin supplementation provided modest cognitive benefit for kidney transplant recipients with elevated baseline tHcy. Since nearly all participants were folate and vitamin B12 sufficient at baseline, the potential cognitive benefits of folate and B12 supplementation in individuals with poor B-vitamin status remains to be determined.
T.M. Scott ; G. Rogers ; D.E. Weiner ; K. Livingston ; J. Selhub ; P.F. Jacques ; I.H. Rosenberg ; A.M. Troen ; for the FACT Study Investigators (2017): B-Vitamin Therapy for Kidney Transplant Recipients Lowers Homocysteine and Improves Selective Cognitive Outcomes in the Randomized FAVORIT Ancillary Cognitive Trial. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.15
THE ROSAS COHORT: A PROSPECTIVE, LONGITUDINAL STUDY OF BIOMARKERS FOR ALZHEIMER’S DISEASE. STRATEGY, METHODS AND INITIAL RESULTS
A. de Mauléon, M. Soto, V. Kiyasova, J. Delrieu, I. Guignot, S. Galtier, M. Lilamand, C. Cantet, F. Lala, N. Sastre, S. Andrieu, M. Pueyo, P.J. Ousset, B. Vellas
J Prev Alz Dis 2017;4(3):183-193Show summaryHide summary
Objective: The aims of the Research Of biomarkers in Alzheimer’s diseaSe (ROSAS) study were to determine the biofluid and imaging biomarkers permitting an early diagnosis of Alzheimer’s disease and better characterisation of cognitive and behavioural course of the pathology. This paper outlines the overall strategy, methodology of the study, baseline characteristics of the population and first longitudinal results from the ROSAS cohort.
Methods: Longitudinal prospective monocentric observational study performed at the Alzheimer’s disease Research centre in Toulouse. A total of 387 patients were studied and analyzed in 3 groups: 184 patients with dementia of Alzheimer’s type, 96 patients with memory disorders without dementia (Mild Cognitive Impairment) and 107 patients without abnormal memory tests (control group), and were followed up during 4 years. Patient’s sociodemographic characteristics, risk factors, medical conditions, previous and current medications, neuropsychological assessment and overall cognitive status were recorded. Blood and urine samples were collected at every year, Magnetic Resonance Imaging were performed at inclusion, after one year of follow-up and at the end of the study.
Results: At baseline, three different groups of the cohort differed interestingly in age, level of education, and in percentage of ApoEε4 carriers whereas the history of cardiovascular and endocrine pathologies were similar among the groups. During the follow-up period (3-4 years) 42 mild cognitive impairment patients (43.8%) progressed to dementia, 7 controls progressed into mild cognitive impairment and 1 patient in the control group converted from mild cognitive impairment group to dementia of Alzheimer’s type group. During the first year of follow up, the incidence of progression from mild cognitive impairment to dementia of Alzheimer’s type was 12.7 per 100, during the second year 33.9 per 100 and 46.7 per 100 for the third year.
Conclusion: This paper presents the baseline characteristics of the unique French prospective monocenter study in which the natural course of dementia of Alzheimer’s type was evaluated. Future analysis of blood and urine samples collection from the ROSAS study will permit to identify possible biofluid biomarkers predicting the early stages of the dementia of Alzheimer’s type and risk of progression from Mild Cognitive Impairment to Alzheimer’s disease.
A. de Mauléon ; M. Soto ; V. Kiyasova ; J. Delrieu ; I. Guignot ; S. Galtier ; M. Lilamand ; C. Cantet ; F. Lala ; N. Sastre ; S. Andrieu ; M. Pueyo ; P.J. Ousset ; B. Vellas (2017): The ROSAS Cohort: A Prospective, Longitudinal Study of Biomarkers for Alzheimer’s Disease. Strategy, Methods and Initial Results. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.8
OBJECTIVE COGNITIVE IMPAIRMENT AND PROGRESSION TO DEMENTIA IN WOMEN: THE PROSPECTIVE EPIDEMIOLOGICAL RISK FACTOR STUDY
J. Skov Neergaard, K. Dragsbæk, C. Christiansen, M. Asser Karsdal, S. Brix, K. Henriksen
J Prev Alz Dis 2017;4(3):194-200Show summaryHide summary
Background: Identification of subjects with a progressive disease phenotype is an urgent need in the pharmaceutical industry where most of the recent clinical trials in Alzheimer’s disease have failed.
Objectives: The objective of this study was to identify subgroups of individuals with objective cognitive impairment (OCI), who were most likely to progress to dementia and to identify the risk factors associated with progression.
Design: Prospective cohort study.
Participants: 5,380 elderly women from Denmark.
Measurements: The Short Blessed Test and a category fluency test with animal naming, was used to assess cognitive function, and to classify them into different groups of OCI.
Results: OCI was identified in 852 subjects at baseline. The risk of dementia was elevated for OCI subjects as compared to subjects with normal cognition (HR 1.46[1.19-1.79]). The courses of OCI were studied in a sub-cohort who completed the cognitive assessment at both the baseline and the follow-up visit (n = 1,933). Of these subjects 203 had OCI at baseline. The multi-domain subtypes of OCI were associated with progressive OCI. Subjects most likely to progress were older, physically inactive, had a higher level of total cholesterol (>6.5 mmol/L) and had a history of depression as compared to subjects with a non-progressive course of OCI.
Conclusions: In this cohort we identified a risk profile associated with progression from OCI in older women. The degree of impairment at baseline was an important predictor of conversion to dementia, additionally several modifiable risk factors were associated with progression.
J. Skov Neergaard ; K. Dragsbæk ; C. Christiansen ; M. Asser Karsdal ; S. Brix ; K. Henriksen (2017): Objective Cognitive Impairment and Progression to Dementia in Women: The Prospective Epidemiological Risk Factor Study. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.4
EVALUATION OF THE NEUROPROTECTIVE POTENTIAL OF N-ACETYLCYSTEINE FOR PREVENTION AND TREATMENT OF COGNITIVE AGING AND DEMENTIA
Y. Hara, N. McKeehan, P.A. Dacks, H.M. Fillit
J Prev Alz Dis 2017;4(3):201-206Show summaryHide summary
Alzheimer’s disease is a progressive neurodegenerative disease for which there is no cure and only a few treatments providing little relief. Increased oxidative stress that is associated with aging is strongly implicated in the pathogenesis and progression of Alzheimer’s disease. Studies have shown that levels of the endogenous antioxidant glutathione decline at an early stage of Alzheimer’s disease with decreased levels correlating with worse cognitive functions. N-acetylcysteine, a drug also widely available as a dietary supplement, is a precursor of L-cysteine, which in turn is a component of glutathione. Because cysteine availability is a limiting factor for glutathione synthesis, treatment with N-acetylcysteine may increase glutathione levels and thereby counter oxidative stress, promote redox -regulated cell signaling, and improve immune responses. In this review, we evaluate the existing literature and the potential of N-acetylcysteine in promoting cognitive health and alleviating cognitive decline associated with dementia. Discussion will also include possible mechanisms of action of N-acetylcysteine, its effects on aging biology, and safety of long-term use. Based on the available literature, a nutraceutical formulation containing N-acetylcysteine among other compounds has shown some pro-cognitive benefits in Alzheimer’s patients and older adults, but the evidence for N-acetylcysteine alone is less robust. Although N-acetylcysteine crosses the blood-brain-barrier, low bioavailability is an obstacle. One promising avenue of research may be to explore derivatives of N-acetylcysteine such as N-acetylcysteine amide, which has been reported in preclinical studies to have higher permeability through cellular and mitochondrial membranes with increased central nervous system bioavailability compared to N-acetylcysteine.
Y. Hara ; N. McKeehan ; P.A. Dacks ; H.M. Fillit (2017): Evaluation of the Neuroprotective Potential of N-Acetylcysteine for Prevention and Treatment of Cognitive Aging and Dementia. The Journal of Prevention of Alzheimer’s Disease (JPAD). http://dx.doi.org/10.14283/jpad.2017.22