-
1.
Cortical β-Amyloid in Older Adults Is Associated with Multidomain Interventions with and without Omega 3 Polyunsaturated Fatty Acid Supplementation.
Hooper, C, Coley, N, De Souto Barreto, P, Payoux, P, Salabert, AS, Andrieu, S, Weiner, M, Vellas, B
The journal of prevention of Alzheimer's disease. 2020;(2):128-134
Abstract
Multidomain lifestyle interventions (including combinations of physical exercise, cognitive training and nutritional guidance) are attracting increasing research attention for reducing the risk of Alzheimer's disease (AD). Here we examined for the first time the cross-sectional relationship between cortical β-amyloid (Aβ) and multidomain lifestyle interventions (nutritional and exercise counselling and cognitive training), omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or their combination in 269 participants of the Multidomain Alzheimer Preventive Trial (MAPT). In adjusted multiple linear regression models, compared to the control group (receiving placebo alone), cortical Aβ, measured once during follow-up (mean 512.7 ± 249.6 days post-baseline), was significantly lower in the groups receiving multidomain lifestyle intervention + placebo (mean difference, -0.088, 95 % CI, -0.148,-0.029, p = 0.004) or multidomain lifestyle intervention + n-3 PUFA (-0.100, 95 % CI, -0.160,-0.041, p = 0.001), but there was no difference in the n-3 PUFA supplementation alone group (-0.011, 95 % CI, -0.072,0.051, p = 0.729). Secondary analysis provided mixed results. Our findings suggest that multidomain interventions both with and without n-3 PUFA supplementation might be associated with lower cerebral Aβ. Future trials should investigate if such multidomain lifestyle interventions are causally associated with a reduction or the prevention of the accumulation of cerebral Aβ.
-
2.
Sleep deprivation and cerebrospinal fluid biomarkers for Alzheimer's disease.
Olsson, M, Ärlig, J, Hedner, J, Blennow, K, Zetterberg, H
Sleep. 2018;(5)
Abstract
STUDY OBJECTIVES To investigate the cumulative effect of five consecutive nights of partial sleep deprivation (PSD) on a panel of cerebrospinal fluid (CSF) biomarkers in healthy adults. METHODS A randomized, cross-over study conducted at the University of Gothenburg. The participants (N = 13) were healthy adults (20-40 years of age) with a normal sleeping pattern. The participants underwent a baseline sleep period consisting of five nights with 8 hr spent in bed. A subsequent period with PSD consisted of five nights of maximum 4 hr of sleep per night. Four participants were also subjected to a prolonged period of PSD consisting of eight nights with 4 hr of sleep per night. Sleep was monitored by means of observation, actigraphy, and continuous polysomnographic recordings. CSF samples were collected by routine lumbar puncture after each period. CSF biomarkers included the 38, 40, and 42 amino acid-long Aβ isoforms, total-τ, phospho-τ, orexin, monoamine metabolites (3-methoxy-4-hydroxyphenylglycol, homovanillinic acid, and 5-hydroxyindoleacetic acid), neuron-derived biomarkers (neurofilament light, neuron-specific enolase, and fatty acid-binding protein), and astro- and microglia-derived biomarkers (glial fibrillary acidic protein, S-100B, and YKL-40). RESULTS PSD was associated with a 27 per cent increase in CSF orexin concentrations (p = 0.001). No PSD-related changes in CSF biomarkers for amyloid build-up in the brain, Alzheimer's disease (AD)-type neurodegeneration, or astroglial activation were observed. PSD led to a shortening of time spent in all sleep stages except slow-wave sleep (SWS). CONCLUSION Five to eight consecutive nights of PSD, with preserved SWS, increased CSF orexin but had no effect on CSF biomarkers for amyloid deposition, neuronal injury, and astroglial activation.
-
3.
Safety, tolerability and immunogenicity of an active anti-Aβ40 vaccine (ABvac40) in patients with Alzheimer's disease: a randomised, double-blind, placebo-controlled, phase I trial.
Lacosta, AM, Pascual-Lucas, M, Pesini, P, Casabona, D, Pérez-Grijalba, V, Marcos-Campos, I, Sarasa, L, Canudas, J, Badi, H, Monleón, I, et al
Alzheimer's research & therapy. 2018;(1):12
Abstract
BACKGROUND Immunotherapy targeting the amyloid-β (Aβ) peptide is a promising strategy for the treatment of Alzheimer's disease (AD); however, none of the active or passive vaccines tested have been demonstrated to be effective to date. We have developed the first active vaccine against the C-terminal end of Aβ40, ABvac40, and assessed its safety and tolerability in a phase I clinical trial. METHODS A randomised, double-blind, placebo-controlled, parallel-group, phase I study of ABvac40 was conducted with patients aged 50-85 years with mild to moderate AD. Participants were entered into three separate groups according to time of study entry and were randomly allocated to receive ABvac40 or placebo (overall ratio 2:1). The first group received two half-doses of ABvac40 or placebo, whereas the second and third groups received two and three full doses, respectively. All treatments were administered subcutaneously at 4-week intervals. Patients, carers and investigators were blind to treatment allocation throughout the study. The primary objective was to assess the safety and tolerability of ABvac40 by registering all adverse events (AEs). All patients who received at least one dose of treatment were included in the safety analysis. The secondary objective was to evaluate the immunogenicity of ABvac40 by titration of specific anti-Aβ40 antibodies in plasma. RESULTS Twenty-four patients were randomly allocated: 16 patients to the ABvac40 group and 8 patients to the placebo group. All randomised patients completed the study, therefore the intention-to-treat and safety populations were identical. Overall, 71 AEs affecting 18 patients were recorded: 11 (69%) in the ABvac40 group and 7 (88%) in the placebo group (p = 0.6214). Neither incident vasogenic oedema nor sulcal effusion (amyloid-related imaging abnormalities corresponding to vasogenic oedema and sulcal effusions) nor microhaemorrhages (amyloid-related imaging abnormalities corresponding to microhaemorrhages and hemosiderin deposits) were detected throughout the study period in the ABvac40-treated patients. Eleven of 12 (~92%) individuals receiving three injections of ABvac40 developed specific anti-Aβ40 antibodies. CONCLUSIONS ABvac40 showed a favourable safety and tolerability profile while eliciting a consistent and specific immune response. An ongoing phase II clinical trial is needed to confirm these results and to explore the clinical efficacy of ABvac40. TRIAL REGISTRATION ClinicalTrials.gov, NCT03113812 . Retrospectively registered on 14 April 2017.
-
4.
Pharmacodynamics of atabecestat (JNJ-54861911), an oral BACE1 inhibitor in patients with early Alzheimer's disease: randomized, double-blind, placebo-controlled study.
Timmers, M, Streffer, JR, Russu, A, Tominaga, Y, Shimizu, H, Shiraishi, A, Tatikola, K, Smekens, P, Börjesson-Hanson, A, Andreasen, N, et al
Alzheimer's research & therapy. 2018;(1):85
Abstract
BACKGROUND β-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer's disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia. METHODS In two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6-8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1-40 [Aβ1-40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated. RESULTS In both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1-40 levels from baseline at day 28 in both the 10-mg (67-68%) and 50-mg (87-90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were - 69.37 (- 72.25; - 61.50) and - 92.74 (- 100.08; - 85.39), and for Japanese with preclinical AD, they were - 62.48 (- 78.32; - 46.64) and - 80.81 (- 96.13; - 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60-70% and 90% Aβ1-40 reductions, respectively. The trend of the reduction was similar across the Aβ1-37, Aβ1-38, and Aβ1-42 fragments in both atabecestat dose groups, consistent with Aβ1-40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period. CONCLUSIONS JNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1-40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults. TRIAL REGISTRATION ALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013. ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.
-
5.
Commentary: Fatty acids and Alzheimer's disease: evidence on cognition and cortical β-amyloid from secondary analyses of the Multidomain Alzheimer Preventive Trial.
Hooper, C, Vellas, B
The journal of prevention of Alzheimer's disease. 2018;(3):168-170
-
6.
Cross-Sectional Associations of Total Plasma Homocysteine with Cortical β-Amyloid Independently and as a Function of Omega 3 Polyunsaturated Fatty Acid Status in Older Adults at Risk of Dementia.
Hooper, C, De Souto Barreto, P, Coley, N, Caussé, E, Payoux, P, Salabert, AS, Cesari, M, Andrieu, S, Bowman, GL, Weiner, M, et al
The journal of nutrition, health & aging. 2017;(10):1075-1080
-
-
Free full text
-
Abstract
OBJECTIVES Elevated total plasma homocysteine is a risk factor for Alzheimer's disease (AD) and there is some evidence that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can modulate the effects of homocysteine-lowering B vitamins on AD related pathologies. Hence we investigated the relationship between total plasma homocysteine and cortical β-amyloid (Aβ) in older adults at risk of dementia. The role of erythrocyte membrane n-3 PUFAs (omega 3 index) on this relationship was also explored. DESIGN This is a cross-sectional study using data from the Multidomain Alzheimer Preventive Trial (MAPT); a randomised controlled trial. SETTING French community dwellers aged 70 or over reporting subjective memory complaints, but free from a diagnosis of clinical dementia. PARTICIPANTS Individuals were from the MAPT trial (n = 177) with data on total plasma homocysteine at baseline and cortical Aβ load. MEASUREMENTS Cortical-to-cerebellar standard uptake value ratios were assessed using [18F] florbetapir positron emission tomography (PET). Total baseline plasma homocysteine was measured using an enzymatic cycling assay. Baseline omega 3 index was measured using gas chromatography. Cross-sectional associations were explored using adjusted multiple linear regression models. RESULTS We found that total baseline plasma homocysteine was not significantly associated with cortical Aβ as demonstrated using multiple linear regression models adjusted for age, sex, education, cognitive status, time interval between baseline and PET-scan, omega-3 index, MAPT group allocation and Apolipoprotein E ε4 status (B-coefficient -0.001, 95 % CI: -0.008,0.006, p = 0.838). Exploratory analysis showed that homocysteine was however significantly associated with cortical Aβ in subjects with low baseline omega-3 index (< 4.72 %) after adjustment for Apolipoprotein E ε4 status (B-coefficient 0.041, 95 % CI: 0.017,0.066, p = 0.005, n = 10), but not in subjects with a high baseline omega-3 index (B-coefficient -0.010, 95 % CI: -0.023,0.003, p = 0.132, n = 66). CONCLUSIONS The role of n-3 PUFAs on the relationship between homocysteine and cerebral Aβ warrants further investigation.
-
7.
Effect of simvastatin on CSF Alzheimer disease biomarkers in cognitively normal adults.
Li, G, Mayer, CL, Morelli, D, Millard, SP, Raskind, WH, Petrie, EC, Cherrier, M, Fagan, AM, Raskind, MA, Peskind, ER
Neurology. 2017;(12):1251-1255
-
-
Free full text
-
Abstract
OBJECTIVE To examine potential disease-modifying effects of statin drugs, we conducted a 12-month randomized, placebo-controlled clinical trial of simvastatin in cognitively normal adults using change in CSF Alzheimer disease biomarkers as primary outcome measure. METHODS Participants were 45-64 years old and statin-naive with normal cognition and normal or mildly elevated cholesterol. Forty-six participants completed the 1-year study per protocol (25 in the simvastatin and 21 in the placebo group). Simvastatin was titrated to 40 mg/d. CSF Aβ42, total tau, and p-tau181 were measured at baseline and after 12 months of treatment using the INNO-BIA AlzBio3 assay. We used analysis of covariance to assess differences in biomarker change from baseline between treatment groups, adjusting for age, sex, and APOE ε4 status. RESULTS Changes from baseline did not differ significantly between treatment groups for any CSF biomarker, with p values of 0.53, 0.36, and 0.25 for CSF Aβ42, total tau, and p-tau181, respectively. There was no significant modifying effect of sex, APOE ε4, or baseline high-density lipoprotein or triglycerides on treatment group for any of the biomarkers (all p > 0.18). However, a significant interaction between treatment group and baseline low-density lipoprotein (LDL) was observed for p-tau181 (p = 0.003), where greater decreases from baseline in CSF p-tau181 concentrations were associated with higher baseline LDL level for the simvastatin group. CONCLUSIONS Simvastatin-related reductions in CSF p-tau181 concentrations may be modulated by LDL cholesterol. The potential disease-modifying effects of simvastatin on CSF phospho-tau should be further investigated in persons with hypercholesterolemia.
-
8.
Vitamin D Supplementation Appears to Increase Plasma Aβ40 in Vitamin D Insufficient Older Adults: A Pilot Randomized Controlled Trial.
Miller, BJ, Whisner, CM, Johnston, CS
Journal of Alzheimer's disease : JAD. 2016;(3):843-7
Abstract
Low plasma amyloid-β (Aβ) is linked to Alzheimer's disease. Since vitamin D cleared brain Aβ in vitro, this 8-week trial examined whether vitamin D increased plasma Aβ40. Vitamin D insufficient adults (6/18 M/F; 64.3 ± 10.9 y) were randomized to placebo or vitamin (50,000 IU/week) treatments. The vitamin group experienced greater plasma Aβ40 change than controls, +14.9 ± 12.0 and +12.8 ± 12.8 pg/mL (p = 0.045; effect size, 0.228). Change in Aβ40 for older participants (≥60 y) was +18.3 ± 33.6 and -3.2 ± 44.5 pg/mL for vitamin (n = 4) and placebo (n = 4) groups (effect size, 0.295). Thus, vitamin D may increase plasma Aβ, particularly in older adults, suggesting decreased brain Aβ.
-
9.
CSF tau and tau/Aβ42 predict cognitive decline in Parkinson's disease.
Liu, C, Cholerton, B, Shi, M, Ginghina, C, Cain, KC, Auinger, P, , , Zhang, J
Parkinsonism & related disorders. 2015;(3):271-6
-
-
Free full text
-
Abstract
INTRODUCTION A substantial proportion of patients with Parkinson's disease (PD) have concomitant cognitive dysfunction. Identification of biomarker profiles that predict which PD patients have a greater likelihood for progression of cognitive symptoms is pressingly needed for future treatment and prevention approaches. METHODS Subjects were drawn from the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism (DATATOP) study, a large clinical trial that enrolled initially untreated PD patients. For the current study, Phase One encompassed trial baseline until just prior to levodopa administration (n = 403), and Phase Two spanned the initiation of levodopa treatment until the end of cognitive follow-up (n = 305). Correlations and linear mixed models were performed to determine cross-sectional and longitudinal associations between baseline amyloid β1-42 (Aβ42), total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF) and measures of memory and executive function. Analyses also considered APOE genotype and tremor- vs. rigidity-dominant phenotype. RESULTS No association was found between baseline CSF biomarkers and cognitive test performance during Phase One. However, once levodopa treatment was initiated, higher p-tau and p-tau/Aβ42 predicted subsequent decline on cognitive tasks involving both memory and executive functions. The interactions between biomarkers and cognition decline did not appear to be influenced by levodopa dosage, APOE genotype or motor phenotype. CONCLUSIONS The current study has, for the first time, demonstrated the possible involvement of tau species, whose gene (MAPT) has been consistently linked to the risk of PD by genome-wide association studies, in the progression of cognitive symptoms in PD.
-
10.
Longitudinal assessment of tau and amyloid beta in cerebrospinal fluid of Parkinson disease.
Zhang, J, Mattison, HA, Liu, C, Ginghina, C, Auinger, P, McDermott, MP, Stewart, T, Kang, UJ, , , Cain, KC, et al
Acta neuropathologica. 2013;(5):671-82
-
-
Free full text
-
Abstract
Tau gene has been consistently associated with the risk of Parkinson disease in recent genome wide association studies. In addition, alterations of the levels of total tau, phosphorylated tau [181P], and amyloid beta 1-42 in cerebrospinal fluid have been reported in patients with sporadic Parkinson disease and asymptomatic carriers of leucine-rich repeat kinase 2 mutations, in patterns that clearly differ from those typically described for patients with Alzheimer disease. To further determine the potential roles of these molecules in Parkinson disease pathogenesis and/or in tracking the disease progression, especially at early stages, the current study assessed all three proteins in 403 Parkinson disease patients enrolled in the DATATOP (Deprenyl and tocopherol antioxidative therapy of parkinsonism) placebo-controlled clinical trial, the largest cohort to date with cerebrospinal fluid samples collected longitudinally. These initially drug-naive patients at early disease stages were clinically evaluated, and cerebrospinal fluid was collected at baseline and then at endpoint, defined as the time at which symptomatic anti-Parkinson disease medications were determined to be required. General linear models were used to test for associations between baseline cerebrospinal fluid biomarker levels or their rates of change and changes in the Unified Parkinson Disease Rating Scale (total or part III motor score) over time. Robust associations among candidate markers are readily noted. Baseline levels of amyloid beta were weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores. Baseline phosphorylated tau/total tau and phosphorylated tau/amyloid beta were significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change. While medications (deprenyl and/or tocopherol) did not appear to alter biomarkers appreciably, a weak but significant positive correlation between the rate of change in total tau or total tau/amyloid beta levels and the change of the Unified Parkinson Disease Rating Scale was observed. Notably, these correlations did not appear to be influenced by APOE genotype. These results are one of the very first pieces of evidence suggesting that tau and amyloid beta are critically involved in early Parkinson disease progression, potentially by a different mechanism than that in Alzheimer disease, although their applications as Parkinson disease progression markers will likely require the addition of other proteins.