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Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells.
Janitschke, D, Lauer, AA, Bachmann, CM, Seyfried, M, Grimm, HS, Hartmann, T, Grimm, MOW
International journal of molecular sciences. 2020;(23)
Abstract
Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer's disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines-caffeine, theophylline and theobromine-and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class.
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Comparing the efficacy and safety of Crocus sativus L. with memantine in patients with moderate to severe Alzheimer's disease: a double-blind randomized clinical trial.
Farokhnia, M, Shafiee Sabet, M, Iranpour, N, Gougol, A, Yekehtaz, H, Alimardani, R, Farsad, F, Kamalipour, M, Akhondzadeh, S
Human psychopharmacology. 2014;(4):351-9
Abstract
OBJECTIVES Limited pharmacological options are available for the management of Alzheimer's disease (AD) in severe stages. Cognitive-enhancing properties of saffron, the dried stigma of Crocus sativus L., have been evidenced in different studies. We aimed to compare the efficacy and safety of saffron extract versus memantine in reducing cognitive deterioration of patients with moderate to severe AD. METHODS In this randomized double-blind parallel-group study, 68 patients with moderate to severe AD (Mini-Mental State Examination score of 8-14) received memantine (20 mg/day) or saffron extract (30 mg/day) capsules for 12 months. Participants were evaluated every month by Severe Cognitive Impairment Rating Scale (SCIRS) and Functional Assessment Staging (FAST) in addition to recording the probable adverse events. RESULTS Both treatment groups showed similar outcomes as demonstrated by insignificant effect for time × treatment interaction on SCIRS scores [F(2.95, 194.78) = 2.25, p = 0.08]. There was no significant difference between the two groups in the scores changes from baseline to the endpoint on SCIRS (p = 0.38) and FAST (p = 0.87). The frequency of adverse events was not significantly different between the two groups as well. CONCLUSIONS In addition to its favorable safety profile, 1-year administration of saffron extract capsules showed to be comparable with memantine in reducing cognitive decline in patients with moderate to severe AD. Confirmatory studies with larger sample sizes and longer follow-up periods are warranted.
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Binary classification of ¹⁸F-flutemetamol PET using machine learning: comparison with visual reads and structural MRI.
Vandenberghe, R, Nelissen, N, Salmon, E, Ivanoiu, A, Hasselbalch, S, Andersen, A, Korner, A, Minthon, L, Brooks, DJ, Van Laere, K, et al
NeuroImage. 2013;:517-25
Abstract
(18)F-flutemetamol is a positron emission tomography (PET) tracer for in vivo amyloid imaging. The ability to classify amyloid scans in a binary manner as 'normal' versus 'Alzheimer-like', is of high clinical relevance. We evaluated whether a supervised machine learning technique, support vector machines (SVM), can replicate the assignments made by visual readers blind to the clinical diagnosis, which image components have highest diagnostic value according to SVM and how (18)F-flutemetamol-based classification using SVM relates to structural MRI-based classification using SVM within the same subjects. By means of SVM with a linear kernel, we analyzed (18)F-flutemetamol scans and volumetric MRI scans from 72 cases from the (18)F-flutemetamol phase 2 study (27 clinically probable Alzheimer's disease (AD), 20 amnestic mild cognitive impairment (MCI), 25 controls). In a leave-one-out approach, we trained the (18)F-flutemetamol based classifier by means of the visual reads and tested whether the classifier was able to reproduce the assignment based on visual reads and which voxels had the highest feature weights. The (18)F-flutemetamol based classifier was able to replicate the assignments obtained by visual reads with 100% accuracy. The voxels with highest feature weights were in the striatum, precuneus, cingulate and middle frontal gyrus. Second, to determine concordance between the gray matter volume- and the (18)F-flutemetamol-based classification, we trained the classifier with the clinical diagnosis as gold standard. Overall sensitivity of the (18)F-flutemetamol- and the gray matter volume-based classifiers were identical (85.2%), albeit with discordant classification in three cases. Specificity of the (18)F-flutemetamol based classifier was 92% compared to 68% for MRI. In the MCI group, the (18)F-flutemetamol based classifier distinguished more reliably between converters and non-converters than the gray matter-based classifier. The visual read-based binary classification of (18)F-flutemetamol scans can be replicated using SVM. In this sample the specificity of (18)F-flutemetamol based SVM for distinguishing AD from controls is higher than that of gray matter volume-based SVM.
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Comparison of non-vertebral fracture between minodronate and risedronate therapy in elderly female patients with Alzheimer disease.
Sato, Y, Honda, Y, Iwamoto, J, Amano, N
Journal of musculoskeletal & neuronal interactions. 2013;(3):346-52
Abstract
OBJECTIVES Minodronate is a nitrogen-containing bisphosphonate that is commercially available for the treatment of osteoporosis in Japan. Preclinical studies demonstrated that minodronate is at least 10 times more potent than alendronate in inhibiting bone resorption in vivo. A high incidence of fractures, particularly of the hip, represents an important problem in Alzheimer disease (AD) patients who are prone to falls and may have osteoporosis. METHODS A total of 256 elderly patients with AD were assigned to daily treatment with 1.0 mg of minodronate or a daily treatment with risedronate combined with daily 1000 IU ergocalciferol and 1200 mg elemental calcium, and followed up for 12 months. RESULTS At baseline, patients of both groups showed low 25-hydroxyvitamin D with compensatory hyperparathyroidism. Non-vertebral fractures occurred in 5 patients in the minodronate group and 7 patients in the risedronate group (5 hip fractures; one fracture each at the distal forearm and pelvis). There was no difference in risk of hip fracture between the two groups (p=.70; odds ratio=0.8). CONCLUSIONS The study medications were well tolerated with relatively few adverse events and were equivalent in reducing the risk of a fracture in elderly patients with AD.
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Validity, significance, strengths, limitations, and evidentiary value of real-world clinical data for combination therapy in Alzheimer's disease: comparison of efficacy and effectiveness studies.
Atri, A, Rountree, SD, Lopez, OL, Doody, RS
Neuro-degenerative diseases. 2012;(1-4):170-4
Abstract
BACKGROUND Randomized controlled efficacy trials (RCTs), the scientific gold standard, are required for regulatory approval of Alzheimer's disease (AD) interventions, yet provide limited information regarding real-world therapeutic effectiveness. OBJECTIVE To compare the nature of evidence regarding the combination of approved AD treatments from RCTs versus long-term observational controlled studies (LTOCs). METHODS Comparisons of strengths, limitations, and evidence level for monotherapy [cholinesterase inhibitor (ChEI) or memantine] and combination therapy (ChEI + memantine) in RCTs versus LTOCs. RESULTS RCTs examined highly selected populations over months. LTOCs collected data across multiple AD stages in large populations over many years. RCTs and LTOCs show similar patterns favoring combination over monotherapy over placebo/no treatment. Long-term combination therapy compared to monotherapy reduced cognitive and functional decline and delayed time to nursing home admission. Persistent treatment was associated with slower decline. While LTOCs used control groups, adjusted for multiple covariates, had higher external validity, and favorable ethical, practical and cost considerations, their limitations included potential selection bias due to lack of placebo comparisons and randomization. CONCLUSIONS Naturalistic LTOCs provide complementary long-term level II evidence to complement level I evidence from short-term RCTs regarding therapeutic effectiveness in AD that may otherwise be unobtainable. A coordinated strategy/consortium to pool LTOC data from multiple centers to estimate long-term comparative effectiveness, risks/benefits, and costs of AD treatments is needed.
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Efficacy of rivastigmine in comparison to ginkgo for treating Alzheimer's dementia.
Nasab, NM, Bahrammi, MA, Nikpour, MR, Rahim, F, Naghibis, SN
JPMA. The Journal of the Pakistan Medical Association. 2012;(7):677-80
Abstract
OBJECTIVES To assess the efficacy of the Ginkgo biloba in patients with dementia of the Alzheimer type in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with rivastigmine. METHODS Total 56 patients aged 50-75 years, suffering from dementia, were allocated into one of the two treatments: group 1) Ginkgo biloba (120 mg daily dose); group 2) rivastigmine (4.5 mg daily dose) in a 24-week randomized double blind study. The degree of severity of dementia was assessed by the Seven Minute test and the Mini-Mental State Examination. RESULTS Our results confirm the clinical efficacy of rivastigmine in the dementia of the Alzheimer type, comparing to Ginkgo biloba. There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia. This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type. CONCLUSION Our study suggests that there are differences in the efficacy of Ginkgo biloba and rivastigmine in the treatment of Alzheimer's dementia. In addition, this study suggested that cholinesterase inhibitors should be used in preference to Ginkgo biloba in patients with mild to moderate AD.
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Increasing walking and bright light exposure to improve sleep in community-dwelling persons with Alzheimer's disease: results of a randomized, controlled trial.
McCurry, SM, Pike, KC, Vitiello, MV, Logsdon, RG, Larson, EB, Teri, L
Journal of the American Geriatrics Society. 2011;(8):1393-402
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Abstract
OBJECTIVES To test the effects of walking, light exposure, and a combination intervention (walking, light, and sleep education) on the sleep of persons with Alzheimer's disease (AD). DESIGN Randomized, controlled trial with blinded assessors. SETTING Independent community living. PARTICIPANTS One hundred thirty-two people with AD and their in-home caregivers. INTERVENTIONS Participants were randomly assigned to one of three active treatments (walking, light, combination treatment) or contact control and received three or six in-home visits. MEASUREMENTS Primary outcomes were participant total wake time based on wrist actigraphy and caregiver ratings of participant sleep quality on the Sleep Disorders Inventory (SDI). Secondary sleep outcomes included additional actigraphic measurements of sleep percentage, number of awakenings, and total sleep time. RESULTS Participants in walking (P=.05), light (P=.04), and combination treatment (P=.01) had significantly greater improvements in total wake time at posttest (effect size 0.51-0.63) than controls but no significant improvement on the SDI. Moderate effect size improvements in actigraphic sleep percentage were also observed in active treatment participants. There were no significant differences between the active treatment groups and no group differences for any sleep outcomes at 6 months. Participants with better adherence (4 d/wk) to walking and light exposure recommendations had significantly less total wake time (P=.006) and better sleep efficiency (P=.005) at posttest than those with poorer adherence. CONCLUSION Walking, light exposure, and their combination are potentially effective treatments for improving sleep in community-dwelling persons with AD, but consistent adherence to treatment recommendations is required.
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Plasma 24S-hydroxycholesterol levels in elderly subjects with late onset Alzheimer's disease or vascular dementia: a case-control study.
Zuliani, G, Donnorso, MP, Bosi, C, Passaro, A, Dalla Nora, E, Zurlo, A, Bonetti, F, Mozzi, AF, Cortese, C
BMC neurology. 2011;:121
Abstract
BACKGROUND In central nervous system cholesterol cannot be degraded but is secreted into circulation predominantly in the form of its polar metabolite 24(S)-hydroxycholesterol (24S-OH-Chol). Some studies suggested an association between 24S-OH-Chol metabolism and different neurological diseases including dementia. A possible decrease in 24S-OH-Chol plasma levels has been reported late onset Alzheimer's disease (LOAD) and vascular dementia (VD), but results of previous studies are partially contradictory. METHODS By high-speed liquid chromatography/tandem mass spectrometry we evaluated the plasma levels of 24S-OH-Chol in a sample of 160 older individuals: 60 patients with LOAD, 35 patients with VD, 25 subjects affected by cognitive impairment no-dementia (CIND), and 40 (144 for genetics study) cognitively normal Controls. We also investigated the possible association between PPARgamma Pro12Ala polymorphism and dementia or 24S-OH-Chol levels. RESULTS Compared with Controls, plasma 24S-OH-Chol levels were higher in LOAD and lower in VD; a slight not-significant increase in CIND was observed (ANOVA p: 0.001). A positive correlation between 24S-OH-Chol/TC ratio and plasma C reactive protein (CRP) levels was found in the whole sample, independent of possible confounders (multiple regression p: 0.04; r2: 0.10). This correlation was strong in LOAD (r: 0.39), still present in CIND (r: 0.20), but was absent in VD patients (r: 0.08). The PPARgamma Pro12Ala polymorphism was not associated with the diagnosis of LOAD, VD, or CIND; no correlation emerged between the Ala allele and 24S-OH-Chol plasma levels. CONCLUSIONS Our results suggest that plasma 24S-OH-Chol levels might be increased in the first stages of LOAD, and this phenomenon might be related with systemic inflammation. The finding of lower 24S-OH-Chol concentrations in VD might be related with a more advanced stage of VD compared with LOAD in our sample, and/or to different pathogenetic mechanisms and evolution of these two forms of dementia.
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Is high homocysteine level a risk factor for cognitive decline in elderly? A systematic review, meta-analysis, and meta-regression.
Ho, RC, Cheung, MW, Fu, E, Win, HH, Zaw, MH, Ng, A, Mak, A
The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry. 2011;(7):607-17
Abstract
OBJECTIVE [corrected] High homocysteine (Hct) has been causatively linked to Alzheimer disease (AD) and vascular dementia (VaD) in old age, but research methodologies and outcome measures are heterogeneous. It remains unclear whether the findings can be generalized across studies. METHODS Random-effects meta-analyses were conducted on studies examining the relationship between Hct level and risk of developing dementia/cognitive decline between comparison groups. Meta-regression identified patient- and trial-related factors, which may contribute to heterogeneity. RESULTS Seventeen relevant studies (6,122 participants; 13 cross-sectional and fourprospective studies) were included. Compared with controls, Hct was significantly elevated in AD (pooled standardized mean difference [SMD]: 0.59; 95% confidence interval [CI]: 0.38-0.80; significant heterogeneity: τ = 0.105) and VaD (pooled SMD: 1.30; 95% CI: 0.75-1.84; significant heterogeneity: τ = 0.378). Meta-regression identified mean age as significant moderator for AD versus controls and mean age and mean folate levels as significant moderators for VaD versus controls. Hct was significantly higher in VaD relative to AD (pooled SMD: 0.48; 95% CI: 0.23-0.73; moderately significant heterogeneity: τ = 0.076); proportion of men and mean folate levels were significant moderators. High-Hct level was not associated with risk of developing dementia in prospective studies (pooled odds ratio: 1.34; 95% CI: 0.94-1.91, nonsignificant heterogeneity: τ = 0.048). CONCLUSION Individuals with AD and VaD have higher Hct levels than controls; however, a causal relationship between high-Hct level and risk of developing dementia is not supported. More prospective studies and randomized controlled trials are required to test the therapeutic benefits of lowering Hct levels.
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Health and nutrition promotion program for patients with dementia (NutriAlz): cluster randomized trial.
Salvà, A, Andrieu, S, Fernandez, E, Schiffrin, EJ, Moulin, J, Decarli, B, Rojano-i-Luque, X, Guigoz, Y, Vellas, B, ,
The journal of nutrition, health & aging. 2011;(10):822-30
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Abstract
OBJECTIVE To assess the effectiveness of health and nutrition program (NutriAlz) versus usual care on functional level in elderly people with dementia living at home, as well as on clinical practice related to nutrition and on the caregiver's burden. DESIGN Cluster randomized multi-centre study with one-year follow-up. SETTING 11 Alzheimer outpatients and day care centres (Barcelona, Spain). PARTICIPANTS Nine hundred and forty six home-living Alzheimer patients with identified caregiver were consecutively recruited (intervention group: 6 centres, 448 patients vs control group: 5 centres, 498 patients). INTERVENTION The intervention was a teaching and training intervention on health and nutrition program, NutriAlz, directed both to physician and main caregiver, as well as persons affected by Alzheimer's disease or other dementias, including a standardised protocol for feeding and nutrition. MAIN OUTCOME MEASURES The main outcome measure was the reduction in the loss of autonomy (Activities of daily living (ADL/IADL) scales) assessed at 6 and 12 months. Secondary outcomes measures were Improvement in nutritional status (Mini Nutritional Assessment (MNA), BMI, and weight changes), and caregiver burden (Zarit scale). RESULTS The one-year assessment was completed for 293 patients (65.4%) in the intervention group and 363 patients (72.9%) in the control group (usual care). The annual rate of ADL change was -0.83 vs -0.62 (p=0.984), and the caregiver's subjective burden 0.59 vs 2.36 (p=0.681) in intervention and control group, respectively. MNA, however, showed an improvement (+0.46 vs -0.66, p=0.028), suggesting an effective nutritional behaviour. CONCLUSION The NutriAlz program had no effect on functional decline in Alzheimer disease patients living at home over one year, but reduced the risk for malnutrition, as recommendations concerning diet and exercise were provided.