Current Alzheimer Research (v.13, #12)

Meet Our Associate Editor by George Perry (1311-1311).

Alzheimer's disease (AD) is currently the most common incurable forms of dementia. The number of people affected by this disease is expected to grow rapidly in the next decades due to the present demographic changes. Since the pharmacological treatment of AD is quite costly, researchers try to look for alternative treatments for patients suffering from AD. One of such nonpharmacological approaches is nutritional intervention. The purpose of this minireview is to explore the issue of multi-nutrient intervention in the management of AD with special focus on medical foods and Mediterranean diet. The methods include a method of literature review of available sources, and a method of comparison of different research studies analyzing this topic. The findings of this review study indicate that multi-nutrient intervention seem to bring many benefits for AD patients such as the delay of cognitive decline, non-invasive and less costly treatment or none or fewer side effects. In addition, to minimize the risk of AD, a multi-factorial healthy lifestyle approach should be implemented by people already at their mid-life.

The Anti-Inflammatory Role of Minocycline in Alzheimers Disease by J. Budni, M. L. Garcez, J. de Medeiros, E. Cassaro, T. Bellettini-Santos, F. Mina, J. Quevedo (1319-1329).
Alzheimer's disease (AD) is a neurodegenerative disorder where the main risk factor is age, since its incidence increases dramatically after the age of 60. It is the most common form of dementia, and is accompanied by memory loss and cognitive impairment. Although AD was discovered over a century ago, the only drugs approved by the US Food and Drug Administration for use in its treatment are four cholinesterase inhibitors and memantine. However, these drugs are not fully effective in the treatment of AD. Therefore, the incessant search for new methods of treating AD continues, with the hope of improving both the effectiveness of therapies and the quality of life for patients suffering with AD. Current evidence suggests that the antibiotic minocycline could be a potential therapeutic drug for use in the treatment of AD due to its anti-neuroinflammatory effects. Minocycline is a tetracycline derivative that combines an anti-inflammatory property that is capable of crossing the blood brain barrier with neuroprotective properties that work by limiting inflammation and oxidative stress. Several studies have established the presence of inflammatory markers in the brains of patients suffering with AD, including elevated levels of cytokines/chemokines and microgliosis in damaged regions. Cytokines have been associated with increased tau phosphorylation and decreased levels of synaptophysin, establishing their roles in the cytoskeletal and synaptic alterations that take place in AD. Therefore, pharmacological approaches that allow for the discovery and development of new anti-inflammatory agents such as minocycline will be welcomed in the continuing struggle against AD. Considering these facts, this review will discuss the anti-inflammatory mechanisms underlying the neuroprotective effects of minocycline as a novel therapeutic approach for the treatment of AD.

Drug Development of Small-Molecule Inhibitors of AD-Relevant Kinases as Novel Perspective Multitargeted Approach by V. Tell, I. Hilbrich, M. Holzer, Frank Totzke, Christoph Schachtele, Inna Slynko, Wolfgang Sippl, A. Hilgeroth (1330-1336).
So far monotargeted therapies in Alzheimers disease (AD) led to insufficient results. Slight improvements in the AD symptomatics have been limited to patients in the early stage of the disease. So multitargeting approaches have been started addressing amyloid plaques as preferred primary target structures beside acetylcholine esterase inhibition. Various protein kinases have been discussed to make a contribution to the progression of AD. So protein kinases are promising target structures for a perspective multitargeting. We identified substituted smallmolecule protein kinase inhibitors of the tricyclic benzofuropyridine type which showed partly nanomolar affinities to AD-relevant glycogen synthase kinase (gsk) 3?, extracellular-signal regulated kinase (ERK) 2 and C-Jun-N-terminal kinase (JNK) 3. Substituent-dependent effects on the respective kinase inhibitions are discussed and inhibitor binding modes to those kinases are presented based on enzyme docking studies. Inhibitor effects on the tau protein target structure are shown for first compounds in cellular studies to prove the enzyme conditioned effects.

Serum Insulin Degrading Enzyme Level and Other Factors in Type 2 Diabetic Patients with Mild Cognitive Impairment by Jie Sun, Wenqing Xia, Rongrong Cai, Pin Wang, Rong Huang, Haixia Sun, Sai Tian, Xue Dong, Shaohua Wang (1337-1345).
Background and Aims: Insulin degrading enzyme (IDE) contributes to the degradation processes of insulin and A?. We aimed to investigate the role of IDE in type 2 diabetes patients with mild cognitive impairment (MCI).
Methods: A total of 146 individuals with type 2 diabetes were enrolled and divided into two groups according to the Montreal Cognitive Assessment (MoCA) score. Demographic characteristics, cognitive function and serum IDE level were examined.
Results: There were 75 patients with MCI and 71 patients without MCI. Diabetic patients with MCI had a higher serum level of IDE compared with the control group (p < 0.001). Among patients with MCI, serum IDE level was positively correlated with the MoCA score (r = 0.839; p < 0.001). Correlation analysis demonstrated that IDE was positively correlated with MoCA score (r = 0.815; p < 0.001) but negatively correlated with the Trail Making Test-B (r = ?0.413; p < 0.001), fasting blood-glucose (r = ?0.372; p < 0.001), glycosylated hemoglobin (r = ?0.214; p = 0.015), homeostasis model of assessment for insulin resistance (r = ?0.560; p < 0.001) and the mean amplitude of glycemic excursions (r = ?0.551; p < 0.001) in all subjects. In logistic regression analysis for MCI, IDE (p = 0.010) was an independent variable, after adjusting for age, sex, education, liver function, kidney function, and lipid levels.
Conclusion: This study demonstrated a greater likelihood of MCI with decreasing serum IDE in patients with type 2 diabetes.

Neuroinflammation has emerged as an important cause of cognitive decline during aging and in Alzheimer's disease (AD). Chronic low-grade inflammation is observed in obesity and diabetes, which are important risk factors for AD. Therefore, we examined the markers of inflammation in the brain hippocampal samples of Zucker diabetic fatty (ZDF) rats. Pathway-specific gene expression profiling revealed significant increases in the expression of oxidative stress and inflammatory genes. Western blot analysis further showed the activation of NF-kB, defective CREB phosphorylation, and decreases in the levels of neuroprotective CREB target proteins, including Bcl-2, BDNF, and BIRC3 in the diabetic rat brain samples, all of which are related to AD pathology. As therapies based on glucagon-like peptide-1 (GLP-1) are effective in controlling blood glucose levels in type 2 diabetic patients, we tested the in vivo actions of GLP-1 in the diabetic brain by a 10-wk treatment of ZDF rats with alogliptin, an inhibitor of dipeptidyl peptidase. Alogliptin increased the circulating levels of GLP-1 by 125% and decreased blood glucose in diabetic rats by 59%. Normalization of defective signaling to CREB in the hippocampal samples of treated diabetic rats resulted in the increased expression of CREB targets. Dual actions of GLP-1 in the pancreatic beta cells and in the brain suggest that incretin therapies may reduce cognitive decline in the aging diabetic patients and also have the potential to be used in treating Alzheimer's patients.

The Association Between Alcohol Use and the Progression of Alzheimer's Disease by Devorah Heymann, Yaakov Stern, Stephanie Cosentino, Oksana Tatarina-Nulman, Jhedy N. Dorrejo, Yian Gu (1356-1362).
Objective: To examine the relationship between alcohol, both the amount and type, and cognitive decline in a cohort of Alzheimer's disease (AD) patients.
Methods: A cohort of 360 patients with early AD in New York, Boston, Baltimore and Paris were followed-up biannually for up to 19.28 years. At each visit, the cognitive profile of the patients was assessed using the modified Mini-Mental State Examination (mMMSE), and patients' alcohol intake, including beverage type, was reported by patients' primary caregivers. General estimating equation analysis was used to determine whether baseline alcohol use was associated with the rate of cognitive decline.
Results: Heavy drinkers (8 or more alcoholic drinks/week) had a faster cognitive decline, deteriorating 1.849 more points on their mMMSE score annually compared to abstainers (P = 0.001), or 2.444 more points compared to mild-moderate drinkers (1-7 alcoholic drinks/week) (P = 0.008). There was no significant difference when comparing mild-moderate drinkers to abstainers. Increasing standard drinks of hard liquor, but not beer or wine, was also associated with a faster rate of cognitive decline (? = -0.117 P = 0.001).
Conclusion: Heavy alcohol consumption and more hard liquor are associated with a faster rate of cognitive decline in AD patients, suggesting that they may hasten progression of AD. Our results suggest that alcohol drinking habits might alter the course of AD.

Nanocapsulated Ascorbic Acid in Combating Cerebral Ischemia Reperfusion- Induced Oxidative Injury in Rat Brain by Sibani Sarkar, Abhishek Mukherjee, Snehasikta Swarnakar, Nirmalendu Das (1363-1373).
Recent evidences suggest that cerebral ischemia-reperfusion insult plays significant role in pathogenic diseases like Alzheimer's disease (AD) and other neurodegenerative diseases. Toxic reactive oxygen species (ROS) generated by induced oxidative stress in the episodes of cerebral ischemia-reperfusion (CIR) plays major role in neurodegeneration. As the prime source of ROS generation, neuronal mitochondria, the cellular energy metabolic centre experience severe damage because of CIR-induced oxidative stress. The process of mitochondrial dysfunction is accelerated by CIR that may pave the pathway for neurodegeneration in AD among aged individuals. Prevention of CIR injury may be a shunt in order to minimize the risk of dementia of Alzheimer's type in aged individuals. The use of chemical antioxidants in CIR is not suitable as the blood- brain barrier (BBB) doesn't allow the entry of molecules from blood circulation into the brain. Thus L-ascorbic acid loaded polylactide nanocapsules were prepared and fed orally to assess the role of nanocapsulated ascorbic acid (NAA) against CIR induced oxidative injury in mitochondrial region of rat brains. Mitochondrial injury was assessed by the extent of lipid peroxidation and in situ antioxidant enzyme status. The levels of cytochrome c (cyt c), cyclooxygenase- 2 (COX-2) and iNOS were determined. Results showed that in comparison to free ascorbic acid (AA), NAA exerted better protection to the brain mitochondria by preventing oxidative damage in ROS mediated CIR injury.

Non-Ceruloplasmin Copper Distinguishes A Distinct Subtype of Alzheimer's Disease: A Study of EEG-Derived Brain Activity by Franca Tecchio, Fabrizio Vecchio, Mariacarla Ventriglia, Camillo Porcaro, Francesca Miraglia, Mariacristina Siotto, Paolo M. Rossini, Mauro Rongioletti, Rosanna Squitti (1374-1384).
Background: Meta-analyses show that percentages of non-Cp-Cu—copper that is not bound to ceruloplasmin (also known as 'free' copper)—in serum are higher in Alzheimer's disease (AD) patients. Genetic heterogeneity in AD patients stratified on the basis of non-Cp-Cu cut-off sustains the existence of a copper AD metabolic subtype. Non-Cp-Cu abnormalities correlated with alterations of electroencephalographic rhythms (EEG).
Objective: We aimed to determine whether an EEG-derived brain cortical rhythm's heterogeneity between two AD groups stratified on the basis of a copper marker.
Method: We assessed levels of copper, ceruloplasmin, Non-Cp-Cu, and the APOE4 genotype in 67 AD patients and compared resting EEG-derived eLORETA cortical rhythms between AD groups stratified in terms of 'Normal' and 'High' non-Cp-Cu.
Results: The High non-Cp-Cu group experienced a lower power in all bands (0.2-48 Hz) in the parietal cortices (p=0.019) and a more limited alpha band (8-13 Hz) power in the sensory lobes (temporal, occipital, and parietal p<0.05 consistently) than the Normal non-Cp-Cu AD group. When corrected for MMSE, the non-Cp-Cu levels correlated with a reduction of high-frequency brain activity (from high alpha to gamma, 10.5-48 Hz).
Conclusion: This neurophysiological heterogeneity in EEG-derived brain cortical rhythms between the two AD groups sustains a copper AD metabolic subtype; Non-Cp-Cu is a marker of this copper AD.

Background: Alzheimer's disease (AD) is the most prevalent neurodegenerative disease throughout the world. Most of the clinical symptoms of AD appear at a very later stage, therefore, the identification of disease markers is essential which can help proper detection of AD at an earlier stage and slow down its progression. Studies have implicated that epigenetic biomarkers, such as DNA methylation, histone modification and non coding RNA mediated regulation serve crucial roles in several disease progression including AD.
Objective: The aim of our study was to identify the topologically significant AD-related proteins from experimentally validated human protein-protein interaction database, HPRD (interactome) and find out novel epigenetic biomarkers.
Method: In this computational work, we constructed AD specific diseasome from AD genelist and interactome. Using this diseasome we screened the interactome with the help of novel parameters namely degree band and similarity index and identified AD related proteins. Regulatory network involving AD related proteins, not previously known to be associated with AD was constructed. Several network motifs and epigenetic modification patterns of regulators of these motifs were studied.
Result: Our study identified computationally predicted 22 epigenetic genes and 11 epigenetic miRs, not previously known to be associated with AD, from the network motifs. Most of these genes and miRs show brain specific expression. Further study on the epigenetic modification patterns of these regulators regarding histone modification, CpG island and lncRNAs strengthened their association in AD.
Conclusion: Computationally predicted genes and miRs identified in our study might provide insight into new epigenetic AD therapeutic targets.

Lack of Association between Genetic Polymorphism of Circadian Genes (PER2, PER3, CLOCK and OX2R) with Late Onset Depression and Alzheimer's Disease in a Sample of a Brazilian Population (Circadian Genes, Late-Onset Depression and Alzheimer's Disease) by Patricia Ara&#250;jo Pereira, Ant&#243;nio Alvim-Soares, Maria Aparecida Camargos Bicalho, Edgar Nunes de Moraes, Leandro Malloy-Diniz, Jonas Jardim de Paula, Marco Aur&#233;lio Romano-Silva, Debora Marques Miranda (1397-1406).
Objectives: This study aims to evaluate the association between polymorphisms in circadian genes and Alzheimer's disease (AD) and/or late-onset depression (LOD). AD pathology leads to circadian disturbances, with clear negative influence on quality of life. In addition, there is an increasing evidence that regulators of circadian system have effects on AD and LOD pathology.
Design and Subjects: An exploratory case-control study designed to evaluate SNPs in the PER2, PER3, CLOCK and OX2R genes in a sample composed by 249 AD, 222 LOD and 112 healthy individuals.
Measures: The participants were evaluated using DSM-IV criteria for LOD and NINCDS-ADRDA for AD.
Results: In allelic analysis, the OX2R SNP, rs2134294, showed an association of allele C with LOD (p =0.02, OR= 1.6) and AD (p=0.04, OR =1.5). The rs2134294 also showed a genotypic association C/C (p =0.01) for higher risk to develop LOD compared to the control group, with an odd's ratio of 2.7. The rs9370399 (OX2R) has also shown an association between A allele (p=0.03, OR= 1.4) and AD. These results do not persist after a 1,000 permutations test. For other markers of the OX2R gene and for all other markers of this study no association was found.
Conclusion: In conclusion, the present study found that the investigated Circadian Genes (PER2, PER3, CLOCK and OX2R) polymorphisms were not associated with LOD or AD.

MCI Patients in Europe: Medication and Comorbidities. The DESCRIPA Study by Magda Tsolaki, Vasileios Papaliagkas, Giovanni Frisoni, Roy Jones, Jacques Touchon, Luiza Spiru, Bruno Vellas, Frans Verhey, Bengt Winblad, Pieter Jelle Visser, on behalf of the DESCRIPA Study Group (1407-1413).
Objectives: The main objective of the present study was to investigate the prevalence and type of medication taken by MCI patients in the DECRIPA cohort. A secondary objective was to assess the cognitive function of these patients and the relationship between the results of neuropsychometric tests and medication use.
Materials and Methods: We selected 880 subjects (375 males, 505 females) who were older than 55 years without obvious causes of cognitive impairment. A complete history was obtained for all patients. In addition, demographical data were collected and several factors were studied, including the types and dosages of the medications taken. Comparisons between groups were statistically analyzed in relation to the number of medications.
Results: Most patients (85.7%, n=754) were taking at least one medication during the study period. The median (interquartile range-IQ) number of medications per participant was 3 (1-5), whereas 40% of the patients took at least 4 medications. The types of medications that were most often taken were cardiovascular drugs (62.0%), antidepressants (16.8%), sedatives (14.6%), thyroid drugs (10.0%) and anti-diabetic drugs (7.6%).
Conclusion: On average, MCI patients take three medications for the prevention or treatment of an average of two medical conditions. The most prevalent types of medications were cardiovascular drugs, antidepressants, sedatives and thyroid drugs. Significant differences in the number of medications taken were observed for gender and age.

Are Raw Scores on Memory Tests Better than Age- and Education- Adjusted Scores for Predicting Progression from Amnesic Mild Cognitive Impairment to Alzheimer Disease ? by Davide Quaranta, Guido Gainotti, Maria Gabriella Vita, Giordano Lacidogna, Eugenia Scaricamazza, Chiara Piccininni, Camillo Marra (1414-1420).
In this prospective longitudinal study, conducted in a large sample of amnestic MCI patients over a three-year period, we investigated the recently advanced proposal that unadjusted test scores obtained at baseline on long-term memory tests are more reliable than age- and education-corrected scores in predicting progression from aMCI to AD. Our experimental sample consisted of 270 aMCI patients who underwent extensive neurological and neuropsychological examinations both at baseline and at the follow-up, conducted at least 3 years later. At the follow-up 80 patients had converted to overt dementia. The predictive capacity of raw, age-corrected, education-corrected and fully corrected scores on RAVLT immediate and delayed recall was compared by examining the area under the ROC curves (AUCs) of all of these scores to assess which (raw or corrected) scores achieves the better reliability in predicting conversion to dementia. The condition (aMCI stable vs converted) was analyzed to assess the odds ratios resulting from a logistic regression on the corrected and uncorrected scores of RAVLT immediate and delayed recall. Even if both in immediate and in delayed recall the ROCs of 'raw scores' were generally higher than the other ROCs on corrected scores, these differences did not reach the level of statistical significance, failing to support the claim that unadjusted test scores are superior to age- and education-corrected scores in predicting progression from aMCI to AD.