Volume 39, Number 2, 2014

Pages 223-225
Editorial
Pravat K. Mandal, Karen Ritchie, Vincenzo Fodale
Anesthetics and its Impact on the Brain and Alzheimer’s Disease

Pages 227-232
Short Communication
José L Molinuevo, Ignacio Casado-Naranjo
Clinical Evolution of Alzheimer’s Disease: Is the Age of the Patient a Decisive Factor? Results of the INFLUENCE Study
Abstract: Epidemiological and clinical studies suggest that dementia patients aged ≥85 years are biologically different from those aged 65–84. This study aimed to assess whether patients (>85 years) have a distinct sociodemographic and clinical profile. Older patients had lower educational achievements, different carer relationships, and were more likely to take memantine/concomitant treatments and be institutionalized. Differences were observed with respect to concomitant disease/other risk factors (depression, dyslipidemia, cardiovascular disease, hypertension). Oldest patients had greater impairment (more severe Global Deterioration Scale stage, lower Mini-Mental State Examination scores). Greater concomitant drug use and younger carers associated with older patients suggest higher management and social costs.

Pages 233-237
Short Communication
Firoozeh Nafar and Karen M. Mearow (Handling Associate Editor: Thomas Shea)
Coconut Oil Attenuates the Effects of Amyloid-β on Cortical Neurons in vitro
Abstract: Dietary supplementation has been studied as an approach to ameliorating deficits associated with aging and neurodegeneration. We undertook this pilot study to investigate the effects of coconut oil supplementation directly on cortical neurons treated with amyloid-β (Aβ) peptide in vitro. Our results indicate that neuron survival in cultures co-treated with coconut oil and Aβ is rescued compared to cultures exposed only to Aβ. Coconut oil co-treatment also attenuates Aβ-induced mitochondrial alterations. The results of this pilot study provide a basis for further investigation of the effects of coconut oil, or its constituents, on neuronal survival focusing on mechanisms that may be involved.

Pages 239-251
Shujun Xu, Guilan Liu, Xiaoming Bao, Jie Wu, Shaomin Li, Bangxu Zheng, Roger Anwyl, Qinwen Wang (Handling Associate Editor: Ling-Qiang Zhu)
Rosiglitazone Prevents Amyloid-β Oligomer-induced Impairment of Synapse Formation and Plasticity via Increasing Dendrite and Spine Mitochondrial Number
Abstract: Rosiglitazone has been known to attenuate neurodegeneration in Alzheimer’s disease (AD), but the underlying mechanisms remain to be fully elucidated. In this study, living-cell image, immunocytochemistry, and electrophysiology were used to examine the effects of soluble amyloid-β protein (Aβ) oligomers and rosiglitazone on the synapse formation, plasticity, and mitochondrial distribution in cultured neurons. Incubation of hippocampal cultures with amyloid-β (Aβ)42 oligomers (0.5 μM) for 3 h significantly decreased dendritic filopodium and synapse density. Pretreatment with rosiglitazone (0.5-5 μM) for 24 h prevented the Aβ42-induced loss of dendritic filopodium and synapse in a dose-dependent manner. However, neither Aβ42 oligomer nor rosiglitazone has a significant effect on the velocity and length of dendritic filopodia. Electrophysiological recording showed that acute exposure of slices with 0.5 μM Aβ42 oligomers impaired hippocampal long-term potentiation (LTP). Pre-incubation of hippocampal slices with rosiglitazone significantly prevented the Aβ42-induced LTP deficit, which depended on rosiglitazone concentrations (1-5 μM) and pretreatment period (1-5 h). The beneficial effects of rosiglitazone were abolished by the peroxisome proliferator-activated receptor gamma (PPARγ) specific antagonist, GW9662. Moreover, the mitochondrial numbers in the dendrite and spine were decreased by Aβ42 oligomers, which can be prevented by rosiglitazone. In conclusion, our data suggested that rosiglitazone prevents Aβ42 oligomers-induced impairment via increasing mitochondrial numbers in the dendrite and spine, improving synapse formation and plasticity. This process is most likely through the PPARγ-dependent pathway and in concentration and time dependent manners. The study provides novel insights into the mechanisms for the protective effects of rosiglitzone on AD.

Pages 253-259
Takehiro Kiko, Kiyotaka Nakagawa, Tsuyoshi Tsuduki, Katsutoshi Furukawa, Hiroyuki Arai, Teruo Miyazawa
MicroRNAs in Plasma and Cerebrospinal Fluid as Potential Markers for Alzheimer’s Disease
Abstract: The development of Alzheimer's disease (AD) biomarkers remains an unmet challenge, and new approaches that can improve current AD biomarker strategies are needed. Recent reports suggested that microRNA (miRNA) profiling of biological fluids has emerged as a diagnostic tool for several pathologic conditions. In this study, we measured six candidate miRNAs (miR-9, miR-29a, miR-29b, miR-34a, miR-125b, and miR-146a) in plasma and cerebrospinal fluid (CSF) of AD and normal subjects by using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) to evaluate their potential usability as AD biomarkers. The qRT-PCR results showed that plasma miR-34a and miR-146a levels, and CSF miR-34a, miR-125b, and miR-146a levels in AD patients were significantly lower than in control subjects. On the other hand, CSF miR-29a and miR-29b levels were significantly higher than in control subjects. Our results provide a possibility that miRNAs detected in plasma and CSF can serve as biomarkers for AD.

Pages 261-269
Po H. Lu, Grace J. Lee, Jill Shapira, Elvira Jimenez, Michelle J. Mather, Paul M. Thompson, George Bartzokis, Mario F. Mendez
Regional Differences in White Matter Breakdown Between Frontotemporal Dementia and Early-Onset Alzheimer’s Disease
Abstract: Background: White matter abnormalities have been associated with both behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD). Objective: Using MRI diffusion tensor imaging (DTI) measures, we compared white matter integrity between patients with bvFTD and those with early-onset AD and correlated these biomarkers with behavioral symptoms involving emotional blunting. Methods: We studied 8 bvFTD and 12 AD patients as well as 12 demographically-matched healthy controls (NCs). Using four DTI metrics (fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity), we assessed the frontal lobes (FWM) and genu of the corpus callosum (GWM), which are vulnerable late-myelinating regions, and a contrasting early-myelinating region (splenium of the corpus callosum). The Scale of Emotional Blunting Scale (SEB) was used to assess emotional functioning of the study participants. Results: Compared to AD patients and NCs, the bvFTD subjects exhibited significantly worse FWM and GWM integrity on all four DTI metrics sensitive to myelin and axonal integrity. In contrast, AD patients showed a numerical trend toward worse splenium of the corpus callosum integrity than bvFTD and NC groups. Significant associations between SEB ratings and GWM DTI measures were demonstrated in the combined bvFTD and AD sample. When examined separately, these relationships remained robust for the bvFTD group but not the AD group. Conclusions: The regional DTI alterations suggest that FTD and AD are each associated with a characteristic distribution of white matter degradation. White matter breakdown in late-myelinating regions was associated with symptoms of emotional blunting, particularly within the bvFTD group.

Pages 271-282
Balwinder Singh, Ajay K Parsaik, Michelle M. Mielke, Patricia J. Erwin, David S. Knopman, Ronald C. Petersen, Rosebud O. Roberts (Handling Associate Editor: Francesco Panza)
Association of Mediterranean Diet with Mild Cognitive Impairment and Alzheimer’s Disease: A Systematic Review and Meta-Analysis
Abstract: Background/Objective: To conduct a systematic review of all studies to determine whether there is an association between the Mediterranean diet (MeDi) and cognitive impairment. Methods: We conducted a comprehensive search of the major databases and hand-searched proceedings of major neurology, psychiatry, and dementia conferences through November 2012. Prospective cohort studies examining the MeDi with longitudinal follow-up of at least 1 year and reporting cognitive outcomes (mild cognitive impairment [MCI] or Alzheimer’s disease [AD]) were included. The effect size was estimated as hazard-ratio (HR) with 95% confidence intervals (CIs) using the random-effects model. Heterogeneity was assessed using Cochran's Q-test and I2-statistic. Results: Out of the 664 studies screened, five studies met eligibility criteria. Higher adherence to the MeDi was associated with reduced risk of MCI and AD. The subjects in the highest MeDi tertile had 33% less risk (adjusted HR=0.67; 95% CI, 0.55-0.81; p<0.0001) of cognitive impairment (MCI or AD) as compared to the lowest MeDi score tertile. Among cognitively normal individuals, higher adherence to the MeDi was associated with a reduced risk of MCI (HR=0.73; 95% CI, 0.56-0.96; p=0.02) and AD (HR=0.63; 95% CI, 0.46-0.88; p=0.007). There was no significant heterogeneity in the analyses. Conclusions: While the overall number of studies is small, pooled results suggest that a higher adherence to the MeDi is associated with a reduced risk of developing MCI and AD, and a reduced risk of progressing from MCI to AD. Further prospective-cohort studies with longer follow-up and randomized controlled trials are warranted to consolidate the evidence.

Pages 283-286
Commentary
Vincenzo Solfrizzi, Francesco Panza
Mediterranean Diet and Cognitive Decline. A Lesson from the Whole-Diet Approach: What Challenges Lie Ahead?
Abstract: Higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micronutrients, and macronutrients already separately proposed as potential protective factors against dementia and predementia syndromes. The findings from prospective studies and very recent systematic reviews and meta-analyses suggested that adherence to the MeDi fulfilling the whole-diet approach may affect not only the risk of Alzheimer’s disease, but also of predementia syndromes and their progression to overt dementia. However, some concerns exist regarding how these instruments have been developed for measuring adherence to the MeDi, suggesting a better qualitative and quantitative selection of the individual dietary components and/or food groups to improve their reliability.

Pages 287-300
Xavier Schmitz, Nathalie Bier, Sven Joubert, Caroline Lejeune, Eric Salmon, Isabelle Rouleau, Thierry Meulemans (Handling Associate Editor: Eva Mª Arroyo-Anllo)
The Benefits of Errorless Learning for Serial Reaction Time Performance in Alzheimer’s Disease
Abstract: Identifying the conditions favoring new procedural skill learning in Alzheimer’s disease (AD) could be important for patients’ autonomy. It has been suggested that error elimination is beneficial during skill learning, but no study has explored the advantage of this method in sequential learning situations. In this study, we examined the acquisition of a 6-element perceptual-motor sequence by AD patients and healthy older adults (control group). We compared the impact of two preliminary sequence learning conditions (Errorless versus Errorful) on Serial Reaction Time performance at two different points in the learning process. A significant difference in reaction times for the learned sequence and a new sequence was observed in both conditions in healthy older participants; in AD patients, the difference was significant only in the errorless condition. The learning effect was greater in the errorless than the errorful condition in both groups. However, while the errorless advantage was found at two different times in the learning process in the AD group, in the control group this advantage was observed only at the halfway point. These results support the hypothesis that errorless learning allows for faster automation of a procedure than errorful learning in both AD and healthy older subjects.

Pages 301-314
Dezhi Yu*, Nichole E. LaPointe*, Elmer Guzman, Veronica Pessino, Leslie Wilson, Stuart C. Feinstein, Megan T. Valentine (Handling Associate Editor: Handling Associate Editor) *These authors contributed equally to this work.
Tau Proteins Harboring Neurodegeneration-Linked Mutations Impair Kinesin Translocation in vitro
Abstract: We tested the hypothesis that mutant tau proteins that cause neurodegeneration and dementia differentially alter kinesin translocation along microtubules (MTs) relative to normal tau in vitro. We employed complementary in vitro motility assays using purified recombinant kinesin, purified recombinant tau, and purified bovine brain α:β tubulin to isolate interactions among these components without any contribution by cellular regulatory mechanisms. We found that kinesin translocates slower along MTs assembled by any of three independent tau mutants (4-repeat P301L tau, 4-repeat ΔN296 tau, and 4-repeat R406W tau) relative to its translocation rate along MTs assembled by normal, 4-repeat wild type (WT) tau. Moreover, the R406W mutation exhibited isoform specific effects; while kinesin translocation along 4-repeat R406W tau assembled MTs is slower than along MTs assembled by 4-repeat WT tau, the R406W mutation had no effect in the 3-repeat tau context. These data provide strong support for the notion that aberrant modulation of kinesin translocation is a component of tau-mediated neuronal cell death and dementia. Finally, we showed that assembling MTs with taxol before coating them with mutant tau obscured effects of the mutant tau that were readily apparent using more physiologically relevant MTs assembled with tau alone, raising important issues regarding the use of taxol as an experimental reagent and novel insights into therapeutic mechanisms of taxol action.

Pages 315-329
Charles Métais, Kathryn Brennan, Alex J. Mably, Michael Scott, Dominic M. Walsh, Caroline E. Herron
Simvastatin Treatment Preserves Synaptic Plasticity in AβPPswe/ PS1dE9 Mice
Abstract: Epidemiological evidence suggests that chronic treatment with simvastatin may protect against the development of Alzheimer’s disease (AD), but as yet it is unclear how this effect is mediated. Extensive data also indicates that the amyloid β-protein (Aβ) plays a central role in the disease process, and it has been suggested that the protective effects of simvastatin may be mediated by reducing Aβ production or by counteracting the toxic effects of Aβ. Accordingly, using the AβPPswe/PS1dE9 mouse model of AD, we investigated the effects of simvastatin on long-term potentiation (LTP), amyloid biology, and two key kinases involved in Aβ-mediated toxicity. Since burgeoning data indicate that both fibrillar and non-fibrillar forms of Aβ play a prominent role in AD pathogenesis, we were careful to investigate the effects of simvastatin on three biochemically distinct pools of Aβ. In untreated AβPPswe/PS1dE9 mice, there was a dramatic and significant increase in the levels of water-soluble Aβ between 6 and 8 months, but this remained constant between 8 and 18 months. In contrast, the concentrations of detergent-soluble and formic acid (FA)-soluble Aβ species increased across all ages examined, thus demonstrating that while amyloid deposition continued, the levels of water-soluble Aβ remained relatively constant. LTP was normal at 6 months, but was significantly impaired at 8 and 18 months. Importantly, a diet supplemented with 0.04% simvastatin for one month (at 7 months) positively affected synaptic plasticity in AβPPswe/PS1dE9 mice and did not significantly alter levels of water-soluble, detergent-soluble, or FA-soluble Aβ, but did increase phosphorylation of both Akt and GSK-3, while tau and tau phosphorylation were unaltered. These results indicate that the protective effects of simvastatin may be mediated by maintaining signaling pathways that help to protect and rescue LTP.

Pages 331-346
Yan-Fang Xian, Qing-Qiu Mao, Justin CY Wu, Zi-Ren Su, Jian-Nan Chen, Xiao-Ping Lai, Siu-Po Ip, Zhi-Xiu Lin
Isorhynchophylline Treatment Improves the Amyloid-β-Induced Cognitive Impairment in Rats via Inhibition of Neuronal Apoptosis and Tau Protein Hyperphosphorylation
Abstract: The progressive accumulation of amyloid-β (Aβ) in the form of senile plaques has been recognized as a key causative factor leading to the cognitive deficits seen in Alzheimer’s disease (AD). Recent evidence indicates that Aβ induces neurotoxicity in the primary neuronal cultures as well as in the brain. Previously, we have demonstrated that isorhynchophylline (IRN), the major chemical ingredient of Uncaria rhynchophylla, possessed potent neuroprotective effects. In the present study, we aimed to investigate the effect of IRN on cognitive function, neuronal apoptosis, and tau protein hyperphosphorylation in the hippocampus of the Aβ25-35-treated rats and to elucidate its action mechanisms. We showed that Aβ25-35 injection caused spatial memory impairment, neuronal apoptosis, and tau protein hyperphosphorylation. Treatment with IRN (20 or 40 mg/kg) for 21 days could significantly ameliorate the cognitive deficits induced by Aβ25-35 in the rats. In addition, IRN attenuated the Aβ25-35-induced neuronal apoptosis in hippocampus by down-regulating the protein and mRNA levels of the ratio of Bcl-2/Bax, cleaved caspase-3 and caspase-9, as well as suppressing the tau protein hyperphosphorylation at the Ser396, Ser404, and Thr205 sites. Mechanistic study showed that IRN could inhibit the glycogen synthase kinase 3β (GSK-3β) activity, and activate the phosphorylation of phosphatidylinositol 3-kinase (PI3K) substrate Akt. These results indicate that down-regulation of GSK-3β activity and activation of PI3K/Akt signaling pathway are intimately involved in the neuroprotection of IRN. The experimental findings provide further evidence to affirm the potential of IRN as a worthy candidate for further development into a therapeutic agent for AD and other tau pathology-related neurodegenerative diseases.

Pages 347-355
Beverly M. Francis, Jimao Yang, Byung Jun Song, Saurabh Gupta, Mary Maj, Richard Bazinet, Brian Robinson, Howard T.J. Mount
Reduced Levels of Mitochondrial Complex I Subunit NDUFB8 and Linked Complex I+III Oxidoreductase Activity in the TgCRND8 Mouse Model of Alzheimer’s Disease
Abstract: Bioenergetic failure is a feature of Alzheimer’s disease (AD). We examined mitochondrial function in the amyloid-β protein precursor transgenic ‘TgCRND8’ mouse model of AD. Activities of NADH: cytochrome c reductase (complex I+III) and cytochrome oxidase (complex IV) of the electron transport chain, as well as those of α-ketoglutarate dehydrogenase (α-KGDH) and pyruvate dehydrogenase (PDH) were assessed in brains of 45 week-old mice. Complex I+III activity was reduced by almost 50%, whereas complex IV, α-KGDH, and PDH activities were unaffected. Reduced activity coincided with decreased expression of NDUFB8, a nuclear-DNA encoded subunit integral to the assembly of complex I. The composition and availability of cardiolipin, a major phospholipid in inner mitochondrial membranes, was not altered. To determine whether mitochondrial output is affected by the selective reduction in complex I+III activity, we examined tissue levels of high-energy phosphates. ATP was maintained whereas creatine increased in the cortex and hippocampus. These results suggest disruption of complex I function and the likely role of creatine in sustaining ATP at late stages of dysfunction in TgCRND8 mice.

Pages 357-370
Carlos A. Ribeiro, Sandra Marisa Oliveira, Luis F. Guido, Ana Magalhães, Gregorio Valencia, Gemma Arsequell, Maria João Saraiva, Isabel Cardoso
Transthyretin Stabilization by Iododiflunisal Promotes Amyloid-β Peptide Clearance, Decreases its Deposition, and Ameliorates Cognitive Deficits in an Alzheimer’s Disease Mouse Model
Abstract: Alzheimer’s disease (AD) is the most common form of dementia and now represents 50-70% of total dementia cases. Over the last two decades, transthyretin (TTR) has been associated with AD and, very recently, a novel concept of TTR stability has been established in vitro as a key factor in TTR/amyloid-β (Aβ) interaction. Small compounds, TTR stabilizers (usually non-steroid anti-inflammatory drugs), bind to the thyroxine (T4) central binding channel, increasing TTR tetrameric stability and TTR/Aβ interaction. In this work, we evaluated in vivo the effects of one of the TTR stabilizers identified as improving TTR/Aβ interaction, iododiflunisal (IDIF), in Aβ deposition and other AD features, using AβPPswe/PS1A246E transgenic mice, either carrying two or just one copy of the TTR gene (AD/TTR+/+ or AD/TTR+/-, respectively), available and characterized in our laboratory. The results showed that IDIF administered orally bound TTR in plasma and stabilized the protein, as assessed by T4 displacement assays, and was able to enter the brain as revealed by mass spectrometry analysis of cerebrospinal fluid. TTR levels, both in plasma and cerebrospinal fluid, were not altered. In AD/TTR+/- mice, IDIF administration resulted not only in decreased brain Aβ levels and deposition but also in improved cognitive function associated with the AD-like neuropathology in this mouse model, although no improvements were detectable in the AD/TTR+/+ animals. Further, in AD/TTR+/- mice, Aβ levels were reduced in plasma suggesting TTR promoted Aβ clearance from the brain and from the periphery. Taken together, these results strengthen the importance of TTR stability in the design of therapeutic drugs, highlighting the capacity of IDIF to be used in AD treatment to prevent and to slow the progression of the disease.

Pages 371-383
Ada H.Y. Lo*, Richard J. Woodman*, Nancy A. Pachana, Gerard J. Byrne, Perminder S. Sachdev (Handling Associate Editor: Maheen Adamson) *These authors contributed equally to the manuscript.
Associations Between Lifestyle and Cognitive Function Over Time in Women Aged 40-79 Years
Abstract: Background: Smoking, excessive drinking, and physical inactivity are associated with reduced cognitive function but the independence, domain specific cognitive effects, and trajectories of these associations are not firmly established. Objective: Our aim was to examine these lifestyle-cognitive function associations in middle-to-older aged women across time. Methods: Cohort study design with repeat surveys (2001, 2005, and 2008). Participants were volunteers from a random sample of Australian women on the Brisbane electoral roll; mean (±SD) age 60±11 years in 2001. Outcome measures were the Mini-Mental State Examination (MMSE), Auditory Delayed Index (ADI), Visual Delayed Index (VDI), Working Memory Index (WMI), and Processing Speed Index (PSI). Results: 489 women completed cognitive testing in 2001, 451 in 2005, and 376 in 2008. Mean (±SD) cognitive scores in 2001 were MMSE: 29.1±1.2, ADI: 104.6±13.4, VDI: 107.2±14.0, WMI: 104.1±12.3, and PSI: 102.7±11.8. Multivariate adjusted mean scores (95% CI) over the 7-year study period were higher for moderate drinkers than non-drinkers for the MMSE (β=0.32; 0.04, 0.61), the VDI (β=4.33; 0.96, 7.70), and the WMI (β=3.21; 0.34,6.07). Current smokers performed worse than never-smokers for the MMSE (β=-0.35; 0.64,-0.06), the VDI (β=-3.91; -7.57,-0.26), the WMI (β=-3.42; -6.67,-0.18), and the PSI (β=-5.89; -8.91,-2.87). PSI was higher in women performing strenuous physical activity compared to inactive women (β=2.14; 0.37, 3.90). None of the three lifestyle parameters influenced the changes in cognition across time. Conclusions: Alcohol and exercise were associated with selective protective effects and tobacco with selective harmful effects on cognitive function in middle-to-older aged women. Associations remained consistent across time.

Pages 385-400
Markus Morawski*, Stephan Schilling*, Moritz Kreuzberger*, Alexander Waniek, Carsten Jäger, Birgit Koch, Holger Cynis, Astrid Kehlen, Thomas Arendt, Maike Hartlage-Rübsamen, Hans-Ulrich Demuth, Steffen Roßner (Handling Associate Editor: Stefan Lichtenthaler) *These authors contributed equal to this manuscript.
Glutaminyl Cyclase in Human Cortex: Correlation with (pGlu)-Amyloid-β Load and Cognitive Decline in Alzheimer’s Disease
Abstract: Brains of Alzheimer’s disease (AD) patients are characterized in part by the formation of high molecular weight aggregates of amyloid-β (Aβ) peptides, which interfere with neuronal function and provoke neuronal cell death. The pyroglutamate (pGlu) modification of Aβ was demonstrated to be catalyzed by the enzyme glutaminyl cyclase (QC) and to enhance pathogenicity and neurotoxicity. Here, we addressed the role of QC in AD pathogenesis in human cortex. Two sets of human postmortem brain tissue from a total of 13 non-demented controls and 11 AD cases were analyzed by immunohistochemistry and unbiased stereology, quantitative RT-PCR, and enzymatic activity assays for the expression level of QC in temporal and entorhinal cortex. Additionally, cortical Aβ and pGlu-Aβ concentrations were quantified by ELISA. Data on QC expression and Aβ peptide concentrations were correlated with each other and with the Mini-Mental State Examination (MMSE) of individual cases. In control cases, QC expression was higher in the more vulnerable entorhinal cortex than in temporal cortex. In AD brains, QC mRNA expression and the immunoreactivity of QC were increased in both cortical regions and frequently associated with pGlu-Aβ deposits. The analyses of individual cases revealed significant correlations between QC mRNA levels and the concentration of insoluble pGlu-Aβ aggregates, but not of unmodified Aβ peptides. Elevated pGlu-Aβ load showed a better correlation with the decline in MMSE than elevated concentration of unmodified Aβ. Our observations provide evidence for an involvement of QC in AD pathogenesis and cognitive decline by QC-catalyzed pGlu-Aβ formation.

Pages 401-408
Flávia Gomes de Melo Coelho, Thays Martins Vital, Angelica Miki Stein, Franciel José Arantes, André Veloso Rueda, Elizabeth Teodorov, Ruth Ferreira Santos-Galduróz
Acute Aerobic Exercise Increases Brain Derived Neurotrophic Factor Levels in Elderly with Alzheimer’s Disease
Abstract: Studies indicate the involvement of brain-derived neurotrophic factor (BDNF) in the pathogenesis of Alzheimer’s disease (AD). Decreased BDNF levels may constitute a lack of trophic support and contribute to cognitive impairment in AD. The benefits of acute and chronic physical exercise on BDNF levels are well-documented in humans, however, exercise effects on BDNF levels have not been analyzed in older adults with AD. The aim of this study was to investigate the effects of acute aerobic exercise on BDNF levels in older adults with AD and to verify associations among BDNF levels, aerobic fitness, and level of physical activity. Using a controlled design, twenty-one patients with AD (76.3 ± 6.2 years) and eighteen health older adults (74.6 ± 4.7 years) completed an acute aerobic exercise. The outcomes included measures of BDNF plasma levels, aerobic fitness (treadmill grade, time to exhaustion, VO2, and maximal lactate) and level of physical activity (Baecke Questionnaire Modified for the Elderly). The independent t-test shows differences between groups with respect to the BDNF plasma levels at baseline (p = 0.04; t = 4.53; df = 37). In two-way ANOVA, a significant effect of time was found (p = 0.001; F = 13.63; df = 37), the aerobic exercise significantly increased BDNF plasma levels in AD patients and healthy controls. A significant correlation (p=0.04; r = 0.33) was found between BDNF levels and the level of physical activity. The results of our study suggest that aerobic exercise increases BDNF plasma levels in patients with AD and healthy controls. In addition to that, BDNF levels had association with level of physical activity.

Pages 409-422
Heidi I.L. Jacobs, Lies Clerx, Ed H.B.M. Gronenschild, Pauline Aalten, Frans R.J. Verhey (Handling Associate Editor: Sebastiaan Engelborghs)
White Matter Hyperintensities are Positively Associated with Cortical Thickness in Alzheimer’s Disease
Abstract: White matter hyperintensities are associated with an increased risk of Alzheimer’s disease (AD). White matter hyperintensities are believed to disconnect brain areas. We examined the topographical association between white matter hyperintensities and cortical thickness in controls, mild cognitive impairment (MCI), and AD patients. We examined associations between white matter hyperintensities and cortical thickness among 18 older cognitively healthy participants, 18 amnestic MCI, and 17 mild AD patients. These associations were cluster-size corrected for multiple comparisons. In controls, a positive association between white matter hyperintensities and cortical thickness was found in lateral temporal gyri. In MCI patients, white matter hyperintensities were positively related to cortical thickness in frontal, temporal, and parietal areas. Positive associations between white matter hyperintensities and cortical thickness in AD patients were confined to parietal areas. The results of the interaction group by white matter hyperintensities on cortical thickness were consistent with the findings of positive associations in the parietal lobe for MCI and AD patients separately. In the frontal areas, controls and AD patients showed inverse associations between white matter hyperintensities and cortical thickness, while MCI patients still showed a positive association. These results suggest that a paradoxical relationship between white matter hyperintensities and cortical thickness could be a consequence of neuroinflammatory processes induced by AD-pathology and white matter hyperintensities. Alternatively, it might reflect a region-specific and disease-stage dependent compensatory hypertrophy in response to a compromised network.

Pages 423-440
Taher Darreh-Shori, Sharokh Makvand Hosseini, Agneta Nordberg
Pharmacodynamics of Cholinesterase Inhibitors Suggests Add-On Therapy with a Low-Dose Carbamylating Inhibitor in Patients on Long-Term Treatment with Rapidly Reversible Inhibitors
Abstract: Despite three decades of intensive research in the field of Alzheimer’s disease (AD) and numerous clinical trials of new therapeutic agents, cholinesterase inhibitors (ChEIs) are still the mainstay of therapeutics for AD and dementia with Lewy bodies. Pharmacodynamic analyses of ChEIs provide paradoxical observations. Treatment with the rapidly reversible, noncarbamylating ChEIs (donepezil, galantamine, and tacrine) increases acetylcholinesterase (AChE) protein expression, whereas the carbamylating agent, rivastigmine, produces sustained inhibition with no significant change in AChE protein expression. Still, the symptomatic clinical efficacies of all these agents are similar. We report here for the first time that treatment with phenserine, another carbamylating ChEI, produces a sustained but mild inhibition of AChE in cerebrospinal fluid (CSF) of AD patients. We also show that phenserine treatment reverses donepezil-induced elevation of AChE expression. Further analyses on CSF of another larger patient cohort treated with donepezil revealed that, in addition to its main mode of action, donepezil produced two other pharmacodynamics with potentially contradictory outcomes. Donepezil-induced AChE expression favored an AChE-driven amyloid-β peptide (Aβ) aggregation, whereas donepezil itself concentration-dependently counteracted the AChE-induced Aβ aggregation, most likely by competing with the Aβ peptides for peripheral anionic site on the AChE protein. The reduction of AChE protein expression in the donepezil-treated patients by concomitant administration of the carbamylating agent, phenserine, could allow the donepezil molecule to only prevent interaction between Aβ and AChE. The current study suggests that an add-on therapy with a low-dose formulation of a carbamylating agent in patients on long-term donepezil treatment should be explored as a strategy for enhancing the clinical efficacy of these agents in dementia disorders.

Pages 441-455
Roxanna Perez-Garmendia, Luis Fernando Hernandez-Zimbron, Miguel Angel Morales, José Luna-Muñoz, Raul Mena, Miriam Nava-Catorce, Gonzalo Acero, Vitaly Vasilevko, Amparo Viramontes-Pintos, David H. Cribbs, Goar Gevorkian
Identification of N-Terminally Truncated Pyroglutamate Amyloid-β in Cholesterol-Enriched Diet-Fed Rabbit and AD Brain
Abstract: The main amyloid-β peptide (Aβ) variants detected in the human brain are Aβ1-40 and Aβ1-42; however, a significant proportion of Aβ in Alzheimer’s disease (AD) brain also consists of N-terminal truncated/modified species. AβN3(pE), Aβ peptide bearing amino-terminal pyroglutamate at position 3, has been demonstrated to be a major N-truncated/modified constituent of intracellular, extracellular, and vascular Aβ deposits in AD and Down syndrome brain tissue. It has been previously demonstrated that rabbits fed a diet enriched in cholesterol and given water containing trace copper levels developed AD-like pathology including intraneuronal and extracellular Aβ accumulation, tau hyperphosphorylation, vascular inflammation, astrocytosis, microgliosis, reduced levels of acetylcholine, as well as learning deficits and thus, may be used as a non-transgenic animal model of sporadic AD. In the present study, we have demonstrated for the first time the presence of AβN3(pE) in blood vessels in cholesterol-enriched diet-fed rabbit brain. In addition, we detected AβN3(pE) immunoreactivity in all postmortem AD brain samples studied. We believe that our results are potentially important for evaluation of novel therapeutic molecules/strategies targeting Aβ peptides in a suitable non-transgenic animal model.

Pages 457-465
Ruben Berrocal, Padmaraju Vasudevaraju, Shantinath Satappa Indi, Krothapalli Raja Surya Sambasiva Rao, Kosagisharaf Rao
In vitro Evidence that an Aqueous Extract of Centella asiatica Modulates α-Synuclein Aggregation Dynamics
Abstract: α-Synuclein aggregation is one of the major etiological factors implicated in Parkinson’s disease (PD). The prevention of aggregation of α-synuclein is a potential therapeutic intervention for preventing PD. The discovery of natural products as alternative drugs to treat PD and related disorders is a current trend. The aqueous extract of Centella asiatica (CA) is traditionally used as a brain tonic and CA is known to improve cognition and memory. There are limited data on the role of CA in modulating amyloid-β (Aβ) levels in the brain and in Aβ aggregation. Our study focuses on CA as a modulator of the α-synuclein aggregation pattern in vitro. Our investigation is focused on: (i) whether the CA leaf aqueous extract prevents the formation of aggregates from monomers (Phase I: α-synuclein + extract co-incubation); (ii) whether the CA aqueous extract prevents the formation of fibrils from oligomers (Phase II: extract added after oligomers formation); and (iii) whether the CA aqueous extract disintegrates the pre-formed fibrils (Phase III: extract added to mature fibrils and incubated for 9 days). The aggregation kinetics are studied using a thioflavin-T assay, circular dichroism, and transmission electron microscopy. The results showed that the CA aqueous extract completely inhibited the α-synuclein aggregation from monomers. Further, CA extract significantly inhibited the formation of oligomer aggregates and favored the disintegration of the preformed fibrils. The study provides an insight in finding new natural product for future PD therapeutics.