Volume 15, Number 3, November 2008

Pages 351-355
Olli Tenovuo, Nina Kemppainen, Sargo Aalto, Kjell Någren, Juha O.Rinne
Posterior Cortical Atrophy: A Rare Form of Dementia with in vivo Evidence of Amyloid-β Accumulation
Abstract: Posterior cortical atrophy (PCA) is a rare form of degenerative dementia, which is characterized by progressive atrophy of occipital and parietal cortical areas. It usually manifests as increasing difficulties of visuoperceptive abilities. Later on, memory and other cognitive functions are involved. Various pathologies have been associated with clinical PCA presentation, but most of the patients with autopsy have had Alzheimer-type pathology. Thus, PCA has been considered to be a rare form of Alzheimer-type dementia with unusual pathological distribution. Here we describe a patient who had a typical clinical course for this syndrome and who showed a positive accumulation of amyloid-β in posterior areas studied with positron emission tomography.

Pages 357-372
Davide Vito Moretti, Michela Pievani, Claudia Fracassi, Cristina Geroldi, Marco Calabria, Charles S. De Carli, Paolo Maria Rossini, Giovanni Battista Frisoni
Brain Vascular Damage of Cholinergic Pathways and EEG Markers in Mild Cognitive Impairment
Abstract: We evaluated changes of brain rhythmicity correlating with the cerebrovascular damage of long-range (capsular tract) and short-range (medial and perisylvian tracts) cholinergic pathways in subjects with mild cognitive impairment (MCI). Ninety-four MCI subjects underwent electroencephalographic (EEG) recordings and magnetic resonance imaging (MRI). The EEG relative power spectrum was computed in delta, theta, alpha1, alpha2, alpah3, beta1, beta2, gamma frequency bands. White matter hyperintensities along each cholinergic tract was segmented on MRI. Three MCI subgroups were identified based on increasing damage. A significant increase of delta and theta power band was found in patients with the highest total cholinergic burden as well as in patients with highest capsular pathway damage; total load of cholinergic damage was also associated with decreased gamma power band. Alpha frequency was differentially affected: decrease of alpha3 power band was associated with the greatest damage of the capsular pathway whereas increase of alpha3 power band was associated with the greatest damage of the perisylvian pathway. Multiple regression linear analysis showed independent association of cholinergic damage with delta, theta and gamma frequency, not with alpha frequency. In conclusion, the damage of long-range and short range cholinergic tracts has possible different implications for cognitive functions in MCI subjects.

Pages 373-374
Commentary
   J. Wesson Ashford
   Integration of EEG and Brain Imaging: Advancing the Understanding of Neuro-Cognitive Dysfunction

Pages 375-390
Sozos Ch. Papasozomenos and Harry Papasozomenos
The Activation of Heat Shock Transcription Factor 1 is Differentially Regulated in the Brain of Estrogen- and Testosterone-Treated Heat-Shocked Rats
Abstract: One hundred and fifteen rats were ovariectomized, given daily injections of 10 μg of 17β-estradiol 3-benzoate (EB), 250 μg of testosterone propionate (TP), or 10 μg of EB + 250 μg of TP in sesame oil (SO) or SO alone for 1, 1.5 and 2 mo, and heat shocked at 42°C for 15 min. Immediately after heat shock, the increase in inducibly hyperphosphorylated heat shock transcription factor 1 (pHSF1) was highest in TP-treated and least in EB-treated rats. Heat shock transcription factor 1 (HSF1) also accumulated in the nuclei of neurons in TP-treated and exit the nuclei in EB-treated rats. While the subnuclear distribution of HSF1 was uniform and similar in control and heat-shocked EB-treated rats, it localized predominantly on euchromatin in heat-shocked TP-treated rats. An antibody, which preferentially recognized pHSF1, stained almost exclusively cell nuclei and demonstrated irregularly-shaped and round neuronal nuclei of heat-shocked TP- and EB-treated rats, respectively. Concomitantly, synthesis of the inducible heat shock protein Hsp70 was lowest in EB- and highest in TP-treated rats. In this model, testosterone prevents the heat shock-induced hyperphosphorylation of tau.  Because HSF1 delays aging, its enhanced activation by testosterone strengthens the argument for a therapeutic role of androgens in Alzheimer’s disease.

Pages 391-396
Ian Macreadie, Mehrnoush Lotfi-Miri, Sameera Mohotti, Deborah Shapira, Louise Bennett, Jose Varghese
Validation of Folate in a Convenient Yeast Assay Suited for Identification of Inhibitors of Alzheimer’s Amyloid-β Aggregation
Abstract: Previously in the search for chemopreventatives for Alzheimer’s disease (AD), microbial cells with amyloid-β (Aβ) protein fusions have been used to screen for compounds that reduce the aggregation, misfolding or oligomerization due to Aβ. In the current study, such a system has been used to look at the effect of folate, whose deficiency has been associated with AD. A folate-deficient yeast strain producing Aβ fused to green fluorescent protein (GFP) that spontaneously misfolds/aggregates and suppresses green fluorescence was used to examine the effects of folinic acid on Aβ-GFP fluorescence. At levels that did not affect growth or plasmid stability, increasing levels of folinic acid led to increasing green fluorescence, suggesting folate can assist with preventing Aβ-misfolding/aggregation. This result supports a protective role for folate and suggests that yeast assays may provide significant new approaches for testing of AD chemopreventatives.

Pages 397-407
Xu Zhao, G. William Rebeck, Hyang-Sook Hoe, Peter M. Andrews
Tarenflurbil Protection from Cytotoxicity is Associated with an Upregulation of Neurotrophins
Abstract: Both epidemiological and clinical trial data have demonstrated the value of some non-steroidal anti-inflammatory drugs (NSAIDs) and NSAID derivatives for lowering the incidence, slowing the progression, and reducing the symptomatic severity of Alzheimer’s disease (AD). Tarenflurbil (R-flurbiprofen, MPC-7869, Myriad Pharmaceuticals) is an attractive compound because its usage is not associated with the adverse side effects of NSAIDs. Although tarenflurbil has been reported to be a selective amyloid-β 42 (Aβ42)-lowering agent, the concentrations of drug that achieved an IC50 for Aβ42-lowering activity are approximately two orders of magnitude higher than the concentrations found in the brain (i.e., 1-5 μM). Therefore, the mechanism by which this compound accomplishes behavioral/physiological effects requires further study. The present investigation reports that clinically relevant concentrations of tarenflurbil (i.e., 1-5 μM) protect both cultured human neuroblastoma cell lines and primary neurons from cytotoxicity associated with exposure to Aβ42 or H2O2. In concert with this protection, there is an upregulation of neurotrophins [i.e., nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)]. Furthermore, blocking exogenous NGF or BDNF by binding it to antibody prevents tarenflurbil from protecting human neuronal cells from Aβ42 and H2O2 cytotoxicity. These findings suggest that up-regulation of neurotrophins might represent an underlying mechanism contributing to the beneficial effects seen with tarenflurbil in AD.

Pages 409-417
Simona Vuletic, Ge Li, Elaine R. Peskind, Hal Kennedy, Santica M. Marcovina, James B. Leverenz, Eric Petrie, Virginia M-Y. Lee, Douglas Galasko, Gerard D. Schellenberg, John J. Albers
Apolipoprotein E Highly Correlates with AβPP- and Tau-Related Markers in Human Cerebrospinal Fluid
Abstract: We assessed cerebrospinal fluid (CSF) levels of apolipoprotein E (apoE), phospholipid transfer protein (PLTP) activity, cholesterol, secreted amyloid-β protein precursor α and β (sAβPPα, sAβPPβ), amyloid-β peptides 1-40 (Aβ40) and 1-42 (Aβ42), total tau and tau phosphorylated at threonine 181 (pTau) in neurologically healthy, cognitively intact adults. ApoE significantly correlated with sAβPPα (r=0.679), sAβPPβ (r=0.634), Aβ40 (r=0.609), total and pTau (r=0.589 and r=0.673, respectively, all p<0.001), PLTP activity (r=0.242, p=0.002) and cholesterol (r=0.194, p<0.01). PLTP activity significantly correlated with sAβPPα (r=0.292), sAβPPβ (r=0.281), total and pTau (r=0.265 and 0.258, respectively; all p≤0.001). Using partial correlations of CSF biomarkers with apoE, PLTP activity, age and gender, apoE remained significantly correlated with sAβPPα, sAβPPβ, Aβ40, total and pTau (p<0.001). The presence of apoE ε2 was associated with lower levels of apoE, PLTP activity and Aβ42, while APOE ε4 had no significant impact on any of the measured variables. Our data suggest that there is a significant physiological link between apoE and AβPP, as well as between apoE and tau in neurologically healthy, cognitively intact individuals.

Pages 419-427
N. Kyle Steenland, Courtney M. Auman, Purvi M. Patel, Scott M. Bartell, Felicia C. Goldstein, Allan I. Levey, James J. Lah
Development of a Rapid Screening Instrument for Mild Cognitive Impairment and Undiagnosed Dementia
Abstract: Mild cognitive impairment (MCI) often presages development of Alzheimer’s disease (AD). We recently completed a cross-sectional study to test the hypothesis that a combination of a brief cognitive screening instrument (Mini-Cog) with a functional scale (Functional Activities Questionnaire; FAQ) would accurately identify individuals with MCI and undiagnosed dementia. The Mini-Cog consists of a clock drawing task and 3-item recall, and takes less than 5 minutes to administer. The FAQ is a 30-item questionnaire completed by an informant. In addition to the Mini-Cog and FAQ, a traditional cognitive test battery was administered, and two neurologists and a neuropsychologist determined a consensus diagnosis of Normal, MCI, or Dementia. A classification tree algorithm was used to pick optimal cutpoints, and, using these cutpoints, the combined Mini-Cog and FAQ (MC-FAQ) predicted the consensus diagnosis with an accuracy of 83% and a weighted kappa of 0.81. When the population was divided into Normal and Abnormal, the sensitivity, specificity and positive predictive value were 89%, 90%, and 95%, respectively. The MC-FAQ discriminates individuals with MCI from cognitively normal individuals and those with dementia, and its ease of administration makes it an attractive screening instrument to aid detection of cognitive impairment in the elderly.

Pages 429-441
James A. Joseph, Anna Neuman, Donna F. Bielinski, and Derek R. Fisher
Blueberry Antagonism of C-2 Ceramide Disruption of Ca2+ Responses and Recovery in MAChR-Transfected COS-7 Cells
Abstract: Research indicates that muscarinic receptors (MAChRs) may show selective declines in sensitivity during aging and Alzheimer’s disease (AD), and these decrements may be related to oxidative stress sensitivity. M1AChR - transfected COS-7 cells exhibit greater decrements in Ca2+ buffering following oxotremorine-induced depolarization than M3 cells. This loss, induced via dopamine (DA) or amyloid-β (Aβ), is similar to those reported in many studies with respect to aging and AD, but were antagonized by blueberry (BB) treatment. However, they may be exacerbated by ceramide which shows considerable increases in AD and aging. Thus, the effects of DA, Aβ42 and/or BB were assessed on calcium parameters (e.g., calcium buffering) in the presence or absence of ceramide in M1 and M3 transfected cells. Results indicated that while ceramide did not produce profound deficits in calcium buffering, in either M1- or M3-transfected COS-7 cells, decrements were seen in the ability of M1- and M3-transfected cells to initially respond to oxotremorine, regardless of DA or Aβ42 exposure. BB pre-treatment (prior to ceramide) antagonized the ceramide treatment in M1-transfected cells but not M3-transfected cells, where ceramide suppressed BB effects. Results are discussed in terms of the effects on lipid induced changes in plasma membranes.

Pages 443-450
Jiang Dong, J. David Robertson, William R. Markesbery, Mark A. Lovell
Serum Zinc in the Progression of Alzheimer’s Disease
Abstract: Previous studies show significantly decreased levels of zinc transporter 1 (ZnT-1) in the brain of subjects with mild cognitive impairment (MCI) but significantly increased ZnT-1 in late stage AD (LAD). However, the reason for the apparent dichotomy is unclear. Based on in vivo studies that show animals provided a zinc (Zn) deficient diet demonstrate decreased brain ZnT-1, we used inductively coupled plasma-mass spectrometry (ICP-MS) to quantify serum Zn levels from 18 living mild to moderate AD patients (9 men, 9 women), 19 MCI patients (9 men, 10 women) and 16 age-matched normal control (NC) subjects (9 men, 7 women). Zinc levels for all subjects were not significantly different between any of the three subject groups. However, there was a statistically significant decrease of serum Zn (11.7 ± 0.5 μM) in men with MCI compared to women with MCI (13.7 ± 0.6 µM) and NC men (13.9 ± 0.6 µM). Serum Zn levels in probable AD patients were comparable to those in NC subjects. Overall, these data suggest a significant decrease of serum Zn in men with MCI, may explain the loss of ZnT-1 observed in previous studies and suggest there may be more pronounced sex differences in MCI than were previously recognized.

Pages 451-460
Christoph Laske, Konstantinos Stellos, Elke Stransky, Peter Seizer, Özlem Akcay, Gerhard W. Eschweiler, Thomas Leyhe, Meinrad Gawaz (Communicated by Milan Fiala)
Decreased Plasma and Cerebrospinal Fluid Levels of Stem Cell Factor in Patients with Early Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is characterized by massive neuronal cell loss in the brain. Stem cell factor (SCF) is a hematopoietic growth factor (HGF) that promotes neuroprotective effects and supports neurogenesis in the brain. In the present study, we found significantly lower SCF plasma levels in 30 early AD patients (908.5 ± 181.7 pg/ml) in comparison with 30 age-matched healthy controls (1058.3 ± 221.5 pg/ml; p=0.006). SCF plasma levels in AD patients showed a significant inverse correlation with dementia severity as measured by ADAS-Cog (r=-0.289; p=0.037). AD patients showed significantly lower SCF levels in cerebrospinal fluid (CSF) (131.60 ± 43.03 pg/ml) in comparison with 15 age- and gender-matched patients with other non-inflammatory neurological disease (NIND) (166.03 ± 42.5 pg/ml; p=0.017). In addition, we found significant positive correlations between SCF and CXCL12 (also known as SDF-1) plasma levels in healthy controls (r=0.341; p=0.008) and between SCF and CXCL12 CSF levels in AD patients (r=0.487; p<0.001). In conclusion, decreased SCF plasma and CSF levels in early AD patients may contribute to a deficient hematopoietic brain support with putative pathogenic and clinical relevance. Further studies are needed to examine whether a manipulation of HGFs such as SCF could be a promising new therapeutic strategy for AD.

Pages 461-464
Donald J. Connor and Marwan N. Sabbagh
Administration and Scoring Variance on the ADAS-Cog
Abstract: The Alzheimer’s Disease Assessment Scale – Cognitive (ADAS-Cog) is the most commonly used primary outcome instrument in clinical trials for treatments of dementia. Variations in forms, administration procedures and scoring rules, along with rater turnover and intra-rater drift may decrease the reliability of the instrument. A survey of possible variations in the ADAS-Cog was administered to 26 volunteer raters at a clinical trials meeting. Results indicate notable protocol variations in the forms used, administration procedures, and scoring rules. Since change over time is used to determine treatment effect in clinical trials, standardizing the instrument’s ambiguities and addressing common problems will greatly increase the instrument’s reliability and thereby enhance its sensitivity to treatment effects.

Pages 465-472
Frederick P. Bellinger, Qing-Ping He, Miyoko T. Bellinger, Yanling Lin, Arjun V. Raman, Lon R. White, Marla J. Berry
Association of Selenoprotein P with Alzheimer’s Pathology in Human Cortex
Abstract: Selenium is known for its antioxidant properties, making selenoproteins candidate molecules for mitigation of neurological disorders in which oxidative stress has been implicated. The selenium transport protein, selenoprotein P, is essential for neuronal survival and function. We sought to determine whether selenoprotein P expression is associated with Alzheimer’s disease pathology. We examined postmortem tissue from individuals with the hallmark lesions of Alzheimer’s disease and individuals without these lesions. Selenoprotein P immunoreactivity was co-localized with amyloid-β plaques and neurofibrillary tangles. Dense-core and other non-diffuse amyloid-β plaques were nearly always associated with selenoprotein P immunopositive cells. Analysis of spatial distribution showed a significant association between amyloid-β plaques and selenoprotein P. Numerous cells also exhibited immunoreactivity to selenoprotein P and intraneuronal neurofibrillary tangles. Confocal microscopy confirmed co-localization of amyloid-β protein and selenoprotein P. These findings suggest an association of selenoprotein P with Alzheimer’s pathology.

Pages 473-493
Chandrashekhar D. Kamat, Sunyana Gadal, Molina Mhatre, Kelly S. Williamson, Quentin N. Pye, Kenneth Hensley
Antioxidants in Central Nervous System Diseases: Preclinical Promise and Translational Challenges
Abstract: Oxidative damage is strongly implicated in the pathogenesis of neurodegenerative diseases including Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease and stroke (brain ischemia/reperfusion injury). The availability of transgenic and toxin-inducible models of these conditions has facilitated the preclinical evaluation of putative antioxidant agents ranging from prototypic natural antioxidants such as vitamin E (a-tocopherol) to sophisticated synthetic free radical traps and catalytic oxidants. Literature review shows that antioxidant therapies have enjoyed general success in preclinical studies across disparate animal models, but little benefit in human intervention studies or clinical trials. Recent high-profile failures of vitamin E trials in Parkinson’s disease, and nitrone therapies in stroke, have diminished enthusiasm to pursue antioxidant neuroprotectants in the clinic. The translational disappointment of antioxidants likely arises from a combination of factors including failure to understand the drug candidate’s mechanism of action in relationship to human disease, and failure to conduct preclinical studies using concentration and time parameters relevant to the clinical setting. This review discusses the rationale for using antioxidants in the prophylaxis or mitigation of human neurodiseases, with a critical discussion regarding ways in which future preclinical studies may be adjusted to offer more predictive value in selecting agents for translation into human trials.

Pages 495-504
Review Article
Jeremy Koppel and Peter Davies
Targeting the Endocannabinoid System in Alzheimer’s Disease
Abstract: The endocannabinoid system is rapidly emerging as a potential drug target for a variety of immune-mediated central nervous system diseases. There is a growing body of evidence suggesting that endocannabinoid interventions may have particular relevance to Alzheimer's disease. Here we present a review of endocannabinoid physiology, the evidence that underscores its utility as a potential target for intervention in Alzheimer's disease, and suggest future pathways of research.

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