Volume 14, Number 1, May 2008

Pages 1-16
Marisol Espinoza, Rohan de Silva, Dennis W. Dickson, Peter Davies
Differential Incorporation of Tau Isoforms in Alzheimer’s Disease
Abstract: There are 6 different isoforms of tau expressed in the adult human brain, and little information is available on the cellular distribution of the isoforms. Tau inclusions are found in neurons and occasionally glia in a variety of diseases. Previous studies conducted on brain homogenates suggested that tau isoforms might be differentially incorporated into inclusions. To further elucidate the complex issue of tau isoform composition in Alzheimer’s disease (AD) and other neurodegenerative diseases, monoclonal antibodies that differentiate between tau containing residues encoded by exon 10 (4R tau) and tau lacking exon 10 residues (3R tau) were used in single and double labeling immunohistochemistry as well as biochemical analyses of tau isolated from AD and other neurodegenerative diseases. Immunohistochemical analysis of the hippocampus in 34 AD cases performed with these antibodies showed both 3R and 4R tau isoforms in tangles. While biochemical studies showed that both isoforms were present in insoluble tau aggregates in AD hippocampus and cortex, not all tangles appear to be labeled with the 3R and 4R tau specific monoclonal antibodies. Similar studies in progressive supranuclear palsy and Pick’s disease confirmed that these diseases were characterized by incorporation of specific isoforms in fibrillar lesions, but lesions in neither disease were exclusively composed of 3R tau or 4R tau isoforms.

Pages 17-25
Sara Friederike Gloeckner, Felix Meyne, Fabian Wagner, Uta Heinemann, Anna Krasnianski, Bettina Meissner, Inga Zerr
Quantitative analysis of transthyretin, tau and amyloid-β in patients with dementia
Abstract: We carried out a quantitative analysis of transthyretin (TTR), total tau protein and amyloid-β (Aβ) peptide (1-40 and 1-42) in the lumbar cerebrospinal fluid of 106 patients with different forms of dementia including Alzheimer’s disease (AD), Creutzfeldt-Jakob-disease (CJD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and normal pressure hydrocephalus (NPH) in comparison to healthy controls. Our study revealed that Aβ1-42 levels were decreased in all patients irrespective of dementia type. Tau protein levels were abnormal in all degenerative dementia except of NPH. Tau levels did not allow differential diagnosis of dementia type except for CJD, where we observed extremely high CSF levels. In other dementia types, levels were elevated in a similar range. Transthyretin levels were selectively decreased in AD and NPH, thus revealing the potential of this protein to be used as additional biomarker in the neurochemical differential diagnosis of AD. A significant negative correlation of TTR CSF levels and disease severity in AD was observed.

Pages 27-41
John P. Cogswell, James Ward, Ian A. Taylor, Michelle Waters, Yunling Shi, Brian Cannon, Kevin Kelnar, Jon Kemppainen, David Brown, Caifu Chen, Rab K. Prinjha, Jill C. Richardson, Ann M. Saunders, Allen D. Roses, Cynthia A. Richards
Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways
Abstract: MicroRNAs have essential functional roles in brain development and neuronal specification but their roles in neurodegenerative diseases such as Alzheimer’s disease (AD) is unknown. Using a sensitive qRT-PCR platform we identified regional and stage-specific deregulation of miRNA expression in AD patient brains. We used experimental validation in addition to literature to reveal how the deregulated brain microRNAs are biomarkers for known and novel pathways in AD pathogenesis related to amyloid processing, neurogenesis, insulin resistance, and innate immunity. We additionally recovered miRNAs from cerebrospinal fluid and discovered AD-specific miRNA changes consistent with their role as potential biomarkers of disease.

Supplementary Data for Cogswell et al. article.

Pages 43-50
Beatriz Marcos, Mónica García-Alloza, Francisco J. Gil-Bea, Tsu T. Chuang, Paul T. Francis, Christopher P. Chen, Shirley W.T.Y. Tsang, Mitchell K.P. Lai,  María J. Ramirez (Communicated by Edna Grunblatt)
Involvement of an altered 5-HT6 receptor function in behavioral symptoms of Alzheimer’s disease
Abstract: We studied the hypothesis that disturbances in 5-HT6 receptor function in the temporal cortex may contribute to clinical symptoms of Alzheimer’s disease (AD). 5-HT6 density and 5-HT levels were significantly decreased in a cohort of AD patients prospectively assessed for cognitive/behavioral symptoms. cAMP formation after stimulation with the selective 5-HT6 receptor agonist E-6801 was significantly lower (p<0.01) in AD (170.02±27.53 pmol/mg prot.) compared to controls (823.33±196.67). In addition, the ratio cAMP formation after stimulation with E-6801/5-HT6 receptor density was significantly lower (p<0.01) in AD (6.67±0.83) compared to controls (16.67±3.33). Splitting these results by sex, 5-HT6 receptor activation was significantly lower (p<0.01) in AD females compared to males (121.67±30.02 vs. 231.67±34.17 pmol/mg prot). 5-HT6 density and 5-HT levels were significantly correlated (p≤0.01) in both controls and AD patients, although in AD, this correlation was lost in females. Psychosis factor was the best predictor of reduced 5-HT levels or adenylate cyclase activity after E-6801 stimulation, the former result being due to females. It may be suggested that psychotic symptoms may be related to a dysregulation of 5-HT6 activation by 5-HT in the temporal cortex. These results are discussed in terms of purported influence of sex and therapeutical approaches to psychosis in AD.

Pages 51-57
Sanna-Kaisa Herukka, Corina Pennanen, Hilkka Soininen, Tuula Pirttilä (Communicated by Francesco Panza)
CSF Aβ42, Tau and Phosphorylated Tau Correlate with Medial Temporal Lobe Atrophy
Abstract: Cerebrospinal fluid (CSF) biomarkers and medial temporal lobe (MTL) atrophy predict the progression of mild cognitive impairment (MCI) to Alzheimer's disease (AD). We investigated the association between the CSF biomarkers and MTL atrophy and the ability of these measures to predict AD in MCI patients in the same study population. The study included 21 MCI patients of whom eight progressed to AD during the study. CSF biomarkers were measured by using ELISA method and volumes of MTL structures were assessed by magnetic resonance imaging (MRI). Aβ42 levels were lower and tau and phospho-tau levels were higher in progressive subjects. The progressive subjects had lower volumes in all MRI measures. Tau and phospho-tau correlated inversely with hippocampal volumes and left entorhinal cortex volume in the whole study group. In the stable group, tau correlated with hippocampal volumes. Aβ42 had a negative correlation whereas phospho-tau exhibited a positive correlation with left hippocampal volume in the progressive group. These results indicate that both measures may reflect the ongoing neurodegenerative process in the progressive MCI patients. However, the order of the changes in the CSF biomarkers and MTL atrophy remain unclear due to a small number of studied subjects and study design.

Pages 59-67
Manuel Menendez-Gonzalez*, Patricia Castro*, Ana Suarez, María Teresa Calatayud, Pablo Perez-Pinera, Marta Martinez, Renee Ribacoba, Carmen Gutierrez (*contributed equally to this paper)
Value of measuring plasmatic levels of neurosin in the diagnosis of Alzheimer’s disease
Abstract: The search for molecular biomarkers that allow the diagnosis and classification of dementias is becoming a high priority need. Neurosin (Kallikrein 6, hk6) is one molecule with promising preliminary results since its levels in brain tissue, cerebrospinal fluid and blood have been found to be abnormal in Alzheimer’s disease (AD). In this study, we measured plasmatic levels of neurosin levels in healthy individuals and patients with cognitive symptoms independently of what the final diagnosis was. We collected plasma samples from 228 controls and 447 patients finally diagnosed with either AD, Mild Cognitive Impairment, Dementia with Lewy Bodies or Parkinson-Dementia, Frontotemporal Dementia, Huntington’s disease, Primary Progressive Aphasia, Corticobasal degeneration, Creutzfeldt-Jakob’s disease and Pseudodementia. Plasmatic levels of neurosin increase with age in healthy individuals and decrease in patients with AD. Plasmatic levels of neurosin differ significantly between AD and Vascular Dementia, Pseudodementia and the control group. Analysis comparing any other form of neurodegenerative dementia to the AD group did not show significant differences. Measurement of plasmatic levels of neurosin is useful to distinguish AD patients from subjects without neurodegenerative dementia (either Pseudodementia, Vascular Dementia or controls) although it is not useful to distinguish among neurodegenerative dementias.

Pages 69-84
Maire Percy, Sharon Moalem, Angeles Garcia, Martin J. Somerville, Mark Hicks, David Andrews, Azar Azad, Peter Schwarz, Reza Beheshti Zavareh, Rivka Birkan, Clara Choo, Vinca Chow, Sandeep Dhaliwal, Anthony L. Kupferschmidt, Kyla Lam, Deborah Lightman, Karolina Machalek, Wanna Mar, Frank Nguyen, Piotr J. Rytwinski, Erin Svara, Maithy Tran, Lisa Yeung, Katherine Zanibbi, Rebecca Zener, Melissa Ziraldo, Morris Freedman (Communicated by James Connor)
Involvement of ApoE E4 and H63D in Sporadic Alzheimer Disease in a Folate-Supplemented Ontario Population
Abstract: Dysregulation of iron homeostasis is implicated in Alzheimer disease (AD). In this pilot study, common variants of the apolipoprotein E (APOE) and HFE genes resulting in the iron overload disorder of hereditary hemochromatosis (C282Y, H63D and S65C) were evaluated as factors in sporadic AD in an Ontario sample in which folic acid fortification has been mandatory since 1998. Laboratory studies also were done to search for genetic effects on blood markers of iron status, red cell folates and serum B12. Participants included 58 healthy volunteers (25 males, 33 females) and 54 patients with probable AD (20 males, 34 females). Statistical analyses were interpreted at the 95% confidence level. Contingency table and odds ratio analyses supported the hypothesis that in females of the given age range, E4 significantly predisposed to AD in the presence but not absence of H63D. In males, E4 significantly predisposed to AD in the absence of H63D, and H63D in the absence of E4 appeared protective against AD. Among E4+ AD patients, H63D was associated with significant lowering of red cell folate concentration, possibly as the result of excessive oxidative stress. However, folate levels in the lowest population quartile did not affect the risk of AD. A model is presented to explain the experimental findings.

Pages 85-93
Milena Erić Jovičić, Miroljub Popović, Katica Jovanova Nešić, Natalija Popović, Svetlana Jovičić Pavlović, Ljubisav Rakić (Communicated by Thomas Shea)
Aging, aluminum and basal forebrain lesions modify substrate kinetics of erythrocyte membrane Na, K-ATPase in the rat
Abstract: Several studies suggested that the activity of erythrocyte Na, K-ATPase declines with aging. Here, it is postulated that alterations in the substrate kinetics of the erythrocyte membrane Na, K-ATPase could be more aggravated in conditions of brain cholinergic dysfunction seen in Alzheimer's disease than in normal aging. To test this hypothesis, we compared the Na, K-ATPase activity (Vmax/Km parameters) in aged rats with those in young rats with brain cholinergic dysfunction induced by electrolytic-, kainic acid-lesioned nucleus basalis magnocellularis (NBM) or by intracerebroventricular AlCl3 administration. In the above mentioned groups, Vmax values were significantly lower in comparison to the control animals. Furthermore, Km values were significantly higher in animals with electrolytic-induced NBM lesions, AlCl3 treated rats and aged animals. However, Km was significantly lower in kainic acid-induced NBM lesions compared to the control group. The Na, K-ATPase catalytic efficiency, estimated by the ratio Vm/Km, decreased as followed: young animals > aged animals > kainic acid lesion > electrolityc lesion > AlCl3. Our data suggest that neurodegenerative processes similar to those seen in Alzheimer’s disease affect the sodium/potassium pump functionality which might be detected in peripheral blood erythrocyte membranes.

Pages 95-105
Federica Mafrica and Vincenzo Fodale
Thyroid function, Alzheimer’s Disease and Postoperative Cognitive Dysfunction: A tale of dangerous liaisons?
Abstract: Hypothyroidism and hyperthyroidism are commonly present conditions in adults, leading to neurological symptoms, affecting the central and peripheral nervous system, and to neurocognitive impairment. Several studies investigated a possible association between Alzheimer’s disease (AD) and thyroid dysfunctions. Increasing evidence supports an extensive interrelationship between thyroid hormones and the cholinergic system, which is selectively and early affected in AD. Moreover, thyroid hormones negatively regulate expression of the amyloid-β protein precursor (AβPP), which plays a key role in the development of AD. A condition, the so called euthyroid sick syndrome (ESS), characterized by reduced serum T3 and T4 concentrations without increased serum thyroid stimulation hormone secretion, occurs within hours after major surgery. After surgery, elderly patients often exhibit a transient, reversible state of cognitive alterations. Delirium occurs in 10-26% of general medical patients over 65, and it is associated with a significant increase in morbidity and mortality. Modifications in thyroid hormone functioning may take place as a consequence of psycho-physical stress caused by surgery, and probably as a consequence of reduced conversion of T4 into T3 by the liver engaged in metabolizing anesthetic drugs. Therefore, modifications of thyroid hormones post-surgery, might play a role in the pathogenesis of postoperative cognitive dysfunction.

Pages 107-123
Kurt A. Jellinger (Communicated by Rudy Castellani)
The pathology of "vascular dementia" - a critical update
Abstract: The prevalence, morphology and pathogenesis of vascular dementia (VaD), recently termed vascular cognitive disorder (VCD), are a matter of discussion.VaD is suggested in 8-15% of cognitively impaired aged subjects. Its prevalence in autopsy series ranges from 0.03 to 58% (mean 8-15% in Western series, 22-35% in Japan). Neuropathology shows multifocal and/or diffuse lesions, ranging from lacunes and microinfarcts, often involving subcortical and strategically important brain areas (thalamus, frontobasal, limbic system), white matter lesions and hippocampal sclerosis to multi-infarct encephalopathy and diffuse post-ischemic lesions. They result from systemic, cardiac and local large and small vessel disease. Pathogenesis is multifactorial and pathophysiology affects neuronal networks involved in cognition, behavior, execution and memory. Vascular lesions often coexist with Alzheimer disease (AD) and other pathologies. Minor vascular lesions hardly contribute to cognitive decline in full-blown AD, while both mild Alzheimer pathology and small vessel disease interact synergistically. AD pathology is less severe in the presence of vascular lesions. The lesion pattern in "pure" VaD/VCD) related to microangiopathies differs from that in "mixed dementia" (AD + vascular encephalopathy), often associated with large infarcts, suggesting different pathogenesis. Due to the heterogeneity of cerebrovascular pathology and its causative factors, no validated neuropathologic criteria for VaD are currently available, and a large variability across laboratories still exists in morphologic examination procedures and techniques. Further prospective clinico-pathologic studies are needed to validate diagnostic criteria for VaD and to clarify the impact of vascular lesions on cognitive impairment.