Volume 29, Number 1, March 2012

Pages 1-13
Review
Michael J. Passmore, Anita Ho, Romayne Gallagher (Handling Associate Editor: Antonia Pritchard)
Behavioral and Psychological Symptoms in Moderate to Severe Alzheimer’s Disease: A Palliative Care Approach Emphasizing Recognition of Personhood and Preservation of Dignity
Abstract: The assessment and management of behavioral and psychological symptoms of dementia (BPSD) in moderate to severe Alzheimer’s disease (AD) can be challenging, and ethical dilemmas often arise. Clinicians often perceive a disconnect between evidence-based guidelines and the challenges of treating BPSD in moderate to severe AD. Reconciliation of salient ethical issues can help bridge this disconnect. In view of the fact that AD is a progressive and ultimately fatal disease, and given that there are often competing considerations when managing BPSD in moderate to severe AD, we propose a palliative care approach that prioritizes the recognition of personhood and the preservation of dignity. We present case illustrations, discuss the concepts of dignity and personhood during palliative care in AD, and encourage the use of the bioethical grid in navigating complex clinical challenges.

Pages 15-24
Maëlenn Guerchet, Alain M. Mouanga, Pascal M’belesso, André Tabo, Bébène Bandzouzi, Moussiliou N. Paraïso, Dismand S. Houinato, Pascale Cowppli-Bony, Philippe Nubukpo, Victor Aboyans, Jean-Pierre Clément, Jean-François Dartigues, Pierre-Marie Preux
Factors Associated with Dementia Among Elderly People Living in Two Cities in Central Africa: The EDAC Multicenter Study
Abstract: Risk factors for dementia in American and European countries have been well investigated. However, little research has been carried out in sub-Saharan Africa, where life events as well as environmental, socio-economic, and modifiable risk factors (i.e., cardiovascular risk factors) may differ. Two cross-sectional surveys were conducted in representative samples of the older general population living in Bangui (Central African Republic) and Brazzaville (Congo). Dementia was defined according to the DSM-IV criteria. Multivariate regression analyses were performed in order to identify independent factors associated with dementia. Among the 977 elderly Africans included in this analysis, 75 (7.6%) were diagnosed as having dementia. Increasing age, female gender, hypertension, a body mass index <18.5 kg/m², depressive symptoms, and the lack of a primary education were significantly associated with dementia. Among life events, the death of one parent during childhood and recently having moved house were also associated with dementia. Beyond the usual risk factors for dementia, this study highlights the role of stressful events in low-income countries. Factors associated with dementia in African countries seem different from established factors in high-income countries and require further investigation.

Pages 25-37
Francesca Baglio*, Ilaria Castelli*, Margherita Alberoni, Valeria Blasi, Ludovica Griffanti, Andrea Falini, Raffello Nemni, Antonella Marchetti (Handling Associate Editor: Marco Bozzali) *These authors equally contributed to this work.
The Mindreading Ability Through the Eyes in Amnestic Mild Cognitive Impairment: An fMRI Study
Abstract: Theory of Mind (ToM) undergoes changes at the behavioral level in pathological aging (Alzheimer's disease (AD)) and at the neural level in physiological aging. We aim to discover ToM changes in both the behavioral and neural domains in old subjects with high risk of switching from successful to unsuccessful neurocognitive aging. Amnestic mild cognitive impairment (aMCI) syndrome fits this goal, since it was proposed to fill the gap between normal aging and dementia, such as AD. Sixteen aMCI patients (71 years) and fifteen healthy controls (67 years) with no differences in age and education were submitted to increasingly complex ToM tasks and to an fMRI scanning while performing the Reading the Mind in the Eyes test (RME), which attributes mental states by focusing on eye-gaze. aMCI subjects had worse performances in two second order false belief tasks, confirming the decay of ToM on the behavioral level, but did not show significant differences in the behavioral performances to the RME compared to controls, despite a minor activation of some components (posterior end of the superior temporal sulcus and temporal pole) of the ToM neural circuit. Probably the preservation of the mirror neuron system (precentral gyrus-BA 6; Broca area - BA 44) and the stronger involvement of frontal areas (middle and medial frontal cortex and anterior cingulate cortex) supplied the decay of part of the mentalizing neural circuit, preserving task performance.

Pages 39-49
Hadassa M. Jochemsen, Mirjam I. Geerlings, Anne M. Grool, Koen L. Vincken, Willem PTM Mali, Yolanda van der Graaf, Majon Muller, on behalf of the SMART Study Group
Angiotensin-Converting Enzyme and Progression of White Matter Lesions and Brain Atrophy. The SMART-MR Study
Abstract: High levels of angiotensin-converting-enzyme (ACE) may increase the risk of dementia through blood pressure elevation and subsequent development of cerebral small-vessel disease. However, high ACE levels may also decrease this risk through amyloid degradation which prevents brain atrophy. Within the SMART-MR study, a prospective cohort study among patients with symptomatic atherosclerotic disease, serum ACE levels were measured at baseline and a 1.5 Tesla brain MRI was performed at baseline and after on average (range) 3.9 (3.0-5.8) years of follow-up in 682 persons (mean age 58±10 years). Brain segmentation was used to quantify total, deep, and periventricular white matter lesion (WML) volume, and total brain, cortical gray matter and ventricular volume (%ICV). Lacunar infarcts were rated visually. Regression analyses were used to examine the prospective associations between serum ACE and brain measures. Patients with the highest serum ACE levels (>43.3U/L) had borderline significantly more progression of deep WML volumes than patients with the lowest ACE levels (<21.8U/L); mean difference (95%CI) in change was 0.20 (-0.02; 0.43) %ICV. On the contrary, patients with the highest serum ACE levels had significantly less progression of cortical brain atrophy than patients with the lowest ACE levels; mean difference (95%CI) in change was 0.78 (0.21; 1.36) %ICV. Serum ACE was not associated with subcortical atrophy, periventricular WML, or lacunar infarcts. Our results show that higher ACE activity is associated with somewhat more progression of deep WML volume, but with less progression of cortical brain atrophy. This suggests both detrimental and beneficial effects of high ACE levels on the brain.

Pages 51-62
Mathew T. Mizwicki, Danusa Menegaz, Jun Zhang, Antonio Barrientos-Durán, Stephen Tse, John R. Cashman, Patrick R. Griffin, Milan Fiala (Handling Associate Editor: Selma Yilmazer)
Genomic and Nongenomic Signaling Induced by 1α,25(OH)2-Vitamin D3 Promotes the Recovery of Amyloid-β Phagocytosis by Alzheimer’s Disease Macrophages
Abstract: Brain clearance of amyloid-β (Aβ42) by innate immune cells is necessary for maintenance of normal brain function. Phagocytosis of soluble Aβ42 by Alzheimer’s disease (AD) macrophages is defective, recovered in all “Type I and Type II” AD patients by 1α,25(OH)2-vitamin D3 (1,25D3) and blocked by the nuclear vitamin D receptor (VDR) antagonist (23S)-25-dehydro-1α(OH)-vitamin D3-26,23-lactone (MK). Bisdemethoxycurcumin (BDC) is a VDR ligand and additive with 1,25D3 in promoting Aβ42 phagocytosis by Type I, but not by Type II macrophages. Here, we define the following intracellular mechanisms regulated by 1,25D3 that are associated with recovery of phagocytosis and consistent with the selectivity of BDC: 1) 1,25D3 potentiates a 4,4-diisothiocyanostilbene-2,2-disulfonic acid-sensitive chloride channel (i.e., ClC-3) currents in both Type I and II AD macrophages, but curcumin only potentiates the currents in Type I cells; 2) 1,25D3 is particularly effective in upregulating ClC-3 mRNA expression in Type II peripheral blood mononuclear cells (PBMCs) while both 1,25D3 and the BDC analog, C180, upregulate VDR mRNA, repressed by Aβ42 in Type II PBMCs; and 3) 1,25D3-induced Aβ42 phagocytosis is attenuated by the calcium-dependent ClC-3 blocker, inositol 3,4,5,6-tetraphosphate (IP4), in both AD Types and by the MEK1/2 inhibitor U0126 only in Type II macrophages. VDR hydrogen/deuterium exchange coupled mass spectrometry and computational results show differences between the abilities of 1,25D3 and curcuminoids to stabilize VDR helices associated with the regulation of gene transcription. The structure-function results provide evidence that 1,25D3 activation of VDR-dependent genomic and nongenomic signaling, work in concert to recover dysregulated innate immune function in AD.

Supplementary Data for Mizwicki et al. article (PDF)

Pages 63-77
Ariadna Mendoza-Naranjo, Erick Contreras-Vallejos, Daniel R. Henriquez, Carola Otth, James R. Bamburg, Ricardo B. Maccioni, Christian Gonzalez-Billault
Fibrillar Amyloid-β1-42 Modifies Actin Organization Affecting the Cofilin Phosphorylation State: A Role for Rac1/cdc42 Effector Proteins and the Slingshot Phosphatase
Abstract: The neuronal cytoskeleton regulates numerous processes that occur in normal homeostasis. Under pathological conditions such as those of Alzheimer’s disease (AD), major alterations in cytoskeleton organization have been observed and changes in both microtubules and actin filaments have been reported. Many neurodegenerative consequences of AD are linked to the production and accumulation of amyloid peptides (Aβ) and their oligomers, produced from the internal cleavage of the amyloid-β protein precursor. We previously reported that fibrillar Aβ1-42 (fAβ) treatment of hippocampal neurons induced an increase in Rac1 and Cdc42 activities linking fAβ effects with changes in actin dynamics. Here we show fAβ-induces increased activity of PAK1 and cyclin-dependent kinase 5, and that p21-activated kinase (PAK1) activation targets the LIMK1-cofilin signaling pathway. Increased cofilin dephosphorylation under conditions of enhanced LIM-Kinase 1 (LIMK1) activity suggests that fAβ co-stimulates bifurcating pathways impacting cofilin phosphorylation. Overexpression of slingshot (SSH) prevents the augment of F-actin induced by fAβ after 24 h, suggesting that fAβ-induced changes in actin assembly involve both LIMK1 and SSH. These results suggest that fAb may alter the PAK1/LIMK1/cofilin axis and therefore actin organization in AD.

Supplementary Data for Mendoza-Naranjo et al. article (PDF)

Pages 79-88
Leonardo P. Navarrete, Leonardo Guzmán, Aurelio San Martin, Luis Astudillo-Saavedra, Ricardo B. Maccioni
Molecules of the Quinoline Family Block Tau Self-Aggregation: Implications Toward a Therapeutic Approach for Alzheimer’s Disease
Abstract: The neurofibrillary tangles (NFTs) generated by self-aggregation of anomalous forms of tau represent a neuropathological hallmark of Alzheimer’s disease (AD). These lesions begin to form long before the clinical manifestation of AD, and its severity is correlated with cognitive impairment in patients. We focused on the search for molecules that interact with aggregated tau of the Alzheimer’s type and that may block its aggregation before the formation of NFTs. We show that molecules from a family of quinolines interact specifically with oligomeric forms of tau, inhibiting their assembly into AD filaments. The quinolines 2-(4-methylphenyl)-6-methyl quinoline (THQ-4S) and 2-(4-aminophenyl)-6-methylquinoline (THQ-55) inhibited in vitro aggregation of heparin-induced polymers of purified brain tau and aggregates of human recombinant tau. They also interact with paired helical filaments (PHFs) purified from AD postmortembrains. In vitro studies indicated a significantly lower inhibitory effect of amyloid-β42 on the aggregation, suggesting that tau aggregates are specific targets for quinoline interactions. These compounds showed highly lipophylic properties as corroborated with the analysis of total polar surface areas, and evaluation of their molecular properties. Moreover, these quinolines exhibit physical chemical properties similar to drugs able to penetrate the human brain blood barrier. Docking studies based on tau modeling, as a structural approach to the analysis of the interaction of tau-binding ligands, indicated that a C-terminal tau moiety, involved in the formation of PHFs, seems to be a site for binding of quinolines. Studies suggest the potential clinical use of these quinolines and of their derivatives to inhibit tau aggregation and possible therapeutic routes for AD.

Pages 89-98
Zhiyou Cai, Benyi Li, Keshen Li, Bin Zhao
Down-regulation of Amyloid-β Through AMPK Activation by Inhibitors of GSK-3β in SH-SY5Y and SH-SY5Y-AβPP695 Cells
Abstract: Glycogen synthase kinase 3β (GSK-3β) plays a critical role in the pathogenesis of Alzheimer’s disease (AD), implicating amyloid-β (Aβ) production, neurofibrillary tangle formation, and neuronal apoptosis. The activation of 5' AMP-activated protein kinase (AMPK) has been linked to aberrant processing of amyloid-β protein precursor (AβPP), and AMPK signaling controls Aβ metabolism. It is possible that GSK-3β regulated the activation of the AMPK pathway. To test this hypothesis, the influence of GSK-3β on the expression of AβPP cleavage enzyme (BACE), Aβ, and AMPK in the SH-SY5Y and AβPP695 cells line through three inhibitors of GSK-3β was analyzed. Expression of Aβ, AMPK, and pAMPK172 was measured by Western blot, and BACE was tested by Western blot and RT-PCR. This study demonstrated that suppression of GSK-3β activity, through specific inhibitors, dramatically down-regulated Aβ generation in human SH-SY5Y and SH-SY5Y-AβPP695 cells by enhancing AMPK activity to down-regulate Aβ. These results suggest GSK-3β inhibitors may be promising agents in the prevention and treatment of AD.

Pages 99-108
Amy E. Sanders, Charles B. Hall, Mindy J. Katz, Richard B. Lipton (Handling Associate Editor: Rebecca Gelber)
Non-Native Language Use and Risk of Incident Dementia in the Elderly
Abstract: Cognitive reserve is invoked to explain the protective effects of education and cognitively-stimulating activities against all-cause dementia and Alzheimer’s disease (AD). For non-native English speakers (n-NES), speaking English may be a cognitive activity associated with lower dementia risk. We hypothesized that n-NES have lower risk of incident dementia/AD and that educational level might modify this relationship. Participants took part in the Einstein Aging Study (Bronx, NY), a longitudinal study of aging and dementia. All (n = 1779) spoke fluent English and self-reported birthplace and whether English was their first language. n-NES additionally reported mother tongue, age of English acquisition, and current percentile-use of a non-English language. Nested Cox proportional hazards models progressively adjusted for gender, race, education, and immigrant and marital status estimated hazard ratios (HR) for incident dementia/AD as a function of n-NES status. 390 (22%) participants were n-NES. 126 incident dementia cases occurred during 4174 person-years of follow-up (median 1.44; range 0-16); 101 individuals met criteria for probable/possible AD. There was no statistically-significant association between n-NES status and incident dementia in the fully-adjusted model (HR 1.26; 95% CI 0.76-2.09; p=0.36). Results were similar for AD. Stratification of education into three groups revealed increased risk of dementia for n-NES with ≥16 years of education (HR 3.97; 95% CI 1.62–9.75; p=0.003). We conclude that n-NES status does not appear to have an independent protective effect against incident dementia/AD, and that n-NES status may contribute to risk of dementia in an education-dependent manner.

Pages 109-123
Francis Clément, Sylvie Belleville
Effect of Disease Severity on Neural Compensation of Item and Associative Recognition in Mild Cognitive Impairment
Abstract: It is proposed that the prodromal phase of Alzheimer’s disease is associated with additional brain activation in key regions involved in memory, reflecting compensatory brain plasticity. Very little is known, however, about the evolution of these compensatory mechanisms as the brain acquires more damages. We conducted an fMRI memory study measuring brain activation related to old/new (item recognition) and intact/rearranged (associative recognition) word-pair recognition paradigms in 26 persons with mild cognitive impairment (MCI) and 14 healthy older adults. The Mattis Dementia Rating Scale was used to divide persons with MCI into those with higher and lower cognitive performances. Results indicated more brain activation in MCIs than in controls but disease severity determined which cognitive process was associated with larger activation: Persons with less severe MCI showed hyperactivation during associative recognition only, whereas persons with more severe MCI showed hyperactivation during item recognition only. These hyperactivations were found mainly in brain areas that are typically associated with retrieval mode (e.g., bilateral prefrontal cortex). These findings indicate that neural plasticity occurs during the entire MCI phase but that it is associated with different cognitive components. As they progress in the disease, individuals with MCI will experience a breakdown in the compensatory mechanisms for associative recognition accompanied by emergence of compensatory mechanisms for item recognition.

Pages 125-132
Malin Wennström, Elisabet Londos, Lennart Minthon, Henrietta M Nielsen (Handling Associate Editor: Piotr Lewczuk)
Altered CSF orexin and α-synuclein levels in dementia patients
Abstract: Neurodegenerative dementia, most frequently represented by Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB), is often accompanied by altered sleeping patterns and excessive daytime sleepiness. Studies showing an association between the neuropeptide orexin and AD/DLB-related processes such as amyloid-β (Aβ)1-42 plaque formation, α-synuclein accumulation, and inflammation indicate that orexin might play a pathogenic role similar to the situation in narcolepsy. Our study of patients with AD (n=26), DLB (n=18), and non-demented controls (n=24) shows a decrease in cerebrospinal fluid (CSF) orexin concentrations in DLB versus AD patients and controls. The observed differences in orexin levels were found to be specific to female DLB patients. We also show that the female DLB patients exclusively displayed lower levels of α-synuclein compared to AD patients and controls. Orexin was linked to α-synuclein and total-tau in female non-demented controls whereas associations between orexin and Aβ1-42 concentrations were absent in all groups regardless of gender. Thus, the proposed links between orexin, Aβ, and α-synuclein pathology could not be monitored in CSF protein concentrations. Interestingly, α-synuclein was strongly correlated to the CSF levels of total-tau in all groups, suggesting α-synuclein to be an unspecific marker of neurodegeneration. We conclude that lower levels of CSF orexin are specific to DLB versus AD and appear unrelated to Aβ1-42 and α-synuclein levels in AD and DLB. Alterations in CSF orexin and α-synuclein levels may be related to gender which warrants further investigation.

Pages 133-149
Andrew H. Ford, Osvaldo P. Almeida
Effect of Homocysteine Lowering Treatment on Cognitive Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Abstract: Elevated total plasma homocysteine has been linked to the development of cognitive impairment and dementia in later life and this can be reliably lowered by the daily supplementation of vitamin B6, B12, and folic acid. We performed a systematic review and meta-analysis of 19 English language randomized, placebo-controlled trials of homocysteine lowering B-vitamin supplementation of individuals with and without cognitive impairment at the time of study entry. We standardized scores to facilitate comparison between studies and to enable us to complete a meta-analysis of randomized trials. In addition, we stratified our analyses according to the folate status of the country of origin. B-vitamin supplementation did not show an improvement in cognitive function for individuals with (SMD=0.10, 95%CI -0.08 to 0.28) or without (SMD=-0.03, 95%CI -0.1 to 0.04) significant cognitive impairment. This was irrespective of study duration (SMD=0.05, 95%CI -0.10 to 0.20 and SMD=0, 95%CI -0.08 to 0.08), study size (SMD=0.05, 95%CI -0.09 to 0.19 and SMD=-0.02, 95%CI -0.10 to 0.05), and whether participants came from countries with low folate status (SMD=0.14, 95%CI -0.12 to 0.40 and SMD=-0.10, 95%CI -0.23 to 0.04). Supplementation of vitamins B12, B6, and folic acid alone or in combination does not appear to improve cognitive function in individuals with or without existing cognitive impairment. It remains to be established if prolonged treatment with B-vitamins can reduce the risk of dementia in later life.

Supplementary Data for Ford and Almeida article (PDF)

Pages 151-157
Matthew W. Warren, Linda S. Hynan, Myron F. Weiner and the Texas Alzheimer’s Research and Care Consortium (Handling Associate Editor: Othman Ghribi)
Lipids and Adipokines as Risk Factors for Alzheimer’s Disease
Abstract: To determine if measures of adipokines and other blood lipids differentiate between normal controls and persons with Alzheimer’s disease (AD), we examined levels of leptin, adiponectin, total cholesterol, high density lipoproteins (HDL), calculated low density lipoproteins (LDL), triglycerides and apolipoprotein E allele status in 148 early AD subjects and 198 normal controls. We were unable to demonstrate a significant difference between leptin and adiponectin levels between normal controls and AD subjects. We were able to confirm observations of lower HDL and higher total and LDL cholesterol concentration in AD subjects than in controls. As expected, the presence of the apolipoprotein E4 allele distinguished between the two groups.

Pages 159-170
Montserrat Costa, Ana M. Ortiz, Juan I. Jorquera
Therapeutic Albumin Binding to Remove Amyloid-β
Abstract: Clearance of plasma amyloid-β (Aβ) through plasma exchange and replacement with therapeutic albumin to facilitate net Aβ efflux from the brain to plasma is a novel approach for the treatment of Alzheimer’s disease. Therefore, thorough characterization of the capacity of therapeutic albumin to bind Aβ is warranted. In this study, Aβ40 and Aβ42 were quantified by commercial ELISA or Araclon ABtest® in samples of Grifols’ therapeutic albumin (Albutein®) 5%, 20%, and 25%. The capacity of Albutein® to bind Aβ was assessed by: a) ELISA in serially diluted therapeutic albumin (0-45 mg/ml protein concentration) to which 80 pg/ml of synthetic Aβ peptide (sAβ40 or sAβ42) were added; b) ELISA in samples of the therapeutic albumin containing serially diluted sAβ40 or sAβ42 (60-400 pg/ml); and c) surface plasmon resonance (SPR) for sAβ42 binding. The Aβ content in Albutein® was below the quantification threshold of the ELISA tests (<25 to <62.5 pg/ml) and ABtest® (<3.125 pg/ml). Quantification of exogenously added sAβ42 decreased in parallel with increasing protein concentration (59-78% at 45 mg/ml albumin). Recovery of sAβ serially diluted in Albutein® was ~60% for sAβ40 and ~70% for sAβ42, but was ~100% in control samples without albumin. The KD by SPR analysis for sAβ42 interaction with Albutein® was 1.72 ± 0.24x10-6 M. In conclusion, Grifols’ therapeutic albumin has undetectable content of Aβ40 and Aβ42. Moreover, Grifols’ therapeutic albumin consistently binds peptides containing the primary sequence of human Aβ.

Pages 171-176
Alexander Navarrete Santos, Michael Ewers, Lennart Minthon, Andreas Simm, Rolf-Edgar Silber, Kaj Blennow, David Prvulovic, Oskar Hansson*, Harald Hampel* *These authors contributed equally as senior authors to this work.
Amyloid-β Oligomers in Cerebrospinal Fluid are associated with Cognitive Decline in Patients with Alzheimer’s Disease
Abstract: Oligomers of the amyloid-β peptide (Aβ) are thought to be the most toxic form of Aβ and are linked to the development of Alzheimer’s disease (AD). Here, we used a flow cytometric approach for the detection and assessment of oligomers in cerebrospinal fluid (CSF) from AD patients and other neurological disorders. 30 CSF samples from patients suffering from AD (n = 14), non-demented controls (n = 12), and other neurological disorders (dementia with Lewy bodies, n = 2; vascular dementia, n = 1; primary progressive aphasia, n = 1) were analyzed for the presence of Aβ-oligomers by flow cytometry. The CSF levels of total tau (t-tau), phosphorylated tau (p-tau), and amyloid-β (Aβ)42 were determined using ELISA. CSF Aβ-oligomer levels in AD patients were elevated in comparison to the non-AD group (p = 0.073). The ratio Aβ-oligomers/Aβ42 was significantly elevated in AD subjects compared to non-AD subjects (p = 0.001). Most important, there was a negative correlation between the amount of Aβ-oligomers and the Mini-Mental Status Exam score (r = -0.65; p = 0.013) in AD patients. The detection of Aβ-oligomers using flow cytometry analysis seems to be useful in assessing the stage of AD. This is a novel and important finding as none of the currently used CSF biomarkers are clearly associated with dementia severity.

Pages 177-185
Ira T. Lott, Eric Doran, Vinh Q. Nguyen, Anne Tournay, Nina Movsesyan, Daniel L. Gillen (Handling Associate Editor: Cara Westmark)
Down Syndrome and Dementia: Seizures and Cognitive Decline
Abstract: The objective of this study was to determine the association of seizures and cognitive decline in adults with Down syndrome (DS) and Alzheimer’s-type dementia. A retrospective data analysis was carried out following a controlled study of antioxidant supplementation for dementia in DS. Observations were made at baseline and every 6 months for 2 years. Seizure history was obtained from study records. The primary outcome measures comprised the performance-based Severe Impairment Battery (SIB) and Brief Praxis Test (BPT). Secondary outcome measures comprised the informant-based Dementia Questionnaire for Mentally Retarded Persons and Vineland Adaptive Behavior Scales. Because a large proportion of patients with seizures had such severe cognitive decline as to become untestable on the performance measures, time to “first inability to test” was measured. Adjustments were made for the potentially confounding co-variates of age, gender, APOE4 status, baseline cognitive impairment, years since dementia onset at baseline, and treatment assignment. The estimated odds ratio for the time to “first inability to test” on SIB comparing those with seizures to those without is 11.02 (95% CI: 1.59, 76.27), a ratio that is significantly different from 1 (p = 0.015). Similarly, we estimated an odds ratio of 9.02 (95% CI: 1.90, 42.85) on BPT, a ratio also significantly different than 1 (p = 0.006). Results from a secondary analysis of the informant measures showed significant decline related to seizures. We conclude that there is a strong association of seizures with cognitive decline in demented individuals with DS. Prospective studies exploring this relationship in DS are indicated.

Pages 187-200
Desiree Antequera, Aitziber Portero, Marta Bolos, Gorka Orive, Rosa Mª Hernández, José Luis Pedraz, Eva Carro
Encapsulated VEGF-Secreting Cells Enhance Proliferation of Neuronal Progenitors in the Hippocampus of AβPP/PS1 Mice
Abstract: Vascular endothelial growth factor (VEGF) promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the Alzheimer’s disease (AD) brain is still unknown. We examined the proliferation of neuronal precursors with an ex vivo approach, using encapsulated VEGF secreting cells, in AβPP/PS1 mice, a mouse model of AD. Overexpression of VEGF and VEGF receptor flk-1 was observed in the cerebral cortex from VEGF microcapsules-treated AβPP/PS1 mice at 1, 3, and 6 months after VEGF-microcapsule implantation. Stereological counting of 5-bromodeoxyuridine positive cells revealed that encapsulated VEGF secreting cells significantly enhanced cellular proliferation in the hippocampal dentate gyrus. The number of neuronal precursors in VEGF microcapsules-treated AβPP/PS1 mice was also greater, and this effect remains after 6 months. We also confirmed that encapsulated VEGF secreting cells stimulated angiogenesis in the cerebral cortex and hippocampal dentate gyrus. In addition, we found that VEGF-microcapsule treatment was associated with a depressed expression and activity of acetylcholinesterase in the hippocampus of AβPP/PS1 mice, a similar pattern as first-line medications for the treatment of AD. We conclude that stereologically-implanted VEGF-microcapsules exert an acute and long-standing neurotrophic effects, and could be utilized to improve potential therapies to control the progression of AD.

Supplementary Data for Antequera et al. article (PDF)

Pages 201-209
Qunxing Ding, Haiyan Zhu, Bing Zhang, Augusto Soriano, Roxanne Burns, William R. Markesbery (Handling Associate Editor: Tania Alves)
Increased 5S rRNA Oxidation in Alzheimer’s Disease
Abstract: It is widely accepted that oxidative stress is involved in neurodegenerative disorders such as Alzheimer’s disease (AD). Ribosomal RNA (rRNA) is one of the most abundant molecules in most cells and is affected by oxidative stress in the human brain. Previous data have indicated that total rRNA levels were decreased in the brains of subjects with AD and mild cognitive impairment concomitant with an increase in rRNA oxidation. In addition, level of 5S rRNA, one of the essential components of the ribosome complex, was significantly lower in the inferior parietal lobule (IP) brain area of subjects with AD compared with control subjects. To further evaluate the alteration of 5S rRNA in neurodegenerative human brains, multiple brain regions from both AD and age-matched control subjects were used in this study, including IP, superior and middle temporal gyro, temporal pole, and cerebellum. Different molecular pools including 5S rRNA integrated into ribosome complexes, free 5S rRNA, cytoplasmic 5S rRNA, and nuclear 5S rRNA were studied. Free 5S rRNA levels were significantly decreased in the temporal pole region of AD subjects and the oxidation of ribosome-integrated and free 5S rRNA was significantly increased in multiple brain regions in AD subjects compared with controls. Moreover, a greater amount of oxidized 5S rRNA was detected in the cytoplasm and nucleus of AD subjects compared with controls. These results suggest that the increased oxidation of 5S rRNA, especially the oxidation of free 5S rRNA, may be involved in the neurodegeneration observed in AD.

Pages 211-227
Mario Nizzari, Federica Barbieri, Maria Teresa Gentile, Daniela Passarella, Valentina Caorsi, Alberto Diaspro, Maurizio Taglialatela, Aldo Pagano, Luca Colucci-D’Amato, Tullio Florio, Claudio Russo
Amyloid-β Protein Precursor Regulates Phosphorylation and Cellular Compartmentalization of Microtubule Associated Protein Tau
Abstract: Tau is a multifunctional protein detected in different cellular compartments in neuronal and non-neuronal cells. When hyperphosphorylated and aggregated in atrophic neurons, tau is considered the culprit for neuronal death in familial and sporadic tauopathies. With regards to Alzheimer’s disease (AD) pathogenesis, it is not yet established whether entangled tau represents a cause or a consequence of neurodegeneration. In fact, it is unquestionably accepted that amyloid-β protein precursor (AβPP) plays a pivotal role in the genesis of the disease, and it is postulated that the formation of toxic amyloid-β peptides from AβPP is the primary event that subsequently induces abnormal tau phosphorylation. In this work, we show that in the brain of AD patients there is an imbalance between the nuclear and the cytoskeletal pools of phospho-tau. We observed that in non-AD subjects, there is a stable pool of phospho-tau which remains strictly confined to neuronal nuclei, while nuclear localization of phospho-tau is significantly underrepresented in neurons of AD patients bearing neurofibrillary tangles. A specific phosphorylation of tau is required during mitosis in vitro and in vivo, likely via a Grb2-ERK1/2 signaling cascade. In differentiated neuronal A1 cells, the overexpression of AβPP modulates tau phosphorylation, altering the ratio between cytoskeletal and nuclear pools, and correlates with cell death. Altogether our data provide evidence that AβPP, in addition to amyloid formation, modulates the phosphorylation of tau and its subcellular compartmentalization, an event that may lead to the formation of neurofibrillary tangles and to neurodegeneration when occurring in postmitotic neurons.

Pages 229-238
Lucilla Parnetti*, Davide Chiasserini*, Paolo Eusebi, David Giannandrea, Gianni Bellomo, Claudia De Carlo, Chiara Padiglioni, Sara Mastrocola, Viviana Lisetti, Paolo Calabresi (Handling Associate Editor: Barbara Borroni) *These authors equally contributed to the work.
Performance of Aβ1-40, Aβ1-42, Total Tau, and Phosphorylated Tau as Predictors of Dementia in a Cohort of Patients with Mild Cognitive Impairment
Abstract: Mild cognitive impairment (MCI) is a common condition in the elderly which may remain stable along time (MCI-MCI) or evolve into Alzheimer’s disease (MCI-AD) or other dementias. Cerebrospinal fluid (CSF) classical biomarkers, i.e., amyloid-β 1-42 (Aβ1-42), total tau (t-tau), and phosphorylated tau (p-tau) reflect the neuropathological changes taking place in AD brains, thus disclosing the disease in its prodromal phase. With the aim to evaluate the power of each biomarker and/or their combination in predicting AD progression, we have measured CSF Aβ1-40, Aβ1-42, t-tau, and p-tau in patients with AD, MCI-MCI, MCI-AD, and other neurological diseases without dementia (OND) followed up for four years. Aβ1-42 levels were significantly lower in AD and MCI-AD than in MCI-MCI. T-tau and p-tau levels were significantly increased in AD and MCI-AD versus OND and MCI-MCI. The Aβ1-42/Aβ1-40 ratio showed a significant decrease in AD and MCI-AD as compared to MCI-MCI. Both Aβ1-42/t-tau and Aβ1-42/p-tau ratios showed significantly decreased values in AD and MCI-AD with respect to OND and MCI-MCI. Aβ1-42/p-tau ratio was the best parameter for discriminating MCI-AD from MCI-MCI (sensitivity 81%, specificity 95%), being also correlated with the annual change rate in the Mini Mental State Examination score (MMSE-ACR, rS = -0.71, p < 0.0001). Survival analysis showed that 81% of MCI with a low Aβ1-42/p-tau ratio (<1372) progressed to AD. The best model of logistic regression analysis retained Aβ1-42 and p-tau (sensitivity 75%, 95%CI: 70-80%; specificity 96%, 95%CI: 94-98%). We can conclude that Aβ1-42 and p-tau reliably predict conversion to AD in MCI patients.

Supplementary Data for Parnetti et al. article (PDF)

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