Pages 1-68
Review
Wolfgang Froestl, Andreas Muhs, Andrea Pfeifer
Cognitive Enhancers (Nootropics). Part 2: Drugs interacting with Enzymes. Update 2014
Abstract: Scientists working in the field of Alzheimer’s disease and, in particular, cognitive enhancers are very productive. The review on Drugs interacting with Enzymes was accepted in August 2012. However, this field is very dynamic. New potential targets for the treatment of Alzheimer’s disease were identified. This update describes drugs interacting with 60 enzymes versus 43 enzymes in the first paper. Some compounds progressed in their development, while many others were discontinued. The present review covers the evolution of research in this field through April 2014.
Pages 69-85
Hypothesis
Arash ManafiRad Farshad Farzadfar, Laleh Habibi, Morteza Azhdarzadeh, Haniyeh Aghaverdi, Khadijeh H. Tehrani, Mina Lotfi, Patrick G. Kehoe, Ali Sheidaei, Anoosheh Ghasemian, Ehsan Rezaei Darzi, Ramin Mahmoodi, Morteza Mahmoudi
Is Amyloid-β an Innocent Bystander and Marker in Alzheimer’s Disease? Is the Liability of Multivalent Cation Homeostasis and its Influence on Amyloid-β Function the Real Mechanism?
Abstract: Two decades of the amyloid-β (Aβ) hypothesis in Alzheimer’s disease (AD) and the prominence of Aβ-targeting strategies have yet to meet the levels of original expectation. Disappointing results in numerous Phase II/III studies have called for a re-examination of the validity of the Aβ-targeting approaches as an intervention strategy in AD. The mid-life onset of chronic conditions (e.g., hypertension, diabetes, insulin intolerance, and depression nominated as risk factors for the later development of AD) points to the possibility that each condition could involve mechanisms, which while relatively modest over a short-term, could have significant accumulative effects. What may also not be fully appreciated is that a number of these conditions involve potential disturbances to multivalent cations (MC) levels through various mechanisms such as autophagy, oxidative stress, and apoptosis. Furthermore, some MCs have intimate associations with the mechanisms by which Aβ pathology manifests. Considering various lines of evidence and incorporating statistical analysis on Disability–Adjusted Life Years (DALYs) data of both causes of and prevalence of multifactorial risk factors in different world regions, we propose an MC hypothesis for AD. More specifically, we suggest that MC imbalance marks many chronic conditions and because of their involvement with Aβ pathology, could reflect that Aβ may be a vital manifestation and marker of underlying MC imbalance. Thus, careful targeting of MC imbalance may provide an alternative or complementary interventional approach to current Aβ treatment strategies.
Pages 87-96
Hypothesis
Alba Pesini, Eldris Iglesias, Nuria Garrido, M. Pilar Bayona-Bafaluy, Julio Montoya, Eduardo Ruiz-Pesini
OXPHOS, Pyrimidine Nucleotides, and Alzheimer’s Disease: A Pharmacogenomics Approach
Abstract: We present a new hypothesis on the contribution of a dysfunction of the oxidative phosphorylation system, through a decrease in the de novo synthesis of pyrimidine nucleotides, to the pathogenesis of late onset Alzheimer’s disease (AD). In the light of this proposition, different treatments for AD patients, such as enhancing the electron flow downstream the coenzyme Q10 of the mitochondrial respiratory chain or increasing mitochondrial biogenesis or directly providing pyrimidines, would be possible. AD is a multifactorial disorder and not all patients would benefit from these treatments. Those healthy individuals harboring mtDNA haplotypes related to a coupled OXPHOS function would probably be the better candidates for these preventive therapies.
Pages 97-101
Short Communication
Jonai Pujol-Gimenez, Eva Martisova, Alberto Perez-Mediavilla, María Pilar Lostao, Maria J. Ramirez (Handling Associate Editor: Morty Mamelak)
Expression of the Glucose Transporter GLUT12 in Alzheimer’s Disease Patients
Abstract: Alzheimer’s disease (AD) might be conceptualized as a metabolic disease with progressive impairment of the brain’s capacity to utilize glucose. One of the last glucose transporters discovered is GLUT12. The aim of the present work was to investigate the expression of GLUT12 in frontal cortex from AD patients. Human samples from young control donors barely expressed GLUT12. The level of expression of GLUT12 was significantly higher in AD compare to aged controls. Expression of GLUT12 and Ox-42, a microglia marker, correlate in controls but not in AD. The implications of these findings in AD are discussed further.
Pages 103-107
Short Communication
José Fernando Maya-Vetencourt, Nicola Maria Carucci, Simona Capsoni, Antonino Cattaneo
Amyloid Plaque-Independent Deficit of Early Postnatal Visual Cortical Plasticity in the 5XFAD Transgenic Model of Alzheimer’s Disease
Abstract: Autosomal dominant forms of familial Alzheimer’s disease are linked to an aberrant processing of the amyloid-β protein precursor, which results in an increased production of amyloid-β (Aβ) peptides that first form oligomers and eventually aggregate in the form of extracellular amyloid plaques in the brain. The accumulation of Aβ peptides oligomers seems to correlate with alterations of synaptic transmission in experimental models of Alzheimer’s disease but whether Aβ aggregation disrupts synaptic function independently of amyloid plaques deposition still needs further research. Here we report an amyloid plaque-independent deficit of neuronal plasticity after short-term sensory deprivation in the visual system of 5XFAD mice.
Pages 109-113
Short Communication
Ulrich Müller, Pia Winter, Claus Bolender, Dagmar Nolte (Handling Associate Editor: Luisa Benussi)
Previously Unrecognized Missense Mutation E126K of PSEN2 Segregates with Early Onset Alzheimer’s Disease in a Family
Abstract: Mutations in the gene PSEN2 are a rare cause of early onset Alzheimer’s disease (EOAD). PSEN2 sequence variants are often only found in one patient and pathogenicity cannot be formally documented. Here we describe a previously unrecognized sequence change (c.376G>A) in PSEN2 in an EOAD patient and her likewise affected mother. This change results in the exchange of amino acid glutamic acid (E) by lysine (K) at position 126 of the protein (p.E126K). Pathogenicity of the mutation is shown by segregation with disease, evolutionary conservation of E126, and in silico analysis of the mutation.
Pages 115-118
Short Communication
Danton H. O’Day, Andrew Catalano
A Lack of Correlation between the Incidence of Lyme Disease and Deaths due to Alzheimer’s Disease
Abstract: Reports that Lyme disease (LD) causes Alzheimer’s disease (AD) have appeared in academic journals and online. If the biological agent Borrelia burgdorferi that causes LD also causes AD, then areas with the highest levels of LD should have significantly higher numbers of deaths due to AD compared to low LD areas. Here we show there is no statistically significant correlation between the incidence of LD and deaths due to AD in the US. Furthermore, the 13 states with the highest deaths due to AD were statistically different (p<0.0001) from those with high LD incidence.
Pages 119-135
Luigi Yuri Di Marco, Alberto Marzo, Miguel Muñoz-Ruiz, M. Arfan Ikram, Miia Kivipelto, Daniel Ruefenacht, Annalena Venneri, Hilkka Soinnen, Isabel Wanke, Yiannis A. Ventikos, Alejandro F. Frangi
Modifiable Lifestyle Factors in Dementia: A Systematic Review of Longitudinal Observational Cohort Studies
Abstract: Background: Numerous population-based longitudinal studies suggest an association between modifiable lifestyle factors and late-life dementia. A comprehensive description of these factors and their quantification criteria is an important preliminary step toward the elucidation of causes and mechanisms underlying the onset and progression of dementia. Objective: To present a systematic review of modifiable lifestyle factors associated with dementia risk in longitudinal observational cohort-studies. Methods: A systematic review of original articles, published in English until December 2013, listed in four electronic databases (including PubMed, MEDLINE, PsycINFO) was conducted. Results: 75 papers from 33 epidemiologic studies met the inclusion criteria. Included papers focused on dietary habits (n=26), leisure activities (social, physical, mental) (n=23), beverages (juice, tea, coffee, alcohol) (n=15), smoking (n=13), social network (n=6), and combined lifestyle factors (n=2). Conclusions: Broad consensus emerged on the protective role against dementia of leisure activities. Conflicting results were found for the association between dementia and putative risk factors (smoking) and protective factors (mild-to-moderate alcohol consumption, dietary antioxidants, Mediterranean diet, and living with others). However, studies varied largely in the quantification of lifestyle factors in terms of intensity, frequency and duration of exposure, and in the choice of confounders in statistical analyses. The need for standardized quantification criteria emerges, together with the current limitation in reliably tracking the past history of each patient, from childhood and young adulthood to midlife.
Pages 137-142
Renée F.A.G. de Bruijn, Joseph A.M.J.L. Janssen, Michael P. Brugts, Cornelia M. van Duijn, Albert Hofman, Peter J. Koudstaalb, M. Arfan Ikram (Handling Associate Editor: Eva Carro)
Insulin-Like Growth Factor-I Receptor Stimulating Activity is Associated with Dementia
Abstract: Background: Insulin-like growth factor-I (IGF-I) is a pleiotropic hormone. Several studies have related IGF-I levels to dementia, but evidence remains inconclusive. IGF-I receptor stimulating activity is a more direct measure of biologically available IGF-I than total IGF-I levels. Objective: To investigate whether IGF-I receptor stimulating activity is associated with prevalent and incident dementia. Methods: IGF-I receptor stimulating activity was measured using an IGF-I kinase receptor activation assay in 1,014 persons from the Rotterdam Study. Dementia was assessed at baseline (1997-1999) and continuously during follow-up until September 2011. Associations of IGF-I receptor stimulating activity with prevalent dementia were investigated using logistic regression and with incident dementia using Cox proportional hazards models. All models were adjusted for age and gender, and additionally for hypertension, glucose, waist circumference, APOE-ε4 carrier status, total cholesterol, and HDL-cholesterol. Results: Thirty participants had prevalent dementia and during 8,589 person-years of follow-up, 135 persons developed incident dementia. A higher level of IGF-I receptor stimulating activity was associated with a higher prevalence of dementia (fully adjusted odds ratio 1.47; 95%CI 1.10-1.97) and with higher risk of incident dementia (fully adjusted hazard ratio 1.15; 95%CI 1.00-1.33). Similar associations were found for Alzheimer’s disease and in persons without diabetes mellitus. Conclusions: Higher levels of IGF-I receptor stimulating activity are associated with a higher prevalence and with a higher incidence of dementia. These results suggest that IGF-I increases in response to neuropathological changes in dementia and could reflect a state of IGF-I resistance in dementia.
Pages 143-155
Juan A. Araya, Alejandra E. Ramírez, Daniela Figueroa-Aroca, Gastón J. Sotes, Claudia Pérez, Jose Becerra, Francisco Saez-Orellana, Leonardo Guzmán, Luis G. Aguayo, Jorge Fuentealba
Modulation of Neuronal Nicotinic Receptor by Quinolizidine Alkaloids Causes Neuroprotection on a Cellular Alzheimer Model
Abstract: Alzheimer’s disease (AD) is a progressive and neurodegenerative disorder and one of the current therapies involves strengthening the cholinergic tone in central synapses. Neuroprotective properties for nicotine have been described in AD, through its actions on nicotinic receptors and the further activation of the PI3K/Akt/Bcl-2 survival pathway. We have tested a quinolizidine alkaloid extract (TM0112) obtained from Teline monspessulanna (L.) K. Koch seeds to evaluate its action on nicotinic acetylcholine receptor (nAChR) in a neuronal AD model. Our data show that PC-12 cells pretreated with amyloid-β (Aβ) peptide for 24 h in presence of TM0112 modified Aβ-reduction on cellular viability (Aβ=80±3%; +TM0112=113±4%, n=15). In addition, this effect was blocked with atropine, MLA, and α-BTX (+TM0112+atropine=87±4%; +TM0112+MLA=86±4%; +TM0112+α-BTX=92±3%). Furthermore, similar protective effects were observed in rat cortical neurons (Aβ=63±6%; +TM0112=114±8%), but not in HEK293T cells (Aβ=61.4±6.1%; +TM0112=62.8±5.2) that do no express α7 nAChR. Moreover, the frequency of synaptic activity in the neuronal network (Aβ=51.6±16.9%; +TM0112=210.8±47.9%, n>10), as well as the intracellular Ca2+ transients were recovered by TM0112 (Aβ=61.4±6.9%; +TM0112=112.0±5.7%; n=3) in rat hippocampal neurons. TM0112 increased P-Akt, up to 250% with respect to control, and elevated Bcl-2/Bax percentage (Aβ=61.0±8.2%; +TM0112=105.4±19.5%, n=4), suggesting a coupling between nAChR activation and an intracellular neuroprotective pathway. Our results suggest that TM0112 could be a new potential source for anti-AD drugs.
Pages 157-167
Daniel Alcolea, María Carmona-Iragui, Marc Suárez-Calvet, Mª Belén Sánchez-Saudinós, Isabel Sala, Sofía Antón-Aguirre, Rafael Blesa, Jordi Clarimón, Juan Fortea, Alberto Lleó (Handling Associate Editor: Mikko Hiltunen)
Relationship Between β-Secretase, Inflammation and Core Cerebrospinal Fluid Biomarkers for Alzheimer’s Disease
Abstract: Background: Biomarkers in the cerebrospinal fluid (CSF) can track specific pathophysiological pathways underlying Alzheimer’s disease (AD). The connection between these biomarkers remains unclear. Objective: To study six CSF biomarkers in a clinical cohort of patients with different neurodegenerative conditions. Methods: We measured markers of amyloid-β protein precursor (AβPP) processing (Aβ42, sAβPPβ, β-secretase activity), neuronal damage (total tau, p-tau), and inflammation (YKL-40) in CSF from 194 participants with the following diagnoses: subjective cognitive impairment or non-amnestic mild cognitive impairment (na-SCI, n=44), amnestic mild cognitive impairment (aMCI, n=45), dementia of the Alzheimer type (DAT, n=59), frontotemporal dementia (FTD, n=22), and 24 cognitively normal controls. We compared biomarkers between clinical groups and CSF-profile groups, and we analyzed the correlation between biomarkers. Results: CSF levels of sAβPPβ were decreased in FTD patients compared to the other groups. YKL-40 was elevated in DAT and FTD, and also in aMCI patients with evidence of the AD pathophysiological process. CSF Aβ42 correlated positively with β-secretase activity (RS=0.262) and sAβPPβ (RS=0.341). CSF YKL-40 correlated positively with total tau (RS=0.467) and p-tau (RS=0.429). CSF p-tau and sAβPPβ contributed significantly to distinguish DAT from FTD. Conclusions: CSF biomarkers of AβPP processing correlate with each other and are decreased in FTD. The inflammatory marker YKL-40 is increased in different neurodegenerative diseases, even in early stages, and it correlates with biomarkers of neurodegeneration. This suggests that inflammation is a common feature in AD and FTD. A combination of CSF biomarkers tracking distinct pathophysiological processes may be useful to classify subjects with neurodegenerative conditions.
Pages 169-182
Sandrine Cure, Keith Abrams, Mark Belger, Grazzia dell’agnello, Michael Happich
Systematic Literature Review and Meta-Analysis of Diagnostic Test Accuracy in Alzheimer’s Disease and Other Dementia Using Autopsy as Standard of Truth
Abstract: Background: Early diagnosis of Alzheimer’s disease (AD) is crucial to implement the latest treatment strategies and management of AD symptoms. Diagnostic procedures play a major role in this detection process but evidence on their respective accuracy is still limited. Objective: To conduct a systematic literature on the sensitivity and specificity of different test modalities to identify AD patients and perform meta-analyses on the test accuracy values of studies focusing on autopsy-confirmation as the standard of truth. Methods: The systematic review identified all English papers published between 1984 and 2011 on diagnostic imaging tests and cerebrospinal fluid biomarkers including results on the newest technologies currently investigated in this area. Meta-analyses using bivariate fixed and random-effect models and hierarchical summary receiver operating curve (HSROC) random-effect model were applied. Results: Out of the 1,189 records, 20 publications were identified to report the accuracy of diagnostic tests in distinguishing autopsy-confirmed AD patients from other dementia types and healthy controls. Looking at all tests and comparator populations together, sensitivity was calculated at 85.4% (95% confidence interval [CI]: 80.9%-90.0%) and specificity at 77.7% (95% CI: 70.2%-85.1%). The area under the HSROC curve was 0.88. Sensitivity and specificity values were higher for imaging procedures, and slightly lower for CSF biomarkers. Test-specific random-effect models could not be calculated due to the small number of studies. Conclusion: The review and meta-analysis point to a slight advantage of imaging procedures in correctly detecting AD patients but also highlight the limited evidence on autopsy-confirmations and heterogeneity in study designs.
Pages 183-191
Minna Rusanen, Miia Kivipelto, Esko Levälahti, Tiina Laatikainen, Jaakko Tuomilehto, Hilkka Soininen, Tiia Ngandu (Handling Associate Editor: Carol Brayne)
Heart Diseases and Long-Term Risk of Dementia and Alzheimer’s Disease: A Population-Based CAIDE Study
Abstract: Background: Many cardiovascular risk factors are shown to increase the risk of dementia and Alzheimer’s disease (AD), but the impact of heart disease on later development of dementia is still unclear. Objective: The aim of the study was to investigate the long-term risk of dementia and Alzheimer’s disease (AD) related to midlife and late-life atrial fibrillation (AF), heart failure (HF), and coronary artery disease (CAD) in a population-based study with a follow-up of over 25 years. Methods: Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study includes 2000 participants who were randomly selected from four separate, population-based samples originally studied in midlife (1972, 1977, 1982, or 1987). Re-examinations were carried out in 1998 and 2005-2008. Altogether 1,510 (75.5%) persons participated in at least one re-examination, and 127 (8.4%) persons were diagnosed with dementia (of which 102 had AD). Results: AF in late-life was an independent risk factor for dementia (HR 2.61, 95% CI 1.05–6.47; p=0.039) and AD (HR 2.54, 95% CI 1.04–6.16; p=0.040) in the fully adjusted analyses. The association was even stronger among the apolipoprotein E (APOE) ε4 non-carriers. Late-life HF, but not CAD, tended to increase the risks as well. Heart diseases diagnosed at midlife did not increase the risk of later dementia and AD. Conclusion: Late-life heart diseases increase the subsequent risk of dementia and AD. Prevention and effective treatment of heart diseases may be important also from the perspective of brain health and cognitive functioning.
Pages 193-200
Yuan-Han Yang, Huali Wang, Linda Lam, Wai-Chi Chan, Xin Yu, Tao Li, Wen-Fu Wang, Pai-Yi Chiu, Yu-Te Lin, Chaur-Jong Hu, Jong-Ling Fuh, John C. Morris
Characteristics of Alzheimer’s Disease among Patients in Taiwan, Hong Kong, and Beijing
Abstract: In order to obtain data from patients with Alzheimer’s disease dementia and their informants in a uniform manner and to foster further research among the Chinese and other races, we have conducted an international study to recruit patients diagnosed with Alzheimer’s disease (AD) from Taiwan, Hong Kong, and Beijing. The Uniform Data Set was translated into Chinese and administrated to AD patients and their informants. A total of 1,107 AD dementia patients were recruited, including 691 from Taiwan, 244 from Beijing, and 172 from Hong Kong. There were differences in the AD patients: gender (p=0.099), education (p<0.001), age (p<0.001), and handedness (p=0.007). For informants, age (p=0.679), gender (p=0.117), education (p<0.001), and living together or not (p<0.001) differed in the three samples. Although three areas across the Taiwan Strait are ethnic Chinese, the clinical picture for patients and informants are very different. Further study is needed to clarify the significance of clinical characteristics in Chinese societies.
Pages 201-210
Fiona Kumfor, John R. Hodges, Olivier Piguet (Handling Associate Editor: Ricardo Allegri)
Ecological Assessment of Emotional Enhancement of Memory in Progressive Nonfluent Aphasia and Alzheimer’s Disease
Abstract: Background: Events which are imbued with emotion are typically remembered vividly and with more confidence than similar non-emotional events. The extent that emotional enhancement of memory is compromised in neurodegenerative disorders is unclear, despite differential effects of dementia on emotion processing ability. Objective: To examine emotional enhancement of memory using an ecologically valid task in progressive nonfluent aphasia (PNFA), an expressive language subtype of frontotemporal dementia, in comparison to Alzheimer’s disease (AD) and matched-controls. Methods: Twenty-five dementia patients (13 PNFA, 12 AD) and 10 controls viewed either an emotionally arousing or a closely matched non-emotional story. Multiple-choice recognition memory was tested after a 1-hour delay. The alternate story was presented two weeks later. Results: PNFA showed a similar level of memory for the emotional and neutral story, whereas both controls and AD remembered significantly more details from the emotional than the neutral story. Correlation analyses indicated that in PNFA, emotional story memory correlated with reduced emotion recognition, whereas in AD, neutral story memory correlated with visual recall memory performance only. Furthermore, in PNFA, reduced emotional memory enhancement was associated with increased carer stress and depression. Conclusion: Emotional memory enhancement is absent in PNFA, whereas emotion facilitates memory for real-life events in AD. Disrupted emotional memory enhancement in PNFA is associated with reduced emotion recognition ability, suggesting that widespread emotion processing dysfunction is present in this disease. Crucially, loss of emotional enhancement influences carer wellbeing, which represents an important avenue for future studies to examine.
Pages 211-226
Giuseppina Amadoro*, Veronica Corsetti*, Giulia Maria Sancesario, Adele Lubrano, Gaia Melchiorri, Sergio Bernardini, Pietro Calissano, Giuseppe Sancesario (Handling Associate Editor: Barbara Borroni) *These authors contributed equally to this work.
Cerebrospinal Fluid Levels of a 20-22 kDa NH2 Fragment of Human Tau Provide a Novel Neuronal Injury Biomarker in Alzheimer’s Disease and Other Dementias
Abstract: Truncation at N-terminal domain of tau protein is early associated with neurofibrillary pathology in several human tauopathies, including Alzheimer’s disease (AD). In affected subjects, the monitoring of total (t-tau) and/or phosphorylated tau (p-tau) levels in cerebrospinal fluid (CSF) provides a reliable, indirect evaluation of cellular changes occurring in vivo and the identification of additional CSF biomarkers would better assist with the clinical practice, allowing a broader profile of underlying ongoing neurodegeneration. Here we show that a 20-22 kDa NH2-truncated form of human tau (i.e., NH2htau), a neurotoxic fragment of the full length protein (htau40) that we previously found in synapses from subjects affected by different tauopathies: (i) is not a normal constituent of CSF, unlike t-tau and p-tau, being exceptionally detected in patients without cognitive impairment; (ii) discriminates, with a weak specificity of 65% but a high sensitivity of 85%, patients carrying a large spectrum of neurodegenerative diseases associated with cognitive deterioration (i.e., AD, frontotemporal lobar degeneration, Parkinson’s disease with dementia, vascular dementia, mixed dementia, etc.) from subjects affected by other neurological disorders without mnesic disability; and (iii) is a neuronal injury biomarker as its levels in CSF are not related to the severity and progression of cognitive decline. The dynamic evaluation of NH2htau in CSF might add some useful hints in the ordinary clinical practice as it provides a novel, general biomarker for human tauopathies and other neurodegenerative diseases associated with dementia.
Pages 227-245
Nazia Maroof, Srinivasarao Ravipati, Marie Christine Pardon, David A. Barrett, David A. Kendall
Reductions in Endocannabinoid Levels and Enhanced Coupling of Cannabinoid Receptors in the Striatum are Accompanied by Cognitive Impairments in the AβPPswe/PS1ΔE9 Mouse Model of Alzheimer’s Disease
Abstract: Alterations in the endocannabinoid system (ECS) are thought to play a role in learning and memory impairments observed in Alzheimer’s disease (AD). We aimed to determine the status of the brain ECS in the AβPPswe/PS1∆E9 model of AD. The ECS comprises the neuromodulatory lipid endocannabinoids, anandamide and 2-arachidonoyl glycerol (2AG), which interact with the G protein-coupled type-1 and type-2 cannabinoid receptors. Using mass spectrometry, we quantified endocannabinoid levels and assessed lipidomic profiles of the frontal cortex, hippocampus, and striatum of 4 -8 month old wildtype and AβPPswe/PS1∆E9 mice to determine whether regional variations in endocannabinoids and lipid metabolism are observed with age and disease progression. Additionally, open-field activity, performance in the contextual fear conditioning task, and various other tasks assessing spatial and recognition memory were examined to determine the influence of age and pathology on these parameters. At all ages, AβPPswe/PS1∆E9 mice were significantly hyperactive in the open-field and acquired contextual fear as well as wildtype mice, reflecting intact associative learning. They, however, exhibited enhanced contextual fear memory and reduced contextual fear extinction regardless of age. Disturbances in striatal lipid metabolism were observed in 6 and 8 month old AβPPswe/PS1∆E9 mice. Endocannabinoids increased significantly with age in the hippocampus and frontal cortex of both genotypes. 8 month old AβPPswe/PS1∆E9 mice displayed significantly lower levels of striatal 2AG than wildtype mice, but greater cannabinoid receptor/effector coupling. This study shows that alterations in lipid metabolism and endocannabinoid signaling develop with age in AβPPswe/PS1∆E9 mice, possibly contributing to the development of AD-like behavioral deficits.
Pages 247-260
Joanna Suszyńska-Zajczyk, Magdalena Łuczak, Łukasz Marczak, Hieronim Jakubowski (Handling Associate Editor: Sudha Seshadri)
Inactivation of the Paraoxonase 1 Gene Affects the Expression of Mouse Brain Proteins Involved in Neurodegeneration
Abstract: Homocysteine (Hcy) is a risk factor for Alzheimer’s disease (AD). Paraoxonase 1 (Pon1) participates in Hcy metabolism and is also linked to AD. The inactivation of the Pon1 gene in mice causes the accumulation of Hcy-thiolactone in the brain and increases the susceptibility to Hcy-thiolactone-induced seizures. To gain insight into the brain-related Pon1 function, we used two-dimensional IEF/SDS-PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to study brain proteomes of Pon1-/- and Pon1+/+ mice fed with a hyperhomocysteinemic high-methionine (Met) or a control diet. We found that: 1) proteins involved in brain-specific function (Nrgn), antioxidant defenses (Sod1, DJ-1), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Pon1-null mice; 2) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1), antioxidant defenses (Prdx2, DJ-1), energy metabolism (Ak1), cell cycle (GDI1, Ran), cytoskeleton assembly (Tbcb), and unknown function (Hdhd2) showed differential expression in brains of Pon1-null fed with a hyperhomocysteinemic high-Met diet; 3) most proteins regulated by the Pon1-/- genotype were also regulated by the high-Met diet; 4) the proteins differentially expressed in Pon1-null mouse brains play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Pon1 interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that these interactions are modulated by hyperhomocysteinemia and account for the involvement of Hcy and Pon1 in AD.
Pages 261-273
Helena S. Moreira*, César F. Lima*, Selene G. Vicente *These authors contributed equally to this work.
Examining Executive Dysfunction with the Institute of Cognitive Neurology (INECO) Frontal Screening (IFS): Normative Values from a Healthy Sample and Clinical Utility in Alzheimer’s Disease
Abstract: Background. The Institute of Cognitive Neurology (INECO) Frontal Screening (IFS) is a brief neuropsychological tool recently devised for the evaluation of executive dysfunction in neurodegenerative conditions. Objective. In this study we present a cross-cultural validation of the IFS for the Portuguese population, provide normative values from a healthy sample, determine how age and education affect performance, and inspect its clinical utility in the context of Alzheimer’s disease (AD). A comparison with the Frontal Assessment Battery (FAB) was undertaken, and correlations with other well-established executive functions measures were examined. Methods. The normative sample included 204 participants varying widely in age (20–85 years) and education (3–21 years). The clinical sample (n = 21) was compared with a sample of age- and education-matched controls (n = 21). Healthy participants completed the IFS and the Mini-Mental State Examination (MMSE). In addition to these, the patients (and matched controls) completed the FAB and a battery of other executive tests. Results. IFS scores were positively affected by education and MMSE, and negatively affected by age. Patients underperformed controls on the IFS, and correlations were found with the Clock Drawing Test, Stroop test, and the Zoo Map and Rule Shift Card tests of The Behavioral Assessment of the Dysexecutive Syndrome. A cut-off of 17 optimally differentiated patients from controls. While 88% of the IFS sub-tests discriminated patients from controls, only 67% of the FAB sub-tests did so. Conclusion. Age and education should be taken into account when interpreting performance on the IFS. The IFS is useful to detect executive dysfunction in AD, showing good discriminant and concurrent validities.
Pages 275-289
Mark W. Bondi, Emily C. Edmonds, Amy J. Jak, Lindsay R. Clark, Lisa Delano-Wood, Carrie R. McDonald, Daniel A. Nation, David J. Libon, Rhoda Au, Douglas Galasko, David P. Salmon, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Jason Brandt)
Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates
Abstract: We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n=846; CN: n=304) or Jak/Bondi criteria (MCI: n=401; CN: n=749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method’s susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.
Pages 291-300
Kamolika Roy, Lesley C. Pepin, Marlie Philiossaint, Natacha Lorius, J. Alex Becker, Joseph J. Locascio, Dorene M. Rentz, Reisa A. Sperling, Keith A. Johnson, Gad A. Marshall, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Duygu Tosun-Turgut)
Regional Fluorodeoxyglucose Metabolism and Instrumental Activities of Daily Living across the Alzheimer’s Disease Spectrum
Abstract: Background: Impairment in instrumental activities of daily living (IADL) begins as individuals with amnestic mild cognitive impairment (MCI) transition to Alzheimer’s disease (AD) dementia. IADL impairment in AD dementia has been associated with inferior parietal, inferior temporal, and superior occipital hypometabolism using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Objective: To investigate the relationship between regional FDG metabolism and IADL in clinically normal (CN) elderly, MCI, and mild AD dementia subjects cross-sectionally and longitudinally. Methods: One hundred and four CN, 203 MCI, and 95 AD dementia subjects from the Alzheimer’s Disease Neuroimaging Initiative underwent clinical assessments every 6 to 12 months for up to three years and baseline FDG PET. The subjective, informant-based Functional Activities Questionnaire was used to assess IADL. General linear models and mixed effects models were used, covarying for demographics, cognition, and behavior. Results: The cross-sectional analysis revealed middle frontal and orbitofrontal hypometabolism were significantly associated with greater IADL impairment. Additionally, the interaction of diagnosis with posterior cingulate and with parahippocampal hypometabolism showed a greater decline in IADL performance as metabolism decreased for the AD dementia relative to the MCI group, and the MCI group relative to the CN group. The longitudinal analysis showed that baseline middle frontal and posterior cingulate hypometabolism were significantly associated with greater rate of increase in IADL impairment over time. Conclusion: These results suggest that regional synaptic dysfunction, including the Alzheimer-typical medial parietal and less typical frontal regions, relates to daily functioning decline at baseline and over time across the early AD spectrum.
Pages 301-312
Carolina Martin, Luis Leyton, Yennyfer Arancibia, Alexei Cuevas, Angara Zambrano, Margarita I. Concha, Carola Otth
Modulation of the AMPK/Sirt1 Axis During Neuronal Infection by Herpes Simplex Virus Type 1
Abstract: Currently, it is unclear whether a neuron that undergoes viral reactivation and produces infectious particles survives and resumes latency or is killed, which is intriguing even if still unanswered. Previous reports have shown that herpes simplex virus type 1 (HSV-1) inhibits apoptosis during early infection, but is pro-apoptotic during productive infection. Taking in consideration that the stress sensors AMPK and Sirt1 are involved in neuronal survival and neuroprotection, we hypothesized that HSV-1 could activate the AMPK/Sirt1 axis as a strategy to establish latency through inhibition of apoptosis and restoration of the energy status. These effects could be accomplished through deacetylation of pro-apoptotic protein p53 and regulation of the master regulator of mitochondrial biogenesis and function PGC-1α and its target gene TFAM. Accordingly, we evaluated the AMPK/Sirt1 axis and its targets p53, PGC-1α, and acetyl CoA carboxylase in mice neuronal cultures infected with HSV-1 by western blot, RT-qPCR, and immunofluorescence analyses. Herein, we show that HSV-1 differentially modulates the AMPK/Sirt1 axis during the course of infection. In fact, during early infection (2 hpi) activated AMPK (p-AMPK) was down-regulated, but thereafter recovered gradually. In contrast, the levels of acetylated-p53 increased during the first hours post infection, but afterwards were reduced in parallel with the activation of Sirt1. However, acetylated-p53 peaked again at 18 hpi during productive infection, suggesting an activation of apoptosis. Strikingly, acetylated-p53, Sirt1, and p-AMPK apparently translocate from the nucleus to the cytoplasm after 4 hpi, where they accumulate in discrete foci in the perinuclear region. These results suggest that HSV-1 modulates the AMPK/Sirt1 axis differentially during the course of infection interfering with pro-apoptotic signaling and regulating mitochondrial biogenesis.
Pages 313-324
Debolina Ghosh, Gregory J Brewer (Handling Associate Editor: Debomoy Lahiri)
External cys/cySS Redox State Modification Controls the Intracellular Redox State and Neurodegeneration via Akt in Aging and Alzheimer’s Disease Mouse Model Neurons
Abstract: The extracellular redox environment of cells is mainly set by the redox couple cysteine/cystine (cys/cySS) while intracellular redox is buffered by reduced/oxidized glutathione (GSH/GSSG), but controlled by NAD(P)H/NAD(P). With aging, the extracellular redox environment shifts in the oxidized direction beyond middle-age. Since aging is the primary risk factor in Alzheimer’s disease (AD), here our aim was to determine if a reduced extracellular cys/cySS redox potential of cultured primary mouse neurons changes the intracellular redox environment, affects pAkt levels, and protects against neuron loss. A reductive shift in cys/cySS in the extracellular medium of neuron cultures from young (4 month) and old (21 month) neurons from non-transgenic) and triple transgenic AD-like mice (3xTg-AD) caused an increase in intracellular NAD(P)H and GSH levels along with lower reactive oxygen species levels. Importantly, the imposed reductive shift decreased neuron death markedly in the 21 month neurons of both genotypes. Moreover, a reduced cys/cySS redox state increased the pAkt/Akt ratio in 21 month aging and AD-like neurons that positively correlated with a decreased neuron loss. Our findings demonstrate that manipulating the extracellular redox environment toward a more reduced redox potential is neuroprotective in both aging and AD-like neurons and may be a powerful and pragmatic therapeutic tool in aging and age-related diseases like AD.
Pages 325-332
Javier Olazarán, Belén González, Emma Osa-Ruiz, Silvia Felipe-Ruiz, Inmaculada Boyano, Vania Fontani, Alessandro Castagna, Carolina Mendoza, María Ascensión Zea, Belén Frades, Salvatore Rinaldi, Pablo Martínez-Martín
Motor Effects of Radio Electric Asymmetric Conveyer in Alzheimer’s Disease: Results from a Cross-Over Trial
Abstract: We conducted a randomized, cross-over trial to investigate the feasibility, safety, and motor effects of brain stimulation with radio electric asymmetric conveyer (REAC) technique in patients with Alzheimer’s disease (AD). Neuropostural optimization (NPO) and sham protocol were administered to 60 patients from the nursing home and day care units of the Alzheimer Center Reina Sofía Foundation. The mean age was 84.1 (SD 7.9) years and 86.7% of the subjects were female. Motor measures were collected at baseline (T1), immediately (T2), seven (T3), and 11 days (T4) after treatment and, following cross-over, immediately (T5), seven (T6), and 11 (T7) days after treatment. Close safety surveillance was conducted from seven days before T1 to the end of the study (T7), with total study duration of 35 days. Wilcoxon test was utilized in the efficacy analysis, considering T1 and T5 as independent baseline assessments and using a threshold of p<0.05 (corrected) for statistical significance. The NPO protocol was easily administered and well accepted by the participants. Axial movements improved at T3 and T4 after NPO and at T2 after sham NPO, but no significant effects were observed in axial movements in the second phase of the trial. The effects of NPO in gait performance were not consistent. There were six falls between T2 and T7, but only two of them occurred in patients who had received NPO. In light of safety and feasibility of REAC, a trial with the more intense neuropsycho-physical optimization protocol is warranted.
Pages 333-344
Jhansi Rani Vangavaragu, Koteswara Rao Valasani, Du Fang, Todd D. Williams, Shirley ShiDu Yan (Handling Associate Editor: Hemachandra Reddy)
Determination of Small Molecule ABAD Inhibitors Crossing Blood-Brain Barrier and Pharmacokinetics
Abstract: A major obstacle to the development of effective treatment of Alzheimer’s disease (AD) is successfully delivery of drugs to the brain. We have previously identified a series of benzothiazole phosphonate compounds that block the interaction of amyloid-β peptide with amyloid-β binding alcohol dehydrogenase (ABAD). A selective and sensitive method for the presence of three new benzothiazole ABAD inhibitors in mouse plasma, brain, and artificial cerebrospinal fluid has been developed and validated based on high performance liquid chromatography tandem mass spectrometry. Mass spectra were generated using Micromass Quattro Ultima “triple” quadrupole mass spectrometer equipped with an Electrospray Ionization interface. Good linearity was obtained over a concentration range of 0.05-2.5 μg/ml. The lowest limit of quantification and detection was found to be 0.05 μg/ml. All inter-day accuracies and precisions were within ±15% of the nominal value and ±20%, respectively, at the lower limit of quantitation. The tested compounds were stable at various conditions with recoveries >90.0% (RSD<10%). The method used for pharmacokinetic studies of compounds in mouse cerebrospinal fluid, plasma, and brain is accurate, precise, and specific with no matrix effect. Pharmacokinetic data showed these compounds penetrate the blood-brain barrier yielding 4-50 ng/ml peak brain concentrations and 2 μg/ml peak plasma concentrations from a 10 mg/kg dose. These results indicate that our newly synthesized small molecule ABAD inhibitor have a good drug properties with the ability to cross the blood-brain barrier, which holds a great potential for AD therapy.
