Pages 655-661
Ethics Review
Andrea Tales, Gordon K. Wilcock, Judith E. Phillips, Antony Bayer
Is There More to Subjective Cognitive Impairment than Meets the Eye? A Perspective
Pages 663-664
Review Response
Allyson C. Rosen
Is There More to Subjective Cognitive Impairment than Meets the Eye? Obligations and Opportunities
Pages 665-666
Review Response
Andrea Tales, Gordon K. Wilcock, Judith E. Phillips, Antony Bayer
Is There More to Subjective Cognitive Impairment than Meets the Eye? Raising Awareness
Pages 667-669
Editorial
Thomas B. Shea, Eugene Rogers
Has Prenatal Folate Supplementation Established an At-Risk Population for Age-Related Cognitive Decline?
Abstract: Nutrition exerts a pervasive impact on normal and pathological conditions of the nervous system throughout life. Maternal folate supplementation during pregnancy has reduced developmental disorders of the nervous system, but may have also fostered an increase in individuals harboring genetic polymorphisms that compromise folate usage. Such individuals may harbor a lifetime requirement for additional dietary folate, often not met beyond peri/postnatal periods. An increased association of such polymorphisms has been detected in individuals with autism. Prenatal nutritional supplementation may have inadvertently established latent conditions that, in the absence of continued supplementation, may lead to age-related cognitive decline.
Pages 671-684
Review
Parvathi Rudrabhatla
Regulation of Neuronal Cytoskeletal Protein Phosphorylation in Neurodegenerative Diseases
Abstract: Neuronal cytoskeletal proteins such as neurofilaments (NFs) and tau are aberrantly and hyperphosphorylated in neurodegeneration. Under normal physiological conditions, NFs are synthesized in the cell bodies and phosphorylated and transported in the axonal compartment. However, under neurodegenerative disorders such as Alzheimer’s disease (AD), spinal cord motor neuron inclusions of amyotrophic lateral sclerosis, Lewy bodies of Parkinson’s disease, Pick’s disease, Charcot-Marie-Tooth disease, and diabetic neuropathy, NFs are aberrantly and hyperphosphorylated in cell bodies. The proline directed protein kinases, such as cyclin-dependent protein kinase 5, mitogen activated protein kinase, and glycogen synthase kinase 3β, and the non proline-directed kinases, such as casein kinase 1, are deregulated in AD. Moreover, the reversible phosphorylation by protein phosphatase, PP2A, which mainly carries out the dephosphorylation of tau and NFs, is down regulated in AD brain. The aberrant phosphorylation of cytoskeletal proteins such as tau and NFs results in the axonal transport defects in neurodegeneration. The peptidyl-prolyl isomerase Pin1 plays a regulatory role in the post-phosphorylation mechanism of neuronal cytoskeletal proteins in AD brain. Possible therapeutic interventions for neurodegenerative disorders are 1) inhibition of proline-directed kinases, 2) activation of protein phosphatases such as PP2A, and 3) modulation of peptidyl-prolyl isomerases such as Pin1. Here, I discuss the regulation of neuronal cytoskeletal proteins under physiology and pathology.
Pages 685-708
Review
Farshad Falahati*, Eric Westman*, Andrew Simmons (Handling Associate Editor: Patrizia Mecocci) *These authors contributed equally to this work.
Multivariate Data Analysis and Machine Learning in Alzheimer’s Disease with a Focus on Structural Magnetic Resonance Imaging
Abstract: Machine learning algorithms and multivariate data analysis methods have been widely utilized in the field of Alzheimer’s disease (AD) research in recent years. Advances in medical imaging and medical image analysis have provided a means to generate and extract valuable neuroimaging information. Automatic classification techniques provide tools to analyze this information and observe inherent disease-related patterns in the data. In particular, these classifiers have been used to discriminate AD patients from healthy control subjects and to predict conversion from mild cognitive impairment to AD. In this paper, recent studies are reviewed that have used machine learning and multivariate analysis in the field of AD research. The main focus is on studies that used structural magnetic resonance imaging (MRI), but studies that included positron emission tomography and cerebrospinal fluid biomarkers in addition to MRI are also considered. A wide variety of materials and methods has been employed in different studies, resulting in a range of different outcomes. Influential factors such as classifiers, feature extraction algorithms, feature selection methods, validation approaches, and cohort properties are reviewed, as well as key MRI-based and multi-modal based studies. Current and future trends are discussed.
Pages 709-714
Short Communication
Silvia Testi*, Silvio Peluso*, Gian Maria Fabrizi, Antonella Antenora, Cinzia Valeria Russo, Sabina Pappatà, Alessandro Padovani, Moreno Ferrarini, Alessandro Filla (Handling Associate Editor: Ottavio Arancio) *These authors contributed equally to this work.
A Novel PSEN1 Mutation in a Patient with Sporadic Early-Onset Alzheimer’s Disease and Prominent Cerebellar Ataxia
Abstract: PSEN1 gene mutations represent the first cause of familiar early-onset Alzheimer’s disease (EOAD). More than 190 mutations in PSEN1 have been reported to date. The clinical phenotype is mainly characterized by cognitive decline but movement disorders have been rarely described. We report a novel PSEN1 mutation (p.Thr147Pro) responsible for a sporadic early-onset dementia with prominent cerebellar symptoms, resembling a spinocerebellar syndrome. Neuroradiological and cerebrospinal fluid biomarkers examinations were performed on the patient, showing typical findings of EOAD and suggesting the pathogenicity of the novel mutation. Our study widens the number of unusual phenotypes related to PSEN1 mutations.
Pages 715-717
Commentary Tobias Hartmann, Nick van Wijk, Richard J. Wurtman, Marcel G.M. Olde Rikkert, John W.C. Sijben, Hilkka Soininen, Bruno Vellas, Philip Scheltens
A Nutritional Approach to Ameliorate Altered Phospholipid Metabolism in Alzheimer’s Disease
Abstract: Recently, a biomarker panel of 10 plasma lipids, including 8 phosphatidylcholine species, was identified that could predict phenoconversion from cognitive normal aged adults to amnestic mild cognitive impairment or Alzheimer’s disease (AD) within 2–3 years with >90% accuracy. The reduced levels of these plasma phospholipids could reflect altered phospholipid metabolism in the brain and periphery. We show that a 24-week nutritional intervention in drug-naïve patients with very mild to mild AD significantly increased 5 of the 7 measured biomarker phosphatidylcholine species. By providing nutrients which normally rate-limit phospholipid synthesis, this nutritional intervention could be useful in asymptomatic subjects with a plasma lipid biomarker profile prognostic of AD.
Pages 719-728
Gad A. Marshall, Natacha Lorius, Joseph J. Locascio, Bradley T. Hyman, Dorene M. Rentz, Keith A. Johnson, Reisa A. Sperling, for the Alzheimer’s Disease Neuroimaging Initiative
Regional Cortical Thinning and Cerebrospinal Biomarkers Predict Worsening Daily Functioning Across the Alzheimer’s Disease Spectrum
Abstract: Background: Impairment in instrumental activities of daily living (IADL) heralds the transition from mild cognitive impairment (MCI) to dementia and is a major source of burden for both the patient and caregiver. Objective: To investigate the relationship between IADL and regional cortical thinning and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarkers cross-sectionally and longitudinally in clinically normal (CN) elderly, MCI, and mild AD dementia subjects. Methods: Two hundred and twenty nine CN, 395 MCI, and 188 AD dementia subjects participating in the Alzheimer’s Disease Neuroimaging Initiative underwent baseline magnetic resonance imaging, baseline lumbar puncture, and clinical assessments, including the Functional Activities Questionnaire used to measure IADL, every 6 to 12 months up to 3 years. General linear regression and mixed effects models were employed. Results: IADL impairment was associated with the interactions between lower inferior temporal cortical thickness and diagnosis (p<0.0001), greater lateral occipital cortical thickness and diagnosis (p<0.0001), and greater amyloid-β 1-42 (Aβ1-42) and diagnosis (p=0.0002) at baseline (driven by AD dementia). Lower baseline supramarginal (p=0.02) and inferior temporal (p=0.05) cortical thickness, lower Aβ1-42 (p<0.0001), and greater total tau (t-tau) (p=0.02) were associated with greater rate of IADL impairment over time. Conclusions: Temporal atrophy is associated with IADL impairment in mild AD dementia at baseline, while baseline parietal and temporal atrophy, lower CSF Aβ1-42, and greater t-tau predict worsening IADL impairment over time across the AD spectrum. These results emphasize the importance of assessing IADL at the stage of MCI and even at the transition from CN to MCI.
Pages 729-737
Jin Chu, Elisabetta Lauretti, Caryne P. Craige, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
Pharmacological Modulation of GSAP Reduces Amyloid-β Levels and Tau Phosphorylation in a Mouse Model of Alzheimer’s Disease with Plaques and Tangles
Abstract: Accumulation of neurotoxic amyloid-β (Aβ) is a major hallmark of Alzheimer’s disease (AD) pathology and an important player in its clinical manifestations. Formation of Aβ is controlled by the availability of an enzyme called γ-secretase. Despite its blockers being attractive therapeutic tools for lowering Aβ, this approach has failed because of their serious toxic side-effects. The discovery of the γ-secretase activating protein (GSAP), a co-factor for this protease which facilitates Aβ production without affecting other pathways responsible for the toxicity, is giving us the opportunity to develop a safer anti-Aβ therapy. In this study we have characterized the effect of Imatinib, an inhibitor of GSAP, in the 3xTg mice, a mouse model of AD with plaques and tangles. Compared with controls, mice receiving the drug had a significant reduction in brain Aβ levels and deposition, but no changes in the steady state levels of AβPP, BACE-1, ADAM-10, or the four components of the γ-secretase complex. By contrast, Imatinib-treated animals had a significant increase in CTF-β and a significant reduction in GSAP expression levels. Additionally, we observed that tau phosphorylation was reduced at specific epitopes together with its insoluble fraction. In vitro studies confirmed that Imatinib prevents Aβ formation by modulating γ-secretase activity and GSAP levels. Our findings represent the first in vivo demonstration of the biological role that GSAP plays in the development of the AD-like neuropathologies. They establish this protein as a viable target for a safer anti-Aβ therapeutic approach in AD.
Pages 739-748
Montserrat Alegret, Gemma Cuberas-Borrós, Ana Espinosa, Sergi Valero, Isabel Hernández, Agustín Ruíz, James T. Becker, Maitée Rosende-Roca, Ana Mauleón, Oscar Sotolongoa, Joan Castell-Conesa, Isabel Roca, Lluís Tárraga, Mercè Boada
Cognitive, Genetic, and Brain Perfusion Factors Associated with Four Year Incidence of Alzheimer’s Disease from Mild Cognitive Impairment
Abstract: Background: There is a range of factors that predict the development of Alzheimer’s disease (AD) dementia among patients with amnestic mild cognitive impairment (MCI). Objectives: To identify the neuropsychological, genetic, and functional brain imaging data that best predict conversion to AD dementia in patients with amnestic MCI. Methods: From an initial group of 42 amnestic MCI patients assessed with neurological, neuropsychological, and brain SPECT, 39 (25 converters, 14 non-converters) were followed for 4 years, and 36 had APOE ε4 genotyping. Baseline neuropsychological data and brain SPECT data were used to predict which of the MCI patients would develop dementia by the end of the 4 years of observation. Results: The MCI patients who had converted to AD dementia had poorer performance on long-term visual memory and Semantic Fluency tests. The MCI subjects who developed dementia were more likely to carry at least one copy of the APOE ε4 allele (Hazard Risk = 4.22). There was lower brain perfusion in converters than non-converters, mainly in postcentral gyrus. An additional analysis of the SPECT data found differences between the MCI subjects and controls in the posterior cingulate gyrus and the basal forebrain. When the brain imaging and neuropsychological test data were combined in the same Cox regression model, only the neuropsychological test data were significantly associated with time to dementia. Conclusion: Although the presence of reduced brain perfusion in postcentral gyrus and basal forebrain indicated an at-risk condition, it was the extent of memory impairment that was linked to the speed of decline from MCI to AD.
Pages 749-758
Henry Ka-Fung Mak, Wenshu Qian, Kwok Sing Ng, Queenie Chan, You-Qiang Song, Leung Wing Chu, Kelvin Kai-Wing Yau (Handling Associate Editor: J. Wesson Ashford)
Combination of MRI Hippocampal Volumetry and Arterial Spin Labeling MR Perfusion at 3-Tesla Improves the Efficacy in Discriminating Alzheimer’s Disease from Cognitively Normal Elderly Adults
Abstract: Background: Structural magnetic resonance imaging has been employed for evaluation of medial temporal atrophy in patients with Alzheimer’s disease (AD). Arterial spin labeling (ASL) technique could detect cerebral perfusion abnormalities in AD. Objective: We hypothesized that combination of hippocampal volumetry and cerebral blood flow yield higher accuracy than either method alone in discriminating AD patients from cognitively normal older adults. Materials and Methods: 13 AD patients and 15 healthy controls were studied using a 3-tesla scanner. Standardized T1W 3D volumetric Fast Field Echo and QUASAR ASL sequences were employed for cerebral volumetry and perfusion respectively. Manual right and left hippocampal volumetry was performed by ANALYZE software, with total intracranial volume normalization. ASL data were analyzed by institutional specially-design software to calculate cerebral blood flow of region-of-interests placed at the middle and posterior cingulate gyri. Results: Right and left hippocampal volumes and middle and posterior cingulate gyri cerebral blood flows were significantly lower in the patients than in the controls (independent-samples t-tests , p<0.05), and prediction accuracies of 89.3%, 82.1% 75.0%, and 71.4% were achieved for each of the above parameters, respectively. In distinguishing patients from controls using corresponding optimized cut-off values, various combinations of these parameters were used to create the Receiver Operating Characteristic curves. The highest area under curve value was 0.944, by combining cerebral blood flow at the middle cingulate gyrus, normalized right and left hippocampal volumes. Conclusions: A ‘one-stop-shop’ magnetic resonance study of combined hippocampal volumetry and cerebral perfusion has improved efficacy in discriminating AD patients from cognitively normal older adults.
Pages 759-763
Commentary
J. Wesson Ashford, Ansgar J. Furst
Advancing Brain Imaging for Alzheimer’s Disease: Integrating Anatomic and Physiologic Measures
Pages 765-778
Takashi Tarumi, David I. Dunsky, M. Ayaz Khan, Jie Liu, Candace Hill, Kyle Armstrong, Kristin Martin-Cook, C. Munro Cullum, Rong Zhang (Handling Associate Editor: Jurgen Claassen)
Dynamic Cerebral Autoregulation and Tissue Oxygenation in Amnestic Mild Cognitive Impairment
Abstract: Background: Vascular disease and dysfunction are associated with the higher risk of Alzheimer’s disease hypothetically due to cerebral hypoperfusion. Brain perfusion is protected by cerebral autoregulation, which, under normal conditions, maintains a constant cerebral blood flow and brain tissue oxygenation. Objective: To determine whether dynamic regulation of cerebral blood flow and tissue oxygenation is impaired in patients with amnestic mild cognitive impairment (aMCI). Methods: Twenty-seven patients with aMCI and 15 control subjects with normal cognitive function underwent the measurements of cerebral hemodynamics, brain MR imaging, and neurocognitive assessment. Dynamic regulation of cerebral blood flow and tissue oxygenation were assessed by transfer function analysis of changes in mean blood pressure (MBP), normalized cerebral blood flow velocity (CBFV%), and cerebral tissue oxygenation index (TOI) at baseline and during a sit-stand maneuver. Results: Patients with aMCI demonstrated lower cognitive performance in memory and executive function, accompanied by smaller entorhinal cortex volumes. At baseline, cerebral TOI was lower in patients with aMCI than in control subjects. Lower cerebral TOI was also correlated with lower cognitive performance in memory and executive function in all subjects. Transfer function gain and phase between MBP and CBFV% and between CBFV% and cerebral TOI were not different between the groups. Within aMCI patients, greater oscillations of cerebral TOI and higher transfer function gain between cerebral TOI and CBFV% were associated with the lower scores on delayed recall. Conclusion: Dynamic regulation of cerebral tissue oxygenation is associated with neurocognitive dysfunction in aMCI patients.
Pages 779-791
Andreas Engvig, Anders M. Fjell, Lars T. Westlye, Nina V. Skaane, Anders M. Dale, Dominic Holland, Paulina Due-Tønnessen, Øyvind Sundseth, Kristine B. Walhovd
Effects of Cognitive Training on Gray Matter Volumes in Memory Clinic Patients with Subjective Memory Impairment
Abstract: Subjective memory impairment (SMI) is a common risk factor for Alzheimer’s disease, with few established options for treatment. Here we investigate the effects of two months episodic memory training on regional brain atrophy in 19 memory clinic patients with SMI. We used a sensitive longitudinal magnetic resonance imaging protocol and compared the patients with 42 matched healthy volunteers randomly assigned to a group performing the same training, or a no-training control group. Following intervention, the SMI sample exhibited structural gray matter volume increases in brain regions encompassing the episodic memory network, with cortical volume expansion of comparable extent as healthy training participants. Further, we found significant hippocampal volume increases in the healthy training group but not in the SMI group. Still, individual differences in left hippocampal volume change in the patient group were related to verbal recall improvement following training. The present results reinforce earlier studies indicating intact brain plasticity in aging, and further suggest that training-related brain changes can be evident also in the earliest form of cognitive impairment.
Pages 793-800
Grace J. Lee, Po H. Lu, Michelle J. Mather, Jill Shapira, Elvira Jimenez, Alex D. Leow, Paul M. Thompson, Mario F. Mendez
Neuroanatomical Correlates of Emotional Blunting in Behavioral Variant Frontotemporal Dementia and Early-Onset Alzheimer’s Disease
Abstract: Background: Emotional blunting is a characteristic feature of behavioral variant frontotemporal dementia (bvFTD) and can help discriminate between patients with bvFTD and other forms of younger-onset dementia. Objective: We compared the presence of emotional blunting symptoms in patients with bvFTD and early-onset Alzheimer’s disease (AD), and investigated the neuroanatomical associations between emotional blunting and regional brain volume. Methods: Twenty-five individuals with bvFTD (n=11) and early-onset AD (n=14) underwent magnetic resonance imaging (MRI) and were rated on symptoms of emotional blunting using the Scale for Emotional Blunting (SEB). The two groups were compared on SEB ratings and MRI-derived brain volume using tensor-based morphometry. Voxel-wise linear regression was performed to determine neuroanatomical correlates of SEB scores. Results: The bvFTD group had significantly higher SEB scores compared to the AD group. On MRI, bvFTD patients had smaller bilateral frontal lobe volume compared to AD patients, while AD patients had smaller bilateral temporal and left parietal volume than bvFTD patients. In bvFTD, SEB ratings were strongly correlated with right anterior temporal volume, while the association between SEB and the right orbitofrontal cortex was non-significant. Conclusions: Symptoms of emotional blunting were more prevalent in bvFTD than early-onset AD patients. These symptoms were particularly associated with right-sided atrophy, with significant involvement of the right anterior temporal region. Based on these findings, the SEB appears to measure symptoms of emotional blunting that are localized to the right anterior temporal lobe.
Pages 801-807
Marissa Zwan, Argonde van Harten, Rik Ossenkoppele, Femke Bouwman, Charlotte Teunissen, Sofie Adriaanse, Adriaan Lammertsma, Philip Scheltens, Bart van Berckel, Wiesje van der Flier (Handling Associate Editor: Henryk Barthel)
Concordance Between Cerebrospinal Fluid Biomarkers and [11C]PIB PET in a Memory Clinic Cohort
Abstract: Background: Two approaches are available for measuring Alzheimer’s disease (AD) pathology in vivo. Biomarkers in cerebrospinal fluid (CSF) include amyloid-β1-42 (Aβ42) and tau. Furthermore, amyloid deposition can be visualized using positron emission tomography (PET) and [11C]Pittsburgh compound-B ([11C]PIB). Objective: We investigated concordance between CSF biomarkers and [11C]PIB PET as markers for AD pathology in a memory clinic cohort. Methods: We included 64 AD patients, 34 non-AD dementia patients, 22 patients with mild cognitive impairment (MCI), and 16 controls. [11C]PIB scans were visually rated as positive or negative. CSF biomarkers were considered abnormal based on Aβ42 alone (<550 ng/L), a more lenient Aβ42 cut-off (<640 ng/L) or a combination of both Aβ42 and tau ((373+0.82tau)/Aβ42>1). Concordance between CSF biomarkers and [11C]PIB PET was determined. Results: Overall, concordance between [11C]PIB PET and CSF Aβ42 (<550 ng/L) was 84%. In discordant cases, [11C]PIB PET was more often AD-positive than Aβ42. When a more lenient Aβ42 cut-point (<640 ng/L) or a combination of Aβ42 and tau was used, concordance with [11C]PIB PET appeared to be even higher (90% and 89%). This difference is explained by a subgroup of mostly MCI and AD patients with Aβ42 levels just above cut-off. Now, in discordant cases CSF was more often AD-positive than [11C]PIB PET. Conclusion: Concordance between CSF Aβ42 and [11C]PIB PET was good in all diagnostic groups. Discordance was mostly seen in MCI and AD patients close to the cut-point. These results provide convergent validity for the use of both types of biomarkers as measures of AD pathology.
Pages 809-817
Zvinka Z. Zlatar, Christina E. Wierenga, Katherine J. Bangen, Thomas T. Liu, Amy J. Jak (Handling Associate Editor: Jeff Burns)
Increased Hippocampal Blood Flow in Sedentary Older Adults at Genetic Risk for Alzheimer’s Disease
Abstract: Resting cerebral blood flow (CBF) decreases with age; however regulatory increases in hippocampal CBF have been associated with genetic risk (Apolipoprotein E [APOE] ε4 carriers) for Alzheimer’s disease (AD). Although physical activity exerts beneficial effects on CBF in healthy elderly, the effects of sedentary behaviors on CBF remain unknown. We measured resting hippocampal CBF (via arterial spin labeling magnetic resonance imaging) and sedentary time/physical activity (via accelerometry) on 33 cognitively healthy adults (ages 52-81), 9 of which were APOE ε4 carriers. Results indicate that the relationship between sedentary time and CBF in the left hippocampus differs by APOE status, whereby APOE ε4 carriers show higher CBF as a function of longer sedentary time (B=10.8, β=0.74, t=3.41, p<0.01) compared to noncarriers (B=1.4, SE=2.7, β=0.096, t=0.51, p=0.61), possibly suggesting a CBF regulatory response to compensate for metabolic alterations in dementia risk. These preliminary data suggest that the relationship between CBF and sedentary time is different in APOE carriers and noncarriers and that sedentary time may act as a behavioral risk factor for CBF dysregulation in those at genetic risk for developing AD. More research is needed to further understand the role of sedentary behaviors and physical activity on CBF, especially in individuals at genetic risk of developing AD.
Pages 819-833
Yannick Vermeiren, Debby Van Dam, Tony Aerts, Sebastiaan Engelborghs, Peter P. De Deyn
Brain Region-Specific Monoaminergic Correlates of Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are present during the disease course of nearly all AD patients and consist of psychosis, agitation/aggression, and depression, among others. Given their detrimental consequences regarding life expectancy, cognition, and socio-economic costs, it is essential to elucidate their neurochemical etiology to facilitate the development of novel and effective pharmacotherapeutics. This study attempted to identify brain region-specific monoaminergic correlates of NPS by measuring the levels of eight monoamines and metabolites in nine relevant postmortem brain regions of 40 behaviorally characterized AD patients, i.e., dopamine (DA), serotonin (5-HT), (nor)epinephrine and their respective metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid, 5-hydroxy-3-indoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), using RP-HPLC-ECD. Likewise, Mini-Mental State Examination (MMSE) score correlates of monoaminergic neurotransmitter alterations were calculated. As a result, MMSE scores, used as a measure of dementia severity, correlated positively with hippocampal 5-HIAA levels as well as with 5-HT levels of the superior temporal gyrus and cerebellar cortex. Furthermore, hippocampal 5-HIAA levels inversely correlated with agitation scores, whereas thalamic MHPG levels comparably did with the presence of hallucinations. Finally, in the cerebellar cortex, DOPAC/DA ratios, indicative of DA turnover, correlated with physically agitated behavior while MHPG levels correlated with affective disturbances. These findings support the assumption that specific NPS features in AD might be (in)directly related to brain region-specific monoaminergic neurotransmitter alterations. Additionally, the effect of AD pathology on neurochemical alterations in the cerebellum requires further examination due to its important but underestimated role in the neurochemical pathophysiology of NPS in AD.
Pages 835-844
Yan Zhao*, Hailin Zhao*, Niyati Lobo, Xiangyang Guo, Steve M Gentleman, Daqing Ma *These authors contributed equally to this work.
Celastrol Enhances Cell Viability and Inhibits Amyloid-β Production Induced by Lipopolysaccharide in vitro
Abstract: Background: Neuroinflammation is a notable hallmark of Alzheimer’s disease pathogenesis and can markedly exacerbate amyloid pathology. Celastrol, a pentacyclic-triterpene, has been found to possess anti-inflammatory properties. Objective: The purpose of this study was to characterize the effects of celastrol on cell viability and amyloid-β (Aβ) production induced by lipopolysaccharide (LPS) administration in H4 human neuroglioma cells stably transfected to overexpress human full length APP (H4-APP). Methods: H4-APP cells were exposed to 1, 10, and 100 nM of celastrol in the presence of 0.1 µg/ml or 100 µg/ml of LPS for 24 hours. The effects of celastrol were determined using MTT cell viability assay, immunohistochemistry, western blot, and ELISA. Results: Cell viability tests revealed that H4-APP cells underwent cell death in a dose-dependent manner following administration of LPS. Moreover, celastrol significantly reduced (p < 0.05) cell death induced by LPS compared to LPS alone. Furthermore, the administration of celastrol was associated with a significant reduction in LPS -stimulated Aβ production compared to LPS alone. Western blot and immunofluorescence analysis showed that exposure to celastrol increased HSP-70 and Bcl-2 expression but decreased NFκB activity, phosphorylated glycogen synthase kinase-3β (GSK-3β) at tyrosine 216 and cyclooxygenase-2 (COX-2) expression, Aβ accumulation together with a reduction of superoxide and hydrogen peroxide generation. HSP-70 siRNA abolished celastrol mediated cytoprotection. Conclusion: This study demonstrates that celastrol reduced both LPS-induced inflammation mediated cell death and Aβ production in vitro through increasing HSP-70 and Bcl-2 expression and reducing NFκB, COX-2, and GSK-3β expression and oxidative stress.
Pages 845-854
Carla Cadena-del-Castillo, Christian Valdes-Quezada, Francisco Carmona-Aldana, Clorinda Arias, Federico Bermúdez-Rattoni, Félix Recillas-Targa
Age-Dependent Increment of Hydroxymethylation in the Brain Cortex in the Triple-Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a complex disorder whose etiology is associated with environmental and genetic factors. Recently there have been several attempts to analyze the role of epigenetic alterations in the origin and progression of this neurodegenerative condition. To evaluate the potential participation of the methylation status of the genome that may contribute to AD progression, we have studied the levels and distribution of the 5-methylcytosine and 5-hydroxymethylcytosine in different brain regions at different ages. We analyzed and quantified the immunosignal of these two epigenetic marks in young versus old wild-type mice and in the triple-transgenic mouse model of AD (3xTg-AD). The results show a decline in global 5-methylcytosine mark over time in all studied brain regions concomitant with a notorious and widespread increase in 5-hydroxymethylcytosine mark in the aged transgenic mice in contrast to the age-matched controls. These differences in the methylation pattern of brain DNA in the 3xTg-AD that accumulates along age indicates abnormal formation of permissive chromatin structure associated with the increase in AD-related markers.
Pages 855-865
Yao-Hsiang Shih, Kuen-Jer Tsai, Chu-Wan Lee, Shu-Chu Shiesh, Wei-Ting Chen, Ming-Chyi Pai, Yu-Min Kuo
Apolipoprotein C-III is an Amyloid-β-Binding Protein and an Early Marker for Alzheimer’s Disease
Abstract: It has been demonstrated that peripheral injection of anti-amyloid-β (Aβ) antibodies to patients with Alzheimer’s disease (AD) and AD transgenic mice facilitate Aβ clearance. We hypothesized that peripheral circulating Aβ-binding proteins also possess the ability to enhance Aβ clearance and the levels of circulating Aβ-binding proteins could serve as early AD biomarkers. Circulating Aβ-binding proteins were isolated from plasma and identified by LC-MS/MS. Their levels were compared among non-demented individuals without AD family history (ND), with AD family history (ND-FH), and patients with mild AD. The results showed that most of the identified Aβ-binding proteins were apolipoproteins, i.e., apoA-I, apoB-100, apoC-III, and apoE. Aβ bound preferentially to apoA-I-enriched HDL, followed by apoC-III- and apoE-enriched VLDL, and bound less favorably to apoB-100-enriched LDL. Levels of apoA-I were reduced in AD patients and could be used to discriminate AD from ND groups (AUC: 0.93); whereas levels of apoC-III were reduced in both ND-FH and AD groups and could be used to differentiate ND-FH from ND individuals (AUC: 0.81). Both the levels of apoA-1 and apoC-III positively correlated with CASI and MMSE scores. In conclusion, these results suggest that plasma apoA-I could be a sensitive AD biomarker and individuals with low plasma levels of apoC-III are at risk for AD.
Pages 867-875
Christopher J. Green, Jeffrey M.P. Holly, Antony Bayer, Mark Fish, Shah Ebrahim, John Gallacher, Yoav Ben-Shlomo
The Role of IGF-I, IGF-II, and IGFBP-3 in Male Cognitive Aging and Dementia Risk: The Caerphilly Prospective Study
Abstract: Background: The increasing incidence of cognitive impairment and dementia in an aging population poses a significant burden on healthcare. Consequently, identifying modifiable physiological factors which may influence the onset of cognitive decline are becoming increasingly important. Previous studies have suggested an association between levels of insulin-like growth factors and cognitive function. Objective: To investigate whether low IGF-I, IGF-II, and IGF molar ratio is associated with greater cognitive decline and increased risk of dementia. Methods: We examined prospective associations between IGF-I, IGF-II, and IGFBP-3 and cognitive function in the Caerphilly Prospective Study (CaPS) (n = 746 men) from samples obtained around 1986, with assessment in around 2003 for clinical diagnosis of cognitive impairment but no dementia (CIND) or dementia, as well as with CAMCOG scores at three phases. Results: IGF-II was associated with a reduced odds ratio for CIND (0.76, 95% CI 0.60, 0.96) which hardly altered after further adjustment for confounders. A one standard deviation increase in IGFBP-3 among participants without dementia or CIND was associated with greater decline in cognition (p=0.002) equivalent to 2.4 years difference in age. All the associations between IGF-I and our outcomes were consistent with chance. Conclusion: In this study of men, we found that both IGF-II and IGFBP-3 are associated with both normal age-related cognitive decline and clinical pathology associated with CIND, but we failed to replicate previous associations with IGF-I. Assuming these findings are replicated, they may provide new insights into potential biological mechanisms that underlie age-related cognitive changes and development of dementia.
Pages 877-886
Qiying Sun, Harald Hampel, Kaj Blennow, Simone Lista, Allan Levey, Beisha Tang, Rena Li, Yong Shen (Handling Associate Editor: Jiong Shi)
Increased Plasma TACE Activity in Subjects with Mild Cognitive Impairment and Patients with Alzheimer’s Disease
Abstract: Evidence suggests that the tumor necrosis factor receptor (TNFR)-signaling pathway contributes to the pathogenesis of Alzheimer’s disease (AD). TNF-α converting enzyme (TACE/ADAM-17) can cleave both pro-TNF-α and TNF receptors. Recently, we have shown that TACE activity in the cerebrospinal fluid (CSF) of subjects with mild cognitive impairment (MCI) and AD patients is significantly higher than that of cognitively healthy controls (HC). To date, it is not clear whether TACE activity could be detected in the human plasma and whether TACE activity in MCI and AD patients is different from that in HC. We analyze TACE expression and activity in a large clinical sample of 64 patients with AD, 88 subjects with MCI, and 50 age-matched HC recruited from two distinct academic centers. Plasma TACE protein levels did not differ significantly in the three study groups (AD, MCI, and HC). However, plasma TACE activity in subjects with MCI and AD patients was significantly higher than that in HC. Moreover, in MCI and AD groups, we found a significant correlation between plasma TACE activity and CSF t-tau and Aβ42 levels and CSF Aβ42/tau ratios. In AD patients, the levels of plasma TACE activity correlated significantly and negatively with cognition. These findings further support the role of the TNF-α receptor complex in AD-related neuroinflammation and propose TACE plasma activity as a promising hypothesis-driven biomarker candidate for detection, diagnosis, and prognosis of prodromal and clinical AD.
Pages 887-901
Gonzalo Sánchez-Benavides, Jordi Peña-Casanova, Marta Casals-Coll, Nina Gramunt, José Luís Molinuevo, Beatriz Gómez-Ansón, Miguel Aguilar, Alfredo Robles, Carmen Antúnez, Carlos Martínez-Parra, Anna Frank-García, Manuel Fernández-Martínez, Rafael Blesa, for the NEURONORMA Study Team (Handling Associate Editor: Montse Alegret)
Cognitive and Neuroimaging Profiles in Mild Cognitive Impairment and Alzheimer’s Disease: Data from the Spanish Multicenter Normative Studies (NEURONORMA Project)
Abstract: The aim of this study was to characterize the neuropsychological and neuroimaging profiles of mild cognitive impairment (MCI) and Alzheimer’s disease (AD) patients, and to study the magnitude of the differences by comparing both outcomes with healthy subjects in a cross-sectional manner. Five hundred and thirty-five subjects (356 cognitively normal adults (CONT), 79 MCI, and 100 AD) were assessed with the NEURONORMA neuropsychological battery. Thirty CONT, 23 MCI, and 23 AD subjects from this sample were included in the neuroimaging substudy. Patients’ raw cognitive scores were converted to age and education-adjusted scaled ones (range 2-18) using co-normed reference values. Medians were plotted to examine the cognitive profile. MRIs were processed by means of FreeSurfer. Effect size indices (Cohen’s d) were calculated in order to compare the standardized differences between patients and healthy subjects. Graphically, the observed cognitive profiles for MCI and AD groups produced near to parallel lines. Verbal and visual memories were the most impaired domains in both groups, followed by executive functions and linguistic/semantic ones. The largest effect size between AD and cognitively normal subjects was found for the FCSRT (d = 4.05, AD versus CONT), which doubled the value obtained by the best MRI measure, the right hippocampus (d = 1.65, AD versus CONT). Our results support the notion of a continuum in cognitive profile between MCI and AD. Neuropsychological outcomes, in particular the FCSRT, are better than neuroimaging ones at detecting differences among subjects.
Pages 903-909
Hanne Struyfs, José L. Molinuevo, Jean-Jacques Martin, Peter Paul De Deyn, Sebastiaan Engelborghs (Handling Associate Editor: Piotr Lewczuk)
Validation of the AD-CSF-Index in Autopsy-Confirmed Alzheimer’s Disease Patients and Healthy Controls
Abstract: The cerebrospinal fluid (CSF) biomarkers amyloid-β peptide of 42 amino acids (Aβ1–42), total tau-protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P) are used to diagnose Alzheimer’s disease (AD). In order to increase diagnostic power, several biomarker combinations have been proposed. In that sense, a new CSF biomarker index was developed, the AD-CSF-index, which has been validated in clinically diagnosed AD patients using electrochemoluminescence based MesoScaleDiscovery and single-analyte ELISA kits. This study validated the AD-CSF-index in neuropathologically diagnosed AD patients, using both single-analyte ELISA and multi-analyte Luminex assays. CSF of 51 neuropathologically diagnosed AD patients and of 95 controls was analyzed by commercially available single-analyte ELISA-kits (INNOTEST®, Innogenetics) and by a Research Use Only version of the multi-analyte Luminex xMAP® assay (INNO-BIA AlzBio3, Innogenetics). Subsequently the AD-CSF-indices were calculated. Both T-tau and P-tau181P AD-CSF-indices were significantly increased in AD patients when compared to controls (p<0.001). The diagnostic power of the indices was calculated using ROC analyses, resulting in excellent sensitivity and specificity values that systematically exceeded the 80% threshold for discriminating autopsy-confirmed AD patients from controls, independent of the analytical platform. The power to discriminate between AD and non-AD dementias was not included in this study and should be validated in the future. In conclusion, this study validated the AD-CSF index in autopsy-confirmed AD patients and has shown that its excellent diagnostic accuracy is independent of the analytical platform.
Pages 911-924
María-Letizia Campanari, María-Salud García-Ayllón, Olivia Belbin, Joan Galcerán, Alberto Lleó, Javier Sáez-Valero
Acetylcholinesterase Modulates Presenilin-1 Levels and γ-Secretase Activity
Abstract: The cholinergic enzyme acetylcholinesterase (AChE) and the catalytic component of the γ-secretase complex, presenilin-1 (PS1), are known to interact. In this study, we investigate the consequences of AChE-PS1 interactions, particularly the influence of AChE in PS1 levels and γ-secretase activity. PS1 is able to co-immunoprecipitate all AChE variants (AChE-R and AChE-T) and molecular forms (tetramers and light subunits) present in the human brain. Overexpression of AChE-R or AChE-T, or their respective inactive mutants, all trigger an increase in PS1 protein levels. The AChE species capable of triggering the biggest increase in PS1 levels is a complex of AChE with the membrane anchoring subunit proline-rich membrane anchor (PRiMA), which restricts the localization of the resulting AChE tetramer to the outer plasma membrane. Incubation of cultured cells with soluble AChE demonstrates that AChE is able to increase PS1 at both the protein and transcript levels. However, the increase of PS1 caused by soluble AChE is accompanied by a decrease in γ-secretase activity as shown by the reduction of the processing of the amyloid-β protein precursor. This inhibitory effect of AChE on γ-secretase activity was also demonstrated by directly assessing accumulation of CTF-AβPP in cell-free membrane preparations incubated with AChE. Our data suggest that AChE may function as an inhibitor of γ-secretase activity.
Pages 925-935
Xiaoqing Zhou*, Junying Zhang*, Yaojing Chen, Tao Ma, Yunxia Wang, Jun Wang, Zhanjun Zhang *These authors contributed equally to the manuscript.
Aggravated Cognitive and Brain Functional Impairment in Mild Cognitive Impairment Patients with Type 2 Diabetes: A Resting-State Functional MRI Study
Abstract: Diabetes mellitus type 2 is a metabolic disorder and a risk factor for dementia and mild cognitive impairment (MCI), which could also increase the risk of progression from MCI to dementia. The present study evaluated the spontaneous neuronal activity of 31 patients with MCI using resting-state functional MRI. The patients were divided into two groups (17 MCI patients without diabetes, and 14 patients with type 2 diabetes who were considered as the MCI-DM group) and 17 well-matched healthy controls. The amplitude of low-frequency fluctuations (ALFF) of spontaneous blood oxygen level dependent signals was then applied to assess neuroimaging changes. To further investigate the impact of type 2 diabetes on cognition, neuropsychological tests were carried out on the MCI-DM group, and the correlation of ALFF and the neuropsychological tests for the MCI-DM group were calculated. MCI-DM patients showed diffused ALFF changes in a variety of brain regions that were significantly related to cognitive performance, including the frontal lobe, the temporal lobe, the hippocampus, the amygdala, and the precuneus during a resting state; whereas, the alterations were much less pronounced in the MCI patients without diabetes. These findings provide new insights into understanding essential diabetes mellitus and may help to clarify the relationship between diabetes mellitus and dementia.
Pages 937-945
Jason Brandt, Justin Blehar, Allan Anderson, Alden L. Gross
Further Validation of the Internet-Based Dementia Risk Assessment
Abstract: Most approaches to the detection of presymptomatic or prodromal Alzheimer’s disease require the costly collection and analysis of biological samples or neuroimaging measurements. The Dementia Risk Assessment (DRA) was developed to facilitate this detection by collecting self-report and proxy-report of dementia risk variables and episodic memory performance on a free Internet website. We now report two validation studies. In Study 1, 130 community-residing older adults seeking memory screening at senior health fairs were tested using the Mini-Cog, and were then observed while taking the DRA. They were compared to a demographically-matched subsample from our anonymous Internet sample. Participants seeking memory screening had more dementia risk factors and obtained lower scores on the DRA’s recognition memory test (RMT) than their Internet controls. In addition, those who failed the Mini-Cog obtained much lower scores on the RMT than those who passed the Mini-Cog. In Study 2, 160 older adults seeking evaluation of cognitive difficulties took the DRA prior to diagnostic evaluations at outpatient dementia clinics. Patients who ultimately received the diagnosis of a dementia syndrome scored significantly lower on the RMT than those diagnosed with other conditions or deemed normal. Lower education, family history of dementia, presence of hypercholesterolemia and diabetes, and memory test score distinguished the dementia and no-dementia groups with around 82% accuracy. In addition, score on the RMT correlated highly with scores on other instruments widely used to detect cognitive decline. These findings support the concurrent validity of the DRA for detecting prevalent cognitive impairment. Prospective studies of cognitively normal persons who subsequently develop dementia will be necessary to establish its predictive validity.
Pages 947-956
Marcia C.N. Dourado, Daniel Mograbi, Raquel L. Santos, Maria Fernanda B. Sousa, Marcela L. Nogueira, Tatiana Belfort, Jesus Landeira-Fernandez, Jerson Laks (Handling Associate Editor: Eva Mª Arroyo-Anllo)
Awareness of Disease in Dementia: Factor Structure of the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia
Abstract: Despite the growing understanding of the conceptual complexity of awareness, there currently exists no instrument for assessing different domains of awareness in dementia. In the current study, the psychometric properties of a multidimensional awareness scale, the Assessment Scale of Psychosocial Impact of the Diagnosis of Dementia (ASPIDD), are explored in a sample of 201 people with dementia and their family caregivers. Cronbach’s alpha was high (α=0.87), indicating excellent internal consistency. The mean of corrected item-total correlation coefficients was moderate. ASPIDD presented a four-factor solution with a well-defined structure: awareness of activities of daily living, cognitive functioning and health condition, emotional state, and social functioning and relationships. Functional disability was positively correlated with total ASPIDD, unawareness of activities of daily living, cognitive functioning, and with emotional state. Caregiver burden was correlated with total ASPIDD scores and unawareness of cognitive functioning. The results suggest that ASPIDD is indeed a multidimensional scale, providing a reliable measure of awareness of disease in dementia. Further studies should explore the risk factors associated with different dimensions of awareness in dementia.
