Sim K. Singhrao, Alice Harding, Sasanka Chukkapalli, Ingar Olsen, Lakshmyya Kesavalu*, StJohn Crean* *These authors contributed equally to this work.
Apolipoprotein E Related Co-Morbidities and Alzheimer’s Disease
Abstract: The primary goal of advancement in clinical services is to provide a health care system that enhances an individual’s quality of life. Incidence of diabetes mellitus, cardiovascular disease, and associated dementia coupled with the advancing age of the population, have led to an increase in the worldwide challenge to the healthcare system. In order to overcome these challenges, prior knowledge of common, reliable risk factors and their effectors is essential. Oral health constitutes one such relatively unexplored but indispensable risk factor for aforementioned co-morbidities, in the form of poor oral hygiene and tooth loss during aging. Behavioral traits such as low education, smoking, poor diet, neglect of oral health, lack of exercise, and hypertension are few of the risk factors that are shared commonly among these conditions. In addition, common genetic susceptibility traits such as the apolipoprotein E gene, together with an individual’s lifestyle can also influence the development of co-morbidities such as periodontitis, atherosclerosis/stroke, diabetes, and Alzheimer’s disease. This review specifically addresses the susceptibility of apolipoprotein E gene allele 4 as the plausible commonality for the etiology of co-morbidities that eventually result from periodontal diseases and ultimately progress to dementia.
Katlyn Peck, Todd A. Girard, Frank Russo, Alexandra J. Fiocco
Music and Memory in Alzheimer’s Disease and the Potential Underlying Mechanisms
Abstract: With population aging and a projected exponential expansion of persons diagnosed with Alzheimer’s disease (AD), the development of treatment and prevention programs has become a fervent area of research and discovery. A growing body of evidence suggests that music exposure can enhance memory and emotional function in person with AD. However, there is a paucity of research that aims to identify specific underlying neural mechanisms associated with music’s beneficial effects in this particular population. As such, this paper reviews existing anecdotal and empirical evidence related to the enhancing effects of music exposure on cognitive function and further provides a discussion on the potential underlying mechanisms that may explain music’s beneficial effect. Specifically, this paper will outline the potential role of the dopaminergic system, the autonomic nervous system, and the default network in explaining how music may enhance memory function in persons with AD.
Melissa A. Schilling (Handling Associate Editor: Wei Qiao (Wendy) Qiu)
Unraveling Alzheimer’s: Making Sense of the Relationship between Diabetes and Alzheimer’s Disease
Abstract: Numerous studies have documented a strong association between diabetes and Alzheimer’s disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD.
Ruth F. Itzhaki, Richard Lathe, Brian J. Balin, Melvyn J. Ball, Elaine L. Bearer, Heiko Braak, Maria J. Bullido, Chris Carter, Mario Clerici, S. Louise Cosby, Kelly Del-Tredici, Hugh Field, Tamas Fulop, Claudio Grassi, W. Sue T. Griffin, Jürgen Haas, Alan P. Hudson, Angela R. Kamer, Douglas B. Kell, Federico Licastro, Luc Letenneur, Hugo Lövheim, Roberta Mancuso, Judith Miklossy, Carola Otth Lagunas, Anna Teresa Palamara, George Perry, Christopher Preston, Etheresia Pretorius, Timo Strandberg, Naji Tabet, Simon D. Taylor-Robinson, Judith A. Whittum-Hudson
Microbes and Alzheimer's Disease
Guofeng Lou, Qihao Zhang, Fei Xiao, Qi Xiang, Zhijian Su, Yadong Huang
Intranasal TAT-haFGF Improves Cognition and Amyloid-β Pathology in an AβPP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Neurotoxic amyloid-β (Aβ) peptide causing cognitive function disabilities is one of the most characteristic pathological features in Alzheimer’s disease (AD). A novel fusion protein, TAT-haFGF, was administrated to AβPP/PS1 transgenic mice by intravenous (IV) injection and intranasal (IN) delivery, respectively, for 5 weeks to compare the pharmacodynamics between the two routes of administration. Our results showed that IN administration of TAT-haFGF improved cognition and reduced Aβ plaques more significantly in AβPP/PS1 mice, when compared with IV injection. Our new findings suggest that TAT-haFGF might be a promising new therapy to attenuate AD pathological process.
Ruth Remington, Cynthia Bechtel, David Larsen, Annemarie Samar, Robert Page, Christopher Morrell, Thomas B. Shea
Maintenance of Cognitive Performance and Mood for Individuals with Alzheimer’s Disease Following Consumption of a Nutraceutical Formulation: A One-Year, Open-Label Study
Abstract: Nutritional interventions have shown varied efficacy on cognitive performance during Alzheimer’s disease (AD). Twenty-four individuals diagnosed with AD received a nutraceutical formulation (NF: folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) under open-label conditions (ClinicalTrials.gov NCT01320527). Primary outcome was cognitive performance. Secondary outcomes were behavioral and psychological symptoms of dementia (BPSD) and activities of daily living. Participants maintained their baseline cognitive performance and BPSD over 12 months. These findings are consistent with improvement in cognitive performance and BPSD in prior placebo-controlled studies with NF, and contrast with the routine decline for participants receiving placebo.
Kazuyoshi Sakai, Takao Senda, Ryuji Hata, Makoto Kuroda, Midori Hasegawa, Masao Kato, Masato Abe, Kazunori Kawaguchi, Shigeru Nakai, Yoshiyuki Hiki, Yukio Yuzawa, Nobuya Kitaguchi
Patients That Have Undergone Hemodialysis Exhibit Lower Amyloid Deposition in the Brain: Evidence Supporting a Therapeutic Strategy for Alzheimer’s Disease by Removal of Blood Amyloid
Abstract: As a proof of concept that removal of blood amyloid-β (Aβ) can reduce Aβ deposition in the brains of patients with Alzheimer’s disease, cortices of patients who had undergone hemodialysis (HD), which removes Aβ from the blood, were histochemically analyzed; postmortem brain sections were stained with anti-Aβ antibodies. Brains from patients who had undergone HD had significantly fewer senile plaques than those of patient who had not undergone HD. This significant difference was also confirmed by silver staining. Our findings suggest that removal of blood Aβ by hemodialysis results in lower accumulation of Aβ in the brain.
Jesús de Pedro-Cuesta, Pablo Martínez-Martín, Alberto Rábano, Enrique Alcalde-Cabero, Fernando José García López, Javier Almazán-Isla, María Ruiz-Tovar Maria-José Medrano, Fuencisla Avellanal, Olga Calero, Miguel Calero
Drivers: A Biologically Contextualized, Cross-Inferential View of the Epidemiology of Neurodegenerative Disorders
Abstract: Background: Sutherland et al. (2011) suggested that, instead of risk factors for single neurodegenerative disorders (NDDs), there was a need to identify specific "drivers", i.e., risk factors with impact on specific deposits, such as amyloid-β, tau, or α-synuclein, acting across entities. Objectives and Methods: Redefining drivers as "neither protein/gene- nor entity-specific features identifiable in the clinical and general epidemiology of conformational NDDs (CNDDs) as potential footprints of templating/spread/transfer mechanisms", we conducted an analysis of the epidemiology of ten CNDDs, searching for patterns. Results: We identified seven potential drivers, each of which was shared by at least two CNDDs: 1) an age-at-exposure-related susceptibility to Creutzfeldt-Jakob disease (CJD) and several late-life CNDDs; 2) a relationship between age at onset, survival, and incidence; 3) shared genetic risk factors for CJD and late-life CNNDs; 4) partly shared personal (diagnostic, educational, behavioral, and social risk factors) predating clinical onset of late-life CNDDs; 5) two environmental risk factors, namely, surgery for sporadic CJD and amyotrophic lateral sclerosis, and Bordetella pertussis infection for Parkinson’s disease; 6) reticulo-endothelial system stressors or general drivers (andropause or premenopausal estrogen deficiency, APOEɛ4, and vascular risk factors) for late-life CNDDs such as dementia/Alzheimer's disease, type-2 diabetes mellitus, and some sporadic cardiac and vascular degenerative diseases; and 7) a high, invariant incidence ratio of sporadic to genetic forms of mid- and late-life CNDDs, and type-2 diabetes mellitus. Conclusion: There might be a systematic epidemiologic pattern induced by specific proteins (PrP, TDP-43, SOD1, α-synuclein, amyloid-β, tau, Langerhans islet peptide, and transthyretin) or established combinations of these.
Ryszard Pluta*, Janusz Kocki*, Marzena Ułamek-Kozio*, Alicja Petniak, Paulina Gil-Kulik, Sławomir Januszewski, Jacek Bogucki, Mirosław Jabłoński, Judyta Brzozowska, Wanda Furmaga-Jabłońska, Anna Bogucka-Kocka§, Stanisław J. Czuczwar§ *These authors contributed equally to this work. §These authors are co-senior authors.
Discrepancy in Expression of β-Secretase and Amyloid-β Protein Precursor in Alzheimer-Related Genes in the Rat Medial Temporal Lobe Cortex Following Transient Global Brain Ischemia
Abstract: Brain ischemia may be causally related with Alzheimer’s disease. Presumably, β-secretase and amyloid-β protein precursor gene expression changes may be associated with Alzheimer’s disease neuropathology. Consequently, we have examined quantitative changes in both β-secretase and amyloid-β protein precursor genes in the medial temporal lobe cortex with the use of quantitative rtPCR analysis following 10-min global brain ischemia in rats with survival of 2, 7, and 30 days. The greatest significant overexpression of β-secretase gene was noted on the 2nd day, while on days 7-30 the expression of this gene was only modestly downregulated. Amyloid-β protein precursor gene was downregulated on the 2nd day, but on days 7-30 postischemia, there was a significant reverse tendency. Thus, the demonstrated alterations indicate that the considerable changes of expression of β-secretase and amyloid-β protein precursor genes may be connected with a response of neurons in medial temporal lobe cortex to transient global brain ischemia. Finally, the ischemia-induced gene changes may play a key role in a late and slow onset of Alzheimer-type pathology.
Nicolas R. Barthélemy, Audrey Gabelle, Christophe Hirtz, François Fenaille, Nicolas Sergeant, Susanna Schraen-Maschke, Jérôme Vialaret, Luc Buée, Christophe Junot, François Becher*, Sylvain Lehmann* (Handling Associate Editor: Henrik Zetterberg) *These authors jointly directed this work.
Differential Mass Spectrometry Profiles of Tau Protein in the Cerebrospinal Fluid of Patients with Alzheimer’s Disease, Progressive Supranuclear Palsy, and Dementia with Lewy Bodies
Abstract: Microtubule-associated Tau proteins are major actors in neurological disorders, the so-called tauopathies. In some of them, and specifically in Alzheimer’s disease (AD), hyperphosphorylated forms of Tau aggregate into neurofibrillary tangles. Following and understanding the complexity of Tau’s molecular profile with its multiple isoforms and post-translational modifications represent an important issue, and a major analytical challenge. Immunodetection methods are, in fact, limited by the number, specificity, sensitivity, and capturing property of the available antibodies. Mass spectrometry (MS) has recently allowed protein quantification in complex biological fluids using isotope-labeled recombinant standard for absolute quantification (PSAQ). To study Tau proteins, which are found very low concentrations within the cerebrospinal fluid (CSF), we relied on an innovative two-step pre-fractionation strategy, which was not dependent on immuno-enrichment. We then developed a sensitive multiplex peptide detection capability using targeted high-resolution MS to quantify Tau-specific peptides covering its entire sequence. This approach was used on a clinical cohort of patients with AD, progressive supranuclear palsy (PSP), and dementia with Lewy body (DLB) and with control non-neurodegenerative disorders. We uncovered a common CSF Tau molecular profile characterized by a predominance of central core expression and 1N/3R isoform detection. While PSP and DLB tau profiles showed minimal changes, AD was characterized by a unique pattern with specific modifications of peptide distribution. Taken together these results provide important information on Tau biology for future therapeutic interventions, and improved molecular diagnosis of tauopathies.
Lele Xu, Xia Wu, Rui Li, Kewei Chen, Zhiying Long, Jiacai Zhang, Xiaojuan Guo, Li Yao, for the Alzheimer’s Disease Neuroimaging Initiative
Prediction of Progressive Mild Cognitive Impairment by Multi-Modal Neuroimaging Biomarkers
Abstract: For patients with mild cognitive impairment (MCI), the likelihood of progression to probable Alzheimer’s disease (AD) is important not only for individual patient care, but also for the identification of participants in clinical trial, so as to provide early interventions. Biomarkers based on various neuroimaging modalities could offer complementary information regarding different aspects of disease progression. The current study adopted a weighted multi-modality sparse representation-based classification method to combine data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database, from three imaging modalities: volumetric magnetic resonance imaging (MRI), fluorodeoxyglucose (FDG) positron emission tomography (PET), and florbetapir PET. We included 117 normal controls (NC) and 110 MCI patients, 27 of whom progressed to AD within 36 months (pMCI), while the remaining 83 remained stable (sMCI) over the same time period. Modality-specific biomarkers were identified to distinguish MCI from NC and to predict pMCI among MCI. These included the hippocampus, amygdala, middle temporal and inferior temporal regions for MRI, the posterior cingulum, precentral, and postcentral regions for FDG-PET, and the hippocampus, amygdala, and putamen for florbetapir PET. Results indicated that FDG-PET may be a more effective modality in discriminating MCI from NC and in predicting pMCI than florbetapir PET and MRI. Combining modality-specific sensitive biomarkers from the three modalities boosted the discrimination accuracy of MCI from NC (76.7%) and the prediction accuracy of pMCI (82.5%) when compared with the best single-modality results (73.6% for MCI and 75.6% for pMCI with FDG-PET).
Yoonhee Kim, Chaeyoung Kim, Hye Young Jang, Inhee Mook-Jung (Handling Associate Editor: Bhumsoo Kim)
Inhibition of Cholesterol Biosynthesis Reduces γ-Secretase Activity and Amyloid-β Generation
Abstract: Amyloid-β (Aβ) is one of major molecules contributing to the pathogenesis of Alzheimer’s disease (AD). Aβ is derived from amyloid-β protein precursor (AβPP) through sequential cleavages by β- and γ-secretases. Regulation of these components is thought to be an important factor in Aβ generation during the pathogenesis of AD. AβPP, β-secretase, and γ-secretase reside in lipid rafts, where cholesterol regulates the integrity and flexibility of membrane proteins and Aβ is generated. However, the relationship between cholesterol and Aβ generation is controversial. In this study, we aimed to elucidate the direct effects of cholesterol depletion on AβPP processing using AY9944, which blocks the last step of cholesterol biosynthesis and thus minimizes the unknown side effects of upstream inhibitors, such as HMG-CoA reductase inhibitors. Treatment with AY9944 decreased γ-secretase activity and Aβ generation. These results suggested that changes in membrane composition by lowering cholesterol with AY9944 affected γ-secretase activity and Aβ generation, which is associated with AD pathogenesis.
Olivier Bousiges, Benjamin Cretin, Thomas Lavaux, Nathalie Philippi, Barbara Jung, Sylvie Hezard, Camille Heitz, Catherine Demuynck, Aurelia Gabel, Catherine Martin-Hunyadi, Frédéric Blanc
Diagnostic Value of Cerebrospinal Fluid Biomarkers (Phospho-Tau181, total-Tau, Aβ42, and Aβ40) in Prodromal Stage of Alzheimer’s Disease and Dementia with Lewy Bodies
Abstract: Background: Dementia with Lewy bodies (DLB) symptoms are close to those of Alzheimer’s disease (AD), and the differential diagnosis is difficult especially early in the disease. Unfortunately, AD biomarkers in cerebrospinal fluid (CSF), and more particularly Aβ1-42, appear to be altered in dementia with Lewy bodies (DLB). However, the level of these biomarkers has never been studied in the prodromal stage of the disease. Objective: To compare these biomarkers between DLB and AD, with a particular focus on the prodromal stage. Methods: A total of 166 CSF samples were collected at the memory clinic of Strasbourg. They were obtained from prodromal DLB (pro-DLB), DLB dementia, prodromal AD (pro-AD), and AD dementia patients, and elderly controls. Phospho-Tau181, total-Tau, Aβ42, and Aβ40 were measured in the CSF. Results: At the prodromal stage, contrary to AD patients, DLB patients’ biomarker levels in the CSF were not altered. At the demented stage of DLB, Aβ42 levels were reduced as well as Aβ40 levels. Thus, the Aβ42/Aβ40 ratio remained unchanged between the prodromal and demented stages, contrary to what was observed in AD. Tau and Phospho-Tau181 levels were unaltered in DLB patients. Conclusions: We have shown that at the prodromal stage the DLB patients had no pathological profile. Consequently, CSF AD biomarkers are extremely useful for differentiating AD from DLB patients particularly at this stage when the clinical diagnosis is difficult. Thus, these results open up new perspectives on the interpretation of AD biomarkers in DLB.
Jesus J. Gomar, Concepcion Conejero-Goldberg, Peter Davies, Terry E. Goldberg for the Alzheimer’s Disease Neuroimaging Initiative
Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer’s Disease
Abstract: Background: The earliest stage of preclinical Alzheimer’s disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. Objective: To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. Methods: We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n=15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n=14); and 3) Aβ42 levels consistently abnormal (n=18). Results: In the Aβ42 declining group, suggestive of incipient preclinical AD, using mixed model analysis, CSF phosphorylated tau (p-tau) showed a longitudinal pattern similar of increasing abnormality over time (p=0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho=-0.60; p=0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2=0.47, p=0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p<0.0001) only in this incipient preclinical AD group. In all groups combined, memory decline was predicted by p-tau. Conclusions: The evolution of Aβ42 and p-tau CSF biomarkers in CI subjects follows an anti-correlated trajectory, i.e., as Aβ42 declined p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.
Robert A. Stern, Yorghos Tripodis, Christine M. Baugh, Nathan G. Fritts, Brett M. Martin, Christine Chaisson, Robert C, Cantu, James A. Joyce, Sahil Shah, Tsuneya Ikezu, Jing Zhang, Cicek Gercel-Taylor, Douglas D. Taylor (Handling Associate Editor: Michael Rafii)
Preliminary Study of Plasma Exosomal Tau as a Potential Biomarker for Chronic Traumatic Encephalopathy
Abstract: Background: Chronic traumatic encephalopathy (CTE) is a tauopathy associated with prior exposure to repetitive head impacts, such as those incurred through American football and other collision sports. Diagnosis is made through neuropathological examination. Many of the clinical features of CTE are common in the general population, with and without a history of head impact exposure, making clinical diagnosis difficult. As is now common in the diagnosis of other neurodegenerative disorders, such as Alzheimer’s disease, there is a need for methods to diagnose CTE during life through objective biomarkers. Objective: The aim of this study was to examine tau-positive exosomes in plasma as a potential CTE biomarker. Methods: Subjects were 78 former National Football League (NFL) players and 16 controls. Extracellular vesicles were isolated from plasma. Fluorescent nanoparticle tracking analysis was used to determine the number of vesicles staining positive for tau. Results: The NFL group had higher exosomal tau than the control group (p < 0.0001). Exosomal tau discriminated between the groups, with 82% sensitivity, 100% specificity, 100% positive predictive value, and 53% negative predictive value. Within the NFL group, higher exosomal tau was associated with worse performance on tests of memory (p = 0.0126) and psychomotor speed (p = 0.0093). Conclusion: These preliminary findings suggest that exosomal tau in plasma may be an accurate, noninvasive CTE biomarker.
Yuek Ling Chai*, Hazel Kai-Hui Yeo*, Jiehao Wang, Saima Hilal, Mohammad Kamran Ikram, Narayanaswamy Venketasubramanian, Boon-Seng Wong, Christopher Li-Hsian Chen *These authors contributed equally to this work.
Apolipoprotein ε4 is Associated with Dementia and Cognitive Impairment Predominantly Due to Alzheimer’s Disease and Not with Vascular Cognitive Impairment: A Singapore-Based Cohort
Abstract: Background and Objective: While the association for apolipoprotein ε4 allele (APOE4) with Alzheimer’s disease (AD) has been consistently confirmed, the association with vascular cognitive impairment (VCI) is unclear. We therefore explored the relationship of APOE with both AD and cerebrovascular disease (CeVD) by examining the prevalence of APOE4 in AD, AD with CeVD and vascular dementia (VaD), as well as in cognitive impairment no dementia (CIND) with and without CeVD. Methods: We performed a case-control study with subjects recruited from memory clinics and the community. All subjects underwent standardized brain neuroimaging, clinical and neuropsychological assessments, following which they were classified using research criteria. Results: A total of 411 subjects; 92 controls with no cognitive impairment (NCI), 77 CIND without CeVD, 87 CIND with CeVD, 55 AD without CeVD, 68 AD with CeVD, and 32 VaD patients were recruited. Compared to NCI (16.3%), the prevalence of APOE4 carriers was significantly higher only in CIND (37.7%) and AD in the absence of CeVD (45.5%), but not in the three subgroups of VCI, namely CIND with CeVD (20.7%), AD with CeVD (27.9%) and VaD (25.0%). Logistic regression analyses also showed that APOE4 carriers were more likely to have CIND without CeVD (Odds Ratio [OR]: 3.34; 95% Confidence Interval [CI]: 1.59-7.03) and AD without CeVD (OR: 7.21; 95% CI: 2.74-18.98), but no such association was observed in the VCI subgroups. Conclusion: APOE4 is significantly associated with dementia and CIND due to AD pathology, but not with VCI.
Raffaella Migliaccio, Cécile Gallea, Aurélie Kas, Vincent Perlbarg, Dalila Samri, Laura Trotta, Agnès Michon, Lucette Lacomblez, Bruno Dubois, Stéphane Lehericy, Paolo Bartolomeo
Functional Connectivity of Ventral and Dorsal Visual Streams in Posterior Cortical Atrophy
Abstract: Background: Posterior cortical atrophy (PCA) induces progressive dysfunction of ventral and dorsal visual networks. Little is known, however, about corresponding changes in functional connectivity (FC). Objectives: To investigate FC changes in the visual networks, their relationship with cortical atrophy, and the association with Alzheimer’s disease (AD) pathology. Methods: Ten PCA patients and 28 age-matched controls participated in the study. Using resting state fMRI, we measured FC in ventral and dorsal cortical visual networks, defined on the basis of a priori knowledge of long-range white matter connections. To assess the relationships with AD, we determined AD biomarkers in cerebrospinal fluid and FC in the default mode network (DMN), which is vulnerable to AD pathology. Voxel-based morphometry analysis assessed the pattern of grey matter (GM) atrophy. Results: PCA patients showed GM atrophy in bilateral occipital and inferior parietal regions. PCA patients had lower FC levels in a ventral network than controls, but higher FC in inferior components of the dorsal network. In particular, the increased connectivity correlated with greater GM atrophy in occipital regions. All PCA patients had positive cerebrospinal fluid biomarkers for AD; however, FC in global DMN did not differ from controls. Conclusions: FC in PCA reflects brain structure in a non-univocal way. Hyperconnectivity of dorsal networks may indicate aberrant communication in response to posterior brain atrophy or processes of neural resilience during the initial stage of brain dysfunction. The lack of difference from controls in global DMN FC highlights the atypical nature of PCA with respect to typical AD.
Florence Pasquier, Carl Sadowsky, Ann Holstein, Ghislaine Le Prince Leterme, Yahong Peng, Nicholas Jackson, Nick C. Fox, Nzeera Ketter, Enchi Liu, J. Michael Ryan for the ACC-001 (QS-21) Study Team (Handling Associate Editor: Francesco Amenta)
Two Phase 2 Multiple Ascending–Dose Studies of Vanutide Cridificar (ACC-001) and QS-21 Adjuvant in Mild-to-Moderate Alzheimer’s Disease
Abstract: Vanutide cridificar (ACC-001), an immunotherapeutic vaccine, is a potentially disease-modifying therapy that aims to reduce brain amyloid-β (Aβ) plaques in patients with Alzheimer’s disease (AD). ACC-001 was evaluated in two phase 2a, multicenter, randomized, third party–unblinded, placebo-controlled, multiple ascending–dose studies of ACC 001 (3 µg, 10 µg, 30 µg) with and without QS-21 adjuvant that enrolled patients with mild-to-moderate AD (n = 245). Patients were treated with up to five doses of study vaccine or placebo and followed for safety and tolerability (primary objective) and anti-Aβ IgG immunogenicity (secondary objective) up to 12 months after the last vaccination. Exploratory assessments included cognitive/functional measures, brain magnetic resonance imaging (MRI) volumetry, and pharmacodynamic markers in plasma and cerebrospinal fluid (CSF). The most frequent treatment-emergent adverse events (≥10%) were local injection reactions and headache. Amyloid-related imaging abnormalities with vasogenic edema occurred in two (0.8%) patients (ACC-001 30 µg + QS-21; ACC-001 10 µg). ACC-001 + QS-21 elicited consistently higher peak and sustained anti-Aβ IgG titers compared with ACC-001 alone. Plasma Aβx–40 was significantly higher in all ACC-001 + QS-21 groups versus placebo (weeks 16–56), with no evidence of dose response. Exploratory cognitive evaluations, volumetric brain MRI, and CSF biomarkers did not show differences or trends between treatment groups and placebo. ACC-001 with or without QS-21 adjuvant has an acceptable safety profile in patients with mild-to-moderate AD.
Chatchawan Rattanabannakit, Shannon L. Risacher, Sujuan Gao, Kathleen A. Lane, Steven A. Brown, Brenna C. McDonald, Frederick W. Unverzagt, Liana G. Apostolova, Andrew J. Saykin, Martin R. Farlow (Handling Associate Editor: Carlo Abbate)
The Cognitive Change Index as a Measure of Self and Informant Perception of Cognitive Decline: Relation to Neuropsychological Tests
Abstract: Background: The perception of cognitive decline by individuals and those who know them well (“informants”) has been inconsistently associated with objective cognitive performance, but strongly associated with depressive symptoms. Objective: We investigated associations of self-report, informant-report, and discrepancy between self- and informant-report of cognitive decline obtained from the Cognitive Change Index (CCI) with cognitive test performance and self-reported depressive symptoms. Methods: 267 participants with normal cognition, mild cognitive impairment (MCI), or mild dementia were included from a cohort study and memory clinic. Association of test performance and self-rated depression (Geriatric Depression Scale, GDS) with CCI scores obtained from subjects (CCI-S), their informants (CCI-I), and discrepancy scores between subjects and informants (CCI-D; CCI-S minus CCI-I) were analyzed using correlation and analysis of covariance (ANCOVA) models. Results: CCI-S and CCI-I scores showed high internal consistency (Cronbach alpha 0.96 and 0.98, respectively). Higher scores on CCI-S and CCI-I, and lower scores on the CCI-D, were associated with lower performance on various cognitive tests in both univariate and in ANCOVA models adjusted for age, gender, and education. Adjustment for GDS slightly weakened the relationships between CCI and test performance but most remained significant. Conclusion: Self- and informant-report of cognitive decline, as measured by the CCI, show moderately strong relationships with objective test performance independent of age, gender, education, and depressive symptoms. The CCI appears to be a valid cross-sectional measure of self and informant perception of cognitive decline across the continuum of functioning. Studies are needed to address the relationship of CCI scores to longitudinal outcome.
Florence Guillot, Susanna Kemppainen, Gregoire Lavasseur, Pasi O. Miettinen, Serge Laroche, Heikki Tanila, Sabrina Davis (Handling Associate Editor: Christian Hölscher)
Brain-Specific Basal and Novelty-Induced Alternations in PI3K-Akt and MAPK/ERK Signaling in a Middle-Aged AβPP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Although it is well established that insulin/IGF and BDNF signaling are dysfunctionally regulated in Alzheimer’s disease, there are very few studies documenting changes in major target proteins in different murine models of the disease. We investigated a panel of proteins in the PI3K-Akt and MAPK/ERK cascades in parietal cortex, dentate gyrus and CA1 in 13-month-old AβPP/PS1 transgenic mice to determine whether amyloid pathology is associated with basal dysregulation of these proteins or following exposure to novelty. The most striking effect we found was that there was little common regulation of proteins either by pathology alone or exposure to novelty across the three structures, suggesting dysfunctional mechanisms that occur simultaneously have important structure specificity. CA1 shared certain dysfunctional regulation of proteins in the MAPK/ERK cascade, but shared dysfunctional regulation of the PI3K/Akt cascade with the dentate gyrus. Changes in ERK/CREB in transgenic mice did not result in coordinated dysfunction of the downstream transcription factor, Egr1, as it was overexpressed in a normal manner following exposure to novelty. In the PI3K-Akt cascade, there was a flagrant increase in the levels of proteins associated with inflammation, such as NFκB, and structure specific regulation of proteins associated with autophagy, such as mTOR and FOXO1 and lack of regulation of Beclin-1. Finally, Beclin-1 was increased by novelty in wild-type mice but deficient in transgenic mice. Results are interpreted in terms of structure-specific dysfunctional regulation of signaling mechanisms associated with Alzheimer’s disease.
Qian Yao, Guo-Xin Jiang, Zhi-Ming Zhou, Jin-Mei Chen, Qi Cheng
Metabolic Syndrome and Mild Cognitive Impairment: A Case-Control Study among Elderly in a Shanghai Suburb
Abstract: Background: Metabolic syndrome (MetS) maybe associated with mild cognitive impairment (MCI). Objective: To investigate the relationship between MetS, with its individual or combined components, and MCI among elderly. Methods: A case-control study was conducted among the elderly aged 65 years and over in a community located in the southwestern suburb of Shanghai, China. The Chinese version of the Mini-Mental Status Examination (C-MMSE) was used to screen subjects with MCI. Associations of MetS with its individual or combined components and MCI were analyzed using conditional regression analyses with or without adjustment for gender, education, current smoking, current drinking, and physical activities. Results: There were 379 subjects with MCI and 379 gender- and age-matched healthy controls in the study. Compared with healthy controls in univariate analyses, subjects with MCI were more likely to have less time spent on physical activity, lower C-MMSE score, heavier weight, larger waistline and hipline, higher diastolic blood pressure, higher body mass index, higher abdominal obesity index, higher serum glycated hemoglobin, higher serum triglycerides, higher serum cholesterol, higher serum uric acid, and higher serum alanine aminotransferase. After multivariable adjustment, MetS was significantly associated with an increased risk of MCI (OR=2.277; 95% CI: 1.086-4.773). Among MetS components, abdominal obesity (OR=2.101; 95% CI: 1.224-3.608) and hypertension (OR=2.075; 95% CI: 1.170-3.678) showed a significant association with MCI, respectively; while these two components were combined, the association was stronger (OR=2.459; 95% CI: 1.360-4.447). Conclusion: MetS and its components, particularly abdominal obesity and hypertension, were found to be significantly associated with the risk of MCI.
Brice Ongali, Nektaria Nicolakakis, Xing-Kang Tong, Tahar Aboulkassim, Hans Imboden, Edith Hamel
Enalapril Alone or Co-Administered with Losartan Rescues Cerebrovascular Dysfunction, but not Mnemonic Deficits or Amyloidosis in a Mouse Model of Alzheimer’s Disease
Abstract: The co-administration of angiotensin converting enzyme inhibitors (ACEi) and angiotensin II (AngII) receptor blockers (ARB) that bind angiotensin type 1 receptors (AT1R) may protect from Alzheimer's disease (AD) better than each treatment taken alone. We tested the curative potential of the non brain-penetrant ACEi enalapril (3 mg/kg/day) administered for 3 months either alone or in combination with the brain penetrant ARB losartan (10 mg/kg/day) in aged (~15 months) transgenic mice overexpressing a mutated form of the human amyloid-β protein precursor (AβPP, thereafter APP mice). We studied cerebrovascular function, protein levels of oxidative stress markers (superoxide dismutases SOD1, SOD2 and the NADPH oxidase subunit p67phox), amyloid-β (Aβ) pathology, astrogliosis, cholinergic innervation, AT1R and angiotensin IV receptor (AT4R) levels, together with cognitive performance. Both treatments normalized cerebrovascular reactivity and p67phox protein levels, but they did not reduce the cerebrovascular levels of SOD1. Combined treatment normalized cerebrovascular SOD2 levels, significantly attenuated astrogliosis, but did not reduce the increased levels of cerebrovascular AT1R. Yet, combined therapy enhanced thioflavin-S labeled Aβ plaque burden, a tendency not significant when Aβ1-42 plaque load was considered. None of the treatments rescued cognitive deficits, cortical AT4R or cholinergic innervation. We conclude that both treatments normalized cerebrovascular function by inhibiting the AngII-induced oxidative stress cascade, and that the positive effects of the combined therapy on astrogliosis were likely due to the ability of losartan to enter brain parenchyma. However, enalapril did not potentiate, and may even dampen, the reported cognitive benefits of losartan, raising caution when selecting the most appropriate AD therapy.
Min Son Sung*, Hong-Joon Shin*, Jayoung Byun*, Sun Young Kook, Minho Moon, Yu Jin Chang, Inhee Mook-Jung (Handling Associate Editor: Hyoung-gon Lee) *These authors contributed equally to this work.
Metformin Facilitates Amyloid-β Generation by β- and γ-Secretases via Autophagy Activation
Abstract: The evidence of strong pathological associations between type 2 diabetes and Alzheimer’s disease (AD) has increased in recent years. Contrary to suggestions that anti-diabetes drugs may have potential for treating AD, we demonstrate here that the insulin sensitizing anti-diabetes drug metformin (Glucophage®) increased the generation of amyloid-β (Aβ), one of the major pathological hallmarks of AD, by promoting β- and γ-secretase-mediated cleavage of amyloid-β protein precursor (AβPP) in SH-SY5Y cells. In addition, we show that metformin caused autophagosome accumulation in Tg6799 AD model mice. Extremely high γ-secretase activity was also detected in autophagic vacuoles, apparently a novel site of Aβ peptide generation. Together, these data suggest that metformin-induced accumulation of autophagosomes resulted in increased γ-secretase activity and Aβ generation. Additional experiments indicated that metformin increased phosphorylation of AMP-activated protein kinase, which activates autophagy by suppressing mammalian target of rapamycin (mTOR). The suppression of mTOR then induces the abnormal accumulation of autophagosomes. We conclude that metformin, an anti-diabetes drug, may exacerbate AD pathogenesis by promoting amyloidogenic AβPP processing in autophagosomes.
Montasir Elahi, Zafrul Hasan, Yumiko Motoi, Shin-Ei Matsumoto, Koichi Ishiguro, Nobutaka Hattori
Region-Specific Vulnerability to Oxidative Stress, Neuroinflammation, and Tau Hyperphosphorylation in Experimental Diabetes Mellitus Mice
Abstract: Recent epidemiological evidence suggests that diabetes mellitus (DM) is a risk factor for Alzheimer’s disease (AD). One of the pathological hallmarks of AD is hyperphosphorylated tau protein, which forms neurofibrillary tangles. Oxidative stress and the activation of inflammatory pathways are features that are associated with both DM and AD. However, the brain region specificity of AD-related neurodegeneration, which mainly occurs in the hippocampus while the cerebellum is relatively unaffected, has not yet been clarified. Therefore, we used experimental DM mice (caused by an intraperitoneal injection of streptozotocin [STZ]) to determine whether these neurodegeneration-associated mechanisms were associated with region-specific selective vulnerability or tau phosphorylation. The hippocampus, midbrain, and cerebellum of aged (14 months to 18) non-transgenic (NTg) and transgenic mice overexpressing wild-type human tau (Tg601 mice) were evaluated after a treatment with STZ. The STZ injection increased reactive oxygen species, lipid peroxidation markers such as 4-hydroxynonenal and malondialdehyde in the hippocampus, but not in the midbrain or cerebellum. The STZ treatment also increased the number of Iba-1-positive and CD68-positive microglial cells, astrocytes, and IL-1β, IL-6, IL-10, and IL-18 levels in the hippocampus, but not in the midbrain or cerebellum. Tau hyperphosphorylation was also enhanced in the hippocampus, but not in the midbrain or cerebellum. When the effects of STZ were compared between Tg601 and NTg mice, microglial proliferation and elevations in IL-6 and phosphorylated tau were higher in Tg601 mice. These results suggest that neuroinflammation and oxidative stress in STZ-treated mice are associated with tau hyperphosphorylation, which may contribute to selective neurodegeneration in human AD.
Marie Maxime Lavallée, Delphine Gandini, Isabelle Rouleau, Guillaume T. Vallet, Maude Joannette, Marie-Jeanne Kergoat, Thomas Busigny, Bruno Rossion, Sven Joubert (Handling Associate Editor: Paulo Caramelli)
A Qualitative Impairment in Face Perception in Alzheimer’s Disease: Evidence from a Reduced Face Inversion Effect
Abstract: Prevalent face recognition difficulties in Alzheimer’s disease (AD) have typically been attributed to the underlying episodic and semantic memory impairment. The aim of the current study was to determine if AD patients are also impaired at the perceptual level for faces, more specifically at extracting a visual representation of an individual face. To address this question, we investigated the matching of simultaneously presented individual faces and of other nonface familiar shapes (cars), at both upright and inverted orientation, in a group of mild AD patients and in a group of healthy older controls matched for age and education. AD patients showed a reduced inversion effect (i.e., larger performance for upright than inverted stimuli) for faces, but not for cars, both in terms of error rates and response times. While healthy participants showed a much larger decrease in performance for faces than for cars with inversion, the inversion effect did not differ significantly for faces and cars in AD. This abnormal inversion effect for faces was observed in a large subset of individual patients with AD. These results suggest that AD patients have deficits in higher-level visual processes, more specifically at perceiving individual faces, a function that relies on holistic representations specific to upright face stimuli. These deficits, combined with their memory impairment, may contribute to the difficulties in recognizing familiar people that are often reported in patients suffering from the disease and by their caregivers.
Hana Florian, Andreas Meier, Serge Gauthier, Stanley Lipschitz, Yunzhi Lin, Qi Tang, Ahmed A. Othman, Weining Z. Robieson, Laura M. Gault (Handling Associate Editor: Marwan Sabbagh)
Efficacy and Safety of ABT-126 in Subjects with Mild-to-Moderate Alzheimer’s Disease on Stable Doses of Acetylcholinesterase Inhibitors: A Randomized, Double-Blind, Placebo-Controlled Study
Abstract: Background: ABT 126 is a potent, selective α7 neuronal nicotinic acetylcholine receptor agonist with putative procognitive effects as a monotherapy in treating Alzheimer’s disease (AD). Objective: This randomized, double-blind, placebo-controlled multicenter study (NCT01549834) investigated the efficacy and safety of ABT 126 in subjects with mild-to-moderate AD who were taking stable doses of acetylcholinesterase inhibitors (AChEIs). Methods: Subjects received 25 mg ABT 126 (n=143), 75 mg ABT 126 (n=145), or placebo (n=146) once daily for 24 weeks. Subjects who completed the 24-week double-blind study were eligible to enroll in a 28 week open-label extension study (NCT01690195) and received 75 mg ABT 126 daily. The primary efficacy endpoint was the change from baseline to week 24 in the 11-item total score of the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog). Results: Neither dose of ABT-126 demonstrated significant improvement compared with placebo in the primary efficacy endpoint. However, 25 mg ABT 126 demonstrated significant improvement compared with placebo in ADAS-Cog scores at week 4 (least squares mean difference, −1.21; standard error, 0.51; p < 0.010, one-sided); 75 mg ABT 126 did not demonstrate significant improvements in ADAS-Cog scores compared with placebo at any time point. A treatment effect was not observed for any secondary efficacy measures of cognition, function, or global improvement. ABT 126 was generally well tolerated; the most common adverse events were agitation, constipation, diarrhea, fall, and headache. Conclusions: Overall, the efficacy profile of ABT-126 did not warrant further development as add-on therapy to AChEIs to treat mild-to-moderate AD.
Flora T. Gossink, Annemieke Dols, Welmoed A. Krudop, Sietske A. Sikkes, Cora J. Kerssens, Niels D. Prins, Philip Scheltens, Max L. Stek, Yolande A.L. Pijnenburg (Handling Associate Editor: Carlo Abbate)
Formal Psychiatric Disorders are not Overrepresented in Behavioral Variant Frontotemporal Dementia
Abstract: While psychiatric misdiagnosis is well-known in behavioral variant frontotemporal dementia (bvFTD), a systematic evaluation of standardized criteria for psychiatric disorders in bvFTD is still missing. Our aim was to define frequency and character of DSM-IV psychiatric disorders among patients with probable and definite bvFTD compared to possible bvFTD, other neurodegenerative diseases, and psychiatric diagnoses, using MINI-International Neuropsychiatric Interview. We additionally compared psychiatric prodromes between these groups. Subjects were participants of the late-onset frontal lobe (LOF) study, a longitudinal multicenter study. In each patient, after baseline diagnostic procedure, a neurologist and geriatric psychiatrist made a joint clinical diagnosis. Independently, a structured diagnostic interview according to DSM-IV and ICD-10 criteria (MINI-Plus) was performed by a trained professional blinded to clinical diagnosis. Out of 91 patients, 23 with probable and definite bvFTD, 3 with possible bvFTD, 25 with a non bvFTD neurodegenerative disease, and 40 with a clinical psychiatric diagnosis were included. Overall frequency of formal current and past psychiatric disorders in probable and definite bvFTD (21.7% current, 8.7% past) did not differ from other neurodegenerative diseases (12.0% current, 16.0% past) or possible bvFTD (66.7% current, 66.7% past), but was less than in patients with a clinical psychiatric diagnosis (57.5% current, 62.5% past; p<0.01). In probable and definite bvFTD unipolar mood disorders were most common. Formally diagnosed psychiatric disorders are not overrepresented in probable bvFTD, suggesting that psychiatric misdiagnosis in bvFTD can be reduced by strictly applying diagnostic criteria. In suspected bvFTD close collaboration between neurologists and psychiatrists will advance diagnostics and subsequent treatment.
Anwar M. Masoud, Syed W. Bihaqi, Jason T. Machan, Nasser H. Zawia, William E. Renehan
Early-Life Exposure to Lead (Pb) Alters the Expression of microRNA that Target Proteins Associated with Alzheimer’s Disease
Abstract: There is a growing recognition of the impact of environmental toxins on the epigenetic regulation of gene expression, including the genes that play a critical role in neural development, neural function, and neurodegeneration. We have shown previously that exposure to the heavy metal lead (Pb) in early life results in a latent over-expression of AD-related proteins in rodents and primates. The present study provides evidence that early postnatal exposure to Pb also alters the expression of select miRNA. Mice were exposed to 0.2% Pb acetate from Postnatal Day 1 (PND 1, first 24 h after birth) to PND 20 via their mother’s milk. Brain tissue was harvested at PND 20, 180, or 700, and miRNA were isolated and quantified by qPCR. This exposure produced a transient increase (relative to control) in the expression of miR-106b (binds to AβPP mRNA), miR-29b (targets the mRNA for the transcription factor SP1) and two miRNAs (miR-29b and miR-132) that have the ability to inhibit translation of proteins involved in promoter methylation. The expression of miR-106b decreased over time in the Pb-exposed animals and was significantly less than the levels exhibited by the control animals at PND700. The level of miR-124, which binds to SP1 mRNA, was also reduced (relative to controls) at PND700. In summary, we show that exposure to the heavy metal Pb in early life has a significant impact on the short- and long-term expression of miRNA that target epigenetic mediators and neurotoxic proteins.
Alberto Montesanto*, Paolina Crocco*, Maria Anfossi, Nicoletta Smirne, Gianfranco Puccio, Rosanna Colao, Raffaele Maletta, Giuseppe Passarino, Amalia C. Bruni, Giuseppina Rose (Handling Associate Editor: Israel Ampuero Sánchez) *These authors contributed equally to this work.
The Genetic Variability of UCP4 Affects the Individual Susceptibility to Late-Onset Alzheimer’s Disease and Modifies the Disease’s Risk in APOE-ɛ4 Carriers
Abstract: Uncoupling proteins (UCPs) are a group of five mitochondrial inner membrane transporters with a tissue specific expression that uncouple biofuel oxidation from ATP synthesis and function as regulators of energy homeostasis and antioxidants. Previous data suggested that neuronal UCPs (UCP2, UCP4, and UCP5) can directly influence synaptic plasticity, neurotransmission, and neurodegenerative processes, and have a crucial role in the function and protection of the central nervous system. In fact, it has been observed that the expression of neuronal UCPs significantly decreases in Alzheimer’s disease (AD) patients. Here we analyzed the variability of UCP2, -3, -4, and 5 genes in sporadic and familial cases (n=465) of late-onset AD (LOAD) with respect to healthy controls (n=442). We showed that a genetic variant in the human UCP4, rs9472817, not only significantly affects the individual susceptibility to LOAD, but also modulates the effect of APOE-ɛ4 on AD risk. In fact, rs9472817-C allele was significantly more frequent in both groups of patients with respect to the control group (p=6.934*10-4 for familial and p=1.033*10-3 for sporadic cases). In addition, gene-gene interaction analysis revealed that the effect of APOE-ɛ4 allele on LOAD risk was doubled in homozygote CC subjects; conversely, the risk conferred by the APOE-ε4 allele was annulled in subjects with two copies of the G allele. Our findings are further evidence that the efficiency in mitochondrial energy metabolism and oxidative stress are important factors in AD pathogenesis.
Grazia D. Femminella*, Siddharth Ninan*, Rebecca Atkinson, Zhen Fan, David J. Brooks, Paul Edison *These authors contributed equally to this work.
Does Microglial Activation Influence Hippocampal Volume and Neuronal Function in Alzheimer’s Disease and Parkinson’s Disease Dementia?
Abstract: Background: The influence of neuroinflammation on neuronal function and hippocampal atrophy in Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD) is still unclear. Objectives: Here we investigated whether microglial activation measured by [11C]PK11195 PET is associated with neuronal function measured by cerebral glucose metabolic rate (rCMRGlc) using FDG-PET and hippocampal volume measurements. Methods: We enrolled 25 subjects (9 PDD, 8 AD, and 8 controls) who underwent PET scans with [11C](R)PK11195, [18F]FDG, and volumetric MRI scanning. Results: SPM correlation analysis in AD and PDD showed a negative correlation between hippocampal volume and microglial activation within hippocampus or parahippocampus and with cortical and subcortical areas of projections from hippocampus, while there was a positive correlation between rCMRGlc in cortical and subcortical areas of projections from hippocampus and hippocampal volume. Hippocampal volume was significantly reduced in AD compared to controls but not in PDD. Conclusions: These findings indicate that microglial activation inversely correlated with hippocampal volume and hippocampal rCMRGlc in neurodegenerative diseases with dementia, providing further evidence for the central role of microglial activation in neurodegenerative diseases.