Pages 1-14
Review
Kenneth Hensley, Petri Kursula (Handling Associate Editor: D. Allan Butterfield)
Collapsin Response Mediator Protein-2 (CRMP2) is a Plausible Etiological Factor and Potential Therapeutic Target in Alzheimer’s Disease: Comparison and Contrast with Microtubule-Associated Protein Tau
Abstract: Alzheimer’s disease (AD) has long been viewed as a pathology that must be caused either by aberrant amyloid-β protein precursor (AβPP) processing, dysfunctional tau protein processing, or a combination of these two factors. This is a reasonable assumption because amyloid-β peptide (Aβ) accumulation and tau hyperphosphorylation are the defining histological features in AD, and because AβPP and tau mutations can cause AD in humans or AD-like features in animal models. Nonetheless, other protein players are emerging that one can argue are significant etiological players in subsets of AD and potentially novel, druggable targets. In particular, the microtubule-associated protein CRMP2 (collapsin response mediator protein-2) bears striking analogies to tau and is similarly relevant to AD. Like tau, CRMP2 dynamically regulates microtubule stability; it is acted upon by the same kinases; collects similarly in neurofibrillary tangles (NFTs); and when sequestered in NFTs, complexes with critical synapse-stabilizing factors. Additionally, CRMP2 is becoming recognized as an important adaptor protein involved in vesicle trafficking, amyloidogenesis and autophagy, in ways that tau is not. This review systematically compares the biology of CRMP2 to that of tau in the context of AD and explores the hypothesis that CRMP2 is an etiologically significant protein in AD and participates in pathways that can be rationally engaged for therapeutic benefit.
Pages 15-29
Review
Farida El Gaamouch, Ping Jing, Jiahong Xia, Dongming Cai
Alzheimer’s Disease Risk Genes and Lipid Regulators
Abstract: Brain lipid homeostasis plays an important role in Alzheimer’s disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.
Pages 31-52
Review
Luigi Trojano, Guido Gainotti (Handling Associate Editor: Jason Brandt)
Drawing Disorders in Alzheimer’s Disease and Other Forms of Dementia
Abstract: Drawing is a multicomponential process that can be impaired by many kinds of brain lesions. Drawing disorders are very common in Alzheimer’s disease and other forms of dementia, and can provide clinical information for the distinction of the different dementing diseases. In our review we started from an overview of the neural and cognitive bases of drawing, and from a recollection of the drawing tasks more frequently used for assessing individuals with dementia. Then, we analyzed drawing disorders in dementia, paying special attention to those observed in Alzheimer’s disease, from the prodromal stages of the amnesic mild cognitive impairment to the stages of full-blown dementia, both in the sporadic forms with late onset in the entorhino-hippocampal structures and in those with early onset in the posterior neocortical structures. We reviewed the drawing features that could differentiate Alzheimer’s disease from vascular dementia and from the most frequent forms of degenerative dementia, namely frontotemporal dementia and Lewy body disease. Finally, we examined some peculiar aspects of drawing disorders in dementia, such as perseverations, rotations, and closing-in. We argue that a careful analysis of drawing errors helps to differentiate the different forms of dementia more than overall accuracy in drawing.
Pages 53-67
Review
Judith Schuster, Susanne Aileen Funke (Handling Associate Editor: Charlotte Teunissen)
Methods for the Specific Detection and Quantitation of Amyloid-β Oligomers in Cerebrospinal Fluid
Abstract: Protein misfolding and aggregation are fundamental features of the majority of neurodegenerative diseases, like Alzheimer’s disease (AD), Parkinson’s disease, frontotemporal dementia, and prion diseases. Proteinaceous deposits in the brain of the patient, e.g., amyloid plaques consisting of the amyloid-β (Aβ) peptide and tangles composed of tau protein, are the hallmarks of AD. Soluble oligomers of Aβ and tau play a fundamental role in disease progression, and specific detection and quantification of the respective oligomeric proteins in cerebrospinal fluid may provide presymptomatically detectable biomarkers, paving the way for early diagnosis or even prognosis. Several studies on the development of techniques for the specific detection of Aβ oligomers were published, but some of the existing tools do not yet seem to be satisfactory, and the study results are contradicting. The detection of oligomers is challenging because of their polymorphous and unstable nature, their low concentration, and the presence of competing proteins and Aβ monomers in body fluids. Here, we present an overview of the current state of the development of methods for Aβ oligomer specific detection and quantitation. The methods are divided in the three subgroups: (i) enzyme linked immunosorbent assays (ELISA), (ii) methods for single oligomer detection, and (iii) others, which are mainly biosensor based methods.
Pages 69-72
Short Communication
Judith Neugroschl*, Margaret Sewell*, Angelica De La Fuente, Mari Umpierre, Xiaodong Luo, Mary Sano (Handling Associate Editor: Jeff Burns) *These authors contributed equally to this work.
Attitudes and Perceptions of Research in Aging and Dementia in an Urban Minority Population
Abstract: In dementia trials, minority participation is low. We assessed attitudes toward research in a community based urban poor minority sample of elderly adults attending senior center talks using the 7-item Research Attitudes Questionnaire (RAQ). Presentations on cognitive aging were given at senior centers, and 123 attendees completed the RAQ-7. On trust and safety questions, a significant minority (42-48%) responded neutrally or negatively. Encouragingly, on questions concerning the importance of research, 72-81% answered positively. More work can be done to capitalize on these finding to engage and foster trust, and this can be a focus of outreach.
Pages 73-78
Short Communication
Juan Marín-Muñoz, Mª Fuensanta Noguera-Perea, Estrella Gómez-Tortosa, David López-Motos, Martirio Antequera-Torres, Begoña Martínez-Herrada, Salvadora Manzanares-Sánchez, Laura Vivancos-Moreau, Agustina Legaz-García, Alberto Rábano-Gutiérrez del Arroyo, Carmen Antúnez-Almagro (Handling Associate Editor: Teodoro del Ser)
Novel Mutation (Gly212Val) in the PS2 Gene Associated with Early-Onset Familial Alzheimer’s Disease
Abstract: Mutations in the presenilin 2 gene (PS2) are an extremely rare cause of early-onset autosomal dominant Alzheimer’s disease (AD), accounting for only 5% of these families. These cases represent a particular model of AD, and the scarcity of reports on their clinical phenotypes makes them of great interest. We report a family with early-onset autosomal dominant AD in four members, where the two living siblings were found to carry the novel PS2 mutation Gly212Val (exon 7, transmembrane domain IV) with highly predicted pathogenicity. Age at onset ranged from 60 to 65 years and three of the cases died between ages 74 and 76 years. Clinical phenotype was quite homogeneous among affected members of the family, and overall features, including cognitive decline, tau/p-tau and amyloid-β cerebrospinal fluid markers, neuroimaging, and neuropathology were consistent with typical AD. Lewy bodies were present but restricted to the amygdala.
Pages 79-83
Amy Brodtmann, Hugh Pemberton, David Darby, Adam P. Vogel
Diagnostic Distortions: A Case Report of Progressive Apraxia of Speech
Abstract: Apraxia of speech (AOS) can be the presenting symptom of neurodegenerative disease. The position of primary progressive AOS in the nosology of the dementias is still controversial. Despite seeing many specialists, patients are often misdiagnosed, in part due to a lack of quantitative measures of speech dysfunction. We present a single case report of a patient presenting with AOS, including acoustic analysis, language assessment, and brain imaging. A 52-year-old woman presenting with AOS had remained undiagnosed for 6 years despite seeing 8 specialists. Results of her MRI scans, genetic testing, and computerized speech analysis are provided. AOS is an underdiagnosed clinical syndrome causing great distress to patients and families. Using acoustic analysis of speech may lead to improved diagnostic accuracy. AOS is a complex entity with an expanding phenotype, and quantitative clinical measures will be critical for detection and to assess progression.
Pages 85-93
Afonso Moreira, Maria José Diógenes, Alexandre de Mendonça, Nuno Lunet, Henrique Barros
Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline
Abstract: Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal Mini-Mental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95%CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95%CI 0.38–0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95%CI 0.31–0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans.
Pages 95-106
Michelle Perkins, Andrew B. Wolf, Bernardo Chavira, Daniel Shonebarger, JP Meckel, Lana Leung, Lauren Ballina, Sarah Ly, Aman Saini, T. Bucky Jones, Johana Vallejo, Garilyn Jentarra, Jon Valla (Handling Associate Editor: Russell Swerdlow)
Altered Energy Metabolism Pathways in the Posterior Cingulate in Young Adult Apolipoprotein E ε4 Carriers
Abstract: The APOE gene, encoding apolipoprotein E, is the primary genetic risk factor for late-onset Alzheimer’s disease (AD). Apolipoprotein E ε4 allele (APOE4) carriers have alterations in brain structure and function (as measured by brain imaging) even as young adults. Examination of this population is valuable in further identifying details of these functional changes and their association with vulnerability to AD decades later. Previous work demonstrates functional declines in mitochondrial activity in the posterior cingulate cortex, a key region in the default mode network, which appears to be strongly associated with functional changes relevant to AD risk. Here, we demonstrate alterations in the pathways underlying glucose, ketone, and mitochondrial energy metabolism. Young adult APOE4 carriers displayed upregulation of specific glucose (GLUT1 & GLUT3) and monocarboxylate (MCT2) transporters, the glucose metabolism enzyme hexokinase, the SCOT & AACS enzymes involved in ketone metabolism, and complexes I, II, and IV of the mitochondrial electron transport chain. The monocarboxylate transporter (MCT4) was found to be downregulated in APOE4 carriers. These data suggest that widespread dysregulation of energy metabolism in this at-risk population, even decades before possible disease onset. Therefore, these findings support the idea that alterations in brain energy metabolism may contribute significantly to the risk that APOE4 confers for AD.
Pages 107-116
Eline A.J. Willemse, Sisi Durieux-Lu, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Robert de Jonge, Charlotte E. Teunissen (Handling Associate Editor: Roberta Ghidoni)
Stability of Progranulin Under Pre-Analytical Conditions in Serum and Cerebrospinal Fluid
Abstract: Progranulin (PGRN) levels in blood and cerebrospinal fluid (CSF) are increasingly studied as potential markers for neurodegenerative disorders. We aimed to 1) characterize two commercially available PGRN ELISAs on several assay validation parameters, 2) assess the stability of PGRN in serum and CSF under pre-analytical conditions, and 3) compare stability in the two assays. Intra- and inter-assay variation, inter-lot variation, linearity, lower limit of detection, and kit correlations were assessed for the Adipogen and R&D PGRN ELISA kits. Blood and serum samples were experimentally exposed to ≤9 freeze/thaw cycles, delayed processing for ≤24 h at room temperature and 4°C, and to temperature stability tests for ≤3 weeks at -20°C, 4°C, room temperature, and 37°C. Both commercial PGRN ELISA kits showed acceptable ranges for intra- and inter-assay variation, where the R&D kit performed more accurate than the Adipogen kit, especially for inter-assay variation (intra-assay serum: 6.7 and 8.3%, respectively; inter-assay serum: 9.2 and 21.0%; intra-assay CSF: 3.6 and 12.0%; inter-assay CSF: 16.0 and 44.5%). Absolute serum PGRN concentrations were 1.9-fold higher in Adipogen than R&D (p<0.001) and strongly correlated between both kits (ρ=0.86, p<0.0001) and CSF PGRN levels were on the borderline of detection in both kits. PGRN was typically stable under all pre-analytical conditions addressed, although two weeks at 37°C resulted in decreased PGRN concentrations in CSF, only when using the Adipogen kit. These results support further examination of PGRN as a potential marker in neurodegenerative diseases, since PGRN is stable in serum and CSF and can be measured using ELISA kits from several providers.
Pages 117-125
Irene E. van de Vorst, Huiberdina L. Koek, Michiel L. Bots, Ilonca Vaartjes
Evaluation of Underlying Causes of Death in Patients with Dementia to Support Targeted Advance Care Planning
Abstract: Background: Insight in causes of death in demented patients may help physicians in end-of-life care. Objectives: To investigate underlying causes of death (UCD) in demented patients stratified by age, sex, dementia subtype [Alzheimer’s disease (AD), vascular dementia (VaD)] and to compare them with UCD in the general population (GP). Methods: A nationwide cohort of 59,201 patients with dementia (admitted to a hospital or visiting a day clinic) was constructed [38.7% men, 81.4 years (SD 7.0)] from 2000 through 2010. UCDs were reported and compared to the GP by calculating relative risks (RRs). Results: During follow up [median follow up time 1.3 years (IQR 0.3-3.0)], 64.2% of women and 69.3% of men died. Leading UCDs were dementia (17.5% in men and 23.7% in women) and cardiovascular disease (CVD) (18.7% and 19.2%, respectively). When compared to the GP, dementia was a more common UCD (RR in men 4.65, 95%CI 4.43-4.88), while CVD (RR in men 0.67, 95%CI 0.65-0.68) and cancer (RR 0.40, 95%CI 0.39-0.41) were less common. These differences were more pronounced in patients aged between 60-69 as compared to those aged ≥90 years. Patients with AD died less often of cerebrovascular diseases as compared to VaD (RR in men 0.53, 95%CI 0.47-0.59). Conclusion: UCDs in patients with dementia differs from that of the GP, as dementia is more often and cancer less often an UCD. Although less frequent compared to the GP, CVD also is one of the leading UCDs in patients with dementia. This information is valuable for targeted advance care planning.
Pages 127-133
Ken Uekawa, Yu Hasegawa, Satoru Senju, Naomi Nakagata, Mingjie Ma, Takashi Nakagawa, Nobutaka Koibuchi, Shokei Kim-Mitsuyama (Handling Associate Editor: Masahito Yamada)
Intracerebroventricular Infusion of Angiotensin-(1-7) Ameliorates Cognitive Impairment and Memory Dysfunction in a Mouse Model of Alzheimer’s Disease
Abstract: This work was performed to test our hypothesis that angiotensin-(1-7) can ameliorate cognitive impairment and cerebrovascular reactivity in 5XFAD mice, a useful model of Alzheimer’s disease. 5XFAD mice received intracerebroventricular infusion of (1) vehicle, (2) angiotensin-(1-7), or (3) angiotensin-(1-7) + A779, a specific Mas receptor antagonist, for 4 weeks. Angiotensin-(1-7), through Mas receptor, significantly ameliorated cognitive impairment in 5XFAD mice. As estimated by acetazolamide-induced increase in cerebral blood flow, angiotensin-(1-7), through Mas receptor, enhanced cerebrovascular reactivity in 5XFAD mice. In conclusion, angiotensin-(1-7)/Mas receptor axis improves cognitive function and cerebrovascular function in a mouse model of Alzheimer’s disease.
Pages 135-142
Salka S. Staekenborg, Yolande A.L. Pijnenburg, Afina W. Lemstra, Philip Scheltens, Wiesje M. vd Flier
Dementia and Rapid Mortality: Who is at Risk?
Abstract: Background: Dementia is typically known for its insidious onset and slowly progressive course, but a subgroup deteriorates fast and dies within years or even months. Objective: The purpose of this study was to characterize dementia patients with a rapidly progressive course to death and evaluate their cause of death. Methods: We retrospectively included all patients from the Amsterdam Dementia Cohort who died within two years after diagnosis. We evaluated the characteristics of these rapid progressors and compared them to patients known to be alive two years after diagnosis (‘non-rapid mortality’). Results: We included 129 dementia patients (13% of our total cohort with known follow-up) with rapid mortality (age 72±10 y [29% 0.70). Cause of death was highly variable without a clear relation to dementia diagnosis, with exception of dementia itself in CJD, intracerebral hematoma in VaD, and motor neuron disease in FTD. Conclusions: Short survival is relatively common (~13% in our cohort) and occurs in all different types of dementia, with overrepresentation of non-AD dementias like CJD, VaD, and FTD.
Pages 143-159
Chia-Liang Tsai, Ming-Chyi Pai, Jozef Ukropec, Barbara Ukropcová
The Role of Physical Fitness in the Neurocognitive Performance of Task Switching in Older Persons with Mild Cognitive Impairment
Abstract: Although elderly people with amnestic mild cognitive impairment (aMCI) have been found to show impaired behavioral performance in task switching, no research has yet explored the electrophysiological mechanisms and the potential correlation between physical fitness and neurocognitive (i.e., behavioral and electrophysiological) performance in MCI. The present study was thus aimed to examine whether there are differences in electrophysiological (i.e., event-related potential) performance between aMCI participants and controls when performing a task-switching paradigm, and to investigate the role of physical fitness in the relationship between neurocognitive performance and aMCI. Sixty participants were classified into aMCI (n=30) and control (n=30) groups, and performed a task-switching paradigm with concomitant electrophysiological recording, as well as underwent senior functional physical fitness tests. The aMCI group showed comparable scores on most parts of the physical fitness tests, but reduced lower body flexibility and VO2max as compared to the control group. When performing the task-switching paradigm, the aMCI group showed slower reaction times in the heterogeneous condition and larger global switching costs, although no significant difference was observed in accuracy rates between the two groups. In addition, the aMCI group showed significantly prolonged P3 latencies in the homogeneous and heterogeneous conditions, and a smaller P3 amplitude only in the heterogeneous condition. The level of cardiorespiratory fitness was significantly correlated with P3 amplitude in the aMCI group, particularly in the heterogeneous condition of the task-switching paradigm. These results show that the aMCI group exhibited abnormalities in their neurocognitive performance when performing the task-switching paradigm and such a deficit was likely associated with reduced cardiorespiratory fitness, which was shown to be the important predictor of neurocognitive performance.
Pages 161-170
Eric D. Vidoni, Amber S. Watts, Jeffrey M. Burns, Colby S. Greer, Rasinio S. Graves, Angela Van Sciver, Jessica R. Black, Sarah K. Cooper, Allison C. Nagely, Elaine Uphoff, Jennifer M. Volmer, Natalie A. Zink
Feasibility of a Memory Clinic-Based Physical Activity Prescription Program
Abstract: Background: Effective programs for promoting physical activity are needed for those with cognitive impairment. Objective: To test the feasibility of mobile Health (mHealth) technology-supported physical activity prescription from a tertiary care memory clinic. Methods: This feasibility study was designed as a 16-week randomized, crossover trial of a physical activity prescription: 8 weeks of intervention, 8 weeks of baseline or maintenance phase data collection. We recruited 2 cohorts: 21 individuals with Alzheimer-related cognitive impairment (mean age 72.3 (5.2), 9 females), and 9 individuals with normal cognition (mean age 69.6 (5.8), 8 females). We gave each cohort an mHealth accelerometer-based physical activity prescription to double number of steps taken. Our primary outcomes were feasibility and safety. Our secondary outcomes were change in weekly steps taken, Dementia Quality of Life Scale, Self-efficacy Scale, 6-minute Walk, and mini-Physical Performance Test. Results: Set-up and use of the device was not a barrier to participation. However, only 62% of participants with cognitive impairment completed the intervention. The cohort with cognitive impairment did not change their weekly step count above Week 1. All participants in the cohort with normal cognition were able to set up and use their device and increased their weekly step count above Week 1. There were no differences between Week 1 and Week 8 for any secondary measures in either cohort. Conclusions: Setup and daily use of mHealth technology appears to be feasible for a person with cognitive impairment with the help of a partner, but increasing daily step counts over 8 weeks was not achieved. Future work needs to assess alternative activity prescription goals or additional support for patients and their partners.
Pages 171-183
Michael Happich, Noam Y. Kirson, Urvi Desai, Sarah King, Howard G. Birnbaum, Catherine Reed, Mark Belger, Alan Lenox-Smith, David Price
Excess Costs Associated with Possible Misdiagnosis of Alzheimer’s Disease among Patients with Vascular Dementia in a UK CPRD Population
Abstract: Background: Prior diagnosis of Alzheimer’s disease (AD) among patients later diagnosed with vascular dementia (VaD) has been associated with excess costs, suggesting potential benefits of earlier rule-out of AD diagnosis. Objective: To investigate whether prior diagnosis with AD among patients with VaD is associated with excess costs in the UK. Methods: Patients with a final VaD diagnosis, continuous data visibility for ≥6 months prior to index date, and linkage to Hospital Episode Statistics data were retrospectively selected from de-identified Clinical Practice Research Datalink data. Patients with AD diagnosis before a final VaD diagnosis were matched to similar patients with no prior AD diagnosis using propensity score methods. Annual excess healthcare costs were calculated for 5 years post-index, stratified by time to final diagnosis. Results: Of 9,311 patients with VaD, 508 (6%) had prior AD diagnosis with a median time to VaD diagnosis exceeding 2 years from index date. Over the entire follow-up period, patients with prior AD diagnosis had accumulated healthcare costs that were approximately £2,000 higher than those for matched counterparts (mostly due to higher hospitalization costs). Cost differentials peaked particularly in the period including the final VaD diagnosis, with excess costs quickly declining thereafter. Conclusion: Potential misdiagnosis of AD among UK patients with VaD resulted in substantial excess costs. The decline in excess costs following a final VaD diagnosis suggests potential benefits from earlier rule-out of AD.
Pages 185-195
Junying Zhang*, Zhen Liu*, Zixiao Li*, Yunxia Wang, Yaojing Chen, Xin Li, Kewei Chen, Ni Shu, Zhanjun Zhang (Handling Associate Editor: Lan Zhang) *These authors contributed equally to this work.
Disrupted White Matter Network and Cognitive Decline in Type 2 Diabetes Patients
Abstract: Type 2 diabetes mellitus is accompanied by cognitive impairment and is associated with an increased risk of dementia. Damage to brain structures such as white matter network disruption may underlie this cognitive disturbance. In the present study, 886 non-diabetic and 163 type 2 diabetic participants completed a battery of neuropsychological tests. Among them, 38 diabetic patients and 34 non-diabetic participants that matched the patients for age/sex/education received a magnetic resonance imaging-based diffusion tensor imaging. Then we calculated the topological properties of the white matter network using a graph theoretical method to investigate network efficiency differences between groups. We found that type 2 diabetic patients had inferior performances compared to the non-diabetic controls, in several cognitive domains involving executive function, spatial processing, memory, and attention. We also found that diabetic patients exhibited a disrupted topological organization of the white matter network (including the global network properties, i.e., network strength, global efficiency, local efficiency and shortest path length, and the nodal efficiency of the right rolandic operculum) in the brain. Moreover, those global network properties and the nodal efficiency of the right rolandic operculum both had positive correlations with executive function in the patient group. The results suggest that type 2 diabetes mellitus leads to an alteration in the topological organization of the cortical white matter network and this alteration may account for the observed cognitive decline.
Pages 197-207
Christian Peters*, Fernando J. Sepúlveda*, Eduardo J. Fernández-Pérez, Robert W. Peoples, Luis G. Aguayo *These authors contributed equally to this work.
The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation
Abstract: Alzheimer's disease is a neurodegenerative disorder that affects mostly the elderly. The main histopathological markers are the senile plaques formed by amyloid-β peptide (Aβ) aggregates that can perforate the plasma membrane of cells, increasing the intracellular calcium levels and releasing synaptic vesicles that finally lead to a delayed synaptic failure. Several membrane proteins and lipids interact with Aβ affecting its toxicity in neurons. Here, we focus on NMDA receptors (NMDARs) as proteins that could be modulating the association and neurotoxic perforation induced by Aβ on the plasma membrane. In fact, our results showed that decreasing NMDARs, using enzymatic or siRNA approaches, increased the association of Aβ to the neurons. Furthermore, overexpression of NMDARs also resulted in an enhanced association between NMDA and Aβ. Functionally, the reduction in membrane NMDARs augmented the process of membrane perforation. On the other hand, overexpressing NMDARs had a protective effect because Aβ was now unable to cause membrane perforation, suggesting a complex relationship between Aβ and NMDARs. Because previous studies have recognized that Aβ oligomers are able to increase membrane permeability and produce amyloid pores, the present study supports the conclusion that NMDARs play a critical protective role on Aβ actions in hippocampal neurons. These results could explain the lack of correlation between brain Aβ burden and clinically observed dementia.
Pages 209-219
Bryn Farnsworth, Christiane Peuckert, Bettina Zimmermann, Elena Jazin, Petronella Kettunen, Lina Sors Emilsson (Handling Associate Editor: Daniela Galimberti)
Gene Expression of Quaking in Sporadic Alzheimer’s Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation
Abstract: Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.
Pages 221-236
Wei Tang*, Juan Cheng*, Zheng-Yu Wang, Ke-Yang Chen, Zhen-Min Han, Qi-Hong Wang, Yu-You Yao *These authors contributed equally to this work.
The Synergistic Roles of the Chronic Prenatal and Offspring Stress Exposures in Impairing Offspring Learning and Memory
Abstract: In Alzheimer's disease (AD), extensive experimental studies have demonstrated a negative impact of chronic stress during various stages of life (including prenatal phase) on some aspects of AD pathology. Nevertheless, presently, few studies have been involved in the learning and memory impairments, as well as neuropathology elicited by the chronic prenatal stress (CPS) and the chronic offspring stress (COS) exposures simultaneously, particularly for the adult male APPswe/PS1dE9 murine offspring. Therefore, the aim of the present study was to investigate the influence of CPS on learning and memory impairments induced by COS in 6-month-old male APPswe/PS1dE9 offspring mice and the related mechanism. Our study firstly demonstrates that 14-day exposure to CPS could exacerbate the learning and memory impairments, as well as neuropathological damages in the CA3 regions of the hippocampus and cortex neurons, which is induced by the 28-day exposure to COS in 6-month-old male APPswe/PS1dE9 offspring mice. In addition, CPS could potentiate the production of AβPP, Aβ42, and corticosterone in 6-month-old male APPswe/PS1dE9 offspring that also suffer COS. In conclusion, our novel findings strongly implicate the synergistic roles of the CPS and COS exposures in impairing offspring learning and memory. Moreover, CPS potentiating the production of Aβ42 might be mediated by glucocorticoids through increasing the expression of APP and BACE1 gene.
Pages 237-241
Daniel G. Amen, Kristen Willeumier, Bennet Omalu, Andrew Newberg, Cauligi Raghavendra, Cyrus A. Raji
Perfusion Neuroimaging Abnormalities Alone Distinguish National Football League Players from a Healthy Population
Abstract: Background: National Football League (NFL) players are exposed to multiple head collisions during their careers. Increasing awareness of the adverse long-term effects of repetitive head trauma has raised substantial concern among players, medical professionals, and the general public. Objective: To determine whether low perfusion in specific brain regions on neuroimaging can accurately separate professional football players from healthy controls. Method: A cohort of retired and current NFL players (n = 161) were recruited in a longitudinal study starting in 2009 with ongoing interval follow up. A healthy control group (n = 124) was separately recruited for comparison. Assessments included medical examinations, neuropsychological tests, and perfusion neuroimaging with single photon emission computed tomography (SPECT). Perfusion estimates of each scan were quantified using a standard atlas. We hypothesized that hypoperfusion particularly in the orbital frontal, anterior cingulate, anterior temporal, hippocampal, amygdala, insular, caudate, superior/mid occipital, and cerebellar sub-regions alone would reliably separate controls from NFL players. Cerebral perfusion differences were calculated using a one-way ANOVA and diagnostic separation was determined with discriminant and automatic linear regression predictive models. Results: NFL players showed lower cerebral perfusion on average (p < 0.01) in 36 brain regions. The discriminant analysis subsequently distinguished NFL players from controls with 90% sensitivity, 86% specificity, and 94% accuracy (95% CI 95-99). Automatic linear modeling achieved similar results. Inclusion of age and clinical co-morbidities did not improve diagnostic classification. Conclusion: Specific brain regions commonly damaged in traumatic brain injury show abnormally low perfusion on SPECT in professional NFL players. These same regions alone can distinguish this group from healthy subjects with high diagnostic accuracy. This study carries implications for the neurological safety of NFL players.
Pages 243-257
Ewelina Maliszewska-Cyna, Kristiana Xhima, Isabelle Aubert (Handling Associate Editor: Agneta Nordberg)
A Comparative Study Evaluating the Impact of Physical Exercise on Disease Progression in a Mouse Model of Alzheimer’s Disease
Abstract: Evidence suggests that physical exercise can serve as a preventive strategy against Alzheimer’s disease (AD). In contrast, much less is known about the impact of exercise when it is introduced after cognitive deficits are established. Using the TgCRND8 mouse model of amyloidosis, we compared the effects of exercise as an intervention strategy aimed at altering disease progression. Voluntary running for 1 month or 2 months was introduced in 3-month-old TgCRND8 mice, which exhibit amyloid-beta (Aβ) plaque pathology and cognitive deficits at this age. Specifically, we examined Aβ plaque load, spatial memory, and neurogenesis in the dentate gyrus in the hippocampus. After 1 month of running, TgCRND8 mice spent more time in the novel arm of the Y-maze compared to the familiar arms, indicating improved memory. The levels of doublecortin (a marker of immature neurons) were increased in TgCRND8 mice running for 1 month, but with no significant difference in the number of new mature neurons or plaque burden. As the disease progressed, running prevented further deficits in the Y-maze performance and hippocampal neurogenesis and it reduced plaque load pathology in TgCRND8 mice running for 2 months, compared to non-running transgenics. Therefore, the impact of running on memory, neurogenesis, and amyloid pathology was of greater significance when sustained through later stages of the disease.
Pages 259-272
Nirmal Verma, Han Ly, Miao Liu, Jing Chen, Haining Zhu, Martin Chow, Louis B. Hersh, Florin Despa
Intraneuronal Amylin Deposition, Peroxidative Membrane Injury, and Increased IL-1β Synthesis in Brains of Alzheimer’s Disease Patients with Type-2 Diabetes and in Diabetic HIP Rats
Abstract: Amylin is a hormone synthesized and co-secreted with insulin by pancreatic β-cells that crosses the blood-brain barrier and regulates satiety. Amylin from humans (but not rodents) has an increased propensity to aggregate into pancreatic islet amyloid deposits that contribute to β-cell mass depletion and development of type-2 diabetes by inducing oxidative stress and inflammation. Recent studies demonstrated that aggregated amylin also accumulates in brains of Alzheimer’s disease (AD) patients, preponderantly those with type-2 diabetes. Here, we report that, in addition to amylin plaques and mixed amylin-Aβ deposits, brains of diabetic patients with AD show amylin immunoreactive deposits inside the neurons. Neuronal amylin formed adducts with 4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and increased synthesis of the proinflammatory cytokine interleukin (IL)-1β. These pathological changes were mirrored in rats expressing human amylin in pancreatic islets (HIP rats) and mice intravenously injected with aggregated human amylin, but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin. In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1β synthesis via membrane destabilization and subsequent generation of 4-HNE. These effects were blocked by membrane stabilizers and lipid peroxidation inhibitors. Thus, elevated circulating levels of aggregated amylin negatively affect the neurons causing peroxidative membrane injury and aberrant inflammatory responses independent of other confounding factors of diabetes. The present results are consistent with the pathological role of aggregated amylin in the pancreas, demonstrate a novel contributing mechanism to neurodegeneration, and suggest a direct, potentially treatable link of type-2 diabetes with AD.
Pages 273-287
Mark A. Lovell, Bert C. Lynn, Shuling Fister, Melissa Bradley-Whitman, M. Paul Murphy, Tina L. Beckett, Christopher M. Norris
A Novel Small Molecule Modulator of Amyloid Pathology
Abstract: Because traditional approaches to drug development for Alzheimer’s disease are becoming increasingly expensive and in many cases disappointingly unsuccessful, alternative approaches are required to shift the paradigm. Following leads from investigations of dihydropyridine calcium channel blockers, we observed unique properties from a class of functionalized naphthyridines and sought to develop these as novel therapeutics that minimize amyloid pathology without the adverse effects associated with current therapeutics. Our data show methyl 2,4-dimethyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridine-1-carboxylate (BNC-1) significantly decreases amyloid burden in a well-established mouse model of amyloid pathology through a unique mechanism mediated by Elk-1, a transcriptional repressor of presenilin-1. Additionally, BNC-1 treatment leads to increased levels of synaptophysin and synapsin, markers of synaptic integrity, but does not adversely impact presenilin-2 or processing of Notch-1, thus avoiding negative off target effects associated with pan-gamma secretase inhibition. The molecule developed minimizes amyloid production and increases synaptic integrity without adverse effects associated with current anti-amyloid therapeutics. Our data show BNC-1 significantly decreases amyloid burden and improves markers of synaptic integrity in a well-established mouse model of amyloid deposition by promoting phosphorylation and activation of Elk-1, a transcriptional repressor of presenilin-1 but not presenilin-2. These data suggest BNC-1 might be a novel, disease-modifying therapeutic that will alter the pathogenesis of Alzheimer’s disease.
Pages 289-301
Natalia Bobkova*, Vasily Vorobyov*, Natalia Medvinskaya, Inna Nesterova, Olga Tatarnikova, Pavel Nekrasov, Alexander Samokhin, Alexander Deev, Frank Sengpiel, Dmitry Koroev, Olga Volpina (Handling Associate Editor: Vladimir Buchman) *These authors contributed equally to this work.
Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice
Abstract: Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.
Pages 303-313
Elkin Luis, Alexandra Ortiz, Luis Eudave, Sara Ortega-Cubero, Barbara Borroni, Julie van der Zee, Stefano Gazzina, Paola Caroppo, Elisa Rubino, Federico D'Agata, Isabelle Le Ber, Isabel Santana, Gil Cunha, Maria R. Almeida, Claire Boutoleau-Bretonnière, Didier Hannequin, David Wallon, Innocenzo Rainero, Daniela Galimberti, Christine Van Broeckhoven, Maria A. Pastor, Pau Pastor
Neuroimaging Correlates of Frontotemporal Dementia Associated with SQSTM1 Mutations
Abstract: Background: Frontotemporal lobar degeneration (FTLD) is a progressive dementia characterized by focal atrophy of frontal and/or temporal lobes caused by mutations in the gene coding for sequestosome 1 (SQSTM1), among other genes. Rare SQSTM1 gene mutations have been associated with Paget’s disease of bone, amyotrophic lateral sclerosis, and, more recently, frontotemporal lobar degeneration (FTLD). Objective: The aim of the study was to determine whether a characteristic pattern of grey and white matter loss is associated with SQSTM1 dysfunction. Methods: We performed a voxel-based morphometry (VBM) study in FTD subjects carrying SQSTM1 pathogenic variants (FTD/SQSTM1 mutation carriers; n=10), compared with FTD subjects not carrying SQSTM1 mutations (Sporadic FTD; n=20) and healthy controls with no SQSTM1 mutations (HC/SQSTM1 noncarriers; n=20). The groups were matched according to current age, disease duration, and gender. Results: After comparing FTD/SQSTM1 carriers with Sporadic FTD, a predominantly right cortical atrophy pattern was localized in the inferior frontal, medial orbitofrontal, precentral gyri, and the anterior insula. White matter atrophy was found in both medial and inferior frontal gyri, pallidum, and putamen. FTD/SQSTM1 carriers compared with HC/SQSTM1 noncarriers showed atrophy at frontal, temporal, and parietal lobes of both hemispheres whereas the MRI pattern found in Sporadic FTD compared with controls was frontal and left temporal lobe atrophy, extending toward parietal and occipital lobes of both hemispheres. Conclusions: These results suggest that fronto-orbito-insular regions including corticospinal projections as described in ALS are probably more susceptible to the damaging effect of SQSTM1 mutations delineating a specific gene-linked atrophy pattern.
Pages 315-325
Yukito Ueda, Masayuki Satoh, Ken-ichi Tabei, Hirotaka Kida, Yuichiro Ii, Masaru Asahi, Masayuki Maeda, Hajime Sakuma, Hidekazu Tomimoto (Handling Associate Editor: Jae-Hong Lee)
Neuropsychological Features of Microbleeds and Cortical Microinfarct Detected by High Resolution Magnetic Resonance Imaging
Abstract: Background: Lobar microbleeds (MBs) and cortical microinfarct (CMI) are caused by cerebral amyloid angiopathy in the elderly and increase in number in Alzheimer’s disease. Objective: The aim of this study is to elucidate the effects of lobar MBs and CMIs on cognitive function. Methods: The subjects were outpatients who visited memory clinic of Mie University Hospital. Among 120 subjects, 109 patients fulfilled the inclusion criteria. We quantitatively estimated MBs and CMIs using double inversion recovery and 3D FLAIR images of 3T MRI. Neuropsychological assessments included intellectual, memory, constructional, and frontal lobe function. Results: Of the 109 patients, MBs and CMIs were observed in 68 (62%) and 17 (16%) subjects, respectively. Of the 68 patients with MBs, lobar MBs were found in 28, deep MBs in 8 and mixed MBs in 31. In each age group, the number of MBs increased in patients with CMI (CMI+ group) than those without CMI (CMI- group), and MBs and CMIs additively decreased MMSE scores. In psychological screens, the MBs+ group with more than 10 MBs showed significantly lower scores of category- and letter-WF than MB- group. The CMI+ group showed significantly worse scores than CMI- group in Japanese Raven’s coloured progressive matrices, Trail Making Test-A, category- and letter-word fluency and copy and drawing of figures. Conclusion: Lobar MBs and CMIs in the elderly frequently coexisted with each other and additively contributed to cognitive impairment, which is mainly predisposed to frontal lobe function.
Pages 327-335
Pongsatorn Paholpak, Liang Li-Jung, Drew R. Carr, Elvira Jimenez, Robin J. Barrows, Valeiry Sabodash, Mario F. Mendez (Handling Associate Editor: Grace Lee)
Prolonged Visual Facial Grasp in Frontotemporal Dementia
Abstract: Background: Gaze and eye contact is a critical aspect of social interaction. Patients with behavioral variant frontotemporal dementia (bvFTD) may exhibit abnormally prolonged stare toward human faces. Objective: To study characteristics of social gaze in patients with bvFTD compared to age and education matched-patients with early-onset Alzheimer’s disease (eAD) and healthy controls (HC). Method: Fifty picture stimuli were presented to each participant (bvFTD=12, eAD=18, HC=13). Each stimuli contained two properties: face (facial versus non-facial) and valence (positive, negative, and neutral). The "facial" stimuli contained human faces. The participants Visual Fixation Time (VFT) was measured for each picture stimuli of interest (per facial expressions on the Facial Action Coding System). A linear mixed-effects regression model with participant-level of random effects was used to compare VFTs between groups. Results: The patients with bvFTD showed significantly prolonged VFTs to faces than the patients with eAD and the HC, regardless of valence (all p<0.01). There were no differences in VFTs for non-facial stimuli between patients with bvFTD and eAD. However, patients with bvFTD and eAD had significantly prolonged VFTs to negative non-facial stimuli than the HC (p=0.006 and 0.019, respectively). Conclusion: Patients with bvFTD exhibited a prolonged stare toward human faces. This prolonged visual facial grasp may contribute to the disturbed social interactions of patients with bvFTD and can help distinguish them from those with Alzheimer's disease and other conditions. Additionally, both dementia groups tended to stare at negative stimuli whether faces or non-faces.
Pages 337-347
Kevin N. Hascup, Erin R. Hascup (Handling Associate Editor: D. Allan Butterfield)
Soluble Amyloid-β42 Stimulates Glutamate Release through Activation of the α7 Nicotinic Acetylcholine Receptor
Abstract: Alzheimer’s disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and hippocampal atrophy. Soluble amyloid-β (Aβ)42 and plaque accumulation is implicated as the neurotoxic species in this disorder; however, at physiological concentrations (pM-nM), Aβ42 contributes to neurogenesis, long-term potentiation, and neuromodulation. Because Aβ42 binds the α7 nicotinic acetylcholine receptors (α7nAChRs) located presynaptically on glutamatergic terminals, involved with hippocampal dependent learning and memory, we examined the effects of the human, monomeric isoform of Aβ42 on glutamate release in the dentate gyrus (DG), CA3, and CA1, of isoflurane anesthetized, 6-9 month old male C57BL/6J mice. We utilized an enzyme-based microelectrode array selective for L-glutamate measures with fast temporal (4 Hz), low spatial resolution (50 x 100 µm) and minimal damage to the surrounding parenchyma (50-100 µm). Local application of Aβ42 (0.01, 0.1, 1.0, and 10.0 µM; ~150 nl; 1-2 seconds) elicited robust, reproducible glutamate signals in all hippocampal subfields studied. Local application of 0.1 and 1.0 µM Aβ42 significantly increased the average maximal amplitude of glutamate release compared to saline in the DG and CA1. 10.0 µM Aβ42 significantly elevated glutamate release in the DG and CA3, but not in the CA1. Glutamate release was completely attenuated with coapplication of 10.0 µM α-Bungarotoxin, the potent α7nAChR antagonist. Coapplication of 10.0 µM tetrodotoxin, indicates Aβ42-induced glutamate release originates from neuronal rather than glial sources. This study demonstrates that the human, monomeric Aβ42 isoform evokes glutamate release through the α7nAChR and varies across hippocampal subfields.
Pages 349-361
Walid Tajeddinn, Torbjörn Persson, Javier Calvo-Garrido, Mohammed Seed Ahmed, Silvia Maioli, Swetha Vijayaraghavan, Mehmet Selim Kazokoglu, Cristina Parrado-Fernández, Takashi Yoshitake, Jan Kehr, Paul Francis, Bengt Winblad, Kina Höglund, Angel Cedazo-Minguez, Dag Aarsland
Pharmacological Modulations of the Serotonergic System in a Cell-Model of Familial Alzheimer’s Disease
Abstract: Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer’s disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p<0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p>0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.
