Pages 1481-1493
Review
Abhishek Ankur Balmik, Subashchandrabose Chinnathambi
Multi-Faceted Role of Melatonin in Neuroprotection and Amelioration of Tau Aggregates in Alzheimer's Disease
Abstract: Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-β plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-β needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.
Pages 1495-1506
Review
Maya L. Gosztyla, Holly M. Brothers, Stephen R. Robinson
Alzheimer's Amyloid-β is an Antimicrobial Peptide: A Review of the Evidence
Abstract: The amyloid-β (Aβ) peptide has long been considered to be the driving force behind Alzheimer's disease (AD). However, clinical trials that have successfully reduced Aβ burden in the brain have not slowed the cognitive decline, and in some instances, have resulted in adverse outcomes. While these results can be interpreted in different ways, a more nuanced picture of Aβ is emerging that takes into account the facts that the peptide is evolutionarily conserved and is present throughout life in cognitively normal individuals. Recent evidence indicates a role for Aβ as an antimicrobial peptide (AMP), a class of innate immune defense molecule that utilizes fibrillation to protect the host from a wide range of infectious agents. In humans and in animal models, infection of the brain frequently leads to increased amyloidogenic processing of the amyloid-β protein precursor (AβPP) and resultant fibrillary aggregates of Aβ. Evidence from in vitro and in vivo studies demonstrates that Aβ oligomers have potent, broad-spectrum antimicrobial properties by forming fibrils that entrap pathogens and disrupt cell membranes. Importantly, overexpression of Aβ confers increased resistance to infection from both bacteria and viruses. The antimicrobial role of Aβ may explain why increased rates of infection have been observed in some of the AD clinical trials that depleted Aβ. Perhaps progress toward a cure for AD will accelerate once treatment strategies begin to take into account the likely physiological functions of this enigmatic peptide.
Pages 1507-1518
Review
Roberta Ghidoni, Rosanna Squitti, Mariacristina Siotto, Luisa Benussi
Innovative Biomarkers for Alzheimer's Disease: Focus on the Hidden Disease Biomarkers
Abstract: The criteria for the clinical diagnosis of AD include the analysis of biomarkers of the underlying brain disease pathology; a set of cerebrospinal fluid (CSF) tests, amyloid-β1-42 (Aβ42), total-tau (t-tau), and phosphorylated tau (p-tau), are available and their performance in a clinical setting has been assessed in several studies. Thus, in dementia research, great advances have been made in the discovery of putative biomarkers; however, disappointingly, few of them have been translated into clinically applicable assays. To find biomarkers able to reliably detect AD pathology already at prodromal stages and in blood is even more important. Recent technical breakthroughs have provided ultrasensitive methods that allow the detection of brain-specific proteins in blood. In the present review, we will focus on the usefulness of ultrasensitive technologies for biomarker discovery and trace elements detection; moreover, we will review studies on circulating nano-compartments, a promising novel source of material for molecular diagnostics.
Pages 1519-1525
Short Communication
Hélène Courtemanche, Edith Bigot, Matthieu Pichelin, Béatrice Guyomarch4 Claire Boutoleau-Bretonnière, Cédric Le May, Pascal Derkinderen1, Bertrand Cariou
PCSK9 Concentrations in Cerebrospinal Fluid Are Not Specifically Increased in Alzheimer's Disease
Abstract: The role of PCSK9 in Alzheimer's disease (AD) is controversial. We compared cerebrospinal fluid (CSF) PCSK9 concentrations in 36 AD and 31 non-AD patients. CSF PCSK9 levels did not differ between AD and non-AD groups (2.80 versus 2.62 ng/mL). However, PCSK9 CSF levels were increased in AD and non-AD patients with other neurodegenerative process (non-AD ND, n=20) compared to patients without neurodegenerative disorders (non-ND, n=11): 2.80 versus 2.30 (p<0.005) and 2.83 versus 2.30 ng/mL (p=NS), respectively. CSF PCSK9 were positively correlated with AD biomarkers (Aβ1-42, T-tau, and P-tau). PCSK9 concentrations in CSF are increased in neurodegenerative disorders rather than specifically in AD.
Pages 1527-1530
Short Communication
Faissal Stipho, Robert Jackson, Marwan N. Sabbagh
Pathologically Confirmed Alzheimer's Disease in APOE ε2 Homozygotes is Rare but Does Occur
Abstract: Background: Homozygous APOE ε4 status is a well-known risk factor in the development of Alzheimer's disease (AD). However, other genotypes of APOE have not yet been found to have equal clinical significance. There is a paucity of reports regarding clinically or pathologically described AD in APOE ε2 homozygotes compared to the other alleles. Objective: To notify clinicians that patients with homozygous APOE ε2 are also at risk of developing AD based on results from the largest prospectively gathered registry of brain samples to date. Methods: We queried the National Alzheimer's Coordinating Center (NACC) database for autopsy-confirmed AD cases. Of the Uniform Data Set (UDS) participants who are deceased, 5,779 were diagnosed with dementia at their last UDS visit prior to death, and autopsy data is available for 3,518. Results: Of the brains in the NACC database with pathologically confirmed dementia, seven were found to be homozygous for APOE ε2, which represents only 0.2% of the autopsy-confirmed sample. Furthermore, pathology-confirmed AD represents 29% (2/7) of the APOE ε2/ε2 patients diagnosed with dementia. Conclusions: Although rare, autopsy-confirmed AD can be present in APOE ε2/ε2 carriers.
Pages 1531-1538
Short Communication
Francesc Jiménez-Altayó, Judith Sànchez-Ventura, Elisabet Vila, Lydia Giménez-Llort
Crosstalk between Peripheral Small Vessel Properties and Anxious-like Profiles: Sex, Genotype, and Interaction Effects in Mice with Normal Aging and 3×Tg-AD mice at Advanced Stages of Disease
Abstract: Cardiovascular disease resulting from oxidative stress and inflammation can exacerbate Alzheimer's disease. This brief report provides the first evidence of compromised small peripheral mesenteric resistance artery (MRA) properties in 15-month-old 3xTg-AD mice. Females showed worse physiologically relevant MRA structural (increased passive external and internal diameters, cross sectional area) and functional (increased active internal diameters) alterations suggesting sex-dependent dysfunctions. At both physiological and high intraluminal pressures, vascular alterations correlated with the anxious-like behavioral profile, in a sex-dependent manner. Finally, the results unveil a crosstalk between peripheral small vessel abnormalities and behavior in both 3xTg-AD mice and age-matched counterparts with normal aging.
Pages 1539-1548
Shigeki Hirano, Hitoshi Shinotoh, Hitoshi Shimada, Tsuneyoshi Ota, Koichi Sato, Noriko Tanaka, Ming-Rong Zhang, Makoto Higuchi, Kiyoshi Fukushi, Toshiaki Irie, Satoshi Kuwabara, Tetsuya Suhara
Voxel-Based Acetylcholinesterase PET Study in Early and Late Onset Alzheimer's Disease
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by chronic progressive cognitive decline and displays underlying brain cholinergic dysfunction, providing a rationale for treatment with cholinomimetic medication. The clinical presentations and courses of AD patients may differ by age of onset. Objective: The objective of the present study was to illustrate the regional differences of brain acetylcholinesterase (AChE) activity as quantified by N-[11C]methylpiperidinyl-4-acetate ([11C]MP4A) and PET using parametric whole brain analysis and clarify those differences as a function of age. Methods: 22 early onset AD (EOAD) with age at onset under 65, the remaining 26 as late onset AD (LOAD), and 16 healthy controls (HC) were enrolled. Voxel-based AChE activity estimation of [11C]MP4A PET images was conducted by arterial input and unconstrained nonlinear least-squares method with subsequent parametrical analyses. Statistical threshold was set as Family Wise Error corrected, p-value < 0.05 on cluster-level and cluster extent over 30 voxels. Results: Voxel-based group comparison showed that, compared to HC, both EOAD and LOAD showed cortical AChE decrement in parietal, temporal, and occipital cortices, with wider and stringent cortical involvement in the EOAD group, most prominently demonstrated in the temporal region. There was no significant correlation between age and regional cerebral AChE activity except for a small left superior temporal region in the AD group (Brodmann's area 22, Zmax = 5.13, 396 voxels), whereas no significant cluster was found in the HC counterpart. Conclusion: Difference in cortical cholinergic dysfunction between EOAD and LOAD may shed some light on the cholinomimetic drug efficacy in AD.
Pages 1549-1565
P. Hemachandra Reddy, Maria Manczak, XiangLin Yin, Arubala P. Reddy
Synergistic Protective Effects of Mitochondrial Division Inhibitor 1 and Mitochondria-Targeted Small Peptide SS31 in Alzheimer’s Disease
Abstract: The purpose of our study was to determine the synergistic protective effects of mitochondria-targeted antioxidant SS31 and mitochondria division inhibitor 1 (Mdivi1) in Alzheimer’s disease (AD). Using biochemical methods, we assessed mitochondrial function by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity, mitochondrial ATP, and GTPase Drp1 enzymatic activity in mutant AβPP cells. Using biochemical methods, we also measured cell survival and apoptotic cell death. Amyloid-β (Aβ) levels were measured using sandwich ELISA, and using real-time quantitative RT-PCR, we assessed mtDNA (mtDNA) copy number in relation to nuclear DNA (nDNA) in all groups of cells. We found significantly reduced levels of Aβ40 and Aβ42 in mutant AβPP cells treated with SS31, Mdivi1, and SS31+Mdivi1, and the reduction of Aβ42 levels were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. The levels of mtDNA copy number and cell survival were significantly increased in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the increased levels of mtDNA copy number and cell survival were much higher in SS31+Mdivi1 treated cells than individual treatments of SS31 and Mdivi1. Mitochondrial dysfunction is significantly reduced in SS31, Mdivi1, and SS31+Mdivi1 treated mutant AβPP cells; however, the reduction is much higher in cells treated with both SS31+Mdvi1. Similarly, GTPase Drp1 activity is reduced in all treatments, but reduced much higher in SS31+Mdivi1 treated cells. These observations strongly suggest that combined treatment of SS31+Mdivi1 is effective than individual treatments of SS31 and Mdivi1. Therefore, we propose that combined treatment of SS31+Mdivi1 is a better therapeutic strategy for AD. Ours is the first study to investigate combined treatment of mitochondria-targeted antioxidant SS31 and mitochondrial division inhibitor 1 in AD neurons.
Pages 1567-1578
Madeleine L. Werhane, Kelsey R. Thomas, Emily C. Edmonds, Katherine J. Bangen, My Tran, Alexandra L. Clark, Daniel A. Nation, Paul E. Gilbert, Mark W. Bondi, Lisa Delano-Wood, for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Tânia C. T. Ferraz Alves)
Differential Effect of APOE 4 Status and Elevated Pulse Pressure on Functional Decline in Cognitively Normal Older Adults
Abstract: Background/Objective: The APOE 4 allele and increased vascular risk have both been independently linked to cognitive impairment and dementia. Since few studies have characterized how these risk factors affect everyday functioning, we investigated the relationship between APOE 4 genotype and elevated pulse pressure (PP) on functional change in cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Methods: 738 normally aging participants underwent APOE genotyping, and baseline PP was calculated from blood pressure indices. The Functional Activities Questionnaire (FAQ) was completed by participants' informant at baseline and 6, 12, 24, 36, and 48-month follow-up visits. Multiple linear regression and multilevel modeling were used to examine the effects of PP and APOE 4 genotype on cross-sectional and longitudinal FAQ scores, respectively. Results: Adjusting for demographic and clinical covariates, results showed that both APOE 4 status and elevated PP predicted greater functional difficulty trajectories across four years of follow-up. Interestingly, however, elevated PP was associated with greater functional decline over time in 4 non-carriers versus carriers. Conclusion: Results show that, although APOE 4 status is the prominent predictor of functional difficulty for 4 carriers, an effect of arterial stiffening on functional difficulty was observed in non-carriers. Future studies are needed in order to clarify the etiology of the association between PP and different brain aging processes, and further explore its utility as a marker of dementia risk. The present study underscores the importance of targeting modifiable risk factors such as elevated PP to prevent or slow functional decline and pathological brain aging.
Pages 1579-1594
Vaitsa Giannouli, Dimitrios Stamovlasis, Magda Tsolaki (Handling Associate Editor: Merce Boada)
Exploring the Role of Cognitive Factors in a New Instrument for Elders' Financial Capacity Assessment
Abstract: Background: The influence of cognitive factors on financial capacity across the dementia spectrum of cognitive aging, Alzheimer's disease (AD), and mild cognitive impairment (MCI) has been little investigated, while it has not been investigated at all in other types of dementia as well as in extended samples of elders in Greece. Objective: The aim of this study is to investigate financial capacity, to develop a tool, test its psychometric properties, validate, and then test the tool in groups of healthy controls compared to elders with dementia, while examining other facets of their cognitive performance. Methods: 719 elders from Greece including healthy participants and patients with different types of dementia were examined with Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) and a battery of neuropsychological tests concerning various cognitive functions. Results: Significantly different profiles in the scores and subscores of LCPLTAS for all the groups of dementia patients were found, with a general incapacity finding for all the dementia groups including the MCI patients. Logistic regression showed that Mini-Mental State Examination (MMSE), Geriatric Depression Scale, and Trail Making Part B predicted competence on LCPLTAS for the dementia patients. Persons with MCI and dementia had lower financial knowledge scores than those without cognitive impairment, with MMSE scores below 27 suggestive as an indication of financial incapacity. Conclusion: The LCPLTAS provides information for a strong positive correlation with MMSE, while the use both of MMSE and LCPLTAS as adequate measures of financial (in)capacity is discussed for the Greek legal procedures regarding elder guardianship cases.
Pages 1595-1607
Lisa Flem Kalheim, Tormod Fladby, Christopher Coello, Atle Bjørnerudb Per Selnes (Handling Associate Editor: Andrea Chincarini)
[18F]-Flutemetamol Uptake in Cortex and White Matter: Comparison with Cerebrospinal Fluid Biomarkers and [18F]-Fludeoxyglucose
Abstract: Flutemetamol (18F-Flut) is an [18F]-labelled amyloid PET tracer with increasing availability. The main objectives of this study were to investigate 1) cerebrospinal fluid (CSF) Aβ 1-42 (Aβ42) concentrations associated with regional 18F-Flut uptake, 2) associations between cortical 18F-Flut and [18F]-fludeoxyglucose (18F-FDG)-PET, and 3) the potential use of 18F-Flut in WM pathology. Cognitively impaired, nondemented subjects were recruited (n=44). CSF was drawn, and 18F-Flut-PET, 18F-FDG-PET, and MRI performed. Our main findings were: 1) Different Alzheimer's disease predilection areas showed increased 18F-Flut retention at different CSF Aβ42 concentrations (posterior regions were involved at higher concentrations). 2) There were strong negative correlations between regional cortical 18F-Flut and 18F-FDG uptake. 3) Increased 18F-Flut uptake were observed in multiple subcortical regions in amyloid positive subjects, including investigated reference regions. However, WM hyperintensity 18F-Flut standardized uptake value ratios (SUVr) were not significantly different, thus we cannot definitely conclude that the higher uptake in 18F-Flut(+) is due to amyloid deposition. In conclusion, our findings support clinical use of CSF Aβ42, putatively relate decreasing CSF Aβ42 concentrations to a sequence of regional amyloid deposition, and associate amyloid pathology to cortical hypometabolism. However, we cannot conclude that 18F-Flut-PET is a suitable marker for WM pathology due to high aberrant WM uptake.
Pages 1609-1621
Heyun Yang*, Tingting Hou*, Wei Wang, Yumin Luo, Feng Yan, Jianping Jia *These authors contributed equally to this work.
The Effect of Chronic Cerebral Hypoperfusion on Amyloid-β Metabolism in a Transgenic Mouse Model of Alzheimer's Disease (PS1V97L)
Abstract: Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-β peptides (Aβ) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-β peptide (Aβ) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Aβ (including Aβ oligomers), with decreased α-secretase activity and expression and increased β-secretase activity and expression. Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low-density lipoprotein receptor-related protein 1 (LRP-1); both these are Aβ transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Aβ degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Aβ metabolism by aggravating its abnormal production, transport, and clearance.
Pages 1623-1634
Maurizio Gallucci, Cinzia Piovesan, Maria Elena Di Battista (Handling Associate Editor: Daniela Galimberti)
Associations between the Frailty Index and Brain Atrophy: the Treviso Dementia (TREDEM) Registry
Abstract: Background: Frailty is a condition which is characterized by a reduction in the homeostatic reserves of the individual and which entails an increased vulnerability to stressful endogenous and exogenous agents. The Frailty Index (FI), proposed by Rockwood, was designed following an accumulation of deficits model: the greater the number of deficits in a given individual, the greater the degree of frailty. Objective: The aim of this study was to verify the existence of associations between FI and cerebral atrophy. Methods: The TREDEM Register (Treviso Dementia) provided retrospective observational data from 1,584 patients. The FI was calculated based on 50 variables comprising diseases, disability, behavioral disturbances, and blood chemistry parameters. The severity of atrophy in the cortical and subcortical regions, such as the amplitude of the lateral ventricles, were detected by computerized axial tomography (CAT). Multiple logistic regression models using the stepwise backward method were used to analyze possible associations between FI and atrophy. Results: For each increment of one hundredth of the FI, the probability of cortical atrophy increases by 2%. The female gender is a protective factor for cortical and subcortical atrophy. At each increase of one percent of the FI, the probability of a severe degree of cortical atrophy increases by 3%. The FI was significantly associated with frontal and temporal cortical atrophy. The relationship between overall subcortical atrophy and the FI was not significant, whereas it was the one with the severe degree of subcortical atrophy. The FI is significantly associated with the atrophy of the peri-insular subcortical region. Similar associations were found considering only demented patients. Conclusion: The FI is associated with the presence, degree, and some localization of cerebral atrophy in a population of cognitive-decline patients.
Pages 1635-1649
Pankaj D. Mehta, Bruce A. Patrick, Marc Barshatzky, Sangita P. Mehta, Janusz Frackowiak, Bozena Mazur-Kolecka, Jerzy Wegiel, Thomas Wisniewski, David L. Miller
Generation and Partial Characterization of Rabbit Monoclonal Antibody to Pyroglutamate Amyloid-β3-42 (pE3-Aβ)
Abstract: N-terminally truncated pyroglutamate amyloid-β (Aβ) peptide starting at position 3 represents a significant fraction of Aβ peptides (pE3-Aβ) in amyloid plaques of postmortem brains from patients with Alzheimer's disease (AD) and older persons with Down syndrome (DS). Studies in transgenic mouse models of AD also showed that pE3-Aβ is a major component of plaques, and mouse monoclonal antibody to pE3-Aβ appears to be a desirable therapeutic agent for AD. Since small peptides do not typically elicit a good immune response in mice, but do so favorably in rabbits, our aims were to generate and partially characterize a rabbit monoclonal antibody (RabmAb) to pE3-Aβ. The generated RabmAb was found to be specific for pE3-Aβ, since it showed no reactivity with Aβ16, Aβ40, Aβ42, Aβ3-11, and pE11-17 Aβ peptides in an enzyme linked immunosorbent assay (ELISA). The isotype of the antibody was found to be IgG class. The antibody possesses high affinity to pE3-Aβ with dissociation constant (KD) for the antibody of 1 nM. The epitope of the antibody lies within the sequence of pE3-FRHD. In dot blotting, the optimal detection of pE3-Aβ was at an antibody concentration of 0.5 µg/ml. The threshold of pE3-Aβ detection was 2 fmol. The antibody was sensitive enough to detect 10 pg/ml of pE3-Aβ in sandwich ELISA. pE3-Aβ was detected in AD and DS brain extracts in ELISA and immunoblotting. Immunohistological studies showed immunolabeling of plaques and blood vessels in brains from patients with AD, and DS showing AD pathology. Thus, the antibody can be widely applied in AD and DS research, and therapeutic applications.
Pages 1651-1661
Sohshi Yuki-Nozaki, Moeko Noguchi-Shinohara, Chiaki Domoto, Yoshihisa Ikeda, Miharu Samuraki, Kazuo Iwasa, Masami Yokogawa, Kimiko Asai, Kiyonobu Komai, Hiroyuki Nakamura, Masahito Yamada
Differences in Dementia Beliefs between Non-Demented Public Screeners and In-Home Screeners and Their Potential Impact on Future Dementia Screening Intention: The Nakajima Study
Abstract: In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population-based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, Japan (n = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: "perceived susceptibility," "perceived severity," "perceived barriers," and "perceived benefits." Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p = 0.002). In in-home screeners, low "perceived severity" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32-0.80)]. In both public and in-home screeners, high "perceived benefits" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46-3.10); adjusted OR (95% CI) = 2.56 (1.22-5.35), respectively]. It is necessary to reduce "perceived severity" among in-home screeners to increase dementia screening participants.
Pages 1663-1681
Morgane Cam*, Emilie Durieu*, Marion Bodin, Antigoni Manousopoulou, Svenja Koslowski, Natalia Vasylieva, Bogdan Barnych, Bruce D. Hammock, Bettina Bohl, Philipp Koch, Chiori Omori, Kazuo Yamamoto, Saori Hata, Toshiharu Suzuki, Frank Karg, Patrick Gizzi, Vesna Erakovic Haber, Vlatka Bencetic Mihaljevic, Branka Tavcar, Erik Porteliusl, Josef Pannee, Kaj Blennow, Henrik Zetterberg, Spiros D. Garbis, Pierrick Auvray, Hermeto Gerber, Jeremy Fraering, Patrick C. Fraering, Laurent Meijer * These authors contributed equally to this work.
Induction of Amyloid-β42 Production by Fipronil and Other Pyrazole Insecticides
Abstract: Generation of amyloid-β peptides (Aβs) by proteolytic cleavage of the amyloid-β protein precursor (AβPP), especially increased production of Aβ42/Aβ43 over Aβ40, and their aggregation as oligomers and plaques, represent a characteristic feature of Alzheimer's disease (AD). In familial AD (FAD), altered Aβ production originates from specific mutations of AβPP or presenilins 1/2 (PS1/PS2), the catalytic subunits of γ-secretase. In sporadic AD, the origin of altered production of Aβs remains unknown. We hypothesize that the 'human chemical exposome' contains products able to favor the production of Aβ42/Aβ43 over Aβ40 and shorter Aβs. To detect such products, we screened a library of 3500+ compounds in a cell-based assay for enhanced Aβ42/Aβ43 production. Nine pyrazole insecticides were found to induce a β- and γ-secretase-dependent, 3-10-fold increase in the production of extracellular Aβ42 in various cell lines and neurons differentiated from induced pluripotent stem cells derived from healthy and FAD patients. Immunoprecipitation/mass spectrometry analyses showed increased production of A s cleaved at positions 42/43, and reduced production of peptides cleaved at positions 38 and shorter. Strongly supporting a direct effect on γ-secretase activity, pyrazoles shifted the cleavage pattern of another γ-secretase substrate, alcadeinα, and shifted the cleavage of AβPP by highly purified γ-secretase toward Aβ42/Aβ43. Focusing on fipronil, we showed that some of its metabolites, in particular the persistent fipronil sulfone, also favor the production of Aβ42/Aβ43 in both cell-based and cell-free systems. Fipronil administered orally to mice and rats is known to be metabolized rapidly, mostly to fipronil sulfone, which stably accumulates in adipose tissue and brain. In conclusion, several widely used pyrazole insecticides enhance the production of toxic, aggregation prone Aβ42/Aβ43 peptides, suggesting the possible existence of environmental "Alzheimerogens" which may contribute to the initiation and propagation of the amyloidogenic process in sporadic AD.
Pages 1683-1689
Irene Piaceri, Daniele Imperiale, Enrico Ghidoni, Cristiana Atzori, Silvia Bagnoli, Camilla Ferrari, Silvana Ungari, Luca Ambrogio, Sandro Sorbi, Benedetta Nacmias (Handling Associate Editor: Daniela Galimberti)
Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration
Abstract: Background: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. Objective: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). Methods: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. Results: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X ) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in scientific literature. Conclusion: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia.
Pages 1691-1702
Christopher M. Lee*, Heidi I.L. Jacobs*, Marta Marquié, John A. Becker, Nicolas V. Andrea, David S. Jin, Aaron P. Schultz, Matthew P. Frosch, Teresa Gómez-Isla, Reisa A. Sperling, Keith A. Johnson *These authors contributed equally to this work.
18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal
Abstract: Background: On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. Objective: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. Methods: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124 W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. Results: B/AA individuals had elevated CP and HC SUVR (p<0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p>0.05). CP SUVR was associated with HC SUVR (p<10-14), but with no other ROI SUVR (p>0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. Conclusion: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution.
Pages 1703-1711
Luísa Alves, Sandra Cardoso, João Maroco, Alexandre de Mendonça, Manuela Guerreiro, Dina Silva
Neuropsychological Predictors of Long-Term (10 Years) Mild Cognitive Impairment Stability
Abstract: Background: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer's disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years. Objectives: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability. Methods: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least 10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for. Results: Long-term-stable MCI (n=22) and converter MCI (n=44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven's Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability. Conclusions: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability.
Pages 1713-1724
Katerina A. Tetzloff, Jonathan Graff-Radford, Peter R. Martin, Nirubol Tosakulwong, Mary M. Machulda, Joseph R. Duffy, Heather M. Clark, Matthew L. Senjem, Anthony J. Spychalla, Daniel A. Drubach, Clifford R. Jack, Jr., Val J Lowe, Keith A. Josephs, Jennifer L. Whitwell
Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease
Abstract: Background: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. Objective: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). Methods: Eighteen PCA and 19 lvPPA subjects that showed amyloid- deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional-level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. Results: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. Conclusion: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition.
Pages 1725-1736
Andrea Popelová, Veronika Pražienková, Barbora Neprašová, Barbora Judita Kasperová, Lucie Hrubá, Martina Holubová, Jana Zemenová, David Blum, Blanka Železná, Marie-Christine Galas, Jaroslav Kuneš, Lenka Maletínská
Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy
Abstract: Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3β, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated.
Pages 1737-1746
Jianlan Gu, Nana Jin, Denglei Ma, Dandan Chu, Khalid Iqbal, Cheng-Xin Gong, Fei Liu (Handling Associate Editor: Xuemin Xu)
Calpain I Activation Causes GLUT3 Proteolysis and Downregulation of O-GlcNAcylation in Alzheimer's Disease Brain
Abstract: Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O-GlcNAcylation in AD brain.
Pages 1747-1758
Monica Cations, Brian Draper, Lee-Fay Low, Kylie Radford, Julian Trollor, Henry Brodaty, Perminder Sachdev, Peter Gonski, Gerald Anthony Broe, Adrienne Withall (Handling Associate Editor: Isabelle Rouch)
Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies
Abstract: Background: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. Objective: To examine the association of YOD with cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) in non-autosomal dominant degenerative and/or vascular YOD. Methods: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported. Results: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life. Conclusion: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies.
Pages 1759-1766
William Charles Kreisl, Peng Jin, Seonjoo Lee, Ezra R. Dayan, Shankar Vallabhajosula, Gregory Pelton, José A. Luchsinger, Gnanavalli Pradhaban, D. P. Devanand (Handling Associate Editor: Agneta Nordberg)
Odor Identification Ability Predicts PET Amyloid Status and Memory Decline in Older Adults
Abstract: Background: Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). Objective: To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline. Methods: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. Results: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline. Conclusion: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints.
Pages 1767-1775
Naoki Ito, Hitomi Saito, Shinobu Seki, Fumitaka Ueda, Takashi Asada
Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial
Abstract: Background: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest. Objective: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI. Method: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation. Results: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately. Conclusion: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions.
Pages 1777-1787
Woojin Scott Kim*, Yuhong Fu*, Carol Dobson-Stone, Jen-Hsiang T. Hsiao, Kani Shang, Marianne Hallupp, Peter R. Schofield, Brett Garner, Tim Karl, John B.J. Kwok *These authors contributed equally to this work.
Effect of Fluvoxamine on Amyloid-β Peptide Generation and Memory
Abstract: Alzheimer's disease is characterized by abnormal amyloid-β (Aβ) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Aβ pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-β protein precursor (AβPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Aβ production and improve cognition. We firstly investigated the impact of SIGMAR1 on AβPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected γ-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Aβ production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Aβ production by inhibiting γ-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ~8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Aβ pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on γ-secretase activity and AβPP processing to generate Aβ, and may have a protective effect on cognition in the J20 mice.
Pages 1789-1801
Yanmin Zhang, Ouyang Guo, Yuda Huo, Guan Wang, Heng-Ye Man (Handling Associate Editor: Tao Ma)
Amyloid-β Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease
Abstract: As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer's disease (AD), presumably via amyloid-β (Aβ). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of Aβ triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both Aβ-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of Aβ. Furthermore, AD brain lysates and Aβ-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the Aβ-dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD.
Pages 1803-1813
Ting-ting Hou*, He-Yun Yang*, Wei Wang, Qiao-qi Wu, Yuan-ruhua Tian, Jian-ping Jia *These authors contribute equally to this work.
Sulforaphane Inhibits the Generation of Amyloid-β Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice
Abstract: Abnormal amyloid-β (Aβ) aggregates are a striking feature of Alzheimer's disease (AD), and Aβ oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Aβ can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Aβ. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Aβ. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Aβ oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Aβ oligomer production in AD.
Pages 1815-1826
Dennis M. Kamara*, Umesh Gangishetti*, Marla Gearing, Monica Willis-Parker, Liping Zhao, William T. Hu, Lary C. Walker *These authors contributed equally to this work.
Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease
Abstract: Cerebral amyloid angiopathy (CAA) of the A type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n=18) and Caucasians (n=19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted.
Pages 1827-1839
Mark J.R.J. Bouts, Christiane Möller, Anne Hafkemeijer, John C. van Swieten, Elise Dopper, Wiesje M. van der Flier, Hugo Vrenken, Alle Meije Wink, Yolande A.L. Pijnenburg, Philip Scheltens, Frederik Barkhof, Tijn. M. Schouten, Frank de Vos, Rogier A. Feis, Jeroen van der Grond, Mark de Rooij, Serge A.R.B. Rombouts (Handling Associate Editor: Yu Zhang)
Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging
Abstract: Background/Objective: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to on a subject-basis differentiate these dementia-types is not yet known. Methods: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). Results: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p=0.41). Conclusion: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI.
Pages 1841-1855
Michael A. Sugarman, Michael L. Alosco, Yorghos Tripodis, Eric G. Steinberg, Robert A. Stern
Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment
Abstract: Background: Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. Objective: The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. Method: The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). Results: 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. Conclusion: The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults.
Pages 1857-1863
Charlotte E. Teunissen, Ming-Jang Chiu, Che-Chuan Yang, Shieh-Yueh Yang, Philip Scheltens, Henrik Zetterberg, Kaj Blennow
Plasma Amyloid-β (Aβ42) Correlates with Cerebrospinal Fluid Aβ42 in Alzheimer's Disease
Abstract: The 42 amino acid form of amyloid-β (Aβ42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Aβ42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Aβ42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Aβ42 levels in AD. To confirm the opposite changes of Aβ42 levels in CSF and plasma for AD, we assayed the levels of Aβ42 in plasma of subjects with known CSF Aβ42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Aβ42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Aβ42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Aβ42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Aβ42 transport from brain to peripheral blood, and sample matrix into account.
Pages 1865-1875
Tim Stuckenschneider, Christopher David Askew, Stefanie Rüdiger, Maria Cristina Polidori, Vera Abelna Tobias Vogt, Andreas Krome, Marcel Olde Rikkert, Brian Lawlor, Stefan Schneider, on behalf of the NeuroExercise Study Group (Handling Associate Editor: Silke Matura)
Cardiorespiratory Fitness and Cognitive Function are Positively Related Among Participants with Mild and Subjective Cognitive Impairment
Abstract: Background: By 2030, about 74 million people will be diagnosed with dementia, and many more will experience subjective (SCI) or mild cognitive impairment (MCI). As physical inactivity has been identified to be a strong modifiable risk factor for dementia, exercise and physical activity (PA) may be important parameters to predict the progression from MCI to dementia, but might also represent disease trajectory modifying strategies for SCI and MCI. Objective: A better understanding of the relationship between activity, fitness, and cognitive function across the spectrum of MCI and SCI would provide an insight into the potential utility of PA and fitness as early markers, and treatment targets to prevent cognitive decline. Methods: 121 participants were stratified into three groups, late MCI (LMCI), early MCI (EMCI), and SCI based on the Montreal Cognitive Assessment (MoCA). Cognitive function assessments also included the Trail Making Test A+B, and a verbal fluency test. PA levels were evaluated with an interviewer-administered questionnaire (LAPAQ) and an activity monitor. An incremental exercise test was performed to estimate cardiorespiratory fitness and to determine exercise capacity relative to population normative data. Results: ANCOVA revealed that LMCI subjects had the lowest PA levels (LAPAQ, p=0.018; activity monitor, p=0.041), and the lowest exercise capacity in relation to normative values (p=0.041). Moreover, a modest correlation between MoCA and cardiorespiratory fitness (r=0.25; p<0.05) was found. Conclusion: These findings suggest that during the earliest stages of cognitive impairment PA and exercise capacity might present a marker for the risk of further cognitive decline. This finding warrants further investigation using longitudinal cohort studies.
Pages 1877-1886
Ingmar Skoog*, Silke Kern*, Henrik Zetterberg, Svante Östling, Anne Börjesson-Hanson, Xinxin Guoa, Kaj Blennow *These authors contributed equally to the work.
Low Cerebrospinal Fluid Aβ42 and Aβ40 are Related to White Matter Lesions in Cognitively Normal Elderly
Abstract: Background: Low cerebrospinal fluid (CSF) levels of Aβ42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF A interacts with different brain pathologies early in the disease process is limited. We examined how CSF A markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. Objective: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. Methods: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Aβ42 and Aβ40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. Results: In 85-year-olds without dementia, lower levels of both CSF Aβ42 and CSF Aβ40 were associated with WMLs. CSF Aβ42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Aβ42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. Conclusions: Our findings may suggest that there is an interrelationship between Aβ and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Aβ42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of A deposition than cortical degeneration.
Pages 1887-1900
Maxime Bertoux, Emma C Flanagan, Matthew Hobbs, Amparo Ruiz-Tagle, Carolina Delgado, Marcelo Miranda, Agustín Ibáñez, Andrea Slachevsky*, Michael Hornberger* These authors contributed equally to this work.
Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia
Abstract: Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD.
