Volume 38, Number 3, 2014

Pages 459-479
Review
Nick van Wijk, Laus M. Broersen, Martijn C. de Wilde, Robert J.J. Hageman, Martine Groenendijk, John W.C. Sijben, Patrick J.G.H. Kamphuis (Handling Associate Editor: Thomas Shea)
Targeting Synaptic Dysfunction in Alzheimer’s Disease by Administering a Specific Nutrient Combination
Abstract: Synapse loss and synaptic dysfunction are pathological processes already involved in the early stages of Alzheimer’s disease (AD). Synapses consist principally of neuronal membranes, and the neuronal and synaptic losses observed in AD have been linked to the degeneration and altered composition and structure of these membranes. Consequently, synapse loss and membrane-related pathology provide viable targets for intervention in AD. The specific nutrient combination Fortasyn Connect (FC) is designed to ameliorate synapse loss and synaptic dysfunction in AD by addressing distinct nutritional needs believed to be present in these patients. This nutrient combination comprises uridine, docosahexaenoic acid, eicosapentaenoic acid, choline, phospholipids, folic acid, vitamins B12, B6, C, and E, and selenium, and is present in Souvenaid, a medical food intended for use in early AD. It has been hypothesized that FC counteracts synaptic loss and reduces membrane-related pathology in AD by providing nutritional precursors and cofactors that act together to support neuronal membrane formation and function. Preclinical studies formed the basis of this hypothesis which is being validated in a broad clinical study program investigating the potential of this nutrient combination in AD. Memory dysfunction is one key early manifestation in AD and is associated with synapse loss. The clinical studies to date show that the FC-containing medical food improves memory function and preserves functional brain network organization in mild AD compared with controls, supporting the hypothesis that this intervention counteracts synaptic dysfunction. This review provides a comprehensive overview of basic scientific studies that led to the creation of FC and of its effects in various preclinical models.

Pages 481-495
Review
Guido Gainotti, Davide Quaranta, Gabriella Vita, Camillo Marra
Neuropsychological Predictors of Conversion from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: The construct of mild cognitive impairment (MCI) has been proposed to identify patients at risk of developing Alzheimer’s disease (AD) in the pre-clinical stage. Although subjects with MCI have an increased risk of progressing to dementia, most remain stable or return to normality. The new criteria for diagnosing prodromal AD assume that, to increase the predictive value of the MCI, in addition to a defect of delayed recall there must also be the presence of abnormal biomarkers, investigating structural and molecular neuroimaging and cerebrospinal fluid (CSF) analysis of amyloid-β or tau proteins. Although acknowledging that the use of CSF degeneration biomarkers is advisable not only for research, but also for clinical purposes, the present review is centered upon the neuropsychological markers of conversion to AD, which are equally clinically important. In particular, results of this review suggest the following: (a) measures of delayed recall are the best neuropsychological predictors of conversion from MCI to AD; (b) memory tests providing controlled encoding and cued recall are not necessarily better predictors than free recall tests; (c) stringent cut-off points are necessary to increase the specificity of these predictors; (d) multi-domain amnestic MCI patients are the best candidates for clinical trials, but not for treatment with disease-modifying drugs; and (e) not only episodic but also semantic memory is significantly impaired in patients who will convert to AD. These data and the underlying neural mechanisms will be discussed, trying to distinguish results obtained in MCI patients from those obtained in a pre-MCI stage of the AD progression.

Pages 497-501
Short Communication
Nan Hu*, Meng-Shan Tan*, Jin-Tai Yu, Lei Sun, Lin Tan, Ying-Li Wang, Teng Jiang, Lan Tan *These authors contributed equally to this manuscript.
Increased Expression of TREM2 in Peripheral Blood of Alzheimer’s Disease Patients
Abstract: TREM2 has been reported to be associated with Alzheimer’s disease (AD). Here, we evaluated TREM2 mRNA and protein expressions in peripheral blood from AD patients and healthy controls. Higher levels of TREM2 mRNA (p=0.002) and protein (p<0.001) were identified in AD patients. We observed a significant correlation between TREM2 expressions and MMSE score (mRNA: r= -0.482, protein: r= -0.582; p<0.01). According to ROC curve analysis, the diagnostic accuracy for TREM2 protein levels on monocytes was 70%, with the sensitivity and specificity 68% and 72%, respectively. Our results indicate that TREM2 might serve as a novel noninvasive biomarker for AD diagnosis.

Pages 503-506
Short Communication
Yash B. Joshi, Antonio Di Meco, Domenico Praticò (Handling Associate Editor: Patrizia Mecocci)
Modulation of Amyloid-β Production by Leukotriene B4 via the γ-Secretase Pathway
Abstract: Inflammatory mechanisms have been implicated in Alzheimer’s disease (AD) pathogenesis, and among them, the pro-inflammatory 5-lipoxygenase (5LO) enzyme. While previous work has shown that 5LO modulates the amyloidotic phenotype of AD, the exact metabolic product responsible for this biological action remains unknown. In this study, we challenged neuronal cells with leukotriene B4 (LTB4), a major 5LO product, and found that it increased amyloid-β formation whereby elevating the steady-state levels of the γ-secretase proteins, suggesting that LTB4 is the mediator of the 5LO effect. Therapies that by blocking 5LO activation suppress the formation of LTB4 or its action represent novel AD therapeutic opportunities.

Pages 507-514
Joshua D. Grill, Yan Zhou, Jason Karlawish, David Elashoff
Does Study Partner Type Impact the Rate of Alzheimer’s Disease Progression?
Abstract: Most patients with Alzheimer’s disease (AD) do not have a spouse. Despite this, the majority of AD research participants enroll with a spouse study partner. It remains unclear if differences between AD patients who do and do not have a spouse may bias study results. In this study, we examined whether AD patients with different study partner types (spouse versus adult child) demonstrate different rates of disease progression over two years on three outcome measures commonly used in AD research, including clinical trials. We used data from the National Alzheimer’s Coordinating Center Uniform Data Set to examine disease progression in participants age 55-90 with probable AD dementia. We examined disease progression as measured by the Clinical Dementia Rating Scale-Sum of the Boxes score, the Mini Mental Status Examination, and the Functional Assessment Questionnaire. Analyses were performed on data for all available eligible participants from the NACC UDS and after performing a propensity-matching model to better account for inherent differences between the populations of interest. Propensity matching was successful only when models did not include age and gender. For both propensity-matched analyses and those of all available data, we did not observe any differences between the study partner populations for any outcome measure. These results suggest that if investigators can improve in recruiting AD patients with adult child caregivers to research, the implications to study results may be minimal.

Pages 515-531
Steven J. Kiddle*, Martina Sattlecker*, Petroula Proitsi, Andrew Simmons, Eric Westman, Chantal Bazenet, Sally K. Nelson, Stephen Williams, Angela Hodges, Caroline Johnston, Hilkka Soininen, Iwona Kłoszewska, Patrizia Mecocci, Magda Tsolaki, Bruno Vellas, Stephen Newhouse, Simon Lovestone, Richard Dobson (Handling Associate Editor: Gary Arendash) *These authors contributed equally to this manuscript.
Candidate Blood Proteome Markers of Alzheimer’s Disease Onset and Progression: A Systematic Review and Replication Study
Abstract: A blood-based protein biomarker, or set of protein biomarkers, that could predict onset and progression of AD would have great utility; potentially clinically, but also for clinical trials and especially in the selection of subjects for preventative trials. We reviewed a comprehensive list of 21 published discovery or panel-based (>100 proteins) blood proteomics studies of AD, which had identified a total of 163 candidate biomarkers. Few putative blood-based protein biomarkers replicate in independent studies but we found that some proteins do appear in multiple studies; for example, four candidate biomarkers are found to associate with AD-related phenotypes in five independent research cohorts in these 21 studies: α-1-antitrypsin, α-2-macroglobulin, apolipoprotein E, and complement C3. Using SomaLogic’s SOMAscan proteomics technology, we were able to conduct a large-scale replication study for 94 of the 163 candidate biomarkers from these 21 published studies in plasma samples from 677 subjects from the AddNeuroMed (ANM) and the Alzheimer’s Research UK/Maudsley BRC Dementia Case Registry at King’s Health Partners (ARUK/DCR) research cohorts. Nine of the 94 previously reported candidates were found to associate with AD-related phenotypes (False Discovery Rate (FDR) q-value < 0.1). These proteins show sufficient replication to be considered for further investigation as a biomarker set. Overall, we show that there are some signs of a replicable signal in the range of proteins identified in previous studies and we are able to further replicate some of these. This suggests that AD pathology does affect the blood proteome with some consistency.

Pages 533-539
Roberta Ghidoni, Rosa Flocco, Anna Paterlini, Michela Glionna, Loredana Caruana, Elisa Tonoli, Giuliano Binetti, Luisa Benussi (Handling Associate Editor: Rosanna Squitti)
Secretory Leukocyte Protease Inhibitor Protein Regulates the Penetrance of Frontotemporal Lobar Degeneration in Progranulin Mutation Carriers
Abstract: The discovery that mutations in the gene encoding for progranulin (GRN) cause frontotemporal lobar degeneration (FTLD) and other neurodegenerative diseases leading to dementia has brought renewed interest in progranulin and its functions in the central nervous system. Full length progranulin is preserved from cleavage by secretory leukocyte protease inhibitor (SLPI), one of the smallest serine protease inhibitor circulating in plasma. Herein, we investigated the relationship between circulating SLPI and progranulin in affected and unaffected subjects belonging to 26 Italian pedigrees carrying GRN null mutations. In GRN null mutation carriers, we demonstrated: i) an increase of circulating SLPI levels in affected subjects; ii) an age-related upregulation of the serine-protease inhibitor in response to lifetime progranulin shortage; and iii) a delay in the age of onset in subjects with the highest SLPI protein levels. The study of SLPI and its relation to progranulin suggests the existence of unexpected molecular players in progranulin-associated neurodegeneration.

Pages 541-549
Karim Tifratene, Charlotte Sakarovitch, Amel Rouis, Christian Pradier, Philippe Robert and the participating centers
Mild Cognitive Impairment and Anti-Alzheimer Disease Medications: A Cross Sectional Study of the French National Alzheimer Databank (BNA)
Abstract: Unlike Alzheimer’s disease (AD), there are no drugs approved for the treatment of mild cognitive impairment (MCI). The objective of this study was to evaluate real world prescriptions of anti-AD medications in patients with MCI in France and to determine characteristics associated with treatment. A cross sectional study of the French National Alzheimer Databank (BNA) was conducted. Patients diagnosed with MCI by physicians of the BNA network in 2010 and 2011 were included in this study. We included 16,236 patients with a diagnosis of MCI in the study. Mean age was 76.4 years old and females were 59.5%. Nine hundred eighty five patients (6.1%) were taking an anti-AD medication. Results of a multivariate analysis show that use was associated with older age, lower MMSE score, amnestic MCI subtype, living at home, and higher education. Treatment with antidepressant drugs was also associated with anti-AD medication use (odd ratio: 1.68; 95% confidence interval: 1.44 to 1.96). “Off label” prescription of anti-AD drugs is low in France and seems to be limited to a population at risk of conversion to AD. Similar analysis will be required to monitor this practice in the future.

Pages 551-565
Matthias Schmitz, Katharina Wulf, Sandra C. Signore, Walter J. Schulz-Schaeffer, Pawel Kermer, Mathias Bähr, Fred S. Wouters, Saima Zafar, Inga Zerr
Impact of the Cellular Prion Protein on Amyloid-β and 3PO-Tau Processing
Abstract: Previous studies indicate an important role for the cellular prion protein (PrPC) in the development of Alzheimer’s disease (AD) pathology. In the present study, we analyzed the involvement of PrPC in different pathological mechanisms underlying AD: the processing of the amyloid-β protein precursor (AβPP) and its interaction with AβPP, tau, and different phosphorylated forms of the tau protein (p-tau). The effect of PrPC on tau expression was investigated in various cellular compartments using a HEK293 cell model expressing a tau mutant (3PO-tau) or wild type (WT)-tau and could show that PrPC reduces AβPP cleavage, leading to decreased levels of pathological Aβ40 and sAβPP without changing the protein expression of AβPP, β-secretase, or γ-secretase. We identified tau and its phosphorylated forms as interaction partners for PrPC, raising the question as to whether PrPC might also be involved in tau pathology. Overexpression of PrPC in PRNP and 3PO-tau transfected cells resulted in a reduction of 3PO-tau and p-tau as well as a decrease of 3PO-tau-related toxicity. In addition, we used the transgenic PrPC knockout (Prnp0/0) mouse line to study the dynamics of tau phosphorylation, an important pathological hallmark in the pathogenesis of AD in vivo. There, an effect of PrPC on tau expression could be observed under oxidative stress conditions but not during aging. In summary, we provide further evidence for interactions of PrPC with proteins that are known to be the key players in AD pathogenesis. We identified tau and its phosphorylated forms as potential PrP-interactors and report a novel protective function of PrPC in AD-like tau pathology.

Pages 567-579
Susanna L. Lundström, Hongqian Yang, Yaroslav Lyutvinskiy, Dorothea Rutishauser, Sanna-Kaisa Herukka, Hilkka Soininen, Roman A. Zubarev
Blood Plasma IgG Fc Glycans are Significantly Altered in Alzheimer’s Disease and Progressive Mild Cognitive Impairment
Abstract: Blood-based anti-amyloid-β (Aβ) immunoglobulins (IgGs) and peripheral inflammation are factors correlating with development of Alzheimer’s disease (AD). IgG functionality can drastically change from anti- to pro-inflammatory via alterations in the IgG-Fc N-glycan structure. Herein, we tested if IgG-Fc glycosylation in plasma is indeed altered during the development of AD. Samples from age-matched subjects of 23 controls, 58 patients with stable mild cognitive impairment (SMCI), 34 patients with progressive (P)MCI, and 31 patients with AD were investigated. Label-free shotgun proteomics was applied without glycoprotein enrichment. Glycans on peptides EEQYNSTYR (IgG1) and EEQFNSTFR (IgG2) were quantified, and their abundances were normalized to total IgGn glycoform abundance. Univariate and multivariate statistics were employed to investigate the correlations between the patients groups and the abundances of the IgG glycoforms as well as those of inflammatory mediating proteins. Significant differences (p0.05) were found, with a lower abundance of complex galactosylated and sialylated forms in AD. For females, a decline in glycoform complexity correlated with disease progress but an inverse change was found in males prior to the onset of AD. Principal component analysis (PCA; Males: R2X(cum)=0.65, Q2(cum)=0.34; Females: R2X(cum)=0.62, Q2(cum)=0.36), confirmed the gender similarities (for controls, SMCI, and AD) as well as differences (for PMCI), and showed a close correlation between pro-inflammatory protein markers, AD, female PMCI, and truncated IgG-Fc glycans. The differences observed between genders prior to the onset of AD may indicate a lower ability in females to suppress peripheral inflammation, which may lead to exacerbated disease progression.

Pages 581-587
Maurizio Gallucci, Andrea Zanardo, Matteo Bendini, Francesco Di Paola, Paolo Boldrini, Enzo Grossi
Serum Folate, Homocysteine, Brain Atrophy, and Auto-CM System: The Treviso Dementia (TREDEM) Study
Abstract: Background: The role of folate and homocysteine in brain atrophy associated with Alzheimer’s disease is not completely understood. Objective: The aim of this study was to investigate the relationships between serum folate and homocysteine levels and the degree of cortical-subcortical and hippocampal atrophy in a first relatively preliminary sample of the Treviso Dementia (TREDEM) study using a potent data mining method. Methods: Physiological data, biochemical parameters, clinical assessment data, brain atrophy severity assessed with CT scans, and neuropsycological and disability data were assessed in a group of 232 outpatients (93 men and 139 women, aged 40.2–100 years) enrolled in the TREDEM study carried out in Treviso (Italy). A semantic connectivity map obtained through the Auto-CM system, a fourth generation artificial neural network (ANN), was used to offer some insight regarding the complex biological connections between the studied variables and the degree of brain atrophy. Results: Close associations between low serum folate levels and severe cortical-subcortical atrophy along with severe hippocampal atrophy measured by the width of the temporal horns of lateral ventricles were found. We also showed an association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Conclusion: The role of folate, which is inversely associated with the severity of brain atrophy, was confirmed. Our results also confirm the association between high homocysteine levels and severe cortical-subcortical and hippocampal atrophy. Auto-CM ANN is able to highlight associations sometimes visible only in longitudinal studies through intelligent data mining of a cross-sectional study.

Pages 589-600
Yan Ren, Wen-Lang Lin, Laura Sanchez, Carolina Ceballos, Manuela Polydoro, Tara L. Spires-Jones, Bradley T. Hyman, Dennis W. Dickson, Naruhiko Sahara (Handling Associate Editor: Alexis Stranahan)
Endogenous Tau Aggregates in Oligodendrocytes of rTg4510 Mice Induced by Human P301L Tau
Abstract: Tau belongs to the microtubule-associated family of proteins that maintain cytoskeletal structure by regulating microtubule dynamics. In certain neurodegenerative diseases termed tauopathies, tau is abnormally phosphorylated and accumulates as filamentous inclusions. Transgenic mouse models that overexpress human tau have been widely used to investigate tau pathogenesis. Although many studies have attempted to elucidate the pathological function of transgenic human tau, it remains unknown whether endogenous mouse tau is involved in disease progression. Here we generated an mTau antibody that selectively recognizes mouse and rat tau, but not human tau. In rTg4510 tau transgenic mice, we identified a higher molecular weight mouse tau (~60-kDa) in sarkosyl-insoluble fractions. mTau antibody started to recognize intracellular aggregates and thread-like structures in 4- to 6-month-old rTg4510 mice. Tau inclusions appeared earlier, being detected in 2.5-month-old rTg4510 mice with MC1 antibody. Immunoelectron microscopy confirmed the presence of filamentous aggregates of mouse tau, which were abundant in oligodendrocytes but rare in neurons. Mouse tau inclusions in oligodendrocytes were confirmed by double-labeling with an oligodendrocyte marker. Our data indicate that mouse tau has potential aggregation properties in neurons and non-neurons. The mTau antibody will be useful for investigating the role of mouse tau in mouse models of tauopathy.

Pages 601-609
Yasuyuki Honjo*, Tomohisa Horibe*, Aya Torisawa, Hidefumi Ito, Aki Nakanishi, Hiroshi Mori, Tohru Komiya, Ryosuke Takahashi, Koji Kawakami *These authors contributed equally to this work.
Protein Disulfide Isomerase P5-Immunopositive Inclusions in Patients with Alzheimer’s Disease
Abstract: Amyloid plaques and neurofibrillary tangles (NFTs) are the major pathological characteristics of Alzheimer’s disease (AD). NFTs are composed of tubular filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Another feature of AD is excessive generation of nitric oxide (NO). Protein disulfide isomerase (PDI) is a chaperon protein located in the endoplasmic reticulum (ER). It was recently reported that NO-induced S-nitrosylation of PDI inhibits its enzymatic activity, leading to the accumulation of polyubiquitinated proteins, and activates the unfolded protein response. In addition, we previously reported the presence of PDI-immunopositive NFTs in AD. Here, we found that protein disulfide isomerase P5 (P5), which is a member of the PDI protein family, was co-localized with tau in NFTs. To our knowledge, this is the first report of P5-immunopositive inclusion in AD. Furthermore, we showed that S-nitrosylated P5 was present and the expression level of P5 was decreased in AD brains compared with that of control brains. We also demonstrated that the knock-down of PDI or P5 by siRNA could affect the viability of SH-SY5Y cells under ER stress. Previously, the observation of S-nitrosylated PDI in AD was reported. NO may inhibit P5 by inducing S-nitrosylation in the same manner as PDI, which inhibits its enzymatic activity allowing protein misfolding to occur in AD. The accumulation of misfolded proteins induces ER stress and may cause apoptosis of neuronal cells through S-nitrosylation and down-regulation of PDI and P5 in AD.

Pages 611-620
William B. Grant
Trends in Diet and Alzheimer’s Disease during the Nutrition Transition in Japan and Developing Countries
Abstract: Background: Alzheimer’s disease (AD) rates in Japan and developing countries have risen rapidly in recent years. Researchers have associated factors such as the Western diet, obesity, alcohol consumption, and smoking with risk of AD. Objective: This paper evaluates whether the dietary transition might explain the rising trend of AD prevalence in Japan and in developing countries, evaluating other factors when possible. Methods: This study used two approaches to see whether dietary or other changes could explain AD trends in Japan and developing countries. One approach involved comparing trends of AD in Japan with changes in national dietary supply factors, alcohol consumption, and lung cancer mortality rates from zero to 25 years before the prevalence data. The second compared AD prevalence values for eight developing countries with dietary supply factors from zero to 25 years before the prevalence data. Results: For Japan, alcohol consumption, animal product, meat and rice supply, and lung cancer rates correlated highly with AD prevalence data, with the strongest correlation for a lag of 15–25 years. In the eight-country study, total energy and animal fat correlated highly with AD prevalence data, with a lag of 15–20 years. Mechanisms to explain the findings include increased obesity for the eight countries, and increases in cholesterol, saturated fat, and iron from increases in animal products and meat supply for Japan. Conclusion: Evidently AD rates will continue rising in non-Western countries for some time unless we address major risk factors involving diet, obesity, and smoking.

Pages 621-632
WenJin Xu, Feng Xu, Maria E. Anderson, AnnMarie E. Kotarba, Judianne Davis, John K. Robinson, William E. Van Nostrand (Handling Associate Editor: Paula Grammas)
Cerebral Microvascular rather than Parenchymal Amyloid-β Protein Pathology Promotes Early Cognitive Impairment in Transgenic Mice
Abstract: Alzheimer’s disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. However, the levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline, their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental deposition, respectively, to assess their impact on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory performance and quantitative pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits.

Pages 633-646
Meng-Shan Tan*, Jin-Tai Yu*, Teng Jiang, Xi-Chen Zhu, Hua-Shi Guan, Lan Tan (Handling Associate Editor: Gemma Casadesus) *These authors contributed equally to this manuscript.
IL12/23 p40 Inhibition Ameliorates Alzheimer’s Disease-Associated Neuropathology and Spatial Memory in SAMP8 Mice
Abstract: Progressively increased proinflammatory status is a major characteristic of the aging process and associated with age-related diseases such as Alzheimer’s diseases (AD). However, the regulation and role of common proinflammatory cytokines, including interleukin-12 (IL-12) and IL-23, in the aged brain are still unclear. Using the senescence-accelerated mouse prone-8 (SAMP8) model, we screened the cerebral expression of IL-12/23 in 3-, 7-, and 11-month-old mice and observed that their levels in the brain were upregulated during aging. To further examine whether the heightened activation of inflammatory cytokines may contribute to age-related brain dysfunction, we employed direct in vivo infusion of nonviral small interfering RNA (siRNA) to knock down the common IL-12/23 signaling subunit p40 in the brain. We found that these p40-deficient mice had significantly decreased cerebral amyloid-β levels, reduced synaptic and neuronal loss, and reversed cognitive impairments. Furthermore, in vivo delivery of a neutralizing p40-specific antibody likewise ameliorated AD-associated pathology and cognitive deficits in SAMP8 mice. Thus, our data indicate that the upregulated cerebral IL-12/23 during aging is involved in age-associated brain dysfunction and point to the modulation of IL-12/23 signaling molecule p40 as a promising strategy for the development of an AD therapy.

Pages 647-659
Lara Z. Diaz-de-Grenu, Julio Acosta-Cabronero, Yao Feng Victor Chong, Joao M.S. Pereira, Seyed A. Sajjadi, Guy B. Williams, Peter J. Nestor (Handling Associate Editor: Murray Grossman)
A Brief History of Voxel-Based Grey Matter Analysis in Alzheimer’s Disease
Abstract: Voxel-based morphometry (VBM) and cortical thickness measurement are common techniques to identify regional atrophy in neurodegenerative diseases such as Alzheimer’s disease (AD). Because studies employing these methods draw conclusions regarding patterns of regional cortical degeneration, it is important to be aware of their possible limitations. To evaluate the effect of different VBM versions, we performed voxel-based analyses through successive versions—from SPM99 to SPM8—as well as FSL-VBM on n=20 AD patients and n=20 controls. Reproducibility was assessed in an independent sample, again of n=20 per group, from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Further, we tested the hypothesis that VBM can sensitively detect hippocampal atrophy, but is relatively insensitive to changes in the cortical ribbon, by contrasting VBM with FreeSurfer cortical thickness measurements. The results with both datasets confirmed that VBM preferentially identifies grey matter lesions in the mesial temporal lobe but is largely insensitive to isocortical atrophy. In contrast, FreeSurfer identified thinning of cortical ribbon association cortex more significant in post- rather than pre-Rolandic areas and with relative preservation of primary sensory-motor regions—in other words precisely as would be expected in AD. The results highlight a bias that VBM has toward detecting mesial temporal lobe atrophy. This finding has important implications for interpretation of clinical and cognitive studies in AD.

Pages 661-668
Qolamreza R. Razlighi, Eric Stallard, Jason Brandt, Deborah Blacker, Marilyn Albert, Nikolaos Scarmeas, Bruce Kinosian, Anatoliy I. Yashin, Yaakov Stern
A New Algorithm for Predicting Time to Disease Endpoints in Alzheimer’s Disease Patients
Abstract: Background: The ability to predict the length of time to death and institutionalization has strong implications for Alzheimer’s disease patients and caregivers, health policy, economics, and the design of intervention studies. Objective: To develop and validate a prediction algorithm that uses data from a single visit to estimate time to important disease endpoints for individual Alzheimer’s disease patients. Method: Two separate study cohorts (Predictors 1, N = 252; Predictors 2, N = 254), all initially with mild Alzheimer’s disease, were followed for 10 years at three research centers with semiannual assessments that included cognition, functional capacity, and medical, psychiatric, and neurologic information. The prediction algorithm was based on a longitudinal Grade of Membership model developed using the complete series of semiannually-collected Predictors 1 data. The algorithm was validated on the Predictors 2 data using data only from the initial assessment to predict separate survival curves for three outcomes. Results: For each of the three outcome measures, the predicted survival curves fell well within the 95% confidence intervals of the observed survival curves. Patients were also divided into quintiles for each endpoint to assess the calibration of the algorithm for extreme patient profiles. In all cases, the actual and predicted survival curves were statistically equivalent. Predictive accuracy was maintained even when key baseline variables were excluded, demonstrating the high resilience of the algorithm to missing data. Conclusion: The new prediction algorithm accurately predicts time to death, institutionalization, and need for full-time care in individual Alzheimer’s disease patients; it can be readily adapted to predict other important disease endpoints. The algorithm will serve an unmet clinical, research, and public health need.

Pages 669-679
Jody Kamminga, Claire O’Callaghan, John R. Hodges, Muireann Irish
Differential Prospective Memory Profiles in Frontotemporal Dementia Syndromes
Abstract: Background: Prospective memory (PM) is the ability to remember to execute an intended action either at a future time (Time-based PM) or when a specific event occurs (Event-based PM). Previous studies demonstrate impaired PM in Alzheimer’s disease (AD); however, the status of PM in frontotemporal dementia (FTD) remains unknown. Objective: To examine PM performance and its associated cognitive mechanisms, in two subtypes of FTD: semantic dementia (SD) and the behavioral variant of FTD (bvFTD), in comparison with matched AD and control participants. Methods: Twenty-four dementia patients (SD=8; bvFTD=8; AD=8) and 12 age- and education-matched controls underwent a shortened version of the Cambridge Behavioural Prospective Memory Test, as well as a standard neuropsychological test battery. Results: Compared to controls, SD patients exhibited preserved Time-based PM in the context of impaired Event-based PM, with the latter strongly associated with deficits in semantic processing. In contrast, bvFTD and AD patients demonstrated global PM impairments irrespective of subscale, which strongly correlated with deficits in delayed episodic retrieval for both groups. Caregiver reports of stereotypical behaviors were associated with compromised Event-based PM in SD and Time-based PM in bvFTD, with no such relationship evident in AD. Conclusion: This is the first study to investigate prospective memory in FTD syndromes. A relative sparing of Time-based PM was observed in SD, in contrast with global PM deficits in bvFTD. Disrupted PM processing was found to correlate with stereotypical behaviors in FTD syndromes, a finding that we suggest is worthy of further investigation.

Pages 681-694
Natalia A. Stefanova, Natalia A. Muraleva, Vladimir P. Skulachev, Nataliya G. Kolosova
Alzheimer’s Disease-Like Pathology in Senescence-Accelerated OXYS Rats can be Partially Retarded with Mitochondria-Targeted Antioxidant SkQ1
Abstract: We previously showed that mitochondria-targeted antioxidant SkQ1 (plastoquinonyl-decyltriphenylphosphonium) at nanomolar concentrations is capable of preventing and slowing down some cerebral dysfunctions in accelerated-senescence OXYS rats. Here we demonstrate that OXYS rats develop behavior, learning, and memory deficits against a background of neurodegeneration signs detected by magnetic resonance tomography and amyloid-β (Aβ) pathology similar to those seen in Alzheimer’s disease (AD). Long-term treatment with SkQ1 (250 nmol/kg body weight daily from the age of 1.5 to 23 months) reduced the age-related alterations in behavior and spatial memory deficit in Morris water maze in OXYS and Wistar rats. Furthermore, this is the first report that SkQ1 treatment slows down pathological accumulation of AβPP, Aβ, and hyperphosphorylation of tau-protein in OXYS rats, as well as age-dependent changes in healthy Wistar rats. Our results support the possibility of using the OXYS strain as a rat model of AD-like pathology. It seems probable that the mitochondria-targeted antioxidant SkQ1 can be a good prophylactic strategy to maintain brain health and to treat AD.