Volume 68, Number 1, 2019

Pages 1-24

Harald Hampel, Andrea Vergallo, George Perry, Simone Lista for the Alzheimer Precision Medicine Initiative (APMI) (Handling Associate Editor: Roberta Ghidoni; Handling Editor: Paula Moreira)
The Alzheimer Precision Medicine Initiative
Abstract: Precision medicine (PM) is an evolving scientific renaissance movement implementing key breakthrough technological and scientific advances to overcome the limitations of traditional symptom- and sign-based phenotypic diagnoses and clinical “one-size-fits-all, magic bullet drug development” in these largely heterogeneous target populations. It is a conceptual shift from ineffective treatments for biologically heterogeneous “population averages” to individually-tailored biomarker-guided targeted therapies. PM is defining which therapeutic approach will be the most effective for a specific individual, at a determined disease stage, across multiple medical research fields, including neuroscience, neurology and psychiatry. The launch of the Alzheimer Precision Medicine Initiative (APMI) and its associated cohort program in 2016—facilitated by the academic core coordinating center run by the Sorbonne University Clinical Research Group in Alzheimer Precision Medicine (Sorbonne University GRC n°21 APM)”—is geared at transforming healthcare, conventional clinical diagnostics, and drug development research in Alzheimer’s disease. Ever since the commencement of the APMI, the international interdisciplinary research network has introduced groundbreaking translational neuroscience programs on the basis of agnostic exploratory genomics, systems biology, and systems neurophysiology applying innovative “big data science”, including breakthrough artificial intelligence-based algorithms. Here, we present the scientific breakthrough advances and the pillars of the theoretical and conceptual development leading to the APMI.

Pages 25-31

Liang Shen, Hong-Fang Ji
Associations Between Gut Microbiota and Alzheimer's Disease: Current Evidences and Future Therapeutic and Diagnostic Perspectives
Abstract: Developing novel agents for unexplored targets to combat Alzheimer’s disease (AD) represents an urgent task due to its increasing prevalence worldwide. The present paper summarizes the latest studies emerged in the past few years investigating the associations between the “forgotten organ” gut microbiota and AD from the following two aspects: 1) the associations between gut microbiota and AD development by animal models and human studies; and 2) the effects of gut microbiota modulation-based intervention for AD. Then, we propose future perspectives in two promising research areas: 1) developing gut microbiota modulation-based intervention; and 2) developing gut microbiota-associated diagnostic biomarkers for AD. Knowledge gaps and potential barriers to overcome towards these two goals are also discussed.

Pages 33-38

Xin Wang, Helena R. Zimmermann, Tao Ma
Therapeutic Potential of AMP-Activated Protein Kinase in Alzheimer’s Disease
Abstract: Currently there is no cure or effective disease-modifying therapy for Alzheimer’s disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis. Particularly, hyperactive AMPK via phosphorylation has been linked to AD-associated synaptic plasticity impairments, indicating suppression of AMPK activity might be beneficial for cognitive deficiency in AD. In this review, we will discuss how targeting dysregulation of AMPK signaling could be a feasible therapeutic approach for AD.

Pages 39-64

Kieran J. Marston, Belinda M. Brown, Stephanie R. Rainey-Smith, Jeremiah J. Peiffer
Resistance Exercise-Induced Responses in Physiological Factors Linked with Cognitive Health
Abstract: The global population is aging at an unprecedented rate giving rise to a greater prevalence of age-related illnesses such as dementia and vascular disease. Dementia affects approximately 47 million individuals globally with projections of 130 million by the year 2050. Late-onset Alzheimer’s disease is the most common form of dementia, accounting for approximately 75% of all cases and is characterized by a progressive decline in cognitive function, memory, and cerebral volume. The pathogenesis of Alzheimer’s disease is poorly understood; however, aging, genetics, and an individual’s diet and lifestyle over several decades appear to be key determinants. As there is no current cure for Alzheimer’s disease, postponing or preventing the onset of Alzheimer’s disease and dementia through therapeutic methods should, therefore, be targeted at individuals decades prior to an individual showing signs or symptoms of decline. As a preventative tool, resistance exercise improves memory, attention, spatial awareness, reaction time, planning, and information processing. Improvements in cognitive performance following resistance exercise and training may be mediated by peripheral elevations in the physiological biomarkers (i.e., neural and vascular) explored in this review. The purpose of this review is to discuss vascular and neuronal degeneration as a cause or consequence of dementia and Alzheimer’s disease, and the biological markers of neurogenesis and blood vessel growth, function, and regulation. We will also explore the merits of acute and chronic resistance training as a strategy to postpone the onset of cognitive decline, dementia, and Alzheimer’s disease.

Pages 65-76
Solveig Tiepolt, Julia Luthardt, Marianne Patt, Swen Hesse, Karl-Titus Hoffmann, David Weise, Hermann-Josef Gertz, Osama Sabri, Henryk Barthel
Early after Administration [11C]PiB PET Images Correlate with Cognitive Dysfunction Measured by the CERAD Test Battery
Abstract: Background: Amyloid-β (Aβ) and [18F]FDG PET are established as amyloid pathology and neuronal injury biomarkers. Early after administration Aβ PET images have the potential to replace [18F]FDG PET images allowing dual biomarker delivery by the administration of a single tracer. For [18F]FDG PET data, a correlation with cognitive performance is known. Objective: The aim of this study was to investigate whether early after administration [11C]PiB PET data also correlate with cognitive performance. Methods: The early after administration [11C]PiB PET data of 31 patients with cognitive impairment were evaluated. CERAD subtests were summarized to five cognitive domains. The resulting z scores were correlated with the PET data on a voxel- and VOI-based approach. Additional subgroup analyses (MCI versus dementia, Aβ-positive versus Aβ-negative subjects) were performed. Results: Significant correlations between cognitive performance and early after administration [11C]PiB PET data were found between left temporo-parietal SUVR and language domain, bilateral occipital as well as left temporal SUVR and executive function, left pre- and postcentral SUVRs, and visuospatial abilities. For the episodic and immediate memory domains, the analysis at the high significance level did not show any correlated cluster, however, the exploratory analysis did. Conclusion: Our study revealed correlations between deficits in different cognitive domains and regional early after administration [11C]PiB PET data similar to those known from [18F]FDG PET studies. Thus, our data support the assumption that early [11C]PiB PET data have a potential as neuronal injury biomarker. Head-to-head double-tracer studies of larger cohorts are needed to confirm this assumption.

Pages 77-83

J. Wesson Ashford
The Dichotomy of Alzheimer’s Disease Pathology: Amyloid-β and Tau
Abstract: In this issue, an article by Tiepolt et al. shows that PET scanning using [11C]PiB can demonstrate both cerebral blood flow (CBF) changes and amyloid-β (Aβ) deposition in patients with mild cognitive dysfunction or mild dementia of Alzheimer’s disease (AD). The CBF changes can be determined because the early scan counts (1–9 minutes) reflect the flow of the radiotracer in the blood passing through the brain, while the Aβ levels are measured by later scan counts (40–70 minutes) after the radiotracer has been cleared from regions to which the radiotracer did not bind. Thus, two different diagnostic measures are obtained with a single injection. Unexpectedly, the mild patients with Aβ positivity had scan data with only a weak relationship to memory, while the relationships to executive function and language function were relatively strong. This divergence of findings from studies of severely impaired patients highlights the importance of determining how AD pathology affects the brain. A possibility suggested in this commentary is that Aβ deposits occur early in AD and specifically in critical areas of the neocortex affected only later by the neurofibrillary pathology indicating a different role of the amyloid-β protein precursor (AβPP) in the development of those neocortical regions, and a separate component of AD pathology may selectively impact functions of these neocortical regions. The effects of adverse AβPP metabolism in the medial temporal and brainstem regions occur later possibly because of different developmental issues, and the later, different pathology is clearly more cognitively and socially devastating.

Pages 85-96
Maxime Lussier, Stéphane Adam, Belkacem Chikhaoui, Charles Consel, Mathieu Gagnon, Brigitte Gilbert, Sylvain Giroux, Manon Guay, Carol Hudon, Hélène, Imbeault, Francis Langlois, Joel Macoir, Hélène Pigot, Lise Talbot, Nathalie Bier
Smart Home Technology: A New Approach for Performance Measurements of Activities of Daily Living and Prediction of Mild Cognitive Impairment in Older Adults
Abstract: Background: Functional assessment is of paramount importance when mild cognitive impairment is suspected, but common assessment tools such as questionnaires lack sensitivity. An alternative and innovative approach consists in using sensor technology in smart apartments during scenario-based assessments of instrumental activities of daily living (IADL). However, studies that investigate this approach are scarce and the technology used is not always transposable in healthcare settings. Objective: To explore whether simple and wireless technology used in two different smart environments could add value to performance and rater-based measures of IADL when it comes to predicting mild cognitive impairment (MCI) in older adults. Methods: Twenty-six (26) cognitively healthy older adults (CH) and 22 older adults with MCI were recruited. Functional performance in a set of five scripted tasks was evaluated with sensor-based observations (motion, contact, and electric sensors) and performance-based measures (rated with videotapes). The five tasks could be performed in any order and were detailed on an instruction sheet given to participants. Results: Sensor-based observations showed that participants with MCI spent more time in the kitchen and looking into the fridge and kitchen cabinets than CH participants. Moreover, these measures were negatively associated with memory and executive performances of participants and significantly contributed to the prediction of MCI. Conclusion: Simple, wireless, and sensor-based technology holds potential for the detection of MCI in older adults as they perform daily tasks. However, some limits are discussed and we offer recommendations to improve the usefulness of this innovative approach.

Pages 97-103
Louis Jacob, Jens Bohlken, Karel Kostev
Is There an Association between Antiepileptic Drug Use and Dementia Risk? A Case-Control Study
Abstract: Background: Previous research has found a positive association between the use of antiepileptic drugs (AEDs) and dementia. However, there have been some concerns about the generalizability of its findings. Objective: The goal of this case-control study was to analyze the association between AED use and dementia risk in Germany. Methods: This study included patients who had received a first dementia diagnosis from one of 1,203 general practitioners or 202 neuropsychiatrists between 2013 and 2017 (index date). Controls without dementia were matched (1:1) to dementia cases by age, gender, physician, diagnosis of mild cognitive impairment, and observation time prior to the index date. Two regression models were used to analyze the association between AED use and dementia risk after adjusting for comorbidities and co-prescribed drugs. AEDs were included as a dichotomous variable in Model 1 (ever versus never use) and as a continuous variable in Model 2 (duration of treatment in years). Results: A total of 50,575 cases with dementia and 50,575 controls without dementia were included in this study. Model 1 (odds-ratio [OR]=0.99) and Model 2 (OR=1.00) showed no significant association between AED use and dementia risk. However, prescriptions for levetiracetam generic brands (Model 1: OR=1.70; Model 2: OR=1.36) were associated with an increased dementia risk. Conclusions: Overall, AED use was not significantly associated with dementia risk in patients followed by general practitioners and neuropsychiatrists in Germany between 2013 and 2017. Nonetheless, the potential deleterious effects of levetiracetam generic brands on cognition deserve further investigation.

Pages 105-114
Cassandra Szoeke, Alicia M. Goodwill, Alexandra Gorelik, Lorraine Dennerstein, Karen Caeyenberghs, Steven Simpson Jr., Edward Hill, Stephen Campbell
Apolipoprotein E4 Mediates the Association between Midlife Dyslipidemia and Cerebral Amyloid in Aging Women
Abstract: Cerebral amyloid-β (Aβ) plaques are the hallmark biomarker of Alzheimer’s disease (AD) and are detectable decades before clinical symptoms. Modifying risk factors associated with Aβ accrual offers an opportunity for AD prevention. While midlife vascular health is linked to AD; there is minimal longitudinal evidence regarding the effect of midlife lipids on Aβ. We examined the association between midlife lipids and Aβ 20 years later. One hundred and twenty-two women had serum lipid profiles in midlife (1992, 45–57 years), and cerebral imaging, genotyping, and cognition measured 20 years later (2012/13, 66-77 years). Imaging was performed in 2012/13 via F-18 Florbetaben positron emission tomography (PET) and standard uptake value ratios (SUVR) were calculated. Lipid profiles and other predictors of high PET-SUVR levels (>1.2) were evaluated using multivariable logistic regression. Increases in low-density lipoprotein (LDL) cholesterol in midlife were associated with Aβ, adjusting for age, education, cholesterol medication, and cognition (AdjOR1.81, 95%CI 1.08-3.01, p=0.024), but attenuated on adjustment for apolipoprotein E4 (APOE ε4). Aβ risk increased in women with APOE ε4 and midlife cholesterol >6.2 mmol/L (AdjOR9.59, 95%CI 2.94-31.31, p<0.001), APOE ε4 and LDL >3.3 mmol/L (AdjOR9.00, 95%CI 2.89-28.03, p<0.001), and APOE ε4 and cholesterol to high-density lipoprotein ratio >3.25 (AdjOR8.32, 95%CI 2.32-29.89, p<0.001). Presence of APOE ε4 and midlife dyslipidemia compounded the risk for Aβ deposition, although no independent effect of midlife lipids was found. Lipid-modifying treatment in midlife could mitigate the risk of Aβ in women with a genetic predisposition for AD. To better inform prevention, future consideration should be given toward managing dyslipidemia in women carrying the APOE ε4 allele.

Pages 115-126
Kara B. Duffy, Balmiki Ray, Debomoy K. Lahiri, Edward M. Tilmont, Gregory P. Tinkler, Richard L. Herbert, Nigel H. Greig, Donald K. Ingram, Mary Ann Ottinger*, Julie A. Mattison* (Handling Associate Editor: Sultan Darvesh) *These authors share senior authorship.
Effects of Reducing Norepinephrine Levels via DSP4 Treatment on Amyloid-β Pathology in Female Rhesus Macaques (Macaca Mulatta)
Abstract: The degeneration in the locus coeruleus associated with Alzheimer’s disease suggests an involvement of the noradrenergic system in the disease pathogenesis. The role of depleted norepinephrine was tested in adult and aged rhesus macaques to develop a potential model for testing Alzheimer’s disease interventions. Monkeys were injected with the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) or vehicle at 0, 3, and 6 months; brains were harvested at 9 months. Reduced norepinephrine in the locus coeruleus was accompanied by decreased dopamine β-hydroxylase staining and increased amyloid-β load in the aged group, and the proportion of potentially toxic amyloid-β42 peptide was increased. Immunohistochemistry revealed no effects on microglia or astrocytes. DSP4 treatment altered amyloid processing, but these changes were not associated with the induction of chronic neuroinflammation. These findings suggest norepinephrine deregulation is an essential component of a nonhuman primate model of Alzheimer’s disease, but further refinement is necessary.

Pages 127-136
Heidi Taipale, Pasi Lampela, Marjaana Koponen, Antti Tanskanen, Jari Tiihonen, Sirpa Hartikainen, Anna-Maija Tolppanen (Handling Associate Editor: Julia Gilmartin-Thomas)
Antiepileptic Drug Use Is Associated with an Increased Risk of Pneumonia Among Community-Dwelling Persons with Alzheimer’s Disease-Matched Cohort Study
Abstract: Background: Antiepileptic drugs (AEDs) have sedative properties which may lead to an increased risk of pneumonia. Objectives: To investigate whether incident AED use is associated with an increased risk of pneumonia among community-dwelling persons with Alzheimer’s disease (AD). In addition, we determined the risk according to duration of AED use and specific AEDs. Methods: Persons with AD were identified from the MEDALZ dataset which includes all community-dwelling persons who received a clinically verified diagnosis of AD during 2005-2011 in Finland (N=70,718). New AED users were identified with one-year washout period. A matched cohort (1:1, N=5,769, matching criteria age, gender, and time since AD diagnoses) of nonusers was formed. Data from nationwide registers included dispensed medications which were modelled with PRE2DUP method, hospitalizations, and causes of death. The association between AED use and hospital admission or death due to pneumonia was analyzed with Cox proportional hazard models. Results: AED use was associated with an increased risk of pneumonia (adjusted HR 1.92, 95% CI 1.63-2.26; incidence rate per 100 person-years 12.58, 95% CI 12.49-12.66 during AED use and 6.41, 95% CI 6.37-6.45 during nonuse). The highest risk was observed during the first month of use (aHR 3.59, 95% CI 2.29-5.61) and the risk remained elevated until two years of use. Of specific drug substances, phenytoin, carbamazepine, valproic acid, and pregabalin were associated with an increased risk. Conclusion: Antiepileptic drug use may increase the risk of pneumonia which is concerning as persons with AD have elevated risk of pneumonia.

Pages 137-144
Li Li, Eugene Y. Zhen, Rodney L. Decker, Brian A. Willis, David Waters, Peng Liu, Ann Marie Hake, Ronald Bradley Demattos, Mosun Ayan-Oshodi
Pharmacokinetics and Pharmacodynamics of LY2599666, a PEG-Linked Antigen Binding Fragment that Targets Soluble Monomer Amyloid-β
Abstract: LY2599666 is a humanized, affinity-optimized monoclonal antibody antigen-binding fragment linked to a PEG molecule and targets soluble amyloid-β (Aβ) monomers. This first-in-human dose ascending study assessed pharmacokinetics (PK) (measured as serum free LY2599666 concentration) and pharmacodynamic (PD) effects (measured as plasma total soluble Aβ40 and Aβ42) after a single subcutaneous (SC) dose of 10, 25, 100, and 200 mg LY2599666 in healthy subjects. As LY2599666 binds to multiple soluble Aβ monomers, a two-target mediated drug disposition model (TMDD) was developed to simultaneously fit serum LY2599666 concentration and Aβ monomer levels. Four Alzheimer’s disease patients completed 25 mg once-weekly dosing of LY2599666 for 12 weeks. In addition, single cerebrospinal fluid samples were collected to assess penetration capability across the blood-brain barrier. PK and PD data collected from the multiple dose cohort aligned with model predictions, suggesting the established TMDD model predicted suppression of soluble Aβ40 and Aβ42 in plasma after SC dosing of LY2599666.

Pages 145-158
Teresa Jenica Filshtein*, Brittany N. Dugger*, Lee-Way Jin, John M. Olichney, Sarah T. Farias, Luis Carvajal-Carmona, Paul Lott, Dan Mungas, Bruce Reed, Laurel A. Beckett, Charles DeCarli *These authors contributed equally to this work.
Neuropathological Diagnoses of Demented Hispanic, Black, and Non-Hispanic White Decedents Seen at an Alzheimer’s Disease Center
Abstract: Our nation is becoming increasingly diverse; however, few autopsy studies examine multiple ethnoracial groups, especially Hispanics. We examined differences in neuropathological diagnoses of 435 deceased participants with dementia from three ethnoracial groups (35 Black, 28 Hispanic, and 360 non-Hispanic White) evaluated at the University of California Davis Alzheimer’s Disease Center. We used novel applications of bootstrap resampling and logistic regression standardization to project neuropathological diagnostic rates for non-Hispanic Whites to minority sample characteristics to improve inference of findings. Alzheimer’s disease (AD) without significant cerebrovascular disease (CVD) or other dementia-related pathologies (AD (non-mixed)) was present in 15 Black (43%), 4 Hispanic (14%), and 156 (43%) non-Hispanic Whites. CVD sufficient to contribute to dementia was confirmed in 14 Black (40%), 16 Hispanic (54%), and 101 (28%) non-Hispanic White decedents. The observed CVD prevalence of 40% in Blacks exceeded the predicted 29% [95% CI: 22%-36%]. Despite being outside the 95% confidence interval, the difference between observed and predicted was not statistically significant after bootstrap testing. Conversely, for Hispanics, the observed proportion at 54% exceeded significantly the predicted prevalence of 24% from non-Hispanic Whites [95% CI: 16%-34%], avg. p=0.008). An identical analysis using AD (non-mixed) as the outcome predicted AD (non-mixed) in Blacks averaging 41% [95% CI:34%-48%], nearly equal to observed prevalence. For Hispanics, however, the observed proportion at 14%, was well below predictions (mean=42%, 95% CI:32%-53%], avg. p=0.008). We conclude mixed diagnoses and CVD are more common in Hispanic and Black decedents than Non-Hispanic Whites with dementia in our cohort. The increased prevalence of vascular co-morbidity may be a potential opportunity to intervene more effectively in dementia treatment of those individuals.

Pages 159-171
Yi Leng Fung, Kelly E.T. Ng, Simon J. Vogrin, Catherine Meade, Michael Ngo, Steven J. Collins, Stephen C. Bowden (Handling Associate Editor: Duke Han)
Comparative Utility of Manual versus Automated Segmentation of Hippocampus and Entorhinal Cortex Volumes in a Memory Clinic Sample
Abstract: Structural neuroimaging is a useful non-invasive biomarker commonly employed to evaluate the integrity of mesial temporal lobe structures that are typically compromised in Alzheimer’s disease. Advances in quantitative neuroimaging have permitted the development of automated segmentation protocols (e.g., FreeSurfer) with significantly increased efficiency compared to earlier manual techniques. While these protocols have been found to be suitable for large-scale, multi-site research studies, we were interested in assessing the practical utility and reliability of automated FreeSurfer protocols compared to manual volumetry on routinely acquired clinical scans. Independent validation studies with newer automated segmentation protocols are scarce. Two FreeSurfer protocols for each of two regions of interest—the hippocampus and entorhinal cortex—were compared against manual volumetry. High reliability and agreement was found between FreeSurfer and manual hippocampal protocols; however, there was lower reliability and agreement between FreeSurfer and manual entorhinal protocols. Although based on a the relatively small sample of subjects drawn from a memory clinic (n=27), our study findings suggest further refinements to improve measurement error and most accurately depict true regional brain volumes using automated segmentation protocols are required, especially for non-hippocampal mesial temporal structures, to achieve maximal utility for routine clinical evaluations.

Pages 173-186
Hong Li, Sue Leurgans, Jordan Elm, Mulugeta Gebregziabher
Statistical Methodology for Multiclass Classifications: Applications to Dementia
Abstract: Alzheimer’s disease (AD) is a common, devastating disease which carries a heavy economic burden. Accelerated efforts to identify presymptomatic stages of AD and biomarkers to classify the disease are urgent needs. Currently no biomarkers can perfectly discriminate individuals into multiple disease categories of AD (no cognitive impairment, mild cognitive impairment, and dementia). Although many biomarkers for diagnosis and their various features are being studied, we lack advanced statistical methods which can fully utilize biomarkers to classify AD accurately, thereby facilitating evaluation of putative markers both alone and in combination. In this paper, we propose two approaches: 1) a forward addition procedure in which we adapt an additive logistic regression model to the setting for disease with ordered multiple categories. Using this approach, we select and combine multiple cross-sectional biomarkers to improve diagnostic accuracy, and 2) a method by extending the Neyman-Pearson Lemma to the ordered three disease categories to construct optimal cutoff points to distinguish multiple disease categories. We evaluate the robustness of the proposed model using a simulation study. Then we apply these two methods to data from the Religious Orders Study to examine the feasibility of combining biomarkers, and compare the diagnostic accuracy between the proposed methods and existing methods including model-based methods (ordinal logistic regression and quadratic discriminant analysis), a tree-based method CART, and the Youden index method. The two proposed methods facilitate evaluations of biomarkers for conditions with graded, rather than binary, classifications. The evaluation of the performance of different approaches provides guidance of how to choose approaches to address research questions.

Pages 187-196
Charles DeCarli, Sylvia Villeneuve, Pauline Maillard, Danielle Harvey, Baljeet Singh, Owen Carmichael, Evan Fletcher, John Olichney, Sarah Farias, William Jagust, Bruce Reed, Dan Mungas
Vascular Burden Score Impacts Cognition Independent of Amyloid PET and MRI Measures of Alzheimer’s Disease and Vascular Brain Injury
Abstract: Background/Objective: To determine the impact of vascular burden on rates of decline in episodic memory and executive function. We hypothesize that greater vascular burden will have an additive negative impact on cognition after accounting for baseline cognitive impairment, positron emission tomography (PET) amyloid burden, and magnetic resonance imaging (MRI) measures. Methods: Individuals were followed an average of 5 years with serial cognitive assessments. Predictor variables include vascular burden score (VBS), quantitative brain MRI assessment, and amyloid imaging. Subjects consisted of 65 individuals, 53% of whom were male, aged 73.2 ± 7.2 years on average with an average of 15.5 ± 3.3 years of educational achievement. Results: Baseline cognitive impairment was significantly associated poorer episodic memory (p <0.0001), smaller hippocampal volume (p <0.0001), smaller brain volume (p = 0.0026), and greater global Pittsburg Imaging Compound B (PiB) index (p =0.0008). Greater amyloid burden was associated with greater decline in episodic memory over time (β= -0.20 ± 0.07, p <0.005). VBS was significantly associated with the level of executive function performance (β= -0.14 ± 0.05, p < 0.005) and there was a significant negative interaction between VBS, cognitive impairment, and PiB index (β = -0.065 ± 0.03, p= 0.03). Conclusions: Our results find a significant influence of VBS independent of standard MRI measures and cerebral amyloid burden on executive function. In addition, VBS reduced the amount of cerebral amyloid burden needed to result in cognitive impairment. We conclude that the systemic effects of vascular disease as reflected by the VBS independently influence cognitive ability.

Pages 197-203
Lei Feng, Irwin Kee-Mun Cheah, Maisie Mei-Xi Ng, Jialiang Li, Sue Mei Chan, Su Lin Lim, Rathi Mahendran, Ee-Heok Kua, Barry Halliwell(Handling Associate Editor: Jin-Tai Yu)
The Association between Mushroom Consumption and Mild Cognitive Impairment: A Community-Based Cross-Sectional Study in Singapore
Abstract: We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio=0.43, 95% CI 0.23-0.78, p=0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and their bioactive compounds in delaying neurodegeneration.

Pages 205-217
Elin Byman, Nina Schultz, the Netherlands Brain Bank, Anna M. Blom, Malin Wennström
A Potential Role for α-Amylase in Amyloid-β-Induced Astrocytic Glycogenolysis and Activation
Abstract Background: Astrocytes produce and store the energy reserve glycogen. However, abnormal large glycogen units accumulate if the production or degradation of glycogen is disturbed, a finding often seen in patients with Alzheimer’s disease (AD). We have shown increased activity of glycogen degrading α-amylase in AD patients and α-amylase positive glial cells adjacent to AD characteristic amyloid-β (Aβ) plaques. Objectives: Investigate the role of α-amylase in astrocytic glycogenolysis in presence of Aβ. Methods: Presence of α-amylase and large glycogen units in postmortem entorhinal cortex from AD patients and non-demented controls were analyzed by immunohistological stainings. Impact of different Aβ42 aggregation forms on enzymatic activity (α-amylase, pyruvate kinase, and lactate dehydrogenase), lactate secretion, and accumulation of large glycogen units in cultured astrocytes were analyzed by activity assays, ELISA, and immunocytochemistry, respectively. Results: AD patients showed increased number of α-amylase positive glial cells. The glial cells co-expressed the astrocytic marker glial fibrillary acidic protein, displayed hypertrophic features, and increased amount of large glycogen units. We further found increased load of large glycogen units, α-amylase immunoreactivity and α-amylase activity in cultured astrocytes stimulated with fibril Aβ42, with increased pyruvate kinase activity, but unaltered lactate release as downstream events. The fibril Aβ42-induced α-amylase activity was attenuated by β-adrenergic receptor antagonist propranolol. Discussion: We hypothesize that astrocytes respond to fibril Aβ42 in Aβ plaques by increasing their α-amylase production to either liberate energy or regulate functions needed in reactive processes. These findings indicate α-amylase as an important actor involved in AD associated neuroinflammation.

Pages 219-237
Gurdeep Marwarha, Kate Claycombe-Larson, Jonah Lund, Jared Schommer, Othman Ghribi (Handling Associate Editor: Matthew Pase)
A Diet Enriched in Palmitate and Deficient in Linoleate Exacerbates Oxidative Stress and Amyloid-β Burden in the Hippocampus of 3xTg-AD Mouse Model of Alzheimer’s Disease
Abstract: Epidemiological studies have suggested a positive correlation between saturated fat intake and the risk for developing Alzheimer’s disease (AD). While diets-enriched in the saturated free fatty acid (sFFA) palmitate has been shown to induce cognitive dysfunction and AD-like pathology, polyunsaturated fatty acids (PUFA) such as linoleate have been suggested to protect against AD in mouse models. However, the underlying cellular and molecular mechanisms that mediate the deleterious effects of palmitate or the protective effects of linoleate remain to be characterized. We fed 9-month-old cohorts of triple transgenic AD mice (3xTg-AD) and their-matched controls with a palmitate-enriched/linoleate-deficient diet for three months and determined the impact of the diet on oxidative stress, Bace1 promoter transactivation status, and amyloid-β (Aβ) burden. The palmitate-enriched/linoleate-deficient diet causes a profound increase in oxidative stress burden characterized by significant oxidative damage to lipids, proteins, and nucleic acids concomitant with deficits in the endogenous antioxidant defense capacity in the hippocampi of 3xTg-AD mice. These effects were also associated with increased NF-κB transcriptional activity resulting in NF-κB-mediated transactivation of the Bace1 promoter that culminated in higher BACE1 expression and activity, and Aβ production. Our study unveils a novel mechanism by which a diet enriched in the sFFA palmitate and deficient in the PUFA linoleate exacerbates AD-like pathology involving signaling cross-talk between oxidative stress and NF-κB activation as a critical underlying factor in upregulating BACE1 activity and increasing Aβ burden.

Pages 239-253
Lasse Melvaer Giil, Stein-Erik Hafstad Solvang, Malin Melvaer Giil, Kristoffer H. Hellton, Ragnhild Eide Skogseth, Audun Osland Vik-Mo, Tibor Hortobágyi, Dag Aarsland, Jan Erik Nordrehaug
Serum Potassium Is Associated with Cognitive Decline in Patients with Lewy Body Dementia
Abstract: Background: Epidemiological studies link serum potassium (K+) to cognitive performance, but whether cognitive prognosis in dementia is related to K+ levels is unknown. Objective: To determine if K+ levels predict cognitive prognosis in dementia and if this varies according to diagnosis or neuropathological findings. Methods: This longitudinal cohort study recruited 183 patients with mild Alzheimer’s disease or Lewy body dementia (LBD). Serum K+ and eGFR were measured at baseline and medications which could affect K+ registered. The Mini-Mental State Examination (MMSE) was measured annually over 5 years, and mortality registered. Association between K+ and √(30 -MMSE) was estimated overall, and according to diagnosis (joint model). Associations between MMSE-decline and K+ were assessed in two subgroups with neuropathological examination (linear regression) or repeated measurements of K+ over 3 years (mixed model). Results: Serum K+ at baseline was associated with more errors on MMSE over time (Estimate 0.18, p = 0.003), more so in LBD (p = 0.048). The overall association and LBD interaction were only significant in the 122 patients not using K+ relevant medication. Repeated K+ measures indicated that the association with MMSE errors over time was due to a between-person effect (p < 0.05, n = 57). The association between the annual MMSE decline was stronger in patients with autopsy confirmed LBD and more α-synuclein pathology (all: p < 0.05, n = 41). Conclusion: Higher serum K+ predicts poorer cognitive prognosis in demented patients not using medications which affect K+, likely a between-person effect seen mainly in LBD.

Pages 255-265
Lexiao Li*, Saifudeen Ismael*, Sanaz Nasoohi, Kazuko Sakata, Francesca-Fang Liao, Michael P. McDonald, Tauheed Ishrat *These authors contributed equally to this work.
Thioredoxin-Interacting Protein (TXNIP) Associated NLRP3 Inflammasome Activation in Human Alzheimer’s Disease Brain
Abstract: Alzheimer’s disease (AD) is the most common form of age-associated dementia characterized by amyloid-β plaques and neurofibrillary tangles. Recent studies have demonstrated that thioredoxin-interacting protein (TXNIP), an endogenous regulator of redox/glucose induced stress and inflammation, is now known to be upregulated in stroke, traumatic brain injury, diabetes and AD. We hypothesized that TXNIP overexpression sustains neurodegeneration through activation of the nucleotide binding and oligomerization domain‐like receptor protein 3 in human AD brains. We analyzed TXNIP and the components of the NLP3 inflammasome in the cortex of postmortem human brain samples by western blotting, real-time PCR, and immunohistochemical techniques and compared with age-matched non-demented controls. Our results demonstrate that TXNIP protein as well as its mRNA levels in the cortex was significantly upregulated in AD compared to control brains. Moreover, using double immunofluorescence staining, TXNIP and interlukin-1β (IL-1β) were co-localized near Aβ plaques and tau. These results suggest an association between TXNIP overexpression levels and AD pathogenesis. Further, a significant increased expression of cleaved caspase-1 and IL-1β, the products of inflammasome activation, was detected in the cortex of AD brains. Together, these findings suggest that TXNIP, an upstream promising new therapeutic target, is a molecular link between inflammation and AD. The significant contribution of TXNIP to AD pathology suggests that strategies focusing on specific targeting of the TXNIP-NLRP3 inflammasome may lead to novel therapies for the management of AD and other age-related dementias.

Pages 267-279
Christina Strand-Holm Manniche, Anne-Mette Hejl, Steen Gregers Hasselbalch, Anja H. Simonsen (Handling Associate Editor: Masatsune Ishikawa)
Cerebrospinal Fluid Biomarkers in Idiopathic Normal Pressure Hydrocephalus versus Alzheimer’s Disease and Subcortical Ischemic Vascular Disease: A Systematic Review
Abstract: Background: The diagnostic workup of idiopathic normal pressure hydrocephalus (iNPH) can be challenging due to an overlap in symptoms and neuroimaging features with other disorders. Despite a growing interest, a cerebrospinal fluid (CSF) biomarker profile in iNPH has not yet been identified. Objective: To determine the CSF biomarkers with the greatest evidence for differentiating iNPH from the most common differential diagnoses, Alzheimer’s disease (AD) and subcortical ischemic vascular disease (SIVD). Methods: A systematic literature search was conducted in PubMed to identify relevant articles up to July 2018 using the following MESH-terms: “Cerebrospinal fluid”, “diagnos*”, “hydrocephalus, normal pressure”. Relevant data were extracted to assess the risk of bias in the included studies. Results: Twenty-five studies including 664 patients with iNPH, 502 with AD, 57 with SIVD, 81 with other disorders, and 338 healthy controls (HC) were included. They investigated the diagnostic value of 92 CSF biomarkers. Most evidence existed for amyloid-β 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau) in iNPH versus AD and HC: Aβ42 did not differ between iNPH and AD, but was lower than in HC subjects. T-tau and p-tau were lower in iNPH versus AD on a level comparable to HC subjects. There was moderate or limited evidence for 62 and 88 biomarkers, respectively. Several plausible biases characterize the literature including small sample sizes and inconsistent diagnostic criteria. Conclusion: T-tau and p-tau may differentiate iNPH from AD and Aβ42 from HC. A combination of these biomarkers may improve the diagnostic accuracy in iNPH.

Pages 281-293
Joanna Depciuch, Izabela Zawlik, Marzena Skrzypa, Justyna Pająk, Natalia Potocka, Kornelia Łach, Halina Bartosik-Psujek, Anna Koziorowska, Ewa Kaznowska, Józef Cebulski
FTIR Spectroscopy of Cerebrospinal Fluid Reveals Variations in the Lipid:Protein Ratio at Different Stages of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a disease of advanced civilization and a common form of dementia in people over 65 years of age. We used Fourier transform infrared (FTIR) spectroscopy combined with principal component analysis (PCA) to determine changes in the quantity and quality of the cerebrospinal fluid from AD patients at three different stages of the disease (ADI, ADII, and ADIII), as well as from patients with mild cognitive impairment (MCI). Moreover, based on the FTIR spectra, we calculated the ratio of α-helix and β-sheet secondary protein structures as well as the lipid-protein balance as potential AD markers. The FTIR spectra of cerebrospinal fluid obtained from MCI, ADI, ADII, and ADIII patients showed that peaks corresponding to protein and deoxyribonucleic acid (DNA), and phospholipid and lipid vibrations were shifted in comparison with those of control subjects. Furthermore, the levels of these chemical compounds were lower in the patients than in the control subjects. The β-sheet secondary protein structure levels were increased in the MCI and AD patients compared with the control subjects. In addition, significant changes in the lipid-protein balance were observed. Interestingly, as the disease progressed, the lipid-protein balance became further disrupted, that is, the lipid amount decreased with disease progression. PCA analysis of lipid-protein FTIR regions revealed that the spectra could be used to distinguish between controls and patients with MCI, ADI, ADII, and ADIII.

Pages 295-309
Nira Cedres, Alejandra Machado, Yaiza Molina, Patricia Diaz-Galvan, Juan Andres Hernández-Cabrera, Jose Barroso, Eric Westman, Daniel Ferreira (Handling Associate Editor: Carla Abdelnour Ruiz)
Subjective Cognitive Decline Below and Above the Age of 60: A Multivariate Study on Neuroimaging, Cognitive, Clinical, and Demographic Measures
Abstract: Subjective cognitive complaints in cognitively normal individuals are a relevant predictor of Alzheimer’s disease (AD), cerebrovascular disease, and age-related tauopathy. Complaints starting after the age of 60 increase the likelihood of preclinical AD. However, this criterion is arbitrary and current data show that neurodegenerative disorders likely start before that age. Further, data on the role of subjective complaints below the age of 60 in individuals qualifying for subjective cognitive decline (SCD) are lacking. We investigated the association of subjective cognitive complaints with an extensive number of neuroimaging, demographic, clinical, and cognitive measures in individuals fulfilling criteria for SCD below and above the age of 60. Nine complaints were scored in 416 individuals. Complaints were related to a higher load of white matter signal abnormalities, and this association was stronger the more subclinical changes in personality, interest, and drive were reported. In individuals <60 years, complaints were associated with lower global cognitive performance. In individuals ≥60 years, complaints were related to greater global brain atrophy and smaller total intracranial volume, and this association was stronger the more subclinical difficulties in activities of daily living were reported. Also, complaints were associated with increased depressive symptomatology irrespective of age. We conclude that complaints below the age of 60 may be associated with subtle signs of brain pathology. In the community, screening for risk of future cognitive decline should include subjective cognitive complaints, depressive symptomatology, and subclinical reduced cognition (<60 years)/activities of daily living (≥60 years), supported by basic neuroimaging examinations.

Pages 311-322
Onno N. Groeneveld, Costanza Moneti, Rutger Heinen, Jeroen de Bresser, Hugo J. Kuijf, Lieza G. Exalto, Jooske M.F. Boomsma, L. Jaap Kappelle, Frederik Barkhof, Niels D. Prins, Philip Scheltens, Wiesje M. van der Flier, Geert Jan Biessels, on behalf of the TRACE-VCI study group (Handling Associate Editor: Wei Li)
The Clinical Phenotype of Vascular Cognitive Impairment in Patients with Type 2 Diabetes Mellitus
Abstract: Background: Type 2 diabetes mellitus (T2DM) increases the risk of vascular cognitive impairment (VCI). It is unknown which type of vascular lesions and co-morbid etiologies, in particular Alzheimer’s disease pathology, are associated with T2DM in patients with VCI, and how this relates to cognition and prognosis. Objective: To compare brain MRI and cerebrospinal fluid (CSF) markers, cognition, and prognosis in patients with possible VCI with and without T2DM. Methods: We included 851 memory clinic patients with vascular brain injury on MRI (i.e., possible VCI) from a prospective cohort study (T2DM: n=147, 68.4±7.9 years, 63% men; no T2DM: n=704, 67.6±8.5 years, 52% men). At baseline, we assessed between-group differences in brain MRI abnormalities, CSF markers of Alzheimer’s disease, and cognitive profile. After two years follow-up, we compared occurrence of cognitive decline, stroke, and death. Results: The distribution of clinical diagnoses did not differ between patients with and without T2DM. T2DM patients had more pronounced brain atrophy (total and white matter volume), and more lacunar infarcts, whereas microbleeds were less common (all p<0.05). CSF amyloid-β levels were similar between the groups. T2DM patients performed worse on working memory (effect size: -0.17, p=0.03) than those without, whereas performance on other domains was similar. During follow-up, risk of further cognitive decline was not increased in T2DM. Conclusion: In patients with possible VCI, presence of T2DM is related to more pronounced brain atrophy and a higher burden of lacunar infarcts, but T2DM does not have a major impact on cognitive profile or prognosis.

Pages 323-337
Mai Fujikura, Naotoshi Iwahara, Shin Hisahara, Jun Kawamata, Akihiro Matsumura, Kazuki Yokokawa, Taro Saito, Tatsuo Manabe, Takashi Matsushitaa Syuuichirou Suzuki, Shun Shimohama (Handling Associate Editor: Yasuomi Ouchi)
CD14 and Toll-Like Receptor 4 Promote Fibrillar Aβ42 Uptake by Microglia through a Clathrin-Mediated Pathway
Abstract: We previously demonstrated that microglia play an essential role in clearance of amyloid-β (Aβ) in Alzheimer’s disease (AD)-like pathology. Our prior work also showed that several receptors expressed on microglia participated in Aβ phagocytosis. However, clathrin-mediated endocytosis (CME), which is associated with production and release of Aβ in neurons, has received much less attention in the context of microglial Aβ uptake. To elucidate the detailed mechanisms of microglial Aβ uptake pathways, we focused on CD14 and Toll-like receptor 4 (TLR4), which have been shown to mediate fibrillar Aβ1-42 (fAβ42) phagocytosis in microglia. CD14 has also been known to control lipopolysaccharide-induced internalization of TLR4 in a clathrin-dependent manner. However, it remains unclear whether CD14 and TLR4 engage in CME in microglial fAβ42 uptake, including whether CD14 interacts with TLR4 in the process. In the present study, we found that CD14-positive microglia increased in an age-dependent manner in the cortex of AD model mice. Immunostaining showed that CD14 interacted with TLR4 to internalize fAβ42 in the mouse microglial cell line MG6. Knock-down of CD14 and TLR4 in MG6 cells significantly reduced intracellular fAβ42, showing their involvement in fAβ42 uptake. We also found that clathrin participated in fAβ42 uptake by MG6 cells. Furthermore, CD14 and TLR4 mediated fAβ42 uptake via clathrin-dependent mechanisms. These results indicate that CD14 and TLR4 participate not only in phagocytosis but also in clathrin-dependent fAβ42 internalization in microglia. These findings provide novel molecular understanding of microglial fAβ42 uptake, which could be of therapeutic relevance for AD.

Pages 339-355
Zhijie Han, Weiwei Xue, Lin Tao, Feng Zhu (Handling Associate Editor: Jin-Tai Yu)
Identification of Key Long Non-Coding RNAs in the Pathology of Alzheimer’s Disease and their Functions Based on Genome-Wide Associations Study, Microarray, and RNA-seq Data
Abstract: The pathogenesis of Alzheimer’s disease (AD) is identified to be significantly regulated by long non-coding RNA (lncRNA) based on in vivo and clinical experiments. Single nucleotide polymorphisms (SNPs) can strongly impact expression and function of lncRNA in AD, and previous genome-wide associations studies (GWAS) have discovered substantial amount of risk SNPs associated with AD. However, current studies omit the important information about SNPs when identifying potential AD-related lncRNAs. In addition to single discovery approach and small-scale samples in these studies, the number of lncRNAs discovered as keys in AD is limited. Here, multiple computational methods were integrated to discover novel and key lncRNA of the pathology of AD. First, large-scale GWAS data involved in three ethnicities were collected from two authoritative sources, and meta-analyses were conducted to find SNPs significantly associated with AD (tag SNPs). Second, these tag SNPs together with their linkage disequilibrium information were used to discover potential lncRNAs related to AD. Third, after validation by microarray probe re-annotation of 1,282 samples and RNA-seq data analysis of 117 samples, respectively, a total of five key lncRNAs of AD were identified. Finally, possible function of these lncRNAs was predicted by genome mapping, expression quantitative trait loci, differential co-expression, and gene set enrichment analysis. Based on function prediction, four of the five key lncRNAs were identified to affect the risk of AD by regulating corresponding pathogenic genes and pathways, which are involved in regulation of amyloid-β peptide and the immune system. In summary, these findings can facilitate the discovery of potential disease-related lncRNAs and enhance understanding of the pathogenesis of AD.

Pages 357-365
Sarah C. Conner, Laurent Benayoun, Jayandra J. Himali, Stephanie L. Adams, Qiong Yang, Charles DeCarli, Jan K. Blusztajn, Alexa Beiser, Sudha Seshadri, Ivana Delalle
Methionine Sulfoxide Reductase-B3 Risk Allele Implicated in Alzheimer’s Disease Associates with Increased Odds for Brain Infarcts
Abstract: Genome-wide association studies identified a single nucleotide polymorphism (SNP) in the MSRB3 gene encoding Methionine Sulfoxide Reductase-B3 (MsrB3) to be associated with the risk for low hippocampal volume and late onset Alzheimer’s disease (AD). Subsequently, we identified AD-associated abnormal patterns of neuronal and vascular MsrB3 expression in postmortem hippocampi. The present study investigated the relationship between the MSRB3 SNP rs61921502, G (minor/risk allele) and MRI measures of brain injury including total brain volume, hippocampal volume, and white matter hyperintensities using linear regression models; the presence of brain infarcts using logistic regression models; and the incidence of stroke, dementia, and AD using Cox proportional hazards models in 2,038 Framingham Heart Study Offspring participants with MRI administered close to examination cycle 7 (1998-2001). Participants with neurological conditions that impede evaluation of vascular pathology by MRI, i.e., brain tumors, multiple sclerosis, and major head trauma, were excluded from the study. When adjusted for age and age squared at MRI exam, sex, and presence of Apolipoprotein ε4 allele (APOE4), individuals with MSRB3 rs61921502 minor allele had increased odds for brain infarcts on MRI compared to those with no minor allele. However, in stratified analyses, MSRB3 rs61921502 minor allele was significantly associated with increased odds for MRI brain infarcts only in the absence of APOE4.

Pages 367-381
Jing Guo, Cheng Xu, Shaozhou Ni, Shujuan Zhang, Qihang Li, Peng Zeng, Guilin Pi, Enjie Liu, Dong-Sheng Sun, Yanchao Liu, Zhouyi Wang, Haote Chen, Ying Yang, Jian-Zhi Wang
Elevation of pS262-Tau and Demethylated PP2A in Retina Occurs Earlier than in Hippocampus During Hyperhomocysteinemia
Abstract: Hyperhomocysteinemia is an independent risk factor of Alzheimer’s disease (AD), which is not diagnosed for many years before onset due to lack of peripherally detectable early biomarkers. Visual dysfunction is prevalent in AD patients and correlates with the severity of cognitive defects. Importantly, alterations in eyes can be non-invasively detected. To search for early biomarkers in eyes from high risk factors of AD, we injected homocysteine (Hcy) into the rats via vena caudalis for 3, 7, and 14 days, respectively, and characterized the chronological order of the AD-like pathologies appearing in retina and the hippocampus during the progression of hyperhomocysteinemia, and their correlations with cognitive impairment. We found that administration of Hcy for 14 days, but not 3 or 7 days, induced hyperhomocysteinemia, although a gradually increased blood Hcy level was detected. In retina and/or the hippocampus, significant loss of retinal ganglion cells and stenosis of retinal arteries with the AD-like tau and amyloid-β (Aβ) pathologies and memory deficit were shown only in the 14-day Hcy group. Interestingly, accumulation of Ser262 hyperphosphorylated tau (pS262-tau) but not Aβ with decreased methylation of protein phosphatase-2A catalytic subunit (M-PP2Ac) and increased de-methylated PP2Ac (DM-PP2Ac) was detected in retina of the 3-day Hcy group, in which the retinal pathologies were preceded by those of the hippocampus. These findings suggest that elevated pS262-tau and DM-PP2Ac and reduced M-PP2Ac in retina may serve as surveillance biomarkers for diagnosis of the hyperhomocysteinemia-induced AD in the early stage.

Pages 383-394
Andrea Brugnolo, Fabrizio De Carli, Marco Pagani, Slivia Morbelli, Cathrine Jonsson, Andrea Chincarini, Giovanni B. Frisoni, Samantha Galluzzi, Robert Perneczky, Alexander Drzezga, Bart N.M. van Berckel, Rik Ossenkoppele, Mira Didic, Eric Guedj, Dario Arnaldi, Federico Massa, Matteo Grazzini, Matteo Pardini, Patrizia Mecocci, Massimo E. Dottorini, Matteo Bauckneht, Gianmario Sambuceti, Flavio Nobili
Head-to-Head Comparison among Semi-Quantification Tools of Brain FDG-PET to Aid the Diagnosis of Prodromal Alzheimer’s Disease
Abstract: Background: Several automatic tools have been implemented for semi-quantitative assessment of brain [18]F-FDG-PET. Objective: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer’s disease (pAD) from controls. Methods: Sixty-two pAD patients (MMSE score=27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score=29.2±1.2) were enrolled in five centers of the European Alzheimer’s Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between [18]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). Results: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p < 0.005) better than any of the other methods. Conclusion: The study confirms the good accuracy of [18]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods.

Pages 395-404
Yusuke Seino, Takumi Nakamura, Takeshi Kawarabayashi, Mie Hirohata, Sakiko Narita, Yasuhito Wakasaya, Kozue Kaito, Tetsuya Ueda, Yasuo Harigaya, Mikio Shoji (Handling Associate Editor: Akihiko Nunomura)
Cerebrospinal Fluid and Plasma Biomarkers in Neurodegenerative Diseases
Abstract: Cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and tau are biomarkers for Alzheimer’s disease (AD); however, the effects of other neurodegenerative processes on these biomarkers remain unclear. We measured Aβ40, Aβ42, total tau, phosphorylated-tau, and α-synuclein in CSF and plasma using matched samples from various neurodegenerative diseases to expand our basic knowledge on these biomarkers and their practical applications. A total of 213 CSF and 183 plasma samples were analyzed from cognitively unimpaired subjects, and patients with Alzheimer’s disease dementia (ADD), mild cognitive impairment (MCI), non-AD dementias, and other neurological diseases. The CSF/plasma ratios of Aβ40 and Aβ42 were approximately 25:1. Aβ40/42 ratios in CSF and plasma were both 10:1. The CSF total tau/P181tau ratio was 6:1. The CSF/plasma α-synuclein ratio was 1:65. Significantly decreased Aβ42 levels and an increased Aβ40/42 ratio in CSF in ADD/MCI suggested that these relationships were specifically altered in AD. Increased total tau levels in ADD/MCI, encephalopathy, and multiple system atrophy, and increased P181tau in ADD/MCI indicated that these biomarkers corresponded to neurodegeneration and tauopathy, respectively. Although CSF α-synuclein levels were increased in ADD/MCI, there was no merit in measuring α-synuclein in CSF or plasma as a biomarker. The combination of biomarkers by the Aβ40/42 ratio x p181tau reflected specific changes due to the AD pathology in ADD/MCI. Thus, CSF Aβ40, Aβ42, p181tau, and tau were identified as biomarkers for aggregated Aβ associated state (A), aggregated tau associated state (T), and neurodegeneration state (N) pathologies in AD based on the NIA-AA criteria. Overlaps in these biomarkers need to be considered in clinical practice for differential diagnoses of neurodegenerative diseases.

Pages 405-414
Hui Xia*, Min Wang*, Jie-Qiong Li, Chen-Chen Tan, Xi-Peng Cao, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Benedetta Nacmias) *These authors contributed equally to this work.
The Influence of BDNF Val66Met Polymorphism on Cognition, Cerebrospinal Fluid, and Neuroimaging Markers in Non-Demented Elderly
Abstract: Background: The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism emerged as a risk factor for Alzheimer’s disease (AD). However, little was known about its effects on the process of potential AD. Objective: To explore the effects of the Val66Met polymorphism on cognition, cerebrospinal fluid (CSF), and neuroimaging markers in non-demented elderly individuals. Methods: A total of 1,081 adults without dementia (375 healthy subjects and 706 individuals with mild cognitive impairment) were recruited from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to test the influence of BDNF Val66Met polymorphism on cognitive impairment, brain structure atrophy, and change in the levels of CSF biomarkers. Moreover, we also conducted our study in abnormal amyloid-β (A+) subgroup and normal amyloid-β (A-) subgroup, as well as in APOE ε4 carriers and non-carriers. Results: The BDNF Val66Met polymorphism had significant association with atrophy of the entorhinal cortex and Mini-Mental State Examination (MMSE) scores in the non-demented elderly and A+ subgroup, while no association was found in A- subgroup. What is more, there was a significant effect of interaction between BDNF Val66Met and amyloid-β load in MMSE. In addition, significant associations of BDNF Val66Met with the entorhinal cortex and ventricular volumes were found among APOE ε4 non-carriers, but not APOE ε4 carriers. Conclusions: The BDNF Val66Met polymorphism is associated with cognitive impairment and brain atrophy among the non-demented elderly, APOE ε4 non-carriers and A+ subgroup, implying the potential of the Val66Met polymorphism as an important genetic factor for AD-related neurodegeneration.