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Volume 58, Number 3, IN PRESS

Review
Junjun Sun, Hong Zhou, Feng Bai, Zhijun Zhang, Qingguo Ren
Remyelination: A Potential Therapeutic Strategy for Alzheimer’s Disease?
Abstract: Myelin is a lipid-rich multilamellar membrane that wraps around long segments of neuronal axons and it increases the conduction of action potentials, transports the necessary trophic support to the neuronal axons, and reduces the energy consumed by the neuronal axons. Together with axons, myelin is a prerequisite for the higher functions of the central nervous system and complex forms of network integration. Myelin impairments have been suggested to lead to neuronal dysfunction and cognitive decline. Accumulating evidence, including brain imaging and postmortem and genetic association studies, has implicated myelin impairments in Alzheimer’s disease (AD). Increasing data link myelin impairments with amyloid-β (Aβ) plaques and tau hyperphosphorylation, which are both present in patients with AD. Moreover, aging and apolipoprotein E (ApoE) may be involved in the myelin impairments observed in patients with AD. Decreased neuronal activity, increased Aβ levels, and inflammation further damage myelin in patients with AD. Furthermore, treatments that promote myelination contribute to the recovery of neuronal function and improve cognition. Therefore, strategies targeting myelin impairment may provide therapeutic opportunities for patients with AD.

Review
Lilian Calderón-Garcidueñas, Suzanne M. de la Monte
Apolipoprotein E4, Gender, Body Mass Index, Inflammation, Insulin Resistance, and Air Pollution Interactions: Recipe for Alzheimer's Disease Development in Mexico City Young Females
Abstract: Given the epidemiological trends of increasing Alzheimer’s disease (AD) and growing evidence that exposure and lifestyle factors contribute to AD risk and pathogenesis, attention should be paid to variables such as air pollution, in order to reduce rates of cognitive decline and dementia. Exposure to fine particulate matter (PM2.5) and ozone (O3) above the US EPA standards is associated with AD risk. Mexico City children experienced pre- and postnatal high exposures to PM2.5, O3, combustion-derived iron-rich nanoparticles, metals, polycyclic aromatic hydrocarbons, and endotoxins. Exposures are associated with early brain gene imbalance in oxidative stress, inflammation, innate and adaptive immune responses, along with epigenetic changes, accumulation of misfolded proteins, cognitive deficits, and brain structural and metabolic changes. The Apolipoprotein E (APOE) 4 allele, the most prevalent genetic risk for AD, plays a key role in the response to air pollution in young girls. APOE 4 heterozygous females with >75% to <94% BMI percentiles are at the highest risk of severe cognitive deficits (1.5-2 SD from average IQ). This review focused on the relationships between gender, BMI, systemic and neural inflammation, insulin resistance, hyperleptinemia, dyslipidemia, vascular risk factors, and central nervous system involvement in APOE4 urbanites exposed to PM2.5 and magnetite combustion-derived iron-rich nanoparticles that can reach the brain. APOE4 young female heterozygous carriers constitute a high-risk group for a fatal disease: AD. Multidisciplinary intervention strategies could be critical for prevention or amelioration of cognitive deficits and long-term AD progression in young individuals at high risk.

Review
Jin-Bao Zhu, Chen-Chen Tan, Lan Tan, Jin-Tai Yu
State of Play in Alzheimer’s Disease Genetics
Abstract: Alzheimer’s disease (AD), the main form of dementia in the elderly, is the most common progressive neurodegenerative disease characterized by rapidly progressive cognitive dysfunction and behavior impairment. AD exhibits a considerable heritability and great advances have been made in approaches to searching the genetic etiology of AD. In AD genetic studies, methods have developed from classic linkage-based and candidate-gene-based association studies to genome-wide association studies (GWAS) and next generation sequencing. The identification of new susceptibility genes has provided deeper insights to understand the mechanisms underlying AD. In addition to searching novel genes associated with AD in large samples, the next generation sequencing can also be used to shed light on the ‘black matter’ discover even in smaller samples. The shift in AD genetics between traditional studies and individual sequencing will allow biomaterials of each patient as the central unit of genetic studies. This review will cover genetic findings in AD and consequences of AD genetic findings. Firstly, we will discuss the discovery of mutations in APP, PSEN1, PSEN2, APOE, and ADAM10. Then we will summarize and evaluate the information obtained from GWAS of AD. Finally, we will outline the efforts to identify rare variants associated with AD using next generation sequencing.

Short Communication
Ana-María Lacosta, Daniel Insua, Hassnae Badi, Pedro Pesini, Manuel Sarasa
Neurofibrillary Tangles of Aβx-40 in Alzheimer’s Disease Brains
Abstract: The two pathognomonic lesions in the brain of AD patients are senile plaques and intraneuronal neurofibrillary tangles (NFT). Previous studies have demonstrated that amyloid-β (Aβ) is a component of both senile plaques and NFTs, and have showed that intracellular accumulation of Aβ is toxic for cells and precedes the appearance of extracellular amyloid deposits. Here we report that there are numerous intraneuronal NFT and extraneuronal NFT immunoreactive for Aβx-40 in which there is no co-localization with tau staining suggesting the existence of two different neurodegenerating populations associated with the intracellular accumulation of either tau protein or Aβx-40 in AD.

Short Communication
Anna Raunio, Liisa Myllykangas, Mia Kero, Tuomo Polvikoski, Anders Paetau, Minna Oinas (Handling Associate Editor: Irina Alafuzoff)
Amygdala α-Synuclein Pathology in the Population-Based Vantaa 85+ Study
Abstract: We investigated the frequency of Lewy-related pathology (LRP) in the amygdala among the population-based Vantaa 85+ study. Data of amygdala samples (N=304) immunostained with two α-synuclein antibodies (clone 42 and clone 5G4) was compared with the previously analyzed LRP and AD pathologies from other brain regions. The amygdala LRP was present in one third (33%) of subjects. Only 5% of pure AD subjects, but 85% of pure DLB subjects had LRP in the amygdala. The amygdala LRP was associated with dementia; however, the association was dependent on LRP on other brain regions, and thus was not an independent risk factor. The amygdala-predominant category was a rare (4%) and heterogeneous group.

Ganesh M. Babulal, Sarah H. Stout, Denise Head, David M. Holtzman, Anne M. Fagan, John C. Morris, Catherine M. Roe (Handling Associate Editor: David Knopman)
Neuropsychiatric Symptoms and Alzheimer’s Disease Biomarkers Predict Driving Decline: Brief Report
Abstract: We examined whether neuropsychiatric symptoms (NPS) interact with cerebrospinal fluid (CSF) biomarkers (amyloid-β42 [Aβ42], tau, phosphorylated tau181 [ptau181], tau/Aβ42, and ptau181/Aβ42) of Alzheimer’s disease pathology to predict driving decline among cognitively-normal older adults (N=116) aged ≥65. Cox proportional hazards models examined time to receiving a rating of marginal or fail on the driving test. Age, education, and gender were adjusted in the models. Participants with more abnormal CSF (Aβ42, tau/Aβ42, ptau181/Aβ42) and NPS were faster to receive a marginal/fail on the road test compared to those without NPS. NPS interact with abnormal CSF biomarkers to impact driving performance among cognitively-normal older adults.

Short Communication
Naoki Kasahata, Tomohide Sato, Iichiroh Onishi, Masanobu Kitagawa, Toshiki Uchihara, Katsuiku Hirokawa (Handling Associate Editor: Kurt Jellinger)
Three-Repeat Tau with Grain-Like Structures and Distribution in an 83-Year-Old Man
Abstract: We encountered an 83-year-old man with 3-repeat dominant grain-like tau deposition. Tau-positive lesions exhibited apparent similarity to argyrophilic grains in terms of their distribution in the ambient gyrus, amygdala, and dorsomedial temporal tip and the characteristic comma-like morphology. The abundant oligodendroglial tau immunoreactivities were 3-repeat dominant. Tuft-shaped astrocytes showed partial 3-repeat tau immnoreactivities. These grain-like structures, as well as tuft-shaped astrocytes and oligodendroglia, exhibited predominant 3-repeat tau immunoreactivity, suggesting that grain-like structures and their characteristic distribution are mutually linked and not unique to 4-repeat tau deposition. pTDP immunoreactivity, extensive macrophage infiltration, and spongiosis were associated with these 3-repeat tau deposits.

Yuta Yoshino, Kiyohiro Yamazaki, Yuki Ozaki, Tomoko Sao, Taku Yoshida, Takaaki Mori, Yoko Mori, Shinichiro Ochi, Jun-ichi Iga, Shu-ichi Ueno
INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer’s Disease Subjects
Abstract: Microglial dysfunction and inflammation have recently been shown to be related to the development of Alzheimer’s disease (AD). Inositol polyphosphate-5-phosphatase (INPP5D) functions broadly as a negative regulator of immune signaling, and its locus was associated with development of AD in a large-scale genome-wide association study. Thus, we examined INPP5D mRNA expression and methylation rates of the CpG sites in the upstream region of INPP5D exon 1 in peripheral leukocytes in 50 AD and age- and sex-matched control subjects. INPP5D mRNA expression in AD subjects was significantly higher than that in control subjects (1.16 ± 0.39 versus 1.0 ± 0.23, p = 0.049) and was correlated with the Mini-Mental State Examination score (p = 0.002, r = 0.426) and the total score of the Alzheimer's Disease Assessment Scale (p < 0.001, r = −0.697). Methylation rates in the upstream region of INPP5D exon 1 were not significantly different between AD and control subjects (average rate: 3.5 ± 3.0 versus 2.8 ± 1.3, p = 0.551). Our results suggested that INPP5D mRNA expression was elevated in the early stage and decreased with cognitive decline in AD. INPP5D mRNA expression in leukocytes may be a useful biomarker for the early stage of AD.

Aaron Ritter, Nanako Hawley, Sarah J. Banks, Justin B. Miller
The Association between Montreal Cognitive Assessment Memory Scores and Hippocampal Volume in a Neurodegenerative Disease Sample
Abstract: Despite widespread use, there have been few investigations into the neuroanatomical correlates of the Montreal Cognitive Assessment (MoCA). In a sample of 138 consecutive patients presenting with cognitive complaints, we report significant correlations between lower MoCA memory scores and smaller hippocampal volumes (r = 0.36-0.41, p < 0.001). We also report that the newly devised memory index score, designed to better capture encoding deficits than the standard delayed recall score, was not significantly better for predicting hippocampal volume. These initial results suggest that poor performance on the MoCA’s memory section should prompt further evaluation for hippocampal atrophy.

Yue Yang, Glenda M. Halliday, John R. Hodges, Rachel H. Tan (Handling Associate Editor: Jennifer Whitwell)
von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion
Abstract: Background. The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. Objective. To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. Methods. Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n=13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n=8), sporadic amyotrophic lateral sclerosis (n=7) and controls (n=9). Results. von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. Conclusion. The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

Rita Gordon, Igor Podolski, Ekaterina Makarova, Alexander Deev, Ekaterina Mugantseva, Sergey Khutsyan, Frank Sengpiel, Arkady Murashev, Vasily Vorobyov (Handling Associate Editor: Catherine Pennington)
Intrahippocampal Pathways Involved in Learning/Memory Mechanisms are Affected by Intracerebral Infusions of Amyloid-β25-35 Peptide and Hydrated Fullerene C60 in Rats
Abstract: Primary memory impairments associated with increased level of amyloid-β (Аβ) in the brain have been shown to be linked, partially, with early pathological changes in the entorhinal cortex (EC) which spread on the whole limbic system. While the hippocampus is known to play a key role in learning and memory mechanisms, it is as yet unclear how its structures are involved in the EC pathology. In this study, changes in memory and neuronal morphology in male Wistar rats intrahippocampally injected with Аβ25–35 were correlated on days 14 and 45 after the injection to reveal specific cognitive-structural associations. The main focus was on the dentate gyrus (DG) and hippocampal areas of CA1 and CA3 because of their involvement in afferent flows from EC to the hippocampus through tri-synaptic (EC DG CA3 CA1) and/or mono-synaptic (EC CA1) pathways. Evident memory impairments were observed at both time points after Аβ25–35 injection. However, on day 14, populations of morphological intact neurons were decreased in CA3 and, drastically, in CA1, and the DG supramedial bundle was significantly damaged. On day 45, this bundle largely and СА1 neurons partially recovered, whereas CA3 neurons remained damaged. We suggest that Аβ25–35 primarily affects the tri-synaptic pathway, destroying the granular cells in the DG supramedial area and neurons in CA3 and, through the Schaffer collaterals, in CA1. Intrahippocampal pretreatment with hydrated fullerene С60 allows the neurons and their connections to survive the amyloidosis, thus supporting the memory mechanisms.

Vasiliki Orgeta, Naji Tabet, Ramin Nilforooshan, Robert Howard (Handling Associate Editor: Jeannie-Marie Leoutsakos)
Efficacy of Antidepressants for Depression in Alzheimer’s Disease: Systematic Review and Meta-Analysis
Abstract: Background: Depression is common in people with Alzheimer’s disease (AD) affecting overall outcomes and decreasing quality of life. Although depression in AD is primarily treated with antidepressants, there are few randomized controlled trials (RCTs) assessing efficacy and results have been conflicting. Objectives: To systematically review evidence on efficacy of antidepressant treatments for depression in AD. Methods: Systematic review and meta-analysis of double blind RCTs comparing antidepressants versus placebo for depression in AD. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, the Cochrane Controlled Trials Register and on line national and international registers. Primary outcomes were treatment response and depressive symptoms. Secondary outcomes were cognition, acceptability, and tolerability. Risk of bias was also assessed. Results: Seven studies met inclusion criteria. Three compared sertraline with placebo; one compared both sertraline and mirtazapine to placebo; imipramine, fluoxetine, and clomipramine were evaluated in one study each. In terms of response to treatment (6 studies, 297 patients treated with antidepressants and 223 with placebo), no statistically significant difference between antidepressants and placebo was found (odds ratio (OR) 1.95, 95% CI 0.97-3.92). We found no significant drug-placebo difference for depressive symptoms (5 studies, 311 patients, SMD -0.13; 95% CI -0.49 to 0.24). Overall quality of the evidence was moderate because of methodological limitations in studies and the small number of trials. Conclusion: Despite the importance of depression in people with AD, few RCTs are available on efficacy of antidepressants, limiting clear conclusions of their potential role. There is a need for further high quality RCTs.

Sam C.C. Chan, Chetwyn C.H. Chan, Abiot Y. Derbie, Irene Hui, Davynn G.H. Tan, Marco Y.C. Pang, Stephen C.L. Lau, Kenneth N.K. Fong (Handling Associate Editor: Feng Lin)
Chinese Calligraphy Writing for Augmenting Attentional Control and Working Memory of Older Adults at Risk of Mild Cognitive Impairment: A Randomized Controlled Trial
Abstract: Background: Nonpharmacological intervention for individuals with mild cognitive impairment (MCI) needs further investigation. Objectives: Test efficacy of eight-week Chinese calligraphy writing training improving attentional control and working memory. Methods: Ninety-nine participants with MCI were randomized into the eight-week calligraphy writing (n=48) or control (tablet computer) training (n=51). Outcomes of the interventions were attentional control, working memory, visual scan and processing speed. They were measured at baseline, post-training, and six-month follow-up. Results: Calligraphy writing, when compared with control, significantly improved working memory as reflected from DST-Backward sequence (p=0.009) and span scores (p=0.002), and divided attention as reflected from CTT2 (p<0.001), and at the post-training. The unique improvement in working memory (span: p<0.001; sequence: p=0.008) of the intervention group was also found at follow-up when comparing with those at baseline. Changes in the other outcome measures were not statistically significant. Conclusion: The findings provide support that Chinese calligraphy writing training for eight weeks using a cognitive approach would improve working memory and to a lesser extent attentional control functions of patients with early MCI. They also demonstrate the usefulness of using mind-and-body practice for improving specific cognitive functions.

Jun Ku Chung, Eric Plitman, Shinichiro Nakajima, Fernando Caravaggio, Yusuke Iwata, Philip Gerretsen, Julia Kim, Hiroyoshi Takeuchi, Shunichiro Shinagawa, Raihaan Patel, M. Mallar Chakravarty, Ariel Graff-Guerrero, for the Alzheimer’s Disease Neuroimaging Initiative
Hippocampal and Clinical Trajectories of Mild Cognitive Impairment with Suspected Non-Alzheimer’s Disease Pathology
Abstract: Suspected non-Alzheimer’s disease pathophysiology (SNAP) characterizes individuals showing neurodegeneration (e.g., hypometabolism) without amyloid-β (Aβ). Findings from previous studies regarding clinical and structural trajectories of SNAP are inconsistent. Using data from the Alzheimer’s Disease Neuroimaging Initiative, patients with amnestic mild cognitive impairment (MCI) were categorized into four groups: amyloid positive with hypometabolism (Aβ+ND+), amyloid only (Aβ+ND-), neither amyloid nor hypometabolism (Aβ-ND-), and SNAP (Aβ-ND+). Aβ+ND+ (n= 33), Aβ+ND- (n = 32), and Aβ-ND- (n = 36) were matched to SNAP for age, gender, apolipoprotein E4 (apoE4) genotype, and scores on the Montreal Cognitive Assessment. Elderly controls (n = 40) were also matched to SNAP for age, gender, and apoE4 genotype. Longitudinal changes were compared across groups in terms of hippocampal volume, clinical symptoms, daily functioning, and cognitive functioning over a 2-year period. At baseline, no difference in cognition and functioning was observed between SNAP and Aβ+ groups. SNAP showed worse clinical symptoms and impaired functioning at baseline compared to Aβ-ND- and controls. Two years of follow-up showed no differences in hippocampal volume changes between SNAP and any of the comparison groups. SNAP showed worse functional deterioration in comparison to Aβ-ND- and controls. However, Aβ+ND+ showed more severe changes in clinical symptoms in comparison to SNAP. Thus, patients with MCI and SNAP showed 1) more severe functional deterioration compared to Aβ-ND- and controls, 2) no differences with Aβ+ND-, and 3) less cognitive deterioration than Aβ+ND+. Future studies should investigate what causes SNAP, which is different from typical AD pathology and biomarker cascades.

Lorenzo Pasquini*, Gloria Benson*, Michel J. Grothe, Lukas Utz, Nicholas E. Myers, Igor Yakushev, Timo Grimmer, Martin Scherr, Christian Sorg for the Alzheimer's Disease Neuroimaging Initiative (Handling Associate Editor: Juan Zhou) *These authors contributed equally to this work.
Individual Correspondence of Amyloid-β and Intrinsic Connectivity in the Posterior Default Mode Network Across Stages of Alzheimer’s Disease
Abstract: In Alzheimer’s disease (AD), amyloid-β (Aβ) pathology and intrinsic functional connectivity (iFC) interact. Across stages of AD, we expected individual spatial correspondence of Aβ and iFC to reveal both Aβ accumulation and its detrimental effects on iFC. We used resting-state functional magnetic imaging and Aβ imaging in a cross-sectional sample of 90 subjects across stages of AD and healthy older adults. Global and local correspondence of Aβ and iFC were assessed within the posterior default mode network (pDMN) by within-subject voxel-wise correlations. Beginning at preclinical stages, global Aβ-iFC correspondence was positive for the whole pDMN, showing that Aβ accumulates in areas of high connectivity, and reached a plateau at prodromal stages. Starting at preclinical stages, local correspondence was negative in network centers, indicating that Aβ reduces connectivity of the pDMN as a function of local plaque concentration, and peaked at prodromal stages. Positive global correspondence suggests that Aβ accumulation progresses along iFC, with this effect starting in preclinical stages, and being constant along clinical periods. Negative local correspondence suggests detrimental effects of Aβ on iFC in network centers, starting at preclinical stages, and peaking when first symptoms appear. Data reveal a complex trajectory of Aβ and iFC correspondence, affecting both Aβ accumulation and iFC impairments.

Gunjan D. Manocha, Atreyi Ghatak, Kendra L. Puig, Susan D. Kraner, Christopher M. Norris, Colin K. Combs (Handling Associate Editor: Narayan Bhat)
NFATc2 Modulates Microglial Activation in the AβPP/PS1 Mouse Model of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) brains are characterized by fibrillar amyloid-β (Aβ) peptide containing plaques and associated reactive microglia. The proinflammatory phenotype of the microglia suggests that they may negatively affect disease course and contribute to behavioral decline. This hypothesis predicts that attenuating microglial activation may provide benefit against disease. Prior work from our laboratory and others has characterized a role for the transcription factor, nuclear factor of activated T cells (NFAT), in regulating microglial phenotype in response to different stimuli, including Aβ peptide. We observed that the NFATc2 isoform was the most highly expressed in murine microglia cultures, and inhibition or deletion of NFATc2 was sufficient to attenuate the ability of the microglia to secrete cytokines. In order to determine whether the NFATc2 isoform, in particular, was a valid immunomodulatory target in vivo, we crossed an NFATc2-/- line to a well-known AD mouse model, an AβPP/PS1 mouse line. As expected, the AβPP/PS1 x NFATc2-/- mice had attenuated cytokine levels compared to AβPP/PS1 mice as well as reduced microgliosis and astrogliosis with no effect on plaque load. Although some species differences in relative isoform expression may exist between murine and human microglia, it appears that microglial NFAT activity is a viable target for modulating the proinflammatory changes that occur during AD.

Ciarán O’Driscoll, Madiha Shaikh (Handling Associate Editor: Gilles Chopard)
Cross-Cultural Applicability of the Montreal Cognitive Assessment (MoCA): A Systematic Review
Abstract: The Montreal Cognitive Assessment (MoCA) is widely used to screen for mild cognitive impairment (MCI). While there are many available versions, the cross-cultural validity of the assessment has not been explored sufficiently. We aimed to interrogate the validity of the MoCA in a cross-cultural context: in differentiating MCI from normal controls (NC); and identifying cut-offs and adjustments for age and education where possible. This review sourced a wide range of studies including case-control studies. In addition, we report findings for differentiating dementias from NC and MCI from dementias, however, these were not considered to be an appropriate use of the MoCA. The subject of the review assumes heterogeneity and therefore meta-analyses was not conducted. Quality ratings, forest plots of validated studies (sensitivity and specificity) with covariates (suggested cut-offs, age, education and country), and summary receiver operating characteristic curve are presented. The results showed a wide range in suggested cutoffs for MCI cross-culturally, with variability in levels of sensitivity and specificity ranging from low to high. Poor methodological rigor appears to have affected reported accuracy and validity of the MoCA. The review highlights the necessity for cross-cultural considerations when using the MoCA, and recognizing it as a screen and not a diagnostic tool. Appropriate cutoffs and point adjustments for education are suggested.

Eric Swanson, Leigham Breckenridge, Lloyd McMahon, Sreemoyee Som, Ian McConnell, George S. Bloom (Handling Associate Editor: Alejandro Alonso)
Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction
Abstract: Aggregates composed of the microtubule associated protein, tau, are a hallmark of Alzheimer’s disease and non-Alzheimer’s tauopathies. Extracellular tau can induce the accumulation and aggregation of intracellular tau, and tau pathology can be transmitted along neural networks over time. There are six splice variants of central nervous system tau, and various oligomeric and fibrillar forms are associated with neurodegeneration in vivo. The particular extracellular forms of tau capable of transferring tau pathology from neuron to neuron remain ill defined, however, as do the consequences of intracellular tau aggregation on neuronal physiology. The present study was undertaken to compare the effects of extracellular tau monomers, oligomers, and filaments comprising various tau isoforms on the behavior of cultured neurons. We found that 2N4R or 2N3R tau oligomers provoked aggregation of endogenous intracellular tau much more effectively than monomers or fibrils, or of oligomers made from other tau isoforms, and that a mixture of all six isoforms most potently provoked intracellular tau accumulation. These effects were associated with invasion of tau into the somatodendritic compartment. Finally, we observed that 2N4R oligomers perturbed fast axonal transport of membranous organelles along microtubules. Intracellular tau accumulation was often accompanied by increases in the run length, run time and instantaneous velocity of membranous cargo. This work indicates that extracellular tau oligomers can disrupt normal neuronal homeostasis by triggering axonal tau accumulation and loss of the polarized distribution of tau, and by impairing fast axonal transport.

Mikael Edsbagge, Ulf Andreasson, Khalid Ambarki, Carsten Wikkelsø, Anders Eklund, Kaj Blennow, Henrik Zetterberg, Mats Tullberg
Alzheimer’s Disease-Associated Cerebrospinal Fluid (CSF) Biomarkers do not Correlate with CSF Volumes or CSF Production Rate
Abstract: Background: Neuropathologically, Alzheimer’s disease (AD) is characterized by accumulation of a 42 amino acid peptide called amyloid-β (Aβ42) in extracellular senile plaques together with intraneuronal inclusions of hyperphosphorylated tau protein in neurofibrillary tangles and neuronal degeneration. These changes are reflected in the cerebrospinal fluid (CSF), the volumes and production rates of which vary considerably between individuals, by reduced concentration of Aβ42, increased concentration of phosphorylated tau (P-tau) protein, and increased concentration of total tau (T-tau) protein, respectively. Objective: To examine the outstanding question if CSF concentrations of AD associated biomarkers are influenced by variations in CSF volumes, CSF production rate, and intracranial pressure in healthy individuals. Methods: CSF concentrations of Aβ42, P-tau, and T-tau, as well as a number of other AD-related CSF biomarkers were analyzed together with intracranial subarachnoid, ventricular, and spinal CSF volumes, as assessed by magnetic resonance imaging volumetric measurements, and CSF production rate in 19 cognitively normal healthy subjects (mean age 70.6, SD 3.6 years). Results: Negative correlations were seen between the concentrations of three CSF biomarkers (albumin ratio, Aβ38, and Aβ40), and ventricular CSF volume, but apart from this finding, no significant correlations were observed. Conclusion: These results speak against inter-individual variations in CSF volume and production rate as important confounds in the AD biomarker research field.

Roser Sala-Llonch, Ane-Victoria Idland, Tom Borza, Leiv Otto Watne, Torgeir Bruun Wyller, Anne Brækhus, Henrik Zetterberg, Kaj Blennow, Kristine Beate Walhovd, Anders Martin Fjell
Inflammation, Amyloid, and Atrophy in The Aging Brain: Relationships with Longitudinal Changes in Cognition
Abstract: Amyloid deposition occurs in aging, even in individuals free from cognitive symptoms, and is often interpreted as preclinical Alzheimer’s disease (AD) pathophysiology. YKL-40 is a marker of neuroinflammation, being increased in AD, and hypothesized to interact with amyloid-β (Aβ) in causing cognitive decline early in the cascade of AD pathophysiology. Whether and how Aβ and YKL-40 affect brain and cognitive changes in cognitively healthy older adults is still unknown. We studied 89 participants (mean age: 73.1 years) with cerebrospinal fluid samples at baseline, and both MRI and cognitive assessments from two time-points separated by two years. We tested how baseline levels of Aβ42 and YKL-40 correlated with changes in cortical thickness and cognition. Thickness change correlated with Aβ42 only in Aβ42+ participants (< 600 pg/mL, n=27) in the left motor and premotor cortices. Aβ42 was unrelated to cognitive change. Increased YKL-40 was associated with less preservation of scores on the animal naming test in the total sample (r=-0.28, p=0.012) and less preservation of a score reflecting global cognitive function for Aβ42+ participants (r=-0.58, p=0.004). Our results suggest a role for inflammation in brain atrophy and cognitive changes in cognitively normal older adults, which partly depended on Aβ accumulation.

Wanda M. Snow, Ryan Dale, Zoe O’Brien-Moran, Richard Buist, Danial Peirson, Melanie Martin, Benedict C. Albensi
In Vivo Detection of Gray Matter Neuropathology in the 3xTg Mouse Model of Alzheimer’s Disease with Diffusion Tensor Imaging
Abstract: A diagnosis of Alzheimer’s disease (AD), a neurodegenerative disorder accompanied by severe functional and cognitive decline, is based on clinical findings, with final confirmation of the disease at autopsy by the presence of amyloid-β (Aβ) plaques and neurofibrillary tangles. Given that microstructural brain alterations occur years prior to clinical symptoms, efforts to detect brain changes early could significantly enhance our ability to diagnose AD sooner. Diffusion tensor imaging (DTI), a type of MRI that characterizes the magnitude, orientation, and anisotropy of the diffusion of water in tissues, has been used to infer neuropathological changes in vivo. Its utility in AD, however, is still under investigation. The current study used DTI to examine brain regions susceptible to AD-related pathology; the cerebral cortex, entorhinal cortex, and hippocampus, in 12-14-month-old 3xTg AD mice that possess both Aβ plaques and neurofibrillary tangles. Mean diffusivity did not differ between 3xTg and control mice in any region. Decreased fractional anisotropy (p < 0.01) and axial diffusivity (p < 0.05) were detected in only in the hippocampus, in which both congophilic Aβ plaques and hyperphosphorylated tau accumulation, consistent with neurofibrillary tangle formation, were detected. Pathological tau accumulation was seen in the cortex. The entorhinal cortex was largely spared from AD-related neuropathology. This is the first study to demonstrate DTI abnormalities in gray matter in a mouse model of AD in which both pathological hallmarks are present, suggesting the feasibility of DTI as a non-invasive means of detecting brain pathology in vivo in early-stage AD.

Adrià Tort-Merino, Natalia Valech, Claudia Peñaloza, Petra Grönholm-Nyman, María León, Jaume Olives, Ainara Estanga, Mirian Ecay, Juan Fortea, Pablo Martínez-Lage, Jose L. Molinuevo, Matti Laine, Antoni Rodríguez-Fornells*, Lorena Rami* *These authors contributed equally to this work.
Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer’s Disease Stage 1
Abstract: We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer’s Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n=31; PreAD-1, n=14; PreAD-2, n=4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F=6.98; p=0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F=4.83; p=0.03). Similarly, relearning sessions showed only statistical trends between the groups (F=3.22; p=0.08). In the whole sample, significant correlations between CSF Aβ42/tau ratio and the AFE-T were found, both in the total learning score (r=0.52; p<0.001) and in the three-month cued forgetting rate (r=-0.38; p<0.01). Descriptive subanalyses involving PreAD-2 suggested greater learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer’s disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.

Sonia Ben Jemaa, Neila Attia Romdhane, Amel Bahri-Mrabet, Adel Jendli, Didier Le Gall, Tarek Bellaj (Handling Associate Editor: Robert Friedland)
An Arabic Version of the Cognitive Subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog): Reliability, Validity, and Normative Data
Abstract: The Alzheimer’s Disease Assessment Scale’s cognitive subscale (ADAS-Cog) is the most widely used instrument for screening cognitive dysfunction in Alzheimer's disease. The aim of the present study was to develop an Arabic version of this scale (A-ADAS-Cog), examine its psychometric properties (reliability and validity), and provide normative data. The A-ADAS-Cog), an Arabic version of the Mini-Mental State Examination (A-MMSE), and a Standardized Clinical Dementia Rating Scale (CDR) were administered to three Tunisian groups: 124 normal controls (NC), 33 patients with non-Alzheimer dementia (N-AD), and 25 patients with Alzheimer’s disease (AD). The A-ADAS-Cog scores were significantly affected by age and education. A correction table was constructed to control for these effects. The results showed that the A-ADAS-Cog has good internal consistency and reliability (α=0.82 for AD). The test-retest reliability of the A-ADAS-Cog was stable over time (r=0.97). An evaluation of the construct validity of the A-ADAS-Cog using principal component analysis led to a solution with three factors (memory, language and praxis), which explained 72% of the variance. The concurrent validity of the A-ADAS-Cog was established using the A-MMSE score (r=-0.86), CDR Sum of Boxes score (CDR-SB; r=0.87), and global CDR score (CDR-Global; r=0.74). Finally, the A-ADAS-Cog has an excellent discriminating power in the diagnosis of AD (ROC area=0.92). A cut-off score of 11 (sensitivity=83% and specificity=85%) is indicated for the screening of the AD. Overall, the results indicated that the A-ADAS-Cog is psychometrically reliable and valid and provides promising results for screening of dementia in Arabic speaking patients.

Gail A Laughlin, Donna Kritz-Silverstein, Jaclyn Bergstrom, Emilie T. Reas, Simerjot K. Jassal, Elizabeth Barrett-Connor, Linda K. McEvoy (Handling Associate Editor: Carol Brayne)
Vitamin D Insufficiency and Cognitive Function Trajectories in Older Adults: The Rancho Bernardo Study
Abstract: Background: Evidence of a role for vitamin D (VitD) in cognitive aging is mixed and based primarily on extreme VitD deficiency. We evaluated the association of VitD insufficiency with cognitive function in older, community-dwelling adults living in a temperate climate with year-round sunshine. Methods: A population-based longitudinal study of 1,058 adults (median age 75; 62% women) who had cognitive function assessed and serum levels of 25-hydroxyvitaminD (25OHD) measured in 1997-99 and were followed for up to three additional cognitive function assessments over a 12-year period. Results: Overall, 14% (n=145) of participants had VitD insufficiency defined as 25OHD <30 ng/ml. Adjusting for age, sex, education, and season, VitD insufficiency was associated with poorer baseline performance on the Mini-Mental Status Exam (MMSE) (p=0.013), Trails Making Test B (Trails B) (p=0.015), Category Fluency (p=0.006), and Long Term Retrieval (p=0.019); differences were equivalent to 5 years of age. For those with VitD insufficiency, the odds of mildly impaired performance at baseline were 38% higher for MMSE (p=0.08), 78% higher for Trails B (p=0.017), and 2-fold higher for Category Fluency and Long Term Retrieval (both p=0.001). VitD insufficiency was not related to the rate of cognitive decline on any test or the risk of developing impaired performance during follow-up. Conclusion: In this population with little VitD deficiency, even moderately low VitD was associated with poorer performance on multiple domains of cognitive function. Low VitD did not predict 12-year cognitive decline. Clinical trials are essential to establish a causal link between VitD and cognitive well-being.

Ivonne Suridjan, Nathan Herrmann, Alex Adibfar, Mahwesh Saleem, Ana Andreazza, Paul I. Oh, Krista L. Lanctôt (Handling Associate Editor: Ignacio Casado Naranjo)
Lipid Peroxidation Markers in Coronary Artery Disease Patients with Possible Vascular Mild Cognitive Impairment
Abstract: This study examined associations between lipid peroxidation markers and cognition, and associations between these markers and cognitive response to an exercise intervention program, in adults with coronary artery disease at risk of dementia. Lipid peroxidation products were measured in serum in 118 patients (29 possible vascular mild cognitive impairment and 89 controls). Ratios of early- (lipid hydroperoxides, LPH) to late-stage (8-isoprostane, 8-ISO; 4-hydroxy-2-nonenal, 4-HNE) lipid peroxidation products were calculated. Cognitive performance was assessed before and at completion of a 24-week exercise intervention program. A global effect of group on lipid peroxidation markers was observed, adjusting for sex, years of education, and cardiopulmonary fitness (main effect of group F (3,102) = 2.957, p = 0.036). Lower lipid peroxidation at baseline, as determined by lower 8-ISO concentration, was associated with greater improvement in verbal memory (F (1, 64) = 4.738, p = 0.03) and executive function (F (1, 64) = 5.219, p = 0.026) performance. Similarly, higher ratios of 8-ISO/LPH (F (1, 65) = 6.592, p = 0.013) and (8-ISO+4-HNE) to LPH (F (1, 65) = 3.857, p = 0.054), were associated with less improvement in executive function performance over a 24-week exercise intervention. Lipid peroxidation may be a biomarker of early vascular cognitive impairment, and elevated lipid peroxidation might limit the cognitive benefits of exercise in this high-risk population.

Hongbing Sun
Associations of Spatial Disparities of Alzheimer’s Disease Mortality Rates and Soil Selenium, Sulfur Concentrations, and Risk Factors in the United States
Abstract: Background: Associations between environmental factors and spatial disparity of mortality rates of Alzheimer’s disease (AD) in the US are not well understood. Objective: To find associations between 41 trace elements, four common risk factors, and AD mortality rates in the 48 contiguous states. Methods: Isopleth maps of AD mortality rates of the 48 states and associated factors were examined. Correlations between state average AD mortality rates and concentrations of 41 soil elements, wine consumption, percentage of current smokers, obesity, and diagnosed diabetes of the 48 states between 1999 and 2014 were analyzed. Results: Among 41 elements, soil selenium concentrations have the most significant inverse correlations with AD mortality rates. Rate ratio (RR) of the 6 states with the lowest product of soil selenium and sulfur concentrations is 53% higher than the 6 states with the highest soil selenium sulfur product in the 48 states (RR=1.53, CI95% 1.51-1.54). Soil tin concentrations have the most significant inverse correlation with AD mortality growth rates between 1999 and 2014, followed by soil sulfur concentrations. Percentages of obesity, diagnosed diabetes, smoking, and wine consumption per capita also correlate significantly with AD mortality growth rates. Conclusions: High soil selenium and sulfur concentrations and wine consumption are associated with low AD mortality rates. Given that average soil selenium and sulfur concentrations are indicators of their intakes from food, water, and air by people in a region, long-term exposure to high soil selenium and sulfur concentrations might be beneficial to AD mortality rate reduction in a region.

Isabel Sala*, Ignacio Illán-Gala*, Daniel Alcolea, Mª Belén Sánchez-Saudinós, Sergio Andrés Salgado, Estrella Morenas-Rodríguez, Andrea Subirana, Laura Videla, Jordi Clarimón, María Carmona-Iragui, Roser Ribosa-Nogué, Rafael Blesa, Juan Fortea, Alberto Lleó *These authors contributed equally to this work.
Diagnostic and Prognostic Value of the Combination of Two Measures of Verbal Memory in Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: Episodic memory impairment is the core feature of typical Alzheimer’s disease. Objective: To evaluate the performance of two commonly used verbal memory tests to detect mild cognitive impairment due to Alzheimer’s disease (MCI-AD) and to predict progression to Alzheimer’s disease dementia (AD-d). Methods: Prospective study of MCI patients in a tertiary memory disorder unit. Patients underwent an extensive neuropsychological battery including two tests of declarative verbal memory: The Free and Cued Selective Reminding Test (FCSRT) and the word list learning task from the Consortium to Establish a Registry for Alzheimer’s disease (CERAD-WL). Cerebrospinal fluid (CSF) was obtained from all patients and MCI-AD was defined by means of the t-Tau/A1-42 ratio. Logistic regression analyses tested whether the combination of FCSRT and CERAD-WL measures significantly improved the prediction of MCI-AD. Progression to AD-d was analyzed in a Cox regression model. Results: A total of 202 MCI patients with a mean follow-up of 34.2±24.2 months were included and 98 (48.5%) met the criteria for MCI-AD. The combination of FCSRT and CERAD-WL measures improved MCI-AD classification accuracy based on CSF biomarkers. Both tests yielded similar global predictive values (59.9-65.3% and 59.4-62.8% for FCSRT and CERAD-WL, respectively). MCI-AD patients with deficits in both FCSRT and CERAD-WL had a faster progression to AD-d than patients with deficits in only one test. Conclusions: The combination of FCSRT and CERAD-WL improves the classification of MCI-AD and defines different prognostic profiles. These findings have important implications for clinical practice and the design of clinical trials.

Wang-Sheng Jin, Xian-Le Bu, Ye-Ran Wang, Ling Li, Wei-Wei Li, Yu-Hui Liu, Chi Zhu, Xiu-Qing Yao, Yang Chen, Chang-Yue Gao, Tao Zhang, Chang-Yue Gao, Hua-Dong Zhou, Fan Zeng, Yan-Jiang Wang
Reduced Cardiovascular Functions in Patients with Alzheimer’s Disease
Abstract: Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer’s disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n=34) and age- and gender-matched cognitively normal controls (n=34) were recruited. Comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The lacunae, white matter changes, and plaque in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and a higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.

Hanna Lu, Sandra S.M. Chan, Ada W.T. Fung, Linda C.W. Lam
Beyond a Differential Diagnosis: Cognitive and Morphometric Decoding of Information Processing Speed in Senior Adults with DSM-5 Mild Neurocognitive Disorders
Abstract: Background: Processing speed has been highlighted as a diagnostic item for neurocognitive disorders (NCD) in DSM-5. The utility of information processing speed (IPS) enclosed with multiscale constructs in the diagnosis of NCD warrants exploration. Objective: We aimed to investigate the IPS with two types of measurements in the patients with NCD due to vascular disease (NCD-vascular) and NCD due to Alzheimer’s disease (NCD-AD), and examine the associations between IPS measures and morphometric features. Methods: The IPS was evaluated using trail making test (TMT) and flanker test (n=204). Direct scores, derived scores, and reaction time (RT) were used as IPS measures. Further, surface-based morphometry cortical volume was calculated in a subsample (n=44) with structural MRI data. Results: All IPS measures showed a significant value to differentiate NCD patients from healthy subjects. Only mean RT could distinguish NCD-AD from NCD-vascular groups. TMT-B score and difference score were correlated with gray matter volume (GMV) of inferior frontal gyrus, precuneus and superior temporal cortex. Mean RT was associated with the GMV of post-central gyrus (r = -0.327, p = 0.035), and executive speed was associated with inferior frontal cortex (r = -0.475, p = 0.001), cingulate gyrus (r = -0.497, p = 0.001), and superior temporal gyrus (r = -0.36, p = 0.019). Conclusion: The cognitive and morphometric correlates of IPS measures indicate that complex IPS might be decomposed into the domain-specific components with corresponding neural underpinnings. Our findings may also provide essential insights into the diagnostic item of NCD.

Steffen Wolfsgruber*, Alexandra Polcher*, Alexander Koppara, Luca Kleineidam, Lutz Frölich, Oliver Peters, Michael Hüll, Eckart Rüther, Jens Wiltfang, Wolfgang Maier, Johannes Kornhuber, Piotr Lewczuk, Frank Jessen, Michael Wagner (Handling Associate Editor: Andrea Tales) *These authors contributed equally to this work.
Cerebrospinal Fluid Biomarkers and Clinical Progression in Patients with Subjective Cognitive Decline and Mild Cognitive Impairment
Abstract: Background: There is very limited data on the prevalence of abnormal cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD) and their predictive value for clinical progression in memory clinic patients with subjective cognitive decline (SCD). Objective: To assess the frequency of abnormal CSF biomarkers of AD and their predictive value for clinical progression in memory clinic patients with SCD in comparison to patients with mild cognitive impairment (MCI) from the same cohort. Methods: We analyzed prospective data from memory clinic patients of the German Competence Network Dementia cohort with a baseline diagnosis of SCD (n=82) or MCI (n=134), distinguished by actuarial neuropsychological MCI criteria (“Jak-Bondi criteria”). Risk of clinical progression during 3-year follow-up was evaluated with Cox-Proportional-Hazard models. Results: Prevalence of abnormal values in CSF markers of tau-mediated neurodegeneration (67.8% versus 46.3%) but not of amyloid deposition (40.3% versus 35.4%) was significantly higher in MCI compared to SCD. The rate of incident AD dementia (26.1% versus 12.2%) was also significantly higher in MCI. In SCD, additional 22% progressed to MCI during follow-up. Combined amyloid/tau abnormality was the strongest predictor of clinical progression in both groups. Conclusion: High prevalence of biomarker abnormality and clinical progression, together with the predictive value of CSF biomarkers, in memory clinic patients with SCD support the validity and usefulness of this condition as a "pre-MCI" at risk stage of AD.