Volume 63, Number 2, 2018

Pages 409-421

Giulio Maria Pasinetti, Risham Singh, Susan Westfall, Francis Herman, Jeremiah Faith, Lap Ho
The Role of the Gut Microbiota in the Metabolism of Polyphenols as Characterized by Gnotobiotic Mice
Abstract: A growing body of experimental data suggests that microbes in the gut influence behavior and can alter brain physiology and neurochemistry. Although promising, researchers are only starting to understand the potential of the gut microbiota for use in neurological disease. Recent evidence demonstrated that gastrointestinal activities are linked to mood disorders such as anxiety, depression, and most recently, cognitive functions in age-related neurodegenerative disorders. Studies from our group and others are uncovering new evidence suggesting that the gut microbiota plays a crucial role in the metabolism and bioavailability of certain dietary compounds and synthetic drugs. Based on this evidence, this review article will discuss the implication of the gut microbiota in mechanisms of bioavailability and biotransformation with an emphasis on dietary polyphenol compounds. This will be followed by a survey of ongoing innovative research identifying the ability of individual gut bacteria to enhance the bioavailability of gut-derived, brain-penetrating, bioactive polyphenol metabolites that ultimately influence mechanisms associated with the promotion of resilience against psychological and cognitive impairment in response to stress. Lastly, current research initiatives aimed at promoting the generation of brain bioactive polyphenol metabolites by specialized gut microbes will be discussed, specifically the use of gnotobiotic mice to develop bioengineered second generation probiotics. We propose that leveraging the gut microbial ecosystem to generate brain targeted bioactive metabolites from dietary polyphenols can attenuate lifestyle risk factors and promote resilience against age-related cognitive decline.

Pages 423-444

Jacqueline K. Kueper, Mark Speechley, Manuel Montero-Odasso
The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog): Modifications and Responsiveness in Pre-Dementia Populations. A Narrative Review
Abstract: The Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) was developed in the 1980s to assess the level of cognitive dysfunction in Alzheimer's disease. Advancements in the research field have shifted focus toward pre-dementia populations, and use of the ADAS-Cog has extended into these pre-dementia studies despite concerns about its ability to detect important changes at these milder stages of disease progression. If the ADAS-Cog cannot detect important changes, our understanding of pre-dementia disease progression may be compromised and trials may incorrectly conclude that a novel treatment approach is not beneficial. The purpose of this review was to assess the performance of the ADAS-Cog in pre-dementia populations, and to review all modifications that have been made to the ADAS-Cog to improve its measurement performance in dementia or pre-dementia populations. The contents of this review are based on bibliographic searches of electronic databases to locate all studies using the ADAS-Cog in pre-dementia samples or subsamples, and to locate all modified versions. Citations from relevant articles were also consulted. Overall, our results suggest the original ADAS-Cog is not an optimal outcome measure for pre-dementia studies; however, given the prominence of the ADAS-Cog, care must be taken when considering the use of alternative outcome measures. Thirty-one modified versions of the ADAS-Cog were found. Modification approaches that appear most beneficial include altering scoring methodology or adding tests of memory, executive function, and/or daily functioning. Although modifications improve the performance of the ADAS-Cog, this is at the cost of introducing heterogeneity that may limit between-study comparison.

Pages 445-455
Chen Chen, Haifeng Zhang, Hongliang Xu, Rui Xue, Yake Zheng, Tianwen Wu, Yajun Lian (Handling Associate Editor: Ling-Qiang Zhu)
Harpagoside Rescues the Memory Impairments in Chronic Cerebral Hypoperfusion Rats by Inhibiting PTEN Activity
Abstract: Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer's disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens, a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in A - and MPTP-induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3 , downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD.

Pages 457-463
Nicole C. Burns, Amber Watts, Jaime Perales, Robert Neal Montgomery, Jill K. Morris, Jonathan D. Mahnken, Johnna Lowther , Eric D. Vidoni (Handling Associate Editor: Sophie Vandepitte)
The Impact of Creative Arts in Alzheimer's Disease and Dementia Public Health Education
Abstract: Previous research involving dramatic performances about Alzheimer's disease and dementia perception have targeted health care workers or caretakers. We examined the influence of a theater performance on the emotional affect of a general audience to determine the utility of this type of theater in large-scale public health education efforts. Our study included 147 participants that attended a self-revelatory theater performance based on the social/relationship experiences of those with dementia and those who care for them. This type of theater engages the audience and actors in a dual transformative process, supporting the emotional growth of all involved. Participants completed pre- and post-performance questionnaires regarding their beliefs and feelings surrounding the topic of dementia and the importance of the Arts for educating on issues surrounding dementia care. We tested for change in emotional affect pre- and post-performance using sensitivity and center of gravity statistical analyses. We found a significant change in emotional affect from an initial strong negative affect to slightly more positive/relaxed view after viewing the performance. Findings support self-revelatory theater as a resource to destigmatize preconceived notions of dementia. Large-scale community health education efforts could benefit from using this style of theater to elicit a change in audience perception of disease realities.

Pages 465-477
Barbora Soukupova Urbanova, Jaroslava Paulasova Schwabova, Hana Magerova, Petr Jansky, Hana Markova, Martin Vyhnalek, Jan Laczo, Jakub Hort, Ales Tomek (Handling Associate Editor: Jack de la Torre)
Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment
Abstract: Background: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes. Objective: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver. Methods: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non-amnestic MCI subtypes. Results: Fourteen AD (3 males, 67.9 ± 11.1 years, MMSE 18.0 ± 4.6), 24 MCI (13 males, 71.9 ± 7.3 years, MMSE 28.0 ± 1.6), and 24 risk factor-matched controls (14 males, 67.8 ± 6.4 years, MMSE 29.1 ± 1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test. Conclusion: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI.

Pages 479-487
Pratishtha Chatterjee*, Kathryn Goozee*, Hamid R. Sohrabi, Kaikai Shen, Tejal Shah, Prita R. Asih, Preeti Dave, Candice ManYan, Kevin Taddei, Roger Chung, Henrik Zetterberg, Kaj Blennow, Ralph N. Martins *These authors contributed equally to this work.
Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-β Load and Cognitive Performance in Cognitively Normal Elderly Participants
Abstract: Background: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. Objective: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-β load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. Methods: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65-90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n=65) and high NAL (NAL+, n=35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL-=51, nNAL+=25) and non-SMC (nNAL-=14, nNAL+=10) based on the Memory Assessment Clinic-Questionnaire. Results: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOE ε4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. Conclusion: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD.

Pages 489-502
Zsuzsanna Fodor, Enikő Sirály, András Horváth, Pál Salacz, Zoltán Hidasi, Éva Csibri, Ádám Szabó, Gábor Csukly (Handling Associate Editor: László Vécsei)
Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment
Abstract: Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment.

Pages 503-514
Timothy A. Couttas, Nupur Kain, Collin Tran, Zac Chatterton, John B. Kwok, Anthony S. Don (Handling Associate Editor: Michelle Mielke)
Age-Dependent Changes to Sphingolipid Balance in the Human Hippocampus are Gender-Specific and May Sensitize to Neurodegeneration
Abstract: The greatest risk factor for developing Alzheimer's disease (AD) is aging. The major genetic risk factor for AD is the ε4 allele of the APOE gene, encoding the brain's major lipid transport protein, apolipoprotein E (ApoE). The research community is yet to decipher why the ApoE4 variant pre-disposes to AD, and how aging causes the disease. Studies have shown deregulated levels of sphingolipids, including decreased levels of the neuroprotective signaling lipid sphingosine 1-phosphate (S1P), and increased ceramide content, in brain tissue and serum of people with pre-clinical or very early AD. In this study we investigated whether sphingolipid levels are affected as a function of age or APOE genotype, in the hippocampus of neurologically normal subjects over the age of 65. Lipids were quantified in 80 postmortem tissue samples using liquid chromatography tandem mass spectrometry (LC-MS/MS). Sphingolipid levels were not significantly affected by the presence of one ε4 or ε2 allele. However, ceramide, sphingomyelin, and sulfatide content was very significantly correlated with age in the hippocampus of males. On the other hand, S1P, normalized to its non-phosphorylated precursor sphingosine, was inversely correlated with age in females. Our results therefore establish gender-specific differences in sphingolipid metabolism in the aging human brain. Ceramide is a pro-apoptotic lipid, and heavily implicated as a driver of insulin resistance in metabolic tissues. S1P is a neuroprotective lipid that supports glutamatergic neurotransmission. Increasing ceramide and decreasing S1P levels may contribute significantly to a pro-neurodegenerative phenotype in the aging brain.

Pages 515-527
Esther van den Berg, Mirjam I. Geerlings, Geert Jan Biessels, Paul J. Nederkoornd Raoul P. Kloppenborg (Handling Associate Editor: David Libon)
White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer's Disease: A Domain-Specific Meta-Analysis
Abstract: Background: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) is, however, unclear. Objective: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD. Methods: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (≥1 predefined cognitive domain with ≥1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer's Z was used as the common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined. Results Twelve cross-sectional studies on AD (total n=1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n=2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (-0.25, -0.36 to -0.14) than for AD (-0.11, -0.14 to -0.08; QM=10.7, p < 0.05). For both groups, largest effect sizes were found in attention and executive functions (-0.26, -0.36 to -0.15) and processing speed (-0.21, -0.35 to -0.12). No significant modifying effects of age and gender were found. Conclusion WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co-occurring vascular brain damage in MCI and AD.

Pages 529-538
Daniel G. Amen, Derek V. Taylor, Somayeh Meysami, Cyrus A. Raji
Deficits in Regional Cerebral Blood Flow on Brain SPECT Predict Treatment Resistant Depression
Abstract: Background: Depression remains an important risk factor for Alzheimer's disease, yet few neuroimaging biomarkers are available to identify treatment response in depression. Objective: To analyze and compare functional perfusion neuroimaging in persons with treatment resistant depression (TRD) compared to those experiencing full remission. Methods: A total of 951 subjects from a community psychiatry cohort were scanned with perfusion single photon emission computed tomography (SPECT) of the brain in both resting and task related settings. Of these, 78% experienced either full remission (n = 506) or partial remission (n = 237) and 11% were minimally responsive (n = 103) or non-responsive (11%, n=106). Severity of depression symptoms were used to define these groups with changes in the Beck Depression Inventory prior to and following treatment. Voxel-based analyses of brain SPECT images from full remission compared to the worsening group was conducted with the statistical parametric mapping software, version 8 (SPM 8). Multiple comparisons were accounted for with a false discovery rate (p < 0.001). Results: Persons with depression that worsened following treatment had reduced cerebral perfusion compared to full remission in the multiple regions including the bilateral frontal lobes, right hippocampus, left precuneus, and cerebellar vermis. Such differences were observed on both resting and concentration SPECT scans. Conclusion: Our findings identify imaging-based biomarkers in persons with depression related to treatment response. These findings have implications in understanding both depression to prognosis and its role as a risk factor for dementia.

Pages 539-550
Sergey P. Radko, Svetlana A. Khmeleva, Alexey B. Mantsyzov, Yana Y. Kiseleva, Vladimir A. Mitkevich, Sergey A. Kozin, Alexander A. Makarov (Handling Associate Editor: Vladimir Buchman)
Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-β Peptides
Abstract: Zinc-induced aggregation of amyloid-β peptides (Aβ) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Aβ self-aggregation in vitro, the impact of GAGs on the formation of zinc-induced amorphous Aβ aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Aβ42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Aβ16 peptides to model the Aβ metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Aβ42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Aβ42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Aβ42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Aβ16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Aβ aggregation.

Pages 551-560
Aiqin Zhu*, Zhou Wu*, Xin Zhong, Junjun Ni, Yinglan Li, Jie Meng, Can Du, Xue Zhao, Hiroshi Nakanishi, Shizheng Wu (Handling Associate Editor: Johannes Streffer) *These authors contributed equally to this work.
Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude
Abstract: Background: Systemic inflammation is known as a risk factor of cognitive decline. Objective: To investigate the effects of propolis on cognitive decline and systemic inflammation in elderly people living at high altitude. Methods: Sixty participants (average 72.8 years) living at altitude (2,260 meters) were randomized to receive propolis (0.83g, n=30) or placebo (n=30) for 24 months. Cognitive outcomes were assessed using MMSE and serum cytokine levels were measured for 24 months in a double-blind study. Results: MMSE scores were 26.17 at baseline and 23.87 at 24 months in placebo group. Compared to placebo group, improvements of MMSE scores were significant in propolis-treated subjects (p=0.007) with a response emerging over time (time points × group interaction, p=0.016). In addition, the serum IL-1β and IL-6 levels were significantly different across treatments (p<0.0001) showing upward and downward trends in placebo- and propolis-treated subjects, respectively (p<0.0001). Serum levels of TNF-α were not significantly different across treatment (p=0.0528) but with a response emerging over time (time points × group interaction, p=0.016). In contrast, serum levels of TGFβ1 were significantly different across treatments (p<0.0001) showing downward and upward trends in placebo- and propolis-treated subjects, respectively. Serum levels of IL-10 were significant for the effect of groups (p=0.0411). Furthermore, MMSE scores correlated with the decrease in IL-1β and the increase in TGFβ1 in serum. Conclusion: Elderly people living at high altitude developed to MCI in 24 months with exacerbation of systemic inflammation. Ingestion of propolis (>12 months) protected against cognitive decline after systemic inflammation was reduced.

Pages 561-575
Elena Makovac, Laura Serra, Carlotta Di Domenico, Camillo Marra, Carlo Caltagirone, Mara Cercignani, Marco Bozzali
Quantitative Magnetization Transfer of White Matter Tracts Correlates with Diffusion Tensor Imaging Indices in Predicting the Conversion from Mild Cognitive Impairment to Alzheimer's Disease
Abstract: Patients with amnestic mild cognitive impairment (aMCI) have higher probability to develop Alzheimer's disease (AD) than elderly controls. The detection of subtle changes in brain structure associated with disease progression and the development of tools to identify patients at high risk for dementia in a short time is crucial. Here, we used probabilistic white matter (WM) tractography to explore microstructural alterations within the main association, limbic, and commissural pathways in aMCI patients who converted to AD after 1 year follow-up (MCIconverters) and those who remained stable (MCIstable). Both diffusion tensor imaging (DTI) and quantitative magnetization transfer (qMT) parameters have been considered for a comprehensive pathophysiological characterization of the WM damage. Overall, specific tract-specific parameters derived from qMT and DTI at baseline were able to differentiate aMCI patients who converted to AD from those who remained stable in time. In particular, the qMT exchange rate, RMB0, of the right uncinate fasciculus was significantly decreased in MCIconverters, whereas fractional anisotropy was significantly decreased in the bilateral superior cingulum in MCIconverters compared to MCIstable. These results confirm the involvement of WM and particularly of association fibers in the progression of AD, highlighting disconnection as a potential mechanism.

Pages 577-590
Pierre-François Meyer, Melissa Savard, Judes Poirier, Anne Labonté, Pedro Rosa-Neto, Tara M. Weitz, Terrence Town, John Breitner, for the Alzheimer's Disease Neuroimaging Initiative and the PREVENT-AD Research Group (Handling Associate Editor: Michelle Mielke)
Bi-Directional Association of Cerebrospinal Fluid Immune Markers with Stage of Alzheimer's Disease Pathogenesis
Abstract: Immune mechanisms may be important in the pathogenesis of Alzheimer's disease (AD). Yet, studies comparing healthy and demented individuals' cerebrospinal fluid (CSF) and plasma immune marker levels have yielded conflicting results. We analyzed CSF from 101 members of the parental history-positive PREVENT-AD cohort of healthy aging adults, and 237 participants in the initial cohort of the Alzheimer's Disease Neuroimaging Initiative (ADNI-1). Following recent practice, we used the biomarkers total-tau and amyloid- 1-42 to allocate participants from each study into four stages of AD pathogenesis: Stage 0 (no abnormality), Stage 1 (reduced amyloid- 1-42), Stage 2 (reduced amyloid- 1-42 and increased total-tau), or "Suspected Non-Alzheimer Pathology" (elevated total-tau only). Investigating the PREVENT-AD participants' CSF assay results for 19 immune/inflammatory markers, we found six that showed a distinct bi-directional relationship with pathogenetic stage. Relative to Stage 0, these were diminished at Stage 1 but strongly increased at Stage 2. Among 237 ADNI participants without dementia (90 healthy controls and 147 with mild cognitive impairment), we found that 23 of 83 available CSF markers also showed this distinct pattern. These results support recent observations that immune activation may become apparent only after the onset of both amyloid and tau pathologies. Unexpectedly, they also suggest that immune marker activity may diminish along with earliest appearance of amyloid- plaque pathology. These findings may explain discordant results from past studies, and suggest the importance of characterizing the extent of AD pathology when comparing clinical groups.

Pages 591-601
Jonas Mengel-From, Mette E. Rønne, Anting L. Carlsen, Kristin Skogstrand, Lisbeth A. Larsen, Qihua Tan, Lene Christiansen, Kaare Christensen, Niels H.H. Heegaard
Circulating, Cell-Free Micro-RNA Profiles Reflect Discordant Development of Dementia in Monozygotic Twins
Abstract: We aim to examine if circulating micro-RNA and cytokine levels associate with dementia diagnosis and cognitive scores. To test our hypothesis, we use plasma donated from 48 monozygotic twin pairs in 1997 and 46 micro-RNAs and 10 cytokines were quantified using microfluidic RT-qPCR and multiplex solid-phase immunoassays, respectively. Micro-RNA and cytokine profiling were examined for associations with dementia diagnoses in a longitudinal registry study or with cognitive scores at baseline. Thirty-six micro-RNAs and all cytokines were detected consistently. Micro-RNA profiles associate with diagnoses and cognitive scores at statistically significant levels while cytokine only showed trends pointing at chronic inflammation in twins having or developing dementia. The most notable findings were decreased miR-106a and miR-210, and increased miR-106b expression in twins with a dementia diagnosis. This pioneering evaluation of micro-RNA and cytokine and dementia diagnosis suggests micro-RNA targets in vasculogenesis, lipoprotein transport, and amyloid precursor protein genes.

Pages 603-615
Cynthia M. Stonnington, Yinghua Chen, Cary R. Savage, Wendy Lee, Robert J. Bauer III, Sameen Sharieff, Pradeep Thiyyagura, Gene E. Alexander, Richard J. Caselli, Dona E.C. Locke, Eric M. Reiman, Kewei Chen (Handling Associate Editor: Barbara Bendlin)
Predicting Imminent Progression to Clinically Significant Memory Decline Using Volumetric MRI and FDG PET
Abstract: Background: Brain imaging measurements can provide evidence of possible preclinical Alzheimer's disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. Objective: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years. Methods: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8±0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. Results: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual's imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts). Conclusion: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline.

Pages 617-624
Isabelle Rouch, Elodie Pongan, Yohana Leveque, Barbara Tillmann , Béatrice Trombert, Jean Claude Getenet, Nicolas Auguste, Pierre Krolak-Salmon, the LACMé group, Bernard Laurent, Jean-Michel Dorey
Personality Modulates the Efficacy of Art Intervention on Chronic Pain in a Population of Patients with Alzheimer's Disease
Abstract: Background: Alzheimer's disease (AD) mainly occurs in elderly individuals. Comorbidities and chronic pain are frequent in this population. Previous studies revealed that personality modulates both chronic pain (CP) and AD occurrence and evolution. Moreover, as pain treatments can induce side-effects, non-drugs treatments, such as art interventions, are interesting alternative therapies for decreasing CP in these patients. Objective: Our aim was to assess the potential role of personality traits on art intervention efficacy for reducing CP in a population of patients with mild AD. Methods: Design: multicenter randomized controlled trial. Fifty mild AD patients underwent a 12-week art intervention including singing and painting groups. Personality was assessed with the Big Five Inventory before the sessions. CP was measured with Numeric Rating Scale (NRS) [Usual pain (NRS-U) and most Intense pain (NRS-I)], Simple Visual Scale [Usual pain (SVS-U) and most Intense pain (SVS-I)] and Brief Pain Inventory (BPI) before and after the sessions. The influence of personality traits on CP evolution before and after art intervention was assessed with multiple linear regression models. Results: A positive association was observed between neuroticism and the evolution of three CP measures including NRS-U (B=0.34, p=0.01), SVS-U (B=0.20, p=0.04), and BPI-U (B=0.46, p=0.02) evolution. No significant relationship was observed between neuroticism and NRS-I, SVS-I and BPI-R evolution. Conclusion: Our findings suggest that neuroticism can decrease the efficacy of group art intervention on pain in patients with mild AD. Individual therapies could be more appropriate for these patients. These results emphasize the interest of taking into account patients' personality before proposing them to participate to a group therapy.

Pages 625-633
Daniela Andriuta, Martine Roussel, Mélanie Barbay, Sandrine Despretz-Wannepain, Olivier Godefroy, GRECogVASC study group
Differentiating between Alzheimer's Disease and Vascular Cognitive Impairment: Is the "Memory Versus Executive Function" Contrast Still Relevant?
Abstract: Background: The contrast between memory versus executive function impairments is commonly used to differentiate between neurocognitive disorders (NCDs) due to Alzheimer's disease (AD) and vascular cognitive impairment (VCI). We reconsidered this question because of the current use of AD biomarkers and the recent revision of the criteria for AD, VCI, and dysexecutive syndrome. Objective: To establish and compare the neuropsychological profiles in AD (i.e., with positive CSF biomarkers) and in VCI. Methods: We included 62 patients with mild or major NCDs due to pure AD (with positive CSF biomarker assays), and 174 patients (from the GRECogVASC cohort) with pure VCI. The neuropsychological profiles were compared after stratification for disease severity (mild or major NCD). We defined a memory-executive function index (the mean z score for the third free recall and the delayed free recall in the Free and Cued Selective Reminding Test minus the mean z score for category fluency and the completion time in the Trail Making Test part B) and determined its diagnostic accuracy. Results: Compared with VCI patients, patients with AD had significantly greater memory impairments (p=0.001). Executive function was impaired to a similar extent in the two groups (p=0.11). Behavioral executive disorders were more prominent in the AD group (p=0.001). Although the two groups differed significant with regard to the memory-executive function index (p<0.001), the latter's diagnostic accuracy was only moderate (sensitivity: 63%, specificity: 87%). Conclusion: Although the contrast between memory and executive function impairments was supported at the group level it does not reliably discriminate between AD and VCI at the individual level.

Pages 635-644
Mi-Young Kim*, Yoojin Noh*, Sang Joon Son, Sooyoung Shin, Hee-Young Paik, Sukhyang Lee, Yi-Sook Jung (Handling Associate Editor: Chaeyoung Lee) *These two authors contributed equally to this work.
Effect of Cilostazol on Incident Dementia in Elderly Men and Women with Ischemic Heart Disease
Abstract:> Background: Ischemic heart disease (IHD) is associated with cognitive decline and may contribute to an increased risk of dementia. Objective: The goal of the present study was to investigate whether cilostazol use is associated with a lower risk of incident dementia in Asian patients with IHD, and whether these effects differed based on sex. Methods: This retrospective cohort study was performed using the Korean National Insurance Claim Data of the Health Insurance Review and Assessment Service; the duration of the study was from January 1, 2007 to December 31, 2015. The study group comprised 66,225 patients with IHD, aged >65 years, who had received cilostazol. Age- and sex-matched IHD patients without cilostazol exposure were selected as the control group. The risk of dementia was compared between the cilostazol and control groups. Results: Compared to the control group, total cilostazol users had a marginally significant lower risk of incident dementia. After stratification by sex, the reducing effect of cilostazol on incident dementia was significant in female participants, but not in male participants. Female patients who had cilostazol for over 2 years showed a clinically meaningful preventive effect (HR, 0.85; 95% CI, 0.82-0.88). Conclusions: This study suggested that cilostazol treatment may reduce the risk of incident dementia in Korean patients with IHD. Its beneficial effect was remarkably significant in female patients who received cilostazol for over a 2-year period.

Pages 645-654
Brandon C. Henley, Mahsa Shokouhi, Anushree Y. Mahajan, Omer T. Inan, Ihab Hajjar
Cardiovascular Response to Mental Stress in Mild Cognitive Impairment and its Association with Cerebral Perfusion
Abstract: Mental stress has been linked to various chronic diseases including Alzheimer's disease, but the mechanisms underlying cognitive decline with mental stress are unknown. Reduced cardiovascular response to stress is associated with cardiovascular disease, and the latter is associated with cognitive impairment. We measured electrodermal activity, blood pressure, and cardiac hemodynamics in cognitively normal and mild cognitive impairment (MCI) adults (n = 76, mean age = 58 years, 46% MCI) during rest, a math test, and face-name recall tasks to derive the following cardiovascular indicators: mean arterial pressure, heart rate, stroke volume and cardiac output. These indicators were compared between the two groups. Cerebral blood perfusion via arterial spin-labeling MRI was measured in a subgroup who underwent an MRI scan (n = 30). Following exposure to mental stress, a decrease in stroke volume (p = 0.024) and cardiac output (p = 0.005) was found in the MCI group, but an increase in both parameters in the cognitively normal group. This difference was largest during face-name recall (standardized difference in stroke volume = -0.50, p = 0.029, and in cardiac output = -0.52, p = 0.023). Cardiac output during mental stress, but not at rest, decreased with cerebral perfusion (normal: p = 0.078, β = 1.97, R2 = 0.090; MCI: p = 0.007, β = 2.02, R2 = 0.008). No significant difference was found between the two groups at rest. This preliminary study suggests that individuals with MCI have an insufficient cardiac output, and in turn lower cerebral perfusion in response to mental stress.

Pages 655-664
Sevil Yasar, Vijay R. Varma, Gregory C. Harris, Michelle C. Carlson
Associations of Angiotensin Converting Enzyme-1 and Angiotensin II Blood Levels and Cognitive Function
Abstract: Background: Emerging evidence suggests a possible role of the renin angiotensin system in the pathophysiologic process of Alzheimer's disease, of which angiotensin converting enzyme-1 (ACE-1) and angiotensin II (ANGII) are important proteins. Few studies evaluated associations between blood ACE-1 and none between ANGII levels, and cognition. Objective: Our pilot study was aimed to examine associations between blood ACE-1 and ANG II levels and cognitive function in non-demented participants at baseline and over a 1-year period. Methods: 56 participants were included from the Brain Health Substudy of the Baltimore Experience Corps Study. Linear regression analysis, adjusting for confounders, was used to determine associations between baseline ACE-1 and ANGII, and baseline and 1-year follow-up measures of psychomotor and processing speed, executive function, verbal learning memory and working memory, and whether these associations were mediated by blood pressure. Results: Participants were predominantly female (75%), African-American (93%), with mean age of 67.8 years and education of 14.3 years. There were no associations between baseline ACE-1 or ANGII levels and cognitive function; however, there were significant association between baseline ACE-1 levels and 1-year follow-up Trail Making Test, Part A (β=0.003, p=0.04) and Digit Span (β=-0.001, p=0.02). Conclusions: In this cognitively intact sample, elevated ACE-1 levels were associated with worse processing speed and working memory after 1 year. Findings from this pilot study suggest that changes in the RAS are associated with alterations in cognitive function warranting further assessment of the role of RAS in neurodegenerative disorders.

Pages 665-674
Sarah Gourmaud, Priscilla Thomas, Sylvie Thomasseau, Marion Tible, Claire Abadie, Claire Paquet, Jacques Hugon
Brimapitide Reduced Neuronal Stress Markers and Cognitive Deficits in 5XFAD Transgenic Mice
Abstract: Alzheimer's disease (AD) is characterized by accumulations of amyloid-β (Aβ42) and hyperphosphorylated tau proteins, associated with neuroinflammation, synaptic loss, and neuronal death. Several studies indicate that c-Jun N-terminal kinase (JNK) is implicated in the pathological features of AD. We have investigated in 5XFAD mice, the therapeutic effects of Brimapitide, a JNK-specific inhibitory peptide previously tested with higher concentrations in another AD model (TgCRND8). Three-month-old 5XFAD and wild-type littermate mice were treated by intravenous injections of low doses (10 mg/kg) of Brimapitide every 3 weeks, for 3 or 6 months (n=6-9 per group). Cognitive deficits and brain lesions were assessed using Y-maze, fear-conditioning test, and histological and biochemical methods. Chronic treatment of Brimapitide for 3 months resulted in a reduction of Aβ plaque burden in the cortex of 5XFAD treated mice. After 6 months of treatment, cognitive deficits were reduced but also a significant reduction of cell death markers and the pro-inflammatory IL-1β cytokine in treated mice were detected. The Aβ plaque burden was not anymore modified by the 6 months of treatment. In addition to modulating cognition and amyloid plaque accumulation, depending on the treatment duration, Brimapitide seems experimentally to reduce neuronal stress in 5XFAD mice.

Pages 675-687
Petra Heymann, Regine Gienger, Andreas Hett, Stephan Müller, Christoph Laske, Sibylle Robens, Thomas Ostermann, Ulrich Elbing (Handling Associate Editor: Amy Clements-Cortes)
Early Detection of Alzheimer's Disease Based on the Patient's Creative Drawing Process: First Results with a Novel Neuropsychological Testing Method
Abstract: Based on the knowledge of art therapy, we developed a new neuropsychological drawing test in order to identify individuals with mild cognitive impairment (MCI) as well as dementia patients and healthy controls (HC). By observing a variety of drawing characteristics of 92 participants with a mean age of 67.7, art therapy and dementia experts discriminate HC from MCI, early dementia of the Alzheimer-type (eDAT), and moderate dementia of the Alzheimer-type (mDAT) by the process analysis of tree drawings on a digitizing tablet. The art therapist's average categorical rating of healthy and MCI or demented individuals matched the clinical diagnosis by 88%. In a first small study, we analyzed interrater reliability, sensitivity, specificity, negative and positive predicted values of our tree drawing test (TDT) in comparison with the clock drawing test (CDT). Similar values of moderate interrater reliability were found for the TDT (0.56) as well as for the CDT (0.54). A significant high sensitivity of 0.9 within this binary impairment scale (HC versus impaired or demented) can be demonstrated. Substantial values for the specificity (0.67) could be obtained that however remain under a perfect value of the CDT (1.0). Considering 31 individuals that received the clinical diagnosis "impaired or demented" the TDT shows a higher recognition rate for the MCI group than the CDT. Furthermore in 8 of 12 borderline cases of clinical diagnosis, the outcome of the TDT diagnosis was consistent with the final clinical result.

Pages 689-703
Fenglei Chao, Lin Jiang, Yi Zhang, Chunni Zhou, Lei Zhang, Jing Tang, Xin Liang, Yingqiang Qi, Yanqing Zhu, Jing Ma, Yong Tang
Stereological Investigation of the Effects of Treadmill Running Exercise on the Hippocampal Neurons in Middle-Aged APP/PS1 Transgenic Mice
Abstract: The risk of cognitive decline during Alzheimer's disease (AD) can be reduced if physical activity is maintained; however, the specific neural events underlying this beneficial effect are still uncertain. To quantitatively investigate the neural events underlying the effect of running exercise on middle-aged AD subjects, 12-month-old male APP/PS1 mice were randomly assigned to a control group or running group, and age-matched non-transgenic littermates were used as a wild-type group. AD running group mice were subjected to a treadmill running protocol (regular and moderate intensity) for four months. Spatial learning and memory abilities were assessed using the Morris water maze. Hippocampal amyloid plaques were observed using Thioflavin S staining and immunohistochemistry. Hippocampal volume, number of neurons, and number of newborn cells (BrdU+ cells) in the hippocampus were estimated using stereological techniques, and newborn neurons were observed using double-labelling immunofluorescence. Marked neuronal loss in both the CA1 field and dentate gyrus (DG) and deficits in both the neurogenesis and survival of new neurons in the DG of middle-aged APP/PS1 mice were observed. Running exercise could improve the spatial learning and memory abilities, reduce amyloid plaques in the hippocampi, delay neuronal loss, induce neurogenesis, and promote the survival of newborn neurons in the DG of middle-aged APP/PS1 mice. Exercise-induced protection of neurons and adult neurogenesis within the DG might be part of the important structural basis of the improved spatial learning and memory abilities observed in AD mice.

Pages 705-723
Juan M. Zolezzi, Carolina B. Lindsay, Felipe G. Serrano, Roxana C. Ureta, Cristina Theoduloz, Guillermo Schmeda-Hirschmann, Nibaldo C. Inestrosa
Neuroprotective Effects of Ferruginol, Jatrophone, and Junicedric Acid Against Amyloid-β Injury in Hippocampal Neurons
Abstract: Soluble amyloid-β (Aβ) oligomers have been recognized as early neurotoxic intermediates with a key role in the synaptic dysfunction observed in Alzheimer's disease (AD). Aβ oligomers block hippocampal long-term potentiation (LTP) and impair rodent spatial memory. Additionally, the presence of Aβ oligomers is associated with imbalanced intracellular calcium levels and apoptosis in neurons. In this context, we evaluated the effects of three diterpenes (ferruginol, jatrophone, and junicedric acid) that are found in medicinal plants and have several forms of biological activity. The intracellular calcium levels in hippocampal neurons increased in the presence of ferruginol, jatrophone, and junicedric acid, a result that was consistent with the observed increase in CA1 synaptic transmission in mouse hippocampal slices. Additionally, assays using Aβ peptide demonstrated that diterpenes, particularly ferruginol, restore LTP and reduce apoptosis. Recovery of the Aβ oligomer-induced loss of the synaptic proteins PSD-95, synapsin, VGlut, and NMDA receptor subunit 2A was observed in mouse hippocampal slices treated with junicedric acid. This cascade of events may be associated with the regulation of kinases, e.g., protein kinase C (PKC) and calcium/calmodulin-dependent protein kinase II (CaMKII), in addition to the activation of the canonical Wnt signaling pathway and could thus provide protection against Aβ oligomers, which trigger synaptic dysfunction. Our results suggest a potential neuroprotective role for diterpenes against the Aβ oligomers-induced neurodegenerative alterations, which make them interesting molecules to be further studied in the context of AD.

Pages 725-740
Bardia Nouriziabari, Susmita Sarkar, Stephanie E. Tanninen, Robert D. Dayton, Ronald L. Klein, Kaori Takehara-Nishiuchi (Handling Associate Editor: Claudio Babiloni)
Aberrant Cortical Event-Related Potentials During Associative Learning in Rat Models for Presymptomatic Stages of Alzheimer's Disease
Abstract: Trace eyeblink conditioning is a hippocampus-dependent associative learning paradigm which is impaired in patients with Alzheimer's disease (AD) and animal AD models. Learning in this paradigm accompanies changes in oscillatory activity in forebrain regions, some of which are loci of pathogenic changes in prodromal AD stages. These observations motivated us to examine how cortical event-related potentials (ERPs) during this paradigm are affected by two features of the asymptomatic, AD-related brain abnormality, entorhinal tau accumulation and mild cholinergic deficit. Adult rats received viral overexpression of P301L mutant human tau in the entorhinal cortex, low-dose scopolamine treatment, or both. Electroencephalograms were recorded with epidural electrodes on the surface of the frontal, parietal, and temporal cortices during differential and reversal trace eyeblink conditioning. All rats developed conditioned responses to one of two stimuli (auditory or visual) paired with mild eyelid shock (CS+), but not to the other stimulus presented alone (CS-). They were also able to adjust the response when the stimulus contingency was reversed. With learning, the amplitude of several ERP components in the frontal and temporal cortices came to differentiate the CS+ from CS-. Scopolamine affected the learning-related change in temporal P2 and other learning-unrelated components in three regions. Entorhinal tau overexpression primary affected the amplitude of temporal visual ERPs and learning-unrelated frontal and temporal auditory ERP components. The double manipulation only affected two components of temporal auditory ERPs. Thus, cortical ERPs during differential associative learning are sensitive to asymptomatic brain abnormality associated with AD.

Pages 741-760
Joeke van Santen, Rose-Marie Dröes, Marije Holstege, Olivier Blanson Henkemans, Annelies van Rijn, Ralph de Vries, Annemieke van Straten, Franka Meiland (Handling Associate Editor: Peter Whitehouse)
Effects of Exergaming in People with Dementia: Results of a Systematic Literature Review
Abstract: Background: Physical exercise benefits functioning, health, and well-being. However, people living with dementia in particular hardly engage in exercise. Exergaming (exercise and gaming) is an innovative, fun, and relatively safe way of exercising in a virtual reality or gaming environment. It may help people living with dementia overcome barriers they can experience regarding regular exercise activities. Objective: This systematic literature review aims to provide an overview of the cost-effectiveness of exergaming and its effects on physical, cognitive, emotional, and social functioning, as well as the quality of life in people living with dementia. Methods: PubMed, Embase, Cinahl, PsycINFO, the Cochrane Library, and the Web of Science Core Collection were searched. Selection of studies was carried out by at least two independent researchers. Results: Three studies were found to be eligible and were included in this review. Two of these showed some statistically significant effects of exergaming on physical, cognitive, and emotional functioning in people living with dementia, although based on a very small sample. No articles were found about the cost-effectiveness of exergaming. Conclusion: Only a few controlled studies have been conducted into the effectiveness of exergaming, and these show very little significant benefits. More well-designed studies are necessary to examine the effects of exergaming.

Pages 761-772
Mengzhu Li, Enjie Liu, Qiuzhi Zhou, Shihong Li, Xin Wang, Yanchao Liu, Lin Wang, Dongsheng Sun, Jinwang Ye, Yuan Gao, Xifei Yang, Jianjun Liu, Ying Yang, Jian-Zhi Wang
TRPC1 Null Exacerbates Memory Deficit and Apoptosis Induced by Amyloid-β
Abstract:The transient receptor potential cation (TRPC) channels are widely expressed in nervous system but their functions remain largely unclear. Here, we found that TRPC1 deletion did not affect learning and memory in physiological conditions, while it aggravated learning and memory deficits induced by amyloid-β (Aβ), the major component of the senile plaques observed in the brains of Alzheimer's disease (AD). Further studies demonstrated that TRPC1 deletion did not affect cell apoptosis in physiological condition, but it exacerbated the Aβ-induced cell death in mouse hippocampus. Moreover, the level of TRPC1 was decreased in AD cell and mouse models, and upregulation of TRPC1 decreased Aβ levels with attenuation of apoptosis in the cells stably overexpressing amyloid-β protein precursor (AβPP). Finally, the transmembrane domain of TRPC1 could bind to AβPP and thus decreased Aβ production. These findings indicate that loss of TRPC1 exacerbates Aβ-induced memory deficit and cell apoptosis, though it does not impair cognitive function or induce cell death in physiological conditions.

Pages 773-781
Jen-Hung Wang, Ya-Ju Wu, Boon Lead Tee, Raymond Y. Lo (Handling Associate Editor: Anne Fink)
Medical Comorbidity in Alzheimer's Disease: A Nested Case-Control Study
Abstract: Background: Little is known about the distribution of medical comorbidities in Alzheimer's disease (AD). Objective: We aimed to describe the comorbidity pattern of AD in a nested case-control study. Methods: Incident AD cases were identified by International Classification of Diseases codes in a random sample of 2 million individuals in Taiwan National Health Insurance program during 2001-2011. We further restricted cases to those treated with AD drugs of approved reimbursement. We sampled a set of age- and sex-matched control subjects (2: 1 ratio) and employed conditional logistic regression to estimate the associations between pre-specified 14 comorbidities and AD. The clusters of multiple chronic diseases were then identified by exploratory factor analysis. Results: A total of 2,618 AD cases were identified during 2001-2011 with a mean age of 76.1 years and female preponderance (59%). The most common 5 comorbidities in AD were hypertension (55.1%), osteoarthritis (38.2%), depression (32.3%), diabetes mellitus (DM) (25.7%), and cerebrovascular disease (CVD) (22.7%). After adjusting for age and sex, DM, osteoporosis, depression, and CVD were significantly associated with AD. The number of comorbidity was 3-fold greater in the AD group. The cluster of hypertension, DM, and hyperlipidemia was the most common combination in old age, whereas the cluster osteoarthritis and osteoporosis was the only multimorbidity pattern significantly associated with AD. Conclusion: Multimorbidity is common in AD. Depression, CVD, osteoporosis, and DM are associated with incident AD, supporting that their co-existence is a typical feature of AD at old age. Comorbidity care should be integrated into current management for patients with AD.

Pages 783-796
Enrico R. Fantoni, Anastasia Chalkidou, John T. O' Brien, Gill Farrar, Alexander Hammers (Handling Associate Editor: Kerryn Pike)
A Systematic Review and Aggregated Analysis on the Impact of Amyloid PET Brain Imaging on the Diagnosis, Diagnostic Confidence, and Management of Patients being Evaluated for Alzheimer's Disease
Abstract: Background: Amyloid PET (aPET) imaging could improve patient outcomes in clinical practice, but the extent of impact needs quantification. Objective: To provide an aggregated quantitative analysis of the value added by aPET in cognitively impaired subjects. Methods: Systematic literature searches were performed in Embase and Medline until January 2017. 1,531 cases over 12 studies were included (1,142 cases over seven studies in the primary analysis where aPET was the key biomarker; the remaining cases included as defined groups in the secondary analysis). Data was abstracted by consensus among two observers and assessed for bias. Clinical utility was measured by diagnostic change, diagnostic confidence, and patient management before and after aPET. Three groups were further analyzed: control patients for whom feedback of aPET scan results was delayed; aPET Appropriate Use Criteria (AUC+) cases; and patients undergoing additional FDG/CSF testing. Results: For 1,142 cases with only aPET, 31.3% of diagnoses were revised, whereas 3.2% of diagnoses changed in the delayed aPET control group (p<0.0001). Increased diagnostic confidence following aPET was found for 62.1% of 870 patients. Management changes with aPET were found in 72.2% of 740 cases and in 55.5% of 299 cases in the control group (p<0.0001). The diagnostic value of aPET in AUC+ patients or when FDG/CSF were additionally available did not substantially differ from the value of aPET alone in the wider population. Conclusions: Amyloid PET contributed to diagnostic revision in almost a third of cases and demonstrated value in increasing diagnostic confidence and refining management plans.

Pages 797-819
Alain D. Dekker, Silvia Sacco, Angelo Carfi, Bessy Benejam, Yannick Vermeiren, Gonny Beugelsdijk, Mieke Schippers, Lyanne Hassefras, José Eleveld, Sharina Grefelman, Roelie Fopma, Monique Bomer-Veenboer, Mariángeles Boti, G. Danielle E. Oosterling, Esther Scholten, Marleen Tollenaere, Laura Checkley, André Strydom, Gert Van Goethem, Graziano Onder, Rafael Blesa, Christine zu Eulenburg, Antonia M.W. Coppus, Anne-Sophie Rebillat, Juan Fortea, Peter P. De Deyn (Handling Associate Editor: Elizabeth Head)
The Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) Scale: Comprehensive Assessment of Psychopathology in Down Syndrome
Abstract: People with Down syndrome (DS) are prone to develop Alzheimer's disease (AD). Behavioral and psychological symptoms of dementia (BPSD) are core features, but have not been comprehensively evaluated in DS. In a European multidisciplinary study, the novel Behavioral and Psychological Symptoms of Dementia in Down Syndrome (BPSD-DS) scale was developed to identify frequency and severity of behavioral changes taking account of life-long characteristic behavior. 83 behavioral items in 12 clinically defined sections were evaluated. The central aim was to identify items that change in relation to the dementia status, and thus may differentiate between diagnostic groups. Structured interviews were conducted with informants of persons with DS without dementia (DS, n=149), with questionable dementia (DS+Q, n=65), and with diagnosed dementia (DS+AD, n=67). First exploratory data suggest promising interrater, test-retest, and internal consistency reliability measures. Concerning item relevance, group comparisons revealed pronounced increases in frequency and severity in items of anxiety, sleep disturbances, agitation and stereotypical behavior, aggression, apathy, depressive symptoms, and eating/drinking behavior. The proportion of individuals presenting an increase was highest in DS+AD, intermediate in DS+Q, and lowest in DS. Interestingly, among DS+Q individuals, a substantial proportion already presented increased anxiety, sleep disturbances, apathy, and depressive symptoms, suggesting that these changes occur early in the course of AD. Future efforts should optimize the scale based on current results and clinical experiences, and further study applicability, reliability, and validity. Future application of the scale in daily care may aid caregivers to understand changes, and contribute to timely interventions and adaptation of caregiving.

Pages 821-833
Gustavo Basurto-Islas*, Jin-hua Gu*, Yunn Chyn Tung, Fei Liu, Khalid Iqbal *These authors contributed equally this work.
Mechanism of Tau Hyperphosphorylation Involving Lysosomal Enzyme Asparagine Endopeptidase in a Mouse Model of Brain Ischemia
Abstract: Dementias including Alzheimer's disease (AD) are multifactorial disorders that involve several different etiopathogenic mechanisms. Cerebral ischemia has been suspected in the altered regulation of protein kinases and phosphatases that leads to hyperphosphorylation of tau and further neurofibrillary pathology, a key hallmark of AD and related neurodegenerative diseases. However, the deregulation of these enzymes and their relationship with ischemia and AD remain unclear. Previously, we reported a mechanism by which the lysosomal enzyme asparagine endopeptidase (AEP) is associated with brain acidosis and AD. In this study, we subjected mice to middle cerebral artery occlusion and found that compared with wild type mice, the ischemia-induced brain injury and motor deficit in AEP-knockout mice are reduced, probably because ischemia activates AEP. AEP cleaves inhibitor 2 of protein phosphatase 2A (I2PP2A), which translocates from the neuronal nucleus to the cytoplasm and produces hyperphosphorylation of tau through inhibition of PP2A. These findings suggest a possible mechanism of tau pathology associated with ischemia.

Pages 835-845
Jiaqi Wang*, Yang Yuan*, Rongrong Cai, Rong Huang, Sai Tian, Hongyan Lin, Dan Guo, Shaohua Wang *These authors contributed equally to this work.
Association between Plasma Levels of PAI-1, tPA/PAI-1 Molar Ratio, and Mild Cognitive Impairment in Chinese Patients with Type 2 Diabetes Mellitus
Abstract: Background: Plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) are involved in the complications of type 2 diabetes mellitus (T2DM) and early pathology of Alzheimer's disease. Objective: This study aimed to investigate the association between plasma PAI-1, tPA/PAI-1 molar ratio, and mild cognitive impairment (MCI) in Chinese T2DM patients. Methods: A total of 162 Chinese T2DM patients were recruited and divided into two groups according to the Montreal Cognitive Assessment score. Demographic data were collected, plasma PAI-1 and tPA levels were measured through enzyme-linked immunosorbent assay, tPA/PAI-1 molar ratio was calculated, and neuropsychological test results were examined. The association between PAI-1, tPA/PAI-1 molar ratio, and cognition was analyzed. Results: There were 66 diabetic MCI patients and 96 healthy cognition participants (controls). T2DM patients with MCI displayed significantly increased plasma PAI-1 levels (p = 0.016) and decreased tPA/PAI-1 molar ratio (p = 0.021) compared with the controls. High PAI-1 levels and low tPA/PAI-1 molar ratio were associated with MCI in T2DM patients, e.g., plasma level of PAI-1 were negatively correlated (r = −0.343, p = 0.007) with logic memory in T2DM patients with MCI. Linear regression analysis further revealed that PAI-1 concentration was an independent factor of diabetic MCI (p = 0.001). Conclusions: High PAI-1 levels and low tPA/PAI-1 molar ratio were significantly correlated with T2DM-associated cognitive impairment, especially memory function, in Chinese patients.

Pages 847-860
Aristo Vojdani, Elroy Vojdani, Evan Saidara, Datis Kharrazian
Reaction of Amyloid-β Peptide Antibody with Different Infectious Agents Involved in Alzheimer's Disease
Abstract: As early as the 1980s, molecular virologist Ruth Itzhaki began to investigate if there was a causal connection between infections and neurodegenerative disorder. Although the theory has yet to be universally embraced, in 2016 Itzhaki and 33 other scientists from all over the world published a review article in this very journal presenting evidence for the causal role of pathogens in Alzheimer's disease (AD). Exactly how and in what way pathogens affect the induction of AD has yet to be determined, but one possible answer may involve the cross-reactivity of different pathogens with amyloid-β (Aβ). Aβ autoantibodies have been detected in the serum and cerebrospinal fluid of AD patients and in some healthy individuals. In the present study our major goal was to investigate whether antibodies made against Aβ would react both with other brain proteins as well as pathogens associated with AD as a result of molecular mimicry or the binding of bacterial toxins to Aβ42. Our study used a specific monoclonal antibody made against Aβ42, which not only reacted strongly with Aβ42, tau protein, and -synuclein, but also had from weak to strong reactions with 25 different pathogens or their molecules, some of which have been associated with AD. The homology between peptide stretches of microbial origin and proteins involved in AD could be a mechanism by which antibodies to homologous peptides mount attacks against autoantigens in AD. We concluded that bacterial molecules bind to Aβ protein, forming small oligomers, then encasing pathogens and their molecules to form amyloid plaques, the tell-tale markers of AD. Conversely, these same Aβ peptides induce the production of antibodies to both Aβ42 and bacterial molecules, which may inhibit bacterial pathogenesis, but in the process may promote amyloid plaque formation.

Pages 861-869
Masataka Wada, Yoshihiro Noda, Shunichiro Shinagawa, Jun Ku Chung, Kyosuke Sawada, Kamiyu Ogyu, Ryosuke Tarumi, Sakiko Tsugawa, Takahiro Miyazaki, Bun Yamagata, Ariel Graff-Guerrero, Masaru Mimura, Shinichiro Nakajima, for the Alzheimer's Disease Neuroimaging Initiative
Effect of Education on Alzheimer's Disease-Related Neuroimaging Biomarkers in Healthy Controls, and Participants with Mild Cognitive Impairment and Alzheimer's Disease: A Cross-Sectional Study
Abstract: Background: Cognitive reserve is the acquired capacity reflecting a functional brain adaptability/flexibility in the context of aging. Educational attainment is thought to be among the most important factors that contribute to cognitive reserve. Objective: The aim of this study is to investigate the relationships among duration of education and Alzheimer's disease (AD) related neuroimaging biomarkers such as amyloid-β deposition, glucose metabolism, and brain volumes in each stage of AD. Methods: We reanalyzed a part of the datasets of the Alzheimer's Disease Neuroimaging Initiative. Participants were between 55 and 90 years of age and diagnosed as one of the following: healthy controls (HC), mild cognitive impairment (MCI), or AD. Multiple regression analyses were conducted to examine the relationships among duration of education and amyloid-β deposition (n=825), brain metabolism (n=1,304), and brain volumes (n=1,606) among three groups using data for 18F-Florbetapir (AV-45) imaging, fludeoxyglucose (FDG) positron emission tomography, and T1-weighted magnetic resonance imaging. Results: Duration of education had no correlations with amyloid-β deposition or brain metabolism in any groups. However, duration of education was positively associated with the total brain volume only in participants with MCI. Conclusions: Our findings suggest that education may exert a protective effect on total brain volume in the MCI stage but not in HC or AD. Thus, education may play an important role in preventing the onset of dementia through brain reserve in MCI.