Volume 67, Number 2, 2019

Pages 425-446

Iris Escobar, Jing Xu, Charles W. Jackson, Miguel A. Perez-Pinzon (Handling Associate Editor: K.S. Jagannatha Rao)
Altered Neural Networks in the Papez Circuit: Implications for Cognitive Dysfunction after Cerebral Ischemia
Abstract: Cerebral ischemia remains a leading cause of mortality worldwide. Although the incidence of death has decreased over the years, surviving patients may suffer from long-term cognitive impairments and have an increased risk for dementia. Unfortunately, research aimed toward developing therapies that can improve cognitive outcomes following cerebral ischemia has proved difficult given the fact that little is known about the underlying processes involved. Nevertheless, mechanisms that disrupt neural network activity may provide valuable insight, since disturbances in both local and global networks in the brain have been associated with deficits in cognition. In this review, we suggest that abnormal neural dynamics within different brain networks may arise from disruptions in synaptic plasticity processes and circuitry after ischemia. This discussion primarily concerns disruptions in local network activity within the hippocampus and other extra-hippocampal components of the Papez circuit, given their role in memory processing. However, impaired synaptic plasticity processes and disruptions in structural and functional connections within the Papez circuit have important implications for alterations within the global network, as well. Although much work is required to establish this relationship, evidence thus far suggests there is a link. If pursued further, findings may lead toward a better understanding of how deficits in cognition arise, not only in cerebral ischemia, but in other neurological diseases as well.

Pages 447-467

Rudy J. Castellani, George Perry (Handling Editor: Massimo Tabaton)
Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges
Abstract: There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau’s binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the “tau prion”. Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.

Pages 469-480

John W. Wright, Joseph W. Harding
Contributions by the Brain Renin-Angiotensin System to Memory, Cognition, and Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive neuron losses in memory-associated brain structures that rob patients of their dignity and quality of life. Five drugs have been approved by the FDA to treat AD but none modify or significantly slow disease progression. New therapies are needed to delay the course of this disease with the ultimate goal of preventing neuron losses and preserving memory functioning. In this review we describe the renin-angiotensin II (AngII) system (RAS) with specific regard to its deleterious contributions to hypertension, facilitation of neuroinflammation and oxidative stress, reduced cerebral blood flow, tissue remodeling, and disruption of memory consolidation and retrieval. There is evidence that components of the RAS, AngIV and Ang(1-7), are positioned to counter such damaging influences and these systems are detailed with the goal of drawing attention to their importance as drug development targets. Ang(1-7) binds at the Mas receptor, while AngIV binds at the AT4 receptor subtype, and these receptor numbers are significantly decreased in AD patients, accompanied by declines in brain aminopeptidases A and N, enzymes essential for the synthesis of AngIV. Potent analogs may be useful to counter these changes and facilitate neuronal functioning and reduce apoptosis in memory associated brain structures of AD patients.

Pages 481-488
Short Communication

Patrick Oeckl, Steffen Halbgebauer, Sarah Anderl-Straub, Petra Steinacker, André M. Huss, Hermann Neugebauer, Christine A.F. von Arnim, Janine Diehl-Schmid, Timo Grimmer, Johannes Kornhuber, Piotr Lewczuk, Adrian Danek, German Consortium for Frontotemporal Lobar Degeneration, Albert C. Ludolph, Markus Otto
Glial Fibrillary Acidic Protein in Serum Is Increased in Alzheimer’s Disease and Correlates with Cognitive Impairment
Abstract: Reliable blood biomarkers for Alzheimer’s disease (AD) are missing. We measured astroglial GFAP in patients with AD (n=28), frontotemporal dementia (bvFTD, n=35), Parkinson’s disease (n=11), Lewy body dementias (n=19), and controls (n=34). Serum GFAP was increased in AD (p < 0.001) and DLB/PDD (p < 0.01), and cerebrospinal fluid GFAP was increased in all neurodegenerative diseases (p < 0.001). Serum GFAP correlated with the Mini-Mental State Examination score (r=-0.42, p < 0.001) and might be a follow-up marker in clinical trials. Sensitivity and specificity of serum GFAP for AD versus bvFTD was 89% and 79% and might be the first blood biomarker in the differential diagnosis of AD and bvFTD.

Pages 489-493
Short Communication

Alar Kaskikallio, Mira Karrasch, Juha O. Rinne, Terhi Tuokkola, Riitta Parkkola, Petra Grönholm-Nyman
Cognitive Effects of White Matter Pathology in Normal and Pathological Aging
Abstract: We examined whether cerebrovascular white matter pathology is related to cognition as measured by the compound score of CERAD neuropsychological battery in cognitively normal older adults, patients with mild cognitive impairment, and patients with Alzheimer’s disease (total n=149), controlling for age and education. Trend-level effects of white matter pathology on cognition were only observed in patients with Alzheimer’s disease (p = 0.062, η2 = 0.052), patients with severe frontal white matter pathology performed notably worse than those with milder pathology. This indicates that frontal cerebrovascular pathology may have an additive negative effect on cognition in Alzheimer’s disease.

Pages 495-501

John Gallacher, Frederic de Reydet de Vulpillieres, Billy Amzal, Zuzanna Angehrn, Christin Bexelius, Christophe Bintener, Jacoline C. Bouvy, Laura Campo, Carlos Diaz, Jean Georges, Alastair Gray, Antje Hottgenroth, Pall Jonsson, Brent Mittelstadt, Michele H. Potashman, Catherine Reed, Cathie Sudlow, Robin Thompson, Antje Tockhorn-Heidenreich, Andrew Turner, Johan van der Lei, Pieter Jelle Visser and the ROADMAP Consortium (Handling Associate Editor: Lei Feng)
Challenges for Optimizing Real-World Evidence in Alzheimer’s Disease: The ROADMAP Project
Abstract: ROADMAP is a public-private advisory partnership to evaluate the usability of multiple data sources, including real-world evidence, in the decision-making process for new treatments in Alzheimer’s disease, and to advance key concepts in disease and pharmacoeconomic modeling. ROADMAP identified key disease and patient outcomes for stakeholders to make informed funding and treatment decisions, provided advice on data integration methods and standards, and developed conceptual cost-effectiveness and disease models designed in part to assess whether early treatment provides long-term benefit.

Pages 503-513
Shawn M. Barton, Vaibhav A. Janve, Richard McClure, Adam Anderson, Joanne A. Matsubara, John C. Gore, Wellington Pham
Lipopolysaccharide-Induced Opening of the Blood-Brain Barrier on Aging 5XFAD Mouse Model
Abstract: The development of neurotherapeutics for many neurodegenerative diseases has largely been hindered by limited pharmacologic penetration across the blood-brain barrier (BBB). Previous attempts to target and clear amyloid-β (Aβ) plaques, a key mediator of neurodegenerative changes in Alzheimer’s disease (AD), have had limited clinical success due to low bioavailability in the brain because of the BBB. Here we test the effects of inducing an inflammatory response to disrupt the BBB in the 5XFAD transgenic mouse model of AD. Lipopolysaccharide (LPS), a bacterial endotoxin recognized by the innate immune system, was injected at varying doses. 24 hours later, mice were injected with either thioflavin S, a fluorescent Aβ-binding small molecule or 30 nm superparamagnetic iron oxide (SPIO) nanoparticles, both of which are unable to penetrate the BBB under normal physiologic conditions. Our results showed that when pretreated with 3.0 mg/kg LPS, thioflavin S can be found in the brain bound to Aβ plaques in aged 5XFAD transgenic mice. Following the same LPS pretreatment, SPIO nanoparticles could also be found in the brain. However, when done on wild type or young 5XFAD mice, limited SPIO was detected. Our results suggest that the BBB in aged 5XFAD mouse model is susceptible to increased permeability mediated by LPS, allowing for improved delivery of the small molecule thioflavin S to target Aβ plaques and SPIO nanoparticles, which are significantly larger than antibodies used in clinical trials for immunotherapy of AD. Although this approach demonstrated efficacy for improved delivery to the brain, LPS treatment resulted in significant weight loss even at low doses, resulting from the induced inflammatory response. These findings suggest inducing inflammation can improve delivery of small and large materials to the brain for improved therapeutic or diagnostic efficacy. However, this approach must be balanced with the risks of systemic inflammation.

Pages 515-525
Lanxia Meng*, Mingyang He*, Min Xiong, Xingyu Zhang, Shuke Nie, Jing Xiong, Dan Hu, Zhaohui Zhang, Ling Mao, Zhentao Zhang *These authors contributed equally to this work.
2',3'-Dideoxycytidine, a DNA Polymerase-β Inhibitor, Reverses Memory Deficits in a Mouse Model of Alzheimer’s Disease
Abstract: The etiology and pathogenesis of Alzheimer’s disease (AD) are not fully understood. Thus, there are no drugs available that can provide a cure for it. We and others found that DNA polymerase-β (DNA pol-β) is required for neuronal death in several neurodegenerative models. In the present study, we tested the effect of a DNA pol-β inhibitor 2',3'-Dideoxycytidine (DDC) in AD models both in vitro and in vivo. DDC protected primary neurons from amyloid-β (Aβ)-induced toxicity by inhibiting aberrant DNA replication mediated by DNA pol-β. Chronic oral administration of DDC alleviated Aβ deposition and memory deficits in the Tg2576 mouse model of AD. Moreover, DDC reversed synaptic loss in Tg2576 mice. These results suggest that DDC represents a novel therapeutic agent for the treatment of AD.

Pages 527-539
Ina Zwingmann, Bernhard Michalowsky, Alexander Esser, Anika Kaczynski, Jessica Monsees, Armin Keller, Johannes Hertel, Diana Wucherer, Jochen René Thyrian, Tilly Eichler, Ingo Kilimann, Stefan Teipel, Adina Dreier-Wolfgramm, Wolfgang Hoffmann
Identifying Unmet Needs of Family Dementia Caregivers: Results of the Baseline Assessment of a Cluster-Randomized Controlled Intervention Trial
Abstract: Background: Caregivers providing informal care for people with dementia (PwD) often report unmet needs, burden, and health impairments. Optimal support for family dementia caregivers will likely benefit from better understanding and assessment of the prevalence and types of caregivers’ unmet needs and associated socio-demographic and clinical characteristics. Objective: The present study investigates 1) the number and types of caregivers’ unmet needs, 2) socio-demographic and clinical characteristics of both PwD and caregivers, and 3) caregivers’ burden and health-related outcomes that are related to caregivers’ unmet needs. Methods: The present analyses are based on cross-sectional data of n = 226 dyads of caregivers and their community-dwelling PwD participating in a comprehensive standardized, computer-based caregivers’ needs assessment within a general practitioner (GP)-based, cluster-randomized intervention trial. Results: A total of n = 505 unmet needs were identified for n = 171 caregivers from the intervention group at baseline. Only 24.3% caregivers reported no unmet need (n = 55), whereas 75.7% caregivers had at least one unmet need (n = 171). Caregivers had on average 2.19 unmet needs (mean = 2.19, SD = 2.15). Specifically, 53.1% of caregivers had one up to three unmet needs (n = 120), 18.6% (n = 42) had three up to six unmet needs, and 4.0% (n = 9) had more than six unmet needs. Discussion: Our results underline the importance of a comprehensive needs assessment for family dementia caregivers to develop and implement concepts that can provide family dementia caregivers with optimal support.

Pages 541-553
Charisse N. Winston, Brent Aulston, Edward M. Rockenstein, Anthony Adame, Olga Prikhodko, Kishan N. Dave, Priyanka Mishra, Robert A. Rissman, Shauna H. Yuan
Neuronal Exosome-Derived Human Tau Is Toxic to Recipient Mouse Neurons in vivo
Abstract: Progressive accumulation of aggregation-prone proteins, amyloid-β (Aβ) and hyperphosphorylated tau (p-tau), are the defining hallmarks of Alzheimer’s disease (AD). The mechanisms by which Aβ and p-tau are transmitted throughout the diseased brain are not yet completely understood. Interest in exosome research has grown dramatically over the past few years, specifically due to their potential role as biomarkers for staging of neurodegenerative diseases, including AD. Despite their diagnostic utility, the pathogenic potential of exosomes has yet to be fully elucidated. In this study, we use a series of recombinant tau antibodies to characterize a new model of human tau in vivo. Exosome suspensions derived from neuronally-differentiated, human induced pluripotent stem cells that express the repeat domain of tau P301L and V337M mutations (NiPSCEs) were injected into the wild-type mouse brain and pathological changes were characterized by immunostaining at one- (1m) and two-month (2m) post-injection. We found that tau inclusions were present throughout the brain at 2m post-injection, which were detectable using antibodies raised against full-length tau (K9JA) and misfolded tau (MC1). Furthermore, we found that phosphorylated tau immunoreactivity was elevated 1m post-injection, which was surprisingly normalized after 2m. Finally, we observed extensive degeneration of neuronal dendrites in both ipsilateral and contralateral hippocampi in NiPSCE treated mice. In summary, we demonstrate that exosomes are sufficient to cause long-distance propagation of tau pathology and neurodegeneration in vivo. These novel findings support an active role of exosomes in AD pathogenesis.

Pages 555-570
Martin R. Farlow, Richard E. Thompson, Lee-Jen Wei, Alan J. Tuchman, Elaine Grenier, David Crockford, Susanne Wilke, Daniel L. Alkon
A Randomized, Double-Blind, Placebo-Controlled, Phase II Study Assessing Safety, Tolerability, and Efficacy of Bryostatin in the Treatment of Moderately Severe to Severe Alzheimer’s Disease
Abstract: Background: Bryostatin-activated PKC epsilon pre-clinically induces synaptogenesis, anti-apoptosis, anti-amyloid-β oligomers, and anti-hyperphosphorylated tau. Objectives: To investigate bryostatin safety, tolerability, and efficacy to improve cognition in advanced Alzheimer’s disease (AD) patients. Methods: A double-blind, randomized, placebo-controlled Phase II, 12-week trial of i.v. bryostatin for 150 advanced AD patients (55-85) with MMSE-2 of 4-15, randomized 1:1:1 into 20 μg and 40 μg bryostatin, and placebo arms. The Full Analysis Set (FAS) and the Completer Analysis Set (CAS) were pre-specified alternative assessments (1-sided, p < 0.1 for primary efficacy, and 2-sided, p < 0.05 for pre-specified and post hoc exploratory analyses). Results: The safety profile was similar for 20 μg treatment and placebo patients. The 40 μg patients showed safety and drop-out issues, but no efficacy. Primary improvement of Severe Impairment Battery (SIB) scores at 13 weeks was not significant (p = 0.134) in the FAS, although in the CAS, the SIB comparison favored 20 μg bryostatin compared to placebo patients (p < 0.07). Secondary analyses at weeks 5 and 15 (i.e., 30 days post-final dosing) also favored 20 μg bryostatin compared to placebo patients. A pre-specified ANCOVA for baseline memantine blocking bryostatin and positive post-hoc trend analyses were statistically significant. Conclusion: Although the primary endpoint was not significant in the FAS, primary and secondary analyses in the CAS, and pre-specified exploratory analyses did favor bryostatin 20 μg compared to the placebo cohort. These promising Phase II results support further trials of 20 μg bryostatin—without memantine—to treat AD.

Pages 571-581
Yajun Zhou, Jiangshan Deng, Xiuli Chu, Yuwu Zhao, Yong Guo
Role of Post-Transcriptional Control of Calpain by miR-124-3p in the Development of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disease prevalent in aged people, clinically characterized by progressive memory loss, behavioral and learning dysfunction, and cognitive deficits. The pathogenesis of AD is hallmarked by formation of amyloid-β peptide aggregates (Aβ) and intraneuronal neurofibrillary tangles (NFTs), which are induced by hyperphosphorylation of amyloid-β protein precursor and tau protein, respectively. The hyperphosphorylation is controlled by cyclin-dependent kinase-5 (CDK5), the aberrant activation of which is mediated by calpain (CAPN)-induced cleavage of p35 into p25. However, the regulation of CAPN in AD remains largely unknow. Here, we studied the post-transcriptional control of CAPN1 by microRNAs (miRNAs) in the setting of AD. We found that miR-124-3p, previously reported as a miRNA that was downregulated in AD, was a CAPN1-targeting miRNA that functionally inhibited the protein translation of CAPN1 in a human neural cell line, HCN-2. In vitro, transfection with miR-124-3p reduced the levels of CAPN1 protein, the cleavage of p35 into p25, and cell apoptosis dose-dependently in HCN-2 cells. Moreover, a significant inverse correlation was detected between the levels of miR-124-3p and CAPN1 in AD specimens. Furthermore, intracranial injection of adeno-associated virus expressing miR-124-3p into APP/PS1-AD mice significantly reduced Aβ deposition and significantly improved the AD-mouse behavior in the social recognition test and plus-maze discriminative avoidance task. Together, our data suggest that post-transcriptional control of calpain by miR-124-3p plays an essential role in the development of AD.

Pages 583-619
Xi Chen, Brook Maguire, Henry Brodaty*, Fiona O’Leary* *Equal senior authors
Dietary Patterns and Cognitive Health in Older Adults: A Systematic Review
Abstract: While the role of diet and nutrition in cognitive health and prevention of dementia in older adults has attracted much attention, the efficacy of different dietary patterns remains uncertain. Previous reviews have mainly focused on the Mediterranean diet, but either omitted other dietary patterns, lacked more recent studies, were based on cross-sectional studies, or combined older and younger populations. We followed PRISMA guidelines, and examined the efficacy of current research from randomized controlled trials and cohort studies on the effects of different dietary patterns. We reviewed the Mediterranean diet, Dietary Approach to Stop Hypertension (DASH) diet, the Mediterranean-DASH diet Intervention for Neurodegenerative Delay (MIND) diet, Anti-inflammatory diet, Healthy diet recommended by guidelines via dietary index, or Prudent healthy diets generated via statistical approaches, and their impact on cognitive health among older adults. Of 38 studies, the Mediterranean diet was the most investigated with evidence supporting protection against cognitive decline among older adults. Evidence from other dietary patterns such as the MIND, DASH, Anti-inflammatory, and Prudent healthy diets was more limited but showed promising results, especially for those at risk of cardiovascular disease. Overall, this review found positive effects of dietary patterns including the Mediterranean, DASH, MIND, and Anti-inflammatory diets on cognitive health outcomes in older adults. These dietary patterns are plant-based, rich in poly- and mono-unsaturated fatty acids with lower consumption of processed foods. Better understanding of the underlying mechanisms and effectiveness is needed to develop comprehensive and practical dietary recommendations against age-related cognitive decline among older adult.

Pages 621-629
Yukako Takahashi, Satoshi Saito, Yumi Yamamoto, Toshiyuki Uehara, Chiaki Yokota, Go Sakai, Norifumi Nishida, Ryosuke Takahashi, Raj N. Kalaria, Kazunori Toyoda, Kazuyuki Nagatsuka, Masafumi Ihara (Handling Associate Editor: Robert Friedland)
Visually-Rated Medial Temporal Lobe Atrophy with Lower Educational History as a Quick Indicator of Amnestic Cognitive Impairment after Stroke
Abstract: Background: Time and resource limitations prevent cognitive assessment in acute-to-subacute settings, even in comprehensive stroke centers. Objective: To assess cognitive function in acute stroke patients undergoing routine clinical, laboratory, and radiological investigations, with a view to improving post-stroke care and treatment. Methods: Sixty-nine patients (72.6±11.1 years; 65% male) were prospectively enrolled within 14 days of acute ischemic stroke. Patients with altered consciousness, aphasia, or dysarthria were excluded. Clinical features including modified Rankin and NIH stroke scales, and vascular risk factors were assessed, as well as neuroimaging parameters by semi-quantitative evaluation of medial temporal lobe atrophy (MTLA) using MRA source images, FLAIR images for white matter changes (Fazekas scores), and T2* images for cerebral microbleeds. Neuropsychological screening was conducted using the Montreal Cognitive Assessment (MoCA) test. Univariate and multivariate analyses were used to evaluate the influence of variables on MoCA total and subscale scores. Results: Lower MoCA scores of 22 or less were associated with MTLA [OR (95%CI), 5.3 (1.0–27.5); p=0.045], education years [OR (95%CI), 0.71 (0.55–0.91); p=0.007], and modified Rankin scale at discharge [OR (95%CI), 2.4 (1.3–4.5); p=0.007]. The delayed recall MoCA score was correlated with MTLA (r=–0.452, p<0.001), periventricular (r=–0.273, p=0.024), and deep (r=–0.242, p=0.046), white matter changes. Conclusions: MTLA, together with lower educational history, are quick indicators of amnestic cognitive impairment after stroke. The association between cognitive impairment and physical disability at discharge may signify the importance of earlier cognitive assessment.

Pages 631-638
Daniel J. Levendowski, Charlene Gamaldo, Erik K. St. Louis, Luigi Ferini-Strambi, Joanne M. Hamilton, David Salat, Philip Westbrook, Chris Berka
Head Position during Sleep: Potential Implications for Patients with Neurodegenerative Disease
Abstract: Background: The characterization of sleep in those with neurodegenerative disease (NDD) is essential in understanding the potential neurobiological mechanisms that underlie the connection between sleep disruption and NDD manifestations and progression. Objective: Explore the inter-relationships between NDD and age, sex, diagnosis of obstructive sleep apnea, snoring, and duration of sleep time with the head in the supine and non-supine positions. Methods: A case-control design was used to evaluate differences in sleep position obtained from multi-night, in-home Sleep Profiler recordings in 45 patients with diagnosed NDD (24 with mild cognitive impairment, 15 with Alzheimer's disease, and 6 with Lewy Body, Parkinson's, or other dementias) and 120 age-sex matched controls with normal cognition (NC). Results: The frequency of supine sleep >2 h/night was significantly greater in the NDD than in the NC group (p<0.001, odds ratio=3.7), and remained significant after controlling for age, sex, snoring, and obstructive sleep apnea diagnosis (p=0.01). There were no group differences in nocturnal mobility i.e., number of head position changes/h. Conclusion: This study demonstrates the utility of in-home measurements of sleep in defining the association of supine sleep position with neurodegenerative disorders. Our findings warrant further investigation, particularly in light of the recent evidence suggesting that sleep may an active role in the brain’s ability to clear CNS neurotoxins and metabolites.

Pages 639-651
Payam Emami Khoonsari, Ganna Shevchenko, Stephanie Herman, Julia Remnestål, Vilmantas Giedraitis, RoseMarie Brundin, Malin Degerman Gunnarsson, Lena Kilander, Henrik Zetterberg, Peter Nilsson, Lars Lannfelt, Martin Ingelsson*, Kim Kultima* (Handling Associate Editor: Henrietta Nielsen) * These authors contributed equally to this work.
Improved Differential Diagnosis of Alzheimer’s Disease by Integrating ELISA and Mass Spectrometry-Based Cerebrospinal Fluid Biomarkers
Abstract: Background: Alzheimer’s disease (AD) is diagnosed based on a clinical evaluation as well as analyses of classical biomarkers: Aβ42, total tau (t-tau), and phosphorylated tau (p-tau) in cerebrospinal fluid (CSF). Although the sensitivities and specificities of the classical biomarkers are fairly good for detection of AD, there is still a need to develop novel biochemical markers for early detection of AD. Objective: We explored if integration of novel proteins with classical biomarkers in CSF can better discriminate AD from non-AD subjects. Methods: We applied ELISA, mass spectrometry, and multivariate modeling to investigate classical biomarkers and the CSF proteome in subjects (n=206) with 76 AD patients, 74 mild cognitive impairment (MCI) patients, 11 frontotemporal dementia (FTD) patients, and 45 non-dementia controls. The MCI patients were followed for 4-9 years and 21 of these converted to AD, whereas 53 remained stable. Results: By combining classical CSF biomarkers with twelve novel markers, the area of the ROC curves (AUROCS) of distinguishing AD and MCI/AD converters from non-AD were 93% and 96%, respectively. The FTDs and non-dementia controls were identified versus all other groups with AUROCS of 96% and 87%, respectively. Conclusions: Integration of new and classical CSF biomarkers in a model-based approach can improve the identification of AD, FTD, and non-dementia control subjects.

Pages 653-670
Dominik Özbe, Elmar Graessel, Carolin Donath, Anna Pendergrass (Handling Associate Editor: Isabelle Rouch)
Immediate Intervention Effects of Standardized Multicomponent Group Interventions on People with Cognitive Impairment: A Systematic Review
Abstract: Background: There is no curative medical treatment for dementia. Therefore, researchers turned their attention to non-pharmacological treatment approaches. Many reviews analyzed the efficacy of single-component interventions, but there has been no systematic review of multicomponent interventions so far. Objective: The aim was to systematically review studies using standardized multicomponent group interventions for persons with dementia or persons with mild cognitive impairment (MCI) and to analyze their immediate intervention effects. Methods: The databases PubMed, PsycINFO, PSYNDEX, and CINAHL were systematically searched. We included randomized controlled trials with people with MCI or dementia, which implemented interventions with at least two components that targeted different outcome domains. Additionally, the intervention had to be standardized and in a group setting. Results: Nine studies met the inclusion criteria with a total sample size of N = 513 participants. Six studies applied two, two studies applied three, and one study applied four components. Four studies, which combined at least a physical and a cognitive component, had a positive effect on non-cognitive symptoms of dementia. Two of these interventions additionally had a positive effect on cognitive abilities. One study reported a positive effect on activities of daily living and another study showed an effect on quality of life. Conclusion: In spite of the heterogeneity of the studies, multicomponent interventions suggest a positive effect on non-cognitive symptoms, especially the combination of cognitive and physical components. Single studies had also an effect on additional outcome domains. By trend the effects are dependent on application rate and used assessments.

Pages 671-684
Alfonso J. Alfini, Lauren R. Weiss, Kristy A. Nielson, Matthew D. Verber, J. Carson Smith
Resting Cerebral Blood Flow After Exercise Training in Mild Cognitive Impairment
Abstract: Background: Exercise training has been associated with greater cerebral blood flow (CBF) in cognitively normal older adults (CN). Alterations in CBF, including compensatory perfusion in the prefrontal cortex, may facilitate changes to the brain’s neural infrastructure. Objective: To examine the effects of a 12-week aerobic exercise intervention on resting CBF and cognition in CN and those with mild cognitive impairment (MCI). We hypothesized individuals with MCI (versus CN) would exhibit greater whole brain CBF at baseline and that exercise would mitigate these differences. We also expected CBF changes to parallel cognitive improvements. Methods: Before and after a 12-week exercise intervention, 18 CN and 17 MCI participants (aged 61-88) underwent aerobic fitness testing, neuropsychological assessment, and an MRI scan. Perfusion-weighted images were collected using a GE 3T MR system. Repeated measures analyses of covariance were used to test within- and between-group differences over time, followed by post-hoc analyses to examine links between CBF changes and cognitive improvement. Results: At baseline, individuals with MCI (versus CN) exhibited significantly elevated perfusion in the left insula. Twelve weeks of aerobic exercise reversed this discrepancy. Additionally, exercise improved working memory (measured by the Rey Auditory Verbal Learning Test) and verbal fluency (measured by the Controlled Oral Word Association Test) and differentially altered CBF depending on cognitive status. Among those with MCI, decreased CBF in the left insula and anterior cingulate cortex was associated with improved verbal fluency. Conclusions: Exercise training alters CBF and improves cognitive performance in older adults with and without cognitive impairment. Future studies must evaluate the mediating effects of CBF on the association between exercise training and cognition.

Pages 685-705
Barry Reisberg, Carol Torossian, Melanie B. Shulman, Isabel Monteiro, Istvan Boksay, James Golomb, Francoise Guillo Benarous, Anaztasia Ulysse, Thet Oo, Alok Vedvyas, Julia A. Rao, Karyn Marsh, Alan Kluger, Jaspreet Sangha, Mudasar Hassan, Munther Alshalabi, Fauzia Arain, Naveed Shaikh, Maja Buj, Sunnie Kenowsky, Arjun V. Masurkar, Laura Rabin, Maryam Noroozian, María Belén Sánchez-Saudinós, Rafael Blesa, Stefanie Auer, Yian Zhang, Mony de Leon, Martin Sadowski, Thomas Wisniewski, Serge Gauthier, Yongzhao Shao (Handling Associate Editor: Magda Tsolaki)
Two Year Outcomes, Cognitive and Behavioral Markers of Decline in Healthy, Cognitively Normal Older Persons with Global Deterioration Scale Stage 2 (Subjective Cognitive Decline with Impairment)
Abstract: Background: Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. Objective: Two-year interval behavioral markers were investigated herein. Methods: Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology “SCD(I)” for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. Results: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p<0.001), with component declines in Remote memory (p<0.01), and Functioning/self-care (p=0.01). Conclusion: SCD(I) persons decline at an annual rate of approximately 6.7%/year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.

Pages 707-713
Branko N. Huisa, Ronald G. Thomas, Shelia Jin, Tilman Oltersdorf, Curtis Taylor, Howard H. Feldman
Memantine and Acetylcholinesterase Inhibitor Use in Alzheimer’s Disease Clinical Trials: Potential for Confounding by Indication
Abstract: Background: Acetylcholinesterase inhibitors (AChEIs) and memantine are commonly prescribed medications for Alzheimer’s disease (AD). Their concurrent use in AD randomized clinical trials (RCTs) is generally allowed but their effect in outcome measures is unsettled. Objective: To evaluate whether use of AChEIs and/or memantine across AD RCTs are associated with different rates of cognitive/functional decline. Methods: We pooled data from 5 RCTs of mild to moderate AD conducted by the Alzheimer’s Disease Cooperative Study (ADCS) between 2002-2013. 1,423 participants with MMSE of 14-26 and completion of 12-18 months follow-up visits were analyzed. Trials did not randomize with respect to AChEIs or memantine. We defined 4 groups: AChEI (27%), memantine (16%), AChEIs+memantine (46%), and non-users (11%). Outcome measures were change in ADAS-cog-11, ADCS-ADL, and MMSE from baseline to 18 months. Fisher’s exact test, Wilcoxon signed rank, and Spearman’s tests were used to identify confounding variables. Mixed model repeated measures were used for adjustments and pairwise tests for comparing change in scores. Results: Age, apolipoprotein E, and initial MMSE were identified as covariates. Memantine and/or AChEIs users had greater impairment at entry than non-users. There was a significant decline on the ADAS-cog-11 in the memantine (estimate -4.2 p<0.0001) and AChEIs+memantine groups (estimate -3.5 p<0.0001) than non-users, while there was significantly more decline in MMSE (estimate 2.5 p<0.0001) and ADCS-ADL in the AChEIs+memantine group (estimate 4.3 p<0.0001). Conclusion: Memantine monotherapy or combined with AChEIs are associated with more rapid cognitive and functional decline than non-users. We postulated a potential selection bias by indication.

Pages 715-723
Erik Hessen, Bjørn-Eivind Kirsebom, Cecilia Magdalena Eriksson, Carl Fredrik Eliassen, Arne Exner Nakling, Geir Bråthen, Knut K. Waterloo, Dag Aarsland, Tormod Fladby
In Brief Neuropsychological Assessment, Amnestic Mild Cognitive Impairment (MCI) Is associated with Cerebrospinal Fluid Biomarkers for Cognitive Decline in Contrast to the Prevailing NIA-AA MCI Criterion
Abstract: Background: In the care of persons with cognitive problems, it is important to use a valid mild cognitive impairment (MCI) criterion that discriminates well between normal and pathological aging. Objective: To find the brief neuropsychological screening criterion that best correlates with cerebrospinal fluid (CSF) biomarkers for cognitive decline and dementia in persons seeking help for cognitive problems. Methods: 452 consecutively recruited patients (age 40-80 years) from memory-clinics in the Norwegian national multicentre longitudinal study Dementia Disease Initiation were included. CSF data as well as full data from brief neuropsychological screening were available for all patients. Results: Amnestic MCI, including at least one memory test below T-score 40, outperformed the conventional US National Institute on Aging-Alzheimer’s Association (NIA-AA) MCI criterion. Only amnestic MCI was significantly associated with biomarker pattern of NIA-AA stage 2 (low CSF Aβ42 concentrations and elevated tau) in multivariate regression analysis. Conclusions: The finding that amnestic MCI based on brief neuropsychological assessment is significantly associated with CSF biomarkers for cognitive decline and Alzheimer’s disease is in accordance with longitudinal studies that find memory impairment; both in itself and especially in combination with other cognitive deficit to constitute a risk factor for subsequent cognitive decline and dementia. The prevalence of pathological biomarkers for Alzheimer’s disease is common in the elderly and the clinical significance of present findings depend on longitudinal validation.

Pages 725-735
Liliana Letra, Paulo Matafome, Tiago Rodrigues, Diana Duro, Raquel Lemos, Inês Baldeiras, Miguel Patrício, Miguel Castelo-Branco, Gina Caetano, Raquel Seiça, Isabel Santana
Association between Adipokines and Biomarkers of Alzheimer’s Disease: A Cross-Sectional Study
Abstract: Background: Adipose tissue dysfunction has been implicated in the pathophysiology of Alzheimer’s disease. However, the involvement of adipokines, particularly adiponectin, remains unclear. Objective: To compare serum and cerebrospinal fluid (CSF) levels of adiponectin, leptin and leptin-to-adiponectin ratio in patients within the spectrum of Alzheimer’s disease and evaluate their relationship with classical biomarkers and their value as markers of progression. Methods: Amnestic mild cognitive impairment (MCI, n=71) and Alzheimer’s dementia (AD, n=53) subjects were consecutively recruited for serum and CSF adiponectin and leptin determination using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). Correlations were explored using adjusted Spearman’s correlation coefficients. A logistic regression model and ROC analysis were performed to evaluate the staging predictive value of adipokines. Results: Serum adiponectin was 33% higher in AD when compared to MCI patients. Adiponectin CSF levels, similar in both groups, were positively correlated with Aβ42 and cognitive function, though only in women. The area under the ROC curve was 0.673 (95%CI:0.57-0.78) for serum adiponectin as predictor of dementia stage and the cut-off 10.85 μg/ml maximized the sum of specificity (87%) and sensitivity (44%). Conclusion: Although longitudinal studies are required, we hypothesize that higher serum adiponectin in AD patients constitutes a strategy to compensate possible central signaling defects. In addition, adiponectin might be specifically assigned to neuroprotective functions in women and eventually involved in the female-biased incidence of Alzheimer’s disease.

Pages 737-756
Yi-Chun Chen*, Ya-Jen Chiu*, Chih-Hsin Lin, Wen-Chuin Hsu, Jia-Lu Wu, Chen-Hsiang Huang, Chia-Wei Lin, Ching-Fa Yao, Hei-Jen Huang, Chiung-Mei Chen, Yih-Ru Wu, Kuo-Hsuan Chang, Guey-Jen Lee-Chen, Hsiu Mei Hsieh-Li *These authors contributed equally to this work.
Indole Compound NC009-1 Augments APOE and TRKA in Alzheimer’s Disease Cell and Mouse Models for Neuroprotection and Cognitive Improvement
Abstract: Alzheimer’s disease (AD), associated with abnormal accumulation of amyloid-β (Aβ), is the most common cause of dementia among older people. A few studies have identified substantial AD biomarkers in blood but their results were inconsistent. Here we screened gene expression alterations on Aβ-GFP SH-SY5Y neuronal model for AD, and evaluated the findings on peripheral leukocytes from 78 patients with AD and 56 healthy controls. The therapeutic responses of identified biomarker candidates were further examined in Aβ-GFP SH-SY5Y neuronal and APP/PS1/Tau triple transgenic (3×Tg-AD) mouse models. Downregulation of apolipoprotein E (APOE) and tropomyosin receptor kinase A (TRKA) were detected in Aβ-GFP SH-SY5Y cells and validated by peripheral leukocytes from AD patients. Treatment with an in-house indole compound NC009-1 upregulated the expression of APOE and TRKA accompanied with improvement of neurite outgrowth in Aβ-GFP SH-SY5Y cells. NC009-1 further rescued the downregulated APOE and TRKA and reduced Aβ and tau levels in hippocampus and cortex, and ameliorated cognitive deficits in streptozocin-induced hyperglycemic 3×Tg-AD mice. These results suggest the role of APOE and TRKA as potential peripheral biomarkers in AD, and offer a new drug development target of AD treatment. Further studies of a large series of AD patients will be warranted to verify the findings and confirm the correlation between these markers and therapeutic efficacy.

Pages 757-768
Gad A. Marshall, Jennifer R. Gatchel, Nancy J. Donovan, Martha C. Muniz, Aaron P. Schultz, J. Alex Becker, Jasmeer P. Chhatwal, Bernard J. Hanseeuw, Kathryn V. Papp, Rebecca E. Amariglio, Dorene M. Rentz, Reisa A. Sperling, Keith A. Johnson (Handling Associate Editor: Paul Rosenberg)
Regional Tau Correlates of Instrumental Activities of Daily Living and Apathy in Mild Cognitive Impairment and Alzheimer’s Disease Dementia
Abstract: Background: Instrumental activities of daily living (IADL) impairment and apathy occur in early-stage Alzheimer’s disease (AD) and are associated with regional atrophy and hypometabolism in vivo and greater tau burden at autopsy. Objective: To explore the association between IADL impairment, apathy, and in vivo regional tau in mild cognitive impairment (MCI) and AD dementia. Methods: Forty participants (24 MCI, 16 AD dementia) underwent assessments of IADL (Functional Activities Questionnaire, FAQ) and apathy (Apathy Evaluation Scale Informant report, AES-I). Regional tau was assessed using flortaucipir positron emission tomography (PET) and amyloid using Pittsburgh Compound B PET. Regions with unadjusted associations of p≤0.01 were entered into regression models assessing the relationship between tau and FAQ or AES-I, adjusting for age, sex, and cognition, with/without a tau by amyloid interaction. Results: Unadjusted IADL impairment but not apathy was associated with greater tau in multiple regions. After adjusting for covariates, for medial orbitofrontal and entorhinal cortex the interaction between tau and amyloid was associated with IADL impairment and for anterior cingulate it was not but independent associations with both tau and amyloid were retained. With whole brain analyses, similar results were seen for IADL, while for apathy tau in small clusters within the right anterior cingulate and dorsolateral prefrontal cortices were seen, which were more pronounced in individuals with greater amyloid. Conclusions: This exploratory study suggests that IADL impairment in AD is associated with medial temporal and frontal tau, especially in individuals with elevated amyloid, while apathy may be associated with right frontal tau.

Pages 769-778
Eunjung Lee, Margaret Gatz, Chiuchen Tseng, Lon S. Schneider, Sonia Pawluczyk, Anna H. Wu, Dennis Deapen
Evaluation of Medicare Claims Data as a Tool to Identify Dementia
Abstract: Background: Medicare claims record linkage has been used to identify diagnosed dementia cases in order to estimate dementia prevalence and cost of care. Claims records in the 1990s and early 2000s have been found to provide 85%-~90% sensitivity and specificity. Objective: Considering that dementia awareness has improved over time, we sought to examine sensitivity and specificity of more recent Medicare claims records against a standard criterion, clinical diagnosis of dementia. Methods: For a sample of patients evaluated at the University of Southern California Alzheimer Disease Research Center (ADRC), we performed database linkage with Medicare claims files for a six-year period, 2007-2012. We used clinical diagnosis at the ADRC as the criterion diagnosis in order to calculate sensitivity and specificity. Results: Medicare claims correctly identified 85% of dementia patients and 77% of individuals with normal cognition. About half of patients clinically diagnosed with mild cognitive impairment had dementia diagnoses in Medicare claims. Misclassified dementia patients (i.e., missed diagnosis by Medicare claims) had more favorable Mini-Mental State Examination and Clinical Dementia Rating scores and were less likely to present behavioral symptoms than correctly-classified dementia patients. Conclusions: Database linkage to Medicare claims records is an efficient and reasonably accurate tool to identify dementia cases in a population-based cohort. However, possibilities of obtaining biased results due to misclassification of dementia status need to be carefully considered to use Medicare claims diagnosis for etiologic research studies. Additional confirmation of dementia diagnosis may also be considered. A larger study is warranted to confirm our findings.