Volume 58, Number 2, 2017

Pages 289-301
Ethics Review

John Noel M. Viaña, Merlin Bittlinger, Frederic Gilbert (Handling Editor: Allyson Rosen)
Ethical Considerations for Deep Brain Stimulation Trials in Patients with Early-Onset Alzheimer’s Disease
Abstract: Several studies of deep brain stimulation (DBS) of the fornix or the nucleus basalis of Meynert have been recently conducted in people with Alzheimer’s disease, with several recruiting participants <65 and thus have early-onset Alzheimer’s disease (EOAD). Although EOAD accounts for less than 5.5% of AD cases, ethical considerations must still be made when performing DBS trials including these participants since a portion of people with EOAD, especially those possessing autosomal-dominant mutations, have an atypical and more aggressive disease progression. These considerations include appropriate patient selection and signing of an informed consent for genetic testing; appropriate study design; potential outcomes that people with EOAD could expect; and accurate interpretation and balanced discussion of trial results. Finally, recommendations for future DBS for AD trials will be made to ensure that EOAD patients will not experience avoidable harms should they be enrolled in these experimental studies.

Pages 303-322

Xiang-Zhen Yuan, Sen Sun, Chen-Chen Tan, Jin-Tai Yu, Lan Tan
The Role of ADAM10 in Alzheimer’s Disease
Abstract: As a member of the A Disintegrin And Metalloproteinase (ADAM) family, ADAM10 has been identified as the constitutive α-secretase in the process of amyloid-β protein precursor (AβPP) cleavage and plays a critical role in reducing the generation of the amyloid-β (Aβ) peptides. Recent studies have demonstrated its beneficial role in alleviating the pathologic impairment in Alzheimer’s disease (AD) both in vitro and in vivo. However, the role of ADAM10 in AD and the underlying molecular mechanisms are still not well established. Increasing evidence indicates that ADAM10 not only reduces the generation of Aβ but may also affect the pathology of AD through potential mechanisms including reducing tau pathology, maintaining normal synaptic functions, and promoting hippocampal neurogenesis and the homeostasis of neuronal networks. Mechanistically, ADAM10 regulates these functions by interacting with postsynaptic substrates in brain, especially synaptic cell receptors and adhesion molecules. Furthermore, ADAM10 protein in platelets seems to be a promising biomarker for AD diagnosis. This review will summarize the role of ADAM10 in AD and highlight its functions besides its role as the α-secretase in AβPP cleavage. Meanwhile, we will discuss the therapeutic potential of ADAM10 in treating AD.

Pages 323-335

Lucia Paolacci*, David Giannandrea*, Patrizia Mecocci, Lucilla Parnetti *These authors contributed equally to this work.
Biomarkers for Early Diagnosis of Alzheimer’s Disease in the Oldest Old: Yes or No?
Abstract: In recent years, many efforts have been spent to identify sensitive biomarkers able to improve the accuracy of Alzheimer’s disease (AD) diagnosis. Two different workgroups (NIA-AA and IWG) included cerebrospinal fluid (CSF) and neuroimaging findings in their sets of criteria in order to improve diagnostic accuracy as well as early diagnosis. The number of subjects with cognitive impairment increases with aging but the oldest old (≥85 years of age), the fastest growing age group, is still the most unknown from a biological point of view. For this reason, the aim of our narrative mini-review is to evaluate the pertinence of the new criteria for AD diagnosis in the oldest old. Moreover, since different subgroups of oldest old have been described in scientific literature (escapers, delayers, survivors), we want to outline the clinical profile of the oldest old who could really benefit from the use of biomarkers for early diagnosis. Reviewing the literature on biomarkers included in the diagnostic criteria, we did not find a high degree of evidence for their use in the oldest old, although CSF biomarkers seem to be still the most useful for excluding AD diagnosis in the “fit” subgroup of oldest old subjects, due to the high negative predictive value maintained in this age group.

Pages 337-348

Alice Harding, Sarita Robinson, StJohn Crean, Sim K. Singhrao (Handling Associate Editor: Herbert Allen)
Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer’s Disease?
Abstract: A risk factor relationship exists between periodontal disease and Alzheimer’s disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis, to gain greater virulence. The initial process involves P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-β, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia.

Pages 349-354
Short Communication

Chiemi Yamazaki, Toshio Tamaoki, Akihiko Nunomura*, Kenichi Tamai, Kazuyuki Yasuda, Nobutaka Motohashi
Plasma Amyloid-β and Alzheimer’s Disease-Related Changes in Late-Life Depression
Abstract: To elucidate an involvement of amyloid dysmetabolism in the pathophysiology of depression, we investigated associations of plasma amyloid-β (Aβ) levels with Alzheimer’s disease-related changes in neuroimaging and cognitive dysfunction in patients with late-life depression. Higher plasma Aβ40, but not Aβ42 nor Aβ40/Aβ42 ratio, was associated with higher degree of parahippocampal atrophy and lower verbal fluency performance. Indeed, high plasma Aβ40 predicted poor cognitive prognosis of depressed patients with mild cognitive impairment. As an anti-depressive treatment, electroconvulsive therapy (ECT) resulted in a marginally significant reduction of plasma Aβ40 compared to pharmacotherapy alone, suggesting protective effects of ECT against amyloid dysmetabolism.

Pages 355-359
Short Communication

Ali Yilmaz, Tim Geddes, BeomSoo Han, Ray O. Bahado-Singh, George Wilson, Khaled Imam, Michael Maddens, Stewart F. Graham
Diagnostic Biomarkers of Alzheimer’s Disease as Identified in Saliva using 1H NMR-Based Metabolomics
Abstract: Using 1H NMR metabolomics, we biochemically profiled saliva samples collected from healthy-controls (n=12), mild cognitive impairment (MCI) sufferers (n=8), and Alzheimer’s disease (AD) patients (n=9). We accurately identified significant concentration changes in 22 metabolites in the saliva of MCI and AD patients compared to controls. This pilot study demonstrates the potential for using metabolomics and saliva for the early diagnosis of AD. Given the ease and convenience of collecting saliva, the development of accurate and sensitive salivary biomarkers would be ideal for screening those at greatest risk of developing AD.

Pages 361-371
Kan Li, Wenyaw Chan, Rachelle S. Doody, Joseph Quinn, Sheng Luo, the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Jeannie-Marie Leoutsakos)
Prediction of Conversion to Alzheimer’s Disease with Longitudinal Measures and Time-To-Event Data
Abstract: Background: Identifying predictors of conversion to Alzheimer’s disease (AD) is critically important for AD prevention and targeted treatment. Objective: To compare various clinical and biomarker trajectories for tracking progression and predicting conversion from amnestic mild cognitive impairment to probable AD. Methods: Participants were from the ADNI-1 study. We assessed the ability of 33 longitudinal biomarkers to predict time to AD conversion, accounting for demographic and genetic factors. We used joint modelling of longitudinal and survival data to examine the association between changes of measures and disease progression. We also employed time-dependent receiver operating characteristic method to assess the discriminating capability of the measures. Results: 23 of 33 longitudinal clinical and imaging measures are significant predictors of AD conversion beyond demographic and genetic factors. The strong phenotypic and biological predictors are in the cognitive domain (ADAS-Cog; RAVLT), functional domain (FAQ), and neuroimaging domain (middle temporal gyrus and hippocampal volume). The strongest predictor is ADAS-Cog 13 with an increase of one SD in ADAS-Cog 13 increased the risk of AD conversion by 2.92 times. Conclusion: Prediction of AD conversion can be improved by incorporating longitudinal change information, in addition to baseline characteristics. Cognitive measures are consistently significant and generally stronger predictors than imaging measures.

Pages 373-387
Bahman Mirheidari, Daniel Blackburn, Kirsty Harkness, Traci Walker, Annalena Venneri, Markus Reuber, Heidi Christensen (Handling Associate Editor: Jordi Peña­-Casanova)
Toward the Automation of Diagnostic Conversation Analysis in Patients with Memory Complaints
Abstract: Background: The early diagnosis of dementia is of great clinical and social importance. A recent study using the qualitative methodology of conversation analysis (CA) demonstrated that language and communication problems are evident during interactions between patients and neurologists, and that interactional observations can be used to differentiate between cognitive difficulties due to neurodegenerative disorders (ND) or functional memory disorders (FMD). Objective: This study explores whether the differential diagnostic analysis of doctor-patient interactions in a memory clinic can be automated. Methods: Verbatim transcripts of conversations between neurologists and patients initially presenting with memory problems to a specialist clinic were produced manually (15 with FMD, and 15 with ND). A range of automatically detectable features focusing on acoustic, lexical, semantic, and visual information contained in the transcripts were defined aiming to replicate the diagnostic qualitative observations. The features were used to train a set of five machine learning classifiers to distinguish between ND and FMD. Results: The mean rate of correct classification between ND and FMD was 93% ranging from 97% by the Perceptron classifier to 90% by the Random Forest classifier. Using only the ten best features, the mean correct classification score increased to 95%. Conclusion: This pilot study provides proof-of-principle that a machine learning approach to analyzing transcripts of interactions between neurologists and patients describing memory problems can distinguish people with neurodegenerative dementia from people with FMD.

Pages 389-400
Hadar Segal-Gavish* Ortal Danino*, Yael Barhum, Tali Ben-Zur, Ella Shai, David Varon, Daniel Offen, Bilha Fischer *These authors contributed equally to this work.
A Multifunctional Biocompatible Drug Candidate is Highly Effective in Delaying Pathological Signs of Alzheimer’s Disease in 5XFAD Mice
Abstract: Background: Metal-ion-chelation was suggested to prevent zinc and copper ions-induced amyloid-β (Aβ) aggregation and oxidative stress, both implicated in the pathophysiology of Alzheimer’s disease (AD). In a quest for biocompatible metal-ion chelators potentially useful for AD therapy, we previously tested a series of nucleoside 5'-phosphorothioate derivatives as agents for decomposition of Cu(I)/Cu(II)/Zn(II)-Aβ-aggregates, and as inhibitors of OH radicals formation in Cu(I) or Fe(II) /H2O2 solution. Specifically, in our recent study we have identified 2-SMe-ADP(α-S), designated as SAS, as a most promising neuroprotectant. Objective: To further explore SAS ability to protect the brain from Aβ toxicity both in vitro and in vivo. Methods: We evaluated SAS ability to decompose or inhibit the formation of Aβ42-M(II) aggregates, and rescue primary neurons and astrocytes from Aβ42 toxicity. Furthermore, we aimed at exploring the therapeutic effect of SAS on behavioral and cognitive deficits in the 5XFAD mouse model of AD. Results: We found that SAS can rescue primary culture of neurons and astrocytes from Aβ42 toxicity and to inhibit the formation and dissolve Aβ42-Zn(II)/Cu(II) aggregates. Furthermore, we show that SAS treatment can prevent behavioral disinhibition and ameliorate spatial working memory deficits in 5XFAD mice. Notably, the mice were treated at the age of 2 months, before the onset of AD symptoms, for a duration of 2 months, while the effect was demonstrated at the age of 6 months. Conclusion: Our results indicate that SAS has the potential to delay progression of core pathological characteristics of AD in the 5XFAD mouse model.

Pages 401-411
Michael S. Rafii, Brian G. Skotko, Mary Ellen McDonough, Margaret Pulsifer, Casey Evans, Eric Doran, Gabriela Muranevici, Patrick Kesslak, Susan Abushakra, Ira T. Lott for the ELND005-DS Study Group (Handling Associate Editor: Juan Fortea)
A Randomized, Double‑Blind, Placebo-Controlled, Phase II Study of Oral ELND005 (scyllo-Inositol) in Young Adults with Down Syndrome without Dementia
Abstract: Background: ELND005 (scyllo-Inositol; cyclohexane-1,2,3,4,5,6-hexol) has been evaluated as a potential disease-modifying treatment for Alzheimer’s disease (AD). Individuals with Down syndrome (DS) have an increased risk for developing AD dementia. Objective: To evaluate the safety and tolerability of ELND005 and to determine its pharmacokinetics (PK) and relationship between PK parameters, safety outcome measures, and exploratory efficacy outcome measures in young adults with DS without dementia. Methods: This was a prospective, randomized, double-blind, placebo-controlled, parallel-group, three-arm, multicenter Phase II study of the safety and pharmacokinetics of ELND005 administered orally for 4 weeks (ClinicalTrials.gov NCT01791725). Participants who met study eligibility criteria were randomly assigned in a 2:1:1 ratio to receive ELND005 at either 250 mg twice daily (BID) or 250 mg once daily (QD) or matching placebo for 4 weeks. Results: There were no apparent treatment group-related trends on cognitive or behavioral measures and there were no SAEs and no deaths in the study. Overall, mean changes from baseline in clinical laboratory parameters, vital sign measurements, electrocardiogram results, and other physical findings were unremarkable. ELND005 accumulation averaged approximately 2-fold with QD dosing, and 3- to 4-fold with BID dosing. Conclusion: Overall, treatment of adults with DS with ELND005 at both doses was well tolerated, achieved measurable blood levels and demonstrated no safety findings. Further studies will be needed to test efficacy.

Pages 413-423
Yi Jayne Tan*, Adeline S.L. Ng*, Ashwati Vipin, Joseph K.W. Lim, Russell J. Chander, Fang Ji, Yingwei Qiu, Simon K.S. Ting, Shahul Hameed, Tih-Shih Lee, Li Zeng, Nagaendran Kandiah**, Juan Zhou** (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work. ** Joint senior authors
Higher Peripheral TREM2 mRNA Levels Relate to Cognitive Deficits and Hippocampal Atrophy in Alzheimer’s Disease and Amnestic Mild Cognitive Impairment
Abstract: Background: Variants in triggering receptor expressed on myeloid cells 2 (TREM2) are associated with increased Alzheimer’s disease (AD) risk. Recent studies have reported inconsistent peripheral TREM2 mRNA expression levels and relationship with cognitive scores in AD and mild cognitive impairment (MCI). Additionally, no study has examined the association of peripheral TREM2 levels with neuroimaging measures in AD and MCI. Objective: To determine peripheral TREM2 mRNA levels in AD, amnestic MCI (aMCI) and healthy controls, and the association with cognitive performance and brain structural changes. Methods: We measured peripheral TREM2 mRNA levels in 80 AD, 30 aMCI, and 86 healthy controls using real time polymerase chain reaction. TREM2 levels were correlated with various cognitive performance and brain volumes, correcting for APOE4 status. Results: TREM2 mRNA levels were significantly higher in AD compared to controls and aMCI. Levels did not differ between aMCI and controls. Corrected for APOE4, higher TREM2 levels correlated with lower Mini-Mental State Examination, Montreal Cognitive Assessment (MoCA) and episodic memory scores, and lower total grey matter and right hippocampal volumes. Whole-brain voxel-based morphometry analysis found negative association between TREM2 mRNA levels and grey matter volumes in temporal, parietal and frontal regions. AD subjects with MoCA scores ≤20 had higher TREM2 levels correlating with smaller total grey matter, left hippocampal and right hippocampal volumes. Conclusion: Peripheral TREM2 mRNA levels are higher in AD and are associated with AD-related cognitive deficits and hippocampal atrophy. Our findings suggest that TREM2 may be a potential non-invasive peripheral biomarker for AD diagnosis.

Pages 425-434
Courtney Berezuk, Konstantine K. Zakzanis, Joel Ramirez, Anthony C. Ruocco, Jodi D. Edwards, Brandy L. Callahan, Sandra E. Black, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: David Libon)
Functional Reserve: Experience Participating in Instrumental Activities of Daily Living is Associated with Gender and Functional Independence in Mild Cognitive Impairment
Abstract: Background: Gender differences in instrumental activities of daily living (IADLs) in mild cognitive impairment (MCI) and Alzheimer’s disease may be explained by gender differences in IADL involvement. Objective: We introduce a novel theoretical construct, termed functional reserve, and empirically examine gender differences in IADL experience as a proxy of this reserve. Methods: We cross-sectionally examined men (n=502) and women (n=340) with MCI from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Demographic factors, depressive symptoms, neuropsychological scores, and IADL experience were included as independent variables and total Functional Activities Questionnaire (FAQ) scores as the dependent variable. Regression analyses were performed on the full cohort and stratified by gender to identify differential predictive relationships for men and women. Results: Gender was associated with total FAQ (p<0.05) until adjusting for IADL experience. Furthermore, the combination of cognitive measures accounted for the most variance in functional dependence (12% explained, p<0.001), although IADL experience was the most important single variable (4.8% explained, p<0.001). Stratification by gender revealed that IADL experience accounted for 6.6% of the variance in FAQ score in men (p<0.001) but only 2.4% in women (p=0.001); however, the interaction between gender and experience was not statistically significant. Discussion: A small effect of men showing greater functional dependence in MCI may be explained by lower IADL experience. Additionally, IADL experience was associated with superior functioning in all analyses, potentially through increased functional reserve. This concept of functional reserve may have implications for identifying individuals at risk for IADL dependence, preventing or delaying decline, and potentially treating functional impairment.

Pages 435-448
Sascha Dublin, Rod L. Walker, Shelly L. Gray, Rebecca A. Hubbard, Melissa L. Anderson, Onchee Yu, Thomas J. Montine, Paul K. Crane, Josh A. Sonnen, Eric B. Larson (Handling Associate Editor: Carol Brayne)
Use of Analgesics (Opioids and Nonsteroidal Anti-Inflammatory Drugs) and Dementia-Related Neuropathology in a Community-Based Autopsy Cohort
Abstract: Background: Opioids may influence the development of Alzheimer’s disease (AD). Some studies have observed AD pathology in the brains of opioid abusers. No study has examined the association between prescription opioid use and dementia-related neuropathologic changes. Objective: To examine the relationship between prescription opioid or NSAID use and dementia-related neuropathologic changes. Methods: Within a community-based autopsy cohort (N=420), we ascertained opioid and nonsteroidal anti-inflammatory drug (NSAID) use over a 10-year period from automated pharmacy data and calculated total standardized daily doses (TSDDs). A neuropathologist assessed outcomes including neuritic plaques, neurofibrillary tangles, and macroscopic infarcts. Outcome measures were dichotomized using established cutpoints. We used modified Poisson regression to calculate adjusted relative risks (RR) and 95% confidence intervals (CI), accounting for participant characteristics and using weighting to account for possible selection bias related to selection into the autopsy sample. Results: Heavier opioid exposure was not associated with greater neuropathologic changes. For neuritic plaques, the adjusted RR [95% CI] was 0.99 [0.64-1.47] for 91+ TSDDs of opioids versus little to no use, and for neurofibrillary tangles, 0.97 [0.49-1.78]. People with heavy NSAID use had higher risk of neuritic plaques (RR 1.39 [1.01-1.89]) than those with little to no use, as we have previously reported. Neither opioid nor NSAID use was associated with higher risk of macroscopic infarcts or with Lewy body disease. Conclusion: Prescription opioid use is not associated with dementia-related neuropathologic changes, but heavy NSAID use may be. More research is needed examining chronic pain, its pharmacologic treatments, and neuropathologic changes.

Pages 449-462
Amir A. Sepehry, Philip E. Lee, Ging-Yuek R. Hsiung, B. Lynn Beattie, Howard H. Feldman, Claudia Jacova
The 2002 NIMH Provisional Diagnostic Criteria for Depression of Alzheimer’s Disease (PDC-dAD): Gauging their Validity over a Decade Later
Abstract: Presented herein is evidence for criterion, content, and convergent/discriminant validity of the NIMH-Provisional Diagnostic Criteria for depression of Alzheimer’s Disease (PDC-dAD) that were formulated to address depression in Alzheimer’s disease (AD). Using meta-analytic and systematic review methods, we examined criterion validity evidence in epidemiological and clinical studies comparing the PDC-dAD to Diagnostic and Statistical Manual of Mental Disorders fourth edition (DSM-IV), and International Classification of Disease (ICD 9) depression diagnostic criteria. We estimated prevalence of depression by PDC, DSM, and ICD with an omnibus event rate effect-size. We also examined diagnostic agreement between PDC and DSM. To gauge content validity, we reviewed rates of symptom endorsement for each diagnostic approach. Finally, we examined the PDC’s relationship with assessment scales (global cognition, neuropsychiatric, and depression definition) for convergent validity evidence. The aggregate evidence supports the validity of the PDC-dAD. Our findings suggest that depression in AD differs from other depressive disorders including Major Depressive Disorder (MDD) in that dAD is more prevalent, with generally a milder presentation and with unique features not captured by the DSM. Although the PDC are the current standard for diagnosis of depression in AD, we identified the need for their further optimization based on predictive validity evidence.

Pages 463-470
Dilman Sadiq, Tim Whitfield, Lean Lee, Tim Stevens, Sergi Costafreda, Zuzana Walker (Handling Associate Editor: Flavio Nobili)
Prodromal Dementia with Lewy Bodies and Prodromal Alzheimer’s Disease: A Comparison of the Cognitive and Clinical Profiles
Abstract: Background: Dementia must be diagnosed accurately and early in the disease course to allow pathology-specific treatments to be effective. Dementia with Lewy bodies (DLB) is often misdiagnosed as Alzheimer’s disease (AD), especially at the prodromal stage. Objective: To compare the clinical and neuropsychological profiles of mild cognitive impairment (MCI) patients who, at follow-up, progressed to AD (retrospectively AD-MCI) or DLB (retrospectively DLB-MCI) or remained MCI. Methods: This longitudinal study used an unselected sample from a memory clinic database. A total of 1,848 new patients were seen at the memory clinic between 1994-2015. Of these, 560 patients (30%) had an initial diagnosis of MCI and were considered for the study. Inclusion criteria were patients who had a diagnosis of MCI at initial assessment and a minimum of 12 months’ follow-up. Results: Of the 429 MCI patients with follow-up data, 164 (38%) remained MCI, 107 (25%) progressed to AD, and 21 (5%) progressed to DLB. The remainder progressed to alternative diagnoses. At baseline, DLB-MCI patients performed significantly worse on visuospatial function and letter fluency tests than both AD-MCI and stable-MCI groups, and better on episodic memory tests than the AD-MCI group. At baseline, DLB-MCI patients had a significantly higher mean UPDRS score and were more likely to have REM sleep behavior disorder and fluctuating cognition. Conclusion: DLB-MCI patients have a specific cognitive and neuropsychiatric profile which should alert clinicians to the possibility of prodromal DLB. This is relevant when considered in the context of early disease-specific therapy.

Pages 471-478
Michala Kolarova, Urmi Sengupta, Ales Bartos, Jan Ricny, Rakez Kayed
Tau Oligomers in Sera of Patients with Alzheimer’s Disease and Aged Controls
Abstract: Although tau protein was long regarded as an intracellular protein with several functions inside the cell, new evidence has shown tau secretion into the extracellular space. The active secretion of tau could be a physiological response of neurons to increased intracellular amounts of tau during the progression of tau pathology. We looked for potential differences in the serum levels of toxic tau oligomers in regards to cognitive impairment of subjects. We detected tau oligomers in the serum of Alzheimer’s disease (AD) patients, but they were also present to some extent in the serum of healthy older subjects where the levels positively correlated with aging (Spearman r= 0.26, p= 0.016). On the contrary, we found lower levels of tau oligomers in the serum of mild cognitive impairment (MCI) (p=0.033) and MCI-AD (p=0.006) patients. These results could suggest that clearance of extracellular tau proteins takes place, in part, in the periphery. In the case of MCI patients, the lower levels of tau oligomers could be the result of impaired clearance of tau protein from interstitium to blood and consequent accumulation of tau aggregates in the brain.

Pages 479-489
Noora-Maria Suhonen, Ramona M. Haanpää, Ville Korhonen, Jari Jokelainen, Anni Pitkäniemi, Anna-Leena Heikkinen, Johanna Krüger, Päivi Hartikainen, Seppo Helisalmi, Mikko Hiltunen, Tuomo Hänninen, Anne M. Remes
Neuropsychological Profile in the C9ORF72 Associated Behavioral Variant Frontotemporal Dementia
Abstract: While the C9ORF72 expansion is a major cause of behavioral variant frontotemporal dementia (bvFTD), little is known of the resultant cognitive profile. Our aim was to characterize the neuropsychological profile of the C9ORF72 associated bvFTD. We contrasted structured neuropsychological assessments of the C9ORF72 expansion carrier bvFTD patients (n=26) with non-carrier bvFTD patients (n=47) and those with Alzheimer’s disease (AD) (n=47). As compared to the non-carrier bvFTD patients, the C9ORF72 expansion carriers performed at a higher level in an immediate verbal memory test while showing poorer phonemic verbal fluency. Additionally, the expansion carriers committed more errors in the Stroop test and the Alternating S task relative to the non-carriers. Finally, while the AD patients outperformed both bvFTD patient groups in working memory, their performance was more impaired in episodic memory tasks relative to the bvFTD groups. We conclude that bvFTD patients carrying the C9ORF72 expansion may display more pronounced executive deficits together with less severe verbal memory impairment as compared to their non-carrier bvFTD counterparts. Knowledge of the specific neuropsychological features associated with the C9ORF72 related bvFTD may aid in the early diagnosis of the disease as well as in targeting genetic testing.

Pages 491-505
Ian R. Macdonald, Selena P. Maxwell, G. Andrew Reid, Meghan K. Cash, Drew R. DeBay, Sultan Darvesh (Handling Associate Editor: Debomoy Lahiri)
Quantification of Butyrylcholinesterase Activity as a Sensitive and Specific Biomarker of Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) plaques are a neuropathological hallmark of Alzheimer’s disease (AD); however, a significant number of cognitively normal older adults can also have Aβ plaques. Thus, distinguishing AD from cognitively normal individuals with Aβ plaques (NwAβ) based on Aβ plaque detection is challenging. It has been observed that butyrylcholinesterase (BChE) accumulates in plaques preferentially in AD. Thus, detecting BChE-associated plaques has the potential as an improved AD biomarker. We present Aβ, thioflavin-S, and BChE quantification of 26 postmortem brain tissues; AD (n=8), NwAβ (n=6), cognitively normal without plaques (n=8), and other common dementias including corticobasal degeneration, frontotemporal dementia with tau, dementia with Lewy bodies, and vascular dementia. Pathology burden in the orbitofrontal cortex, entorhinal cortex, amygdala, and hippocampal formation was determined and compared. The predictive value of Aβ and BChE quantification was determined, via receiver-operating characteristic plots, to evaluate their AD diagnostic performance using sensitivity, specificity, and area under curve (AUC) metrics. In general, Aβ and BChE-associated pathology were greater in AD, particularly in the orbitofrontal cortex. In this region, the largest increase (9.3-fold) was in BChE-associated pathology, observed between NwAβ and AD, due to the virtual absence of BChE-associated plaques in NwAβ brains. Furthermore, BChE did not associate with pathology of the other dementias. In this sample, BChE-associated pathology provided a higher diagnostic accuracy (AUC=1.0, sensitivity/specificity=100%/100%) when compared to Aβ (AUC=0.98, 100%/85.7%). These findings highlight the predictive value of BChE as a biomarker for AD that could facilitate timely disease diagnosis and management.

Pages 507-520
Petra Majerova, Peter Barath, Alena Michalicova, Stanislav Katina, Michal Novak, Andrej Kovac
Changes of Cerebrospinal Fluid Peptides due to Tauopathy
Abstract: Alzheimer’s disease (AD) and progressive supranuclear palsy are two common neurodegenerative tauopathies, and the most common cause of progressive brain dementia in elderly affecting more than 35 million people. The tauopathies are characterized by abnormal deposition of microtubule associated protein tau into intracellular neurofibrillary tangles composed mainly of the hyperphosphorylated form of the protein. The diagnosis of tauopathies is based on the presence of clinical features and pathological changes. Over the last decade, there has been an intensive search for novel biochemical markers for clinical diagnosis of AD and other tauopathies. In the present study, we used transgenic rat model for tauopathy expressing human truncated tau protein (aa 151–391/4R) to analyze the cerebrospinal fluid (CSF) peptidome using liquid chromatography – matrix assisted laser desorption/ionization mass spectrometry (LC-MALDI TOF/TOF). From 345 peptides, we identified a total of 175 proteins. Among them, 17 proteins were significantly altered in the CSF of transgenic rats. The following proteins were elevated in the CSF of transgenic rats when compared to the control animals: neurofilament light and medium chain, apolipoprotein E, gamma-synuclein, chromogranin A, reticulon-4, secretogranin-2, calsyntein-1 and -3, endothelin-3, neuroendocrine protein B72A, alpha-1-macroglobulin, and augurin. Interestingly most of the identified proteins were previously linked to AD and other tauopathies, indicating the significance of transgenic animals in biomarker validation.

Pages 521-535
Thomas J. Nelson, Miao-Kun Sun, Chol Lim, Abhik Sen, Tapan Khan , Florin V. Chirila, Daniel L. Alkon
Bryostatin Effects on Cognitive Function and PKCε in Alzheimer’s Disease Phase IIa and Expanded Access Trials
Abstract: Bryostatin 1, a potent activator of protein kinase C epsilon (PKCε), has been shown to reverse synaptic loss and facilitate synaptic maturation in animal models of Alzheimer's disease (AD), Fragile X, stroke, and other neurological disorders. In a single-dose (25 µg/m2) randomized double-blind Phase IIa clinical trial, bryostatin levels reached a maximum at 1–2 h after the start of infusion. In close parallel with peak blood levels of bryostatin, an increase of PBMC PKCε was measured (p=0.0185) within 1 h from the onset of infusion. Of 9 patients with a clinical diagnosis of AD, of which 6 received drug and 3 received vehicle within a double-blind protocol, bryostatin increased the Mini-Mental State Examination (MMSE) score by +1.83 ± 0.70 unit at 3 h versus −1.00 ± 1.53 unit for placebo. Bryostatin was well tolerated in these AD patients and no drug-related adverse events were reported. The 25 µg/m2 administered dose was based on prior clinical experience with three Expanded Access advanced AD patients treated with bryostatin, in which return of major functions such as swallowing, vocalization, and word recognition were noted. In one Expanded Access patient trial, elevated PKCε levels closely tracked cognitive benefits in the first 24 weeks as measured by MMSE and ADCS-ADL psychometrics. Pre-clinical mouse studies showed effective activation of PKCε and increased levels of BDNF and PSD-95. Together, these Phase IIa, Expanded Access, and pre-clinical results provide initial encouragement for bryostatin 1 as a potential treatment for AD.

Pages 537-547
Stephanie J.B. Vos, Martin P. J. van Boxtel, Olga J.G. Schiepers, Kay Deckers, Marjolein de Vugt, Isabelle Carrière, Jean-François Dartigues, Karine Peres, Sylvaine Artero, Karen Ritchie, Lucia Galluzzo, Emanuele Scafato, Giovanni B. Frisoni, Martijn Huisman, Hannie C. Comijs, Simona F. Sacuiu, Ingmar Skoog, Kate Irving, Catherine A. O’Donnell, Frans R.J. Verhey, Pieter Jelle Visser, Sebastian Köhler
Modifiable Risk Factors for Prevention of Dementia in Midlife, Late Life and the Oldest-Old: Validation of the LIBRA Index
Abstract: Background: Recently, the LIfestyle for BRAin health (LIBRA) index was developed to assess an individual’s prevention potential for dementia. Objective: We investigated the predictive validity of the LIBRA index for incident dementia in midlife, late life, and the oldest-old. Methods: 9,387 non-demented individuals were recruited from the European population-based DESCRIPA study. An individual’s LIBRA index was calculated solely based on modifiable risk factors: depression, diabetes, physical activity, hypertension, obesity, smoking, hypercholesterolemia, coronary heart disease, and mild/moderate alcohol use. Cox regression was used to test the predictive validity of LIBRA for dementia at follow-up (mean 7.2 y, range 1-16). Results: In midlife (55-69 y, n=3,256) and late life (70-79 y, n=4,320), the risk for dementia increased with higher LIBRA scores. Individuals in the intermediate- and high-risk groups had a higher risk of dementia than those in the low-risk group. In the oldest-old (80-97 y, n=1,811), higher LIBRA scores did not increase the risk for dementia. Conclusion: LIBRA might be a useful tool to identify individuals for primary prevention interventions of dementia in midlife, and maybe in late life, but not in the oldest-old.

Pages 549-558
Qian Li, Jing Cui, Chen Fang, Min Liu, Guowen Min, Liang Li (Handling Associate Editor: Chengxin Gong)
S-Adenosylmethionine Attenuates Oxidative Stress and Neuroinflammation Induced by Amyloid-β Through Modulation of Glutathione Metabolism
Abstract: Oxidative stress and neuroinflammation are mainly involved in the pathogenic mechanisms of Alzheimer’s disease (AD). Amyloid-β (Aβ), the main component of senile plaques, is a kind of strong inducer of oxidative stress. Glutathione is an endogenous antioxidant protecting cells from oxidative injury. S-adenosylmethionine (SAM) produced in the methionine cycle is the primary methyl donor and the precursor of glutathione. In this study, the Aβ intrahippocampal injection rat model and cultured SH-SY5Y cells were used to explore the neuroprotective effect of SAM. We found that SAM could protect cells against Aβ-induced cellular injury by inhibition of oxidative stress and neuroinflammation. SAM administration could increase the endogenous antioxidant glutathione and potentiate the antioxidant enzymes activities. SAM might act as an antioxidant and be a potential candidate therapy for AD patients.

Pages 559-574
Izumi Maezawa, Bende Zou, Jacopo Di Lucente, William Cao, Conrado Pascual, Sahani Weerasekara, Man Zhang, Xinmin Simon Xie, Duy H. Hua, Lee-Way Jin
The Anti-Amyloid-β and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule
Abstract: There is an urgent unmet need for new therapeutics for Alzheimer’s disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the A oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.

Pages 575-583
Michael Malek-Ahmadi, Sophie Lu, YanYan Chan, Sylvia E. Perez, Kewei Chen, Elliott J. Mufson (Handling Associate Editor: Kalipada Pahan)
Cognitive Domain Dispersion Association with Alzheimer’s Disease Pathology
Abstract: Within neuropsychology, the term dispersion refers to the degree of variation in performance between different cognitive domains for an individual. Previous studies have demonstrated that cognitively normal individuals displaying higher dispersion are at an increased risk for progressing to mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Therefore, we determined 1) whether increased dispersion in older adults was associated with amyloid plaques and neurofibrillary tangles (NFTs) and 2) whether increased cognitive dispersion accurately differentiated MCI and AD from non-cognitively impaired (NCI) individuals. The intra-subject standard deviation (ISD) was used to quantify cognitive dispersion, and receiver operator characteristic (ROC) analysis determined whether ISD differentiated MCI and AD from NCI. Neuropathological scores for diffuse plaques (DPs), neuritic plaques (NPs), and NFTs were used as outcome measures in a series of negative binomial regression models. Regression analyses found that increased ISD was associated with increased NFT pathology (β = 10.93, SE = 3.82, p = 0.004), but not with DPs (β = 1.33, SE = 8.85, p = 0.88) or NPs (β = 14.64, SE = 8.45, p = 0.08) after adjusting for age at death, gender, education, APOE ε4 status, and clinical diagnosis. An interaction term of ISD with age at death also showed a significant negative association (β = -0.13, SE = 0.04, p = 0.004), revealing an age-dependent association between ISD with NFTs. The ISD failed to show an acceptable level of diagnostic accuracy for MCI (AUC = 0.60). These findings suggest that increased cognitive dispersion is related to NFT pathology where age significantly affects this association.

Pages 585-595
Reyes García de Eulate, Irene Goñi, Alvaro Galiano, Marta Vidorreta, Miriam Recio, Mario Riverol, José L. Zubieta, María A. Fernández-Seara (Handling Associate Editor: Mark Bondi)
Reduced Cerebral Blood Flow in Mild Cognitive Impairment Assessed Using Phase-Contrast MRI
Abstract: There is increasing evidence of a vascular contribution to Alzheimer's disease (AD). In some cases, prior work suggests that chronic brain hypoperfusion could play a prime pathogenic role contributing to the accumulation of amyloid-β, while other studies favor the hypothesis that vascular dysfunction and amyloid pathology are independent, although synergistic, mechanisms contributing to cognitive impairment. Vascular dysfunction can be evaluated by assessing cerebral blood flow impairment. Phase contrast velocity mapping by MRI offers a non-invasive means of quantifying the total inflow of blood to the brain. This quantitative parameter could be a sensitive indicator of vascular disease at early stages of AD. In this work, phase contrast MRI was used to evaluate cerebral hemodynamics in patients with subjective memory complaints, amnestic mild cognitive impairment, and mild to moderate AD, and compare them with control subjects. Results showed that blood flow and velocity were decreased in the patients with cognitive dysfunction and the decrease correlated with the degree of cognitive impairment as assessed by means of neuropsychological tests. Total cerebral blood flow measurements were clearly reduced in AD patients, but more importantly appeared to be sensitive enough to distinguish between healthy subjects and those with mild cognitive impairment. A quantitative measurement of total brain blood flow could potentially predict vascular dysfunction and compromised brain perfusion in early stages of AD.