Volume 71, Number 4, IN PRESS

Ethics Review
Meghan K. Mattos, Susan M. Sereika, Scott R. Beach, Hyejin Kim, William E. Klunk, Melissa Knox, Neelesh K. Nadkarni, Lisa S. Parker, J. Scott Roberts, Richard Schulz, Lisa Tamres, Jennifer H. Lingler (Handling Editor: Allyson Rosen)
Research Use of Ecological Momentary Assessment for Adverse Event Monitoring Following Amyloid-β Results Disclosure
Abstract: As calls for transparency in human subjects research grow, investigators conducting Alzheimer’s disease (AD) biomarker research are increasingly required to consider their ethical obligations regarding the return of AD biomarker test results to research participants. When disclosing these test results to potentially vulnerable participants, investigators may face unique challenges to identify adverse events, particularly psychological events. The purpose of this paper is to describe our research team’s experience with developing and implementing a process for enhanced adverse event monitoring following the return of amyloid-β (Aβ) imaging results to research participants with mild cognitive impairment (MCI). Ethical and logistical considerations are presented along with preliminary findings from an ongoing randomized controlled trial of Aβ imaging results disclosure in MCI. Following receipt of amyloid imaging results, participants underwent 14 days of adverse event monitoring using ecological momentary assessment (EMA), a strategy to capture health, behaviors, and mood as they occur in participants’ natural settings in real time. EMA telephone calls were placed at random during waking hours to screen for mood changes. Investigators were alerted for positive depression, anxiety, suicidal ideation screenings, or for two days of failed call attempts. Preliminary feasibility of twenty-four participants with MCI who participated in EMA mood assessments was successfully completed 83% (SD=0.4) of the time over 14 days with no alerts for anxiety or depression screening items. EMA, when used with standard adverse event monitoring, is a promising and novel approach to maximize early detection of negative psychological reactions following AD biomarker results disclosed in research settings.

Ethics Review
Camille Nebeker, Alex D. Leow, Raeanne C. Moore
From Return of Information to Return of Value: Ethical Considerations when Sharing Individual-Level Research Data
Abstract: The implementation of digital health technologies into research studies for Alzheimer’s disease and other clinical populations is on the rise. Digital tools and strategies create opportunities to further expand the framework for conducting research beyond the traditional medical research model. The combination of participatory and community-based research methods, electronic health records, and the creation of multi-dimensional, large-scale research platforms to support precision medicine, along with the Internet of Things era, have led to more engaged and informed research participants. Research participants increasingly possess an expectation they will play a critical role as partners in the design and conduct of research. Moreover, there is growing interest among research participants to have access to individual-level research data in real-time and/or at study completion. The traditional medical research model is largely one-directional where participants contribute data that is analyzed by researchers to yield generalizable knowledge. In this Ethics Review, we discuss a framework for a more nuanced intermediate research model, which is largely bidirectional and individually customized. Based on the seven ethical guidelines adopted by the National Institutes of Health, we speak to the ethical challenges of this intermediate type research. We also introduce a concept we are calling “MyTerms,” in which prospective participants tailor the terms and conditions of informed consent to their personalized preferences for receiving information, including research results. Digital health technologies offer a convenient and flexible approach for researchers to develop protocols that make it possible for participants to obtain access to their study data in a personalized and meaningful way.

Ethics Response
Meghan K. Mattos, Jennifer H. Lingler
Research Data Disclosure in the Digital Age
Abstract: New advances in digital technologies and data-collection methods support expansion of the traditional research model in the current Digital Age. As researchers continue to explore ways to collect, manage, and share individual-level research study data, investigators must also acknowledge new ethical considerations that arise. To ensure protection of research participants, participants must remain a priority across the research continuum by researchers, institutional review boards, funding agencies, and consumers. Big data and data sharing also require additional investments and oversight to ensure proper management and, and even more important, protection of human subjects.

Review
Somaiyeh Taheri-Targhi, Albert Gjedde, Mostafa Araj-Khodaei, Reza Rikhtegar, Zahra Parsian, Sina Zarrintan, Mohammadali Torbati, Manouchehr Seyedi Vafaee
Avicenna (980-1037 CE) and His Early Description and Classification of Dementia
Abstract: According to the World Health Organization (WHO), dementia is a disorder that occurs as result of a neurodegenerative process in brain, and usually is chronic or progressive by nature. Most descriptions of senile dementia date back to Alois Alzheimer. In 1906, Alzheimer described the first patient, Auguste Deter, who suffered from the disorder that later became known as Alzheimer’s disease. Although, the history of the disease before 1906 is quite rich, little has been said about the contributions of ancient and medieval physicians to the understanding of dementia. Over the centuries, the concept of senile dementia changed from an inevitable mental decline with aging, to different sets of clinical features with narrow limits of diagnosis of a disease in its own right. Documentation of the historical origins of prevention, diagnosis, and therapies of dementia would make an important contribution to a more complete understanding of this pathological degeneration of dementia. The present review focuses on the contributions of Avicenna (AD 980-1037) to the development of diagnosis and the discovery of etiology of different forms of dementia, with the goal of revealing the extent to which dementia was understood in the golden age of Islam in Persia.

Commentary
Donald E. Moss
Is Combining an Anticholinergic with a Cholinesterase Inhibitor a Good Strategy for High-Level CNS Cholinesterase Inhibition?
Abstract: The currently approved cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) produce gastrointestinal toxicity which limits dosing to that which produces only about 25% to 35% CNS cholinesterase inhibition in Alzheimer’s disease patients undergoing treatment, below the minimum therapeutic target of about 40% to 50% CNS inhibition considered necessary to treat cognitive impairment. A recent strategy for producing high-level CNS acetylcholinesterase (AChE) inhibition (50% or higher) is to co-administer a muscarinic anticholinergic with the AChE inhibitor to block the dose-limiting cholinergic overstimulation of the gastrointestinal system, allow more robust AChE inhibition in the CNS, and improve efficacy in the treatment of Alzheimer’s disease. Unfortunately, most common muscarinic anticholinergics, including solifenacin, readily penetrate the CNS and are directly associated with long-term exacerbation of the underlying neuropathology of Alzheimer’s disease and increased brain atrophy. The co-administration of an anticholinergic with an AChE inhibitor is a rational strategy for improving efficacy in the symptomatic treatment of dementia, but there are significant long-term risks that have not yet been considered. For long-term safety against accelerating the underlying disease processes in Alzheimer’s disease, anticholinergics used to increase the tolerability of AChE inhibitors should not penetrate, or have very limited penetration, of the blood-brain barrier. Neurotrophic-mediated mechanisms by which cholinergic drugs may affect neurodegeneration in Alzheimer’s disease are explored and improved treatment options are suggested.

David Lanham, Sana Ali, Daniel Davis, Mark James Rawle
Beta-Blockers for the Secondary Prevention of Myocardial Infarction in People with Dementia: A Systematic Review
Abstract: Background: Cardiovascular disease remains the most common cause of death in industrialized countries. The use of beta-blockers is well established as a secondary prevention of myocardial infarction. However, little is known about the benefits of beta-blockers for people living with dementia. Objective: To evaluate the use of beta-blockers in people with dementia who have had a myocardial infarction, in order to identify associations between medication use, mortality, re-infarction and functional decline. Methods: We searched for all studies (randomized trials, observational cohorts) reporting beta-blocker use in populations with both dementia and previous myocardial infarction. Relevant keywords were used in Medline, Embase, and Web of Science up to October 2018. Titles and abstracts were independently screened by two reviewers. Quality of eligible studies was assessed using the Newcastle-Ottawa Scale. PRISMA recommendations were followed throughout. Results: Two observational studies were included, representing 10,992 individuals in a community setting and 129,092 individuals from a hospital record-linkage study. One showed use of beta-blockers reduced all-cause mortality (HR 0.74 (95%CI 0.64-0.86) alongside evidence for an increased rate of functional decline in individuals aged ≥65 with moderate to severe cognitive impairment (OR 1.34 (95%CI 1.11-1.61)). The second study did not find an association between beta-blocker use and mortality in the population living with dementia. Conclusion: There is insufficient evidence to support use of beta-blockers to persons living with dementia. A single study provides limited evidence that beta-blockers improve survival rates but with associated detrimental effects on functional status in nursing home residents with cognitive impairment. Decisions to continue beta-blockers in persons living with dementia should be made on an individual basis.

Yuxia Li, Meimei Kang, Hongxing Wang, He Jin, Xiaozhen Wang, Wenjing Gan, Mingyan Zhao, Xing Zhao, Rong Wang Ying Han
Urinary Alzheimer-Associated Neuronal Thread Protein Is Not Elevated in Patients with Subjective Cognitive Decline and Patients with Depressive State
Abstract: Subjective cognitive decline (SCD) is a risk factor for Alzheimer’s disease (AD). Urinary Alzheimer-associated neuronal thread protein (AD7c-NTP) has been identified as a biomarker for AD. It was hypothesized that if urinary AD7c-NTP were also elevated in SCD, as it is in prodromal AD (mild cognitive impairment stage), it could be a convenient and efficient clinical biomarker for the early diagnosis of SCD. SCD is often accompanied by a depressive state (DS), and the impact of DS on urinary AD7c-NTP levels remains unknown. A total of 297 right-handed Chinese Han subjects were recruited, including 98 subjects with SCD, 92 patients with DS, and 107 well-matched cognitively normal controls (NC). The levels of AD7c-NTP in urine samples were measured using an enzyme-linked immunosorbent assay AD7c-NTP kit. Our results demonstrated that urinary AD7c-NTP levels in the SCD group (0.7561 ± 0.5657 ng/mL) were not significantly higher than in either the DS (0.7527 ± 0.5607 ng/mL) or NC (0.7214 ± 0.5077 ng/mL) groups. Furthermore, urinary AD7c-NTP levels were not correlated with Hamilton Depression Rating Scale and Hamilton Anxiety Scale scores, but they were negatively associated with Mini-Mental State Examination scores (r = –0.222, p = 0.033) and Montreal Cognitive Assessment-Basic scores (r = –0.207, p = 0.048). Urinary AD7c-NTP level is not elevated in SCD and is unaffected by DS. Urinary AD7c-NTP may therefore not be a good potential biomarker for SCD and DS, although it may become elevated with more severe cognitive decline.

Lauren K. Rudenko, Horst Wallrabe, Ammasi Periasamy, Karsten H. Siller, Zdenek Svindrych, Matthew E. Seward, Merci N. Best, George S. Bloom (Handling Associate Editor: Alejandra Alonso)
Intraneuronal Tau Misfolding Induced by Extracellular Amyloid-β Oligomers
Abstract: Abnormal folding and aggregation of the microtubule-associated protein, tau, is a hallmark of several neurodegenerative disorders, including Alzheimer’s disease (AD). Although normal tau is an intrinsically disordered protein, it does exhibit tertiary structure whereby the N- and C-termini are often in close proximity to each other and to the contiguous microtubule-binding repeat domains that extend C-terminally from the middle of the protein. Unfolding of this paperclip-like conformation might precede formation of toxic tau oligomers and filaments, like those found in AD brain. While there are many ways to monitor tau aggregation, methods to monitor changes in tau folding are not well established. Using full length human 2N4R tau doubly labeled with the Förster resonance energy transfer (FRET) compatible fluorescent prote¬ins, Venus and Teal, on the N- and C-termini, respectively (Venus-Tau-Teal), intensity and lifetime FRET measurements were able to distinguish folded from unfolded tau in living cells independently of tau-tau intermolecular interactions. When expression was restricted to low levels in which tau-tau aggregation was minimized, Venus-Tau-Teal was sensitive to microtubule binding, phosphorylation, and pathogenic oligomers. Of particular interest is our finding that amyloid-β oligomers (AβOs) trigger Venus-Tau-Teal unfolding in cultured mouse neurons. We thus provide direct experimental evidence that AβOs convert normally folded tau into a conformation thought to predominate in toxic tau aggregates. This finding provides further evidence for a mechanistic connection between Aβ and tau at seminal stages of AD pathogenesis.

Meng-Yuan Ding, Yi Xu, Ying-Zhe Wang, Pei-Xi Li, Yi-Ting Mao, Jin-Tai Yu, Mei Cui, Qiang Dong (Handling Associate Editor: Ling-Qiang Zhu)
Predictors of Cognitive Impairment After Stroke: A Prospective Stroke Cohort Study
Abstract: Background: Post-stroke cognitive impairment (PSCI) significantly affects stroke survivors’ quality of life and rehabilitation. A risk model identifying cognitive decline at admission would help to improve early detection and management of post-stroke patients. Objective: To develop a new clinical risk score for ischemic stroke survivors in predicting 6-12 months PSCI. Methods: We prospectively enrolled 179 patients diagnosed with acute ischemic stroke within a 7-day onset. Data were analyzed based on baseline demographics, clinical risk factors, and radiological parameters. Logistic regression and area under the receiver operating curve (AUROC) were used to evaluate model efficiency. Results: One hundred forty-five subjects completed a 6-12-month follow-up visit, and 77 patients (53.1%) were diagnosed with PSCI. Age (β = 0.065, OR = 1.067, 95% CI = 1.016-1.120), years of education (β = -0.346, OR = 0.707, 95% CI = 0.607-0.824), periventricular hyperintensity grading (β = 1.253, OR = 3.501, 95% CI = 1.652-7.417), diabetes mellitus (β = 1.762, OR = 5.825, 95% CI = 2.068-16.412), and the number of acute nonlacunar infarcts (β = 0.569, OR = 1.766, 95% CI = 1.243-2.510) were independently associated with 6-12 month PSCI, constituting a model with optimal predictive efficiency (AUC = 0.884, 95% CI = 0.832-0.935). Conclusions: The optimized risk model was effective in screening stroke survivors at high risk of developing 6-12 months PSCI in a simple and pragmatic way. It could be a potential tool to identify patients with a high risk of PSCI at an early stage in clinical practice after further independent external cohort validation.

Isabelle Rouch, Catherine Padovan, Elodie Pongan, Nawèle Boublay, Bernard Laurent, Jean-Michel Dorey*, Pierre Krolak-Salmon* * These authors share senior authorship.
Personality Traits Are Related to Selective Cognitive Impairment in Early Alzheimer’s Disease
Abstract: Background: A link between personality traits and cognitive performances has been shown in normal adults and elderly individuals. Very few studies have evaluated this link in Alzheimer's disease (AD). Objective: To better understand cognitive performance as regards to personality traits, our study was aimed to evaluate the role of premorbid personality on cognitive functioning in a population of patients presenting prodromal or mild AD. Methods: 181 elderly with prodromal or mild AD participated in a cross-sectional, prospective cohort study. The participants completed a personality inventory and a neuropsychological battery exploring memory, attention, executive function, language, and praxis. Cognitive performances were compared according to the level of each personality trait, using multivariate MANOVA models. Results: A higher level of neuroticism was associated with lower performances at similarities test (D=9.49, p=0.003), delayed Free and Cued Selective Reminding test (D=5.22, p=0.02), and digit span score (D=7.99, p=0.006). A higher level of openness was related to better performances at similarities (D=4.33, p=0.04), letter fluency (D=11.45, p=0.001), and category fluency test (D=5.85, p=0.02). Neuroticism interfered negatively with cognitive functioning at the prodromal stage; the association between openness and cognitive function was observed at both prodromal and mild AD stage. Conclusion: These results suggest that personality traits, in particular neuroticism and openness, modulate cognitive abilities in patients with early AD. These results encourage the development of stress management programs to prevent its negative effects on cognitive aging.

Masakazu Hashimoto, Akira Yamazaki, Atsushi Ohno, Toru Kimura, Bengt Winblad, Lars O. Tjernberg
A Fragment of S38AA Is a Novel Plasma Biomarker of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease without a cure. The pathological process starts decades before clinical onset, and thus clinical trials of drugs aimed at treating AD should start at a presymptomatic stage. Therefore, it is critical to diagnose AD at an early stage. Tau, phosphorylated tau, and amyloid-β peptide (Aβ) in cerebrospinal fluid (CSF), and positron emission tomography (PET) imaging of Aβ or tau accumulation are supportive biomarkers for AD diagnosis, but there is no reliable presymptomatic diagnostic marker. Since CSF sampling is invasive, and PET imaging is expensive and available only at specialized centers, a reliable blood biomarker has long been sought for. Here we describe a novel extramembrane fragment from solute carrier family 38 member 10 (SLC38A10, S38AA) that we found to be decreased in pyramidal neurons in AD cases by proteomics and immunohistochemical analysis. We detected a S38AA fragment in CSF and found the levels to correlate with severity of AD and APOE genotype. Importantly, the plasma levels of the fragment also showed a significant correlation with Mini-Mental State Examination scores in AD. Moreover, plasma from other neurodegenerative disease was analyzed and the fragment was found to be increased specifically in AD. Interestingly, the fragment is detected in mouse, rat, and monkey, and increases in amyloid precursor protein transgenic mice as the AD-like pathology progresses. We propose that the S38AA fragment in plasma could be a novel quantitative diagnostic marker for AD and potentially a marker of disease progression in AD.

Zongjun Guo*, Xing Peng*, Hui-Yun Li*, Yunlai Wang, Ying Qian, Zhihong Wang, Dongqing Ye, Xiaoyun Ji, Zhixin Wang, Yanjiang Wang, Dongwan Chen, Hongxing Lei (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Evaluation of Peripheral Immune Dysregulation in Alzheimer’s Disease and Vascular Dementia
Abstract: Immune dysregulation has been observed in the brain and blood of patients with Alzheimer’s disease (AD). However, a convenient assay to evaluate peripheral immune dysregulation in AD has not been developed, partly due to the inconsistent observations from different studies. We hypothesized that peripheral immune dysregulation may only exist in a subpopulation of AD patients; therefore it may be valuable to identify this subpopulation with a convenient assay. Along this line, we selected 14 candidate genes based on our analysis of microarray data on peripheral blood of AD and other diseases. We used RT-qPCR to examine the expression of these 14 genes in a cohort of 288 subjects, including 74 patients with AD, 64 patients with mild cognitive impairment (MCI), 51 patients with vascular dementia (VaD), and 99 elderly controls with no cognitive dysfunction/impairment. Seven of these 14 genes displayed significant difference in group comparison. Switching from group comparison to individualized evaluation revealed more in-depth information. First, there existed a wide dynamic range for the expression of these immune genes in peripheral blood even within the control group. Second, for the vast majority of the patients (AD, VaD, and MCI patients), the expression of these genes fell within the dynamic range of the control group. Third, a small portion of outliers were observed in the patient groups, more so in the VaD group than that in the AD or MCI groups. This is our first attempt to conduct personalized evaluation of peripheral immune dysregulation in AD and VaD. These findings may be applicable to the identification of peripheral immune dysregulation in AD and VaD patients which may lead to tailored treatment toward those patients.

Shunichi Yokoyama, Takuma Yoshinaga, Juntaro Matsuzaki, Hidekazu Suzuki
A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Teprenone in Patients with Alzheimer’s Disease
Abstract: Background: Teprenone (geranylgeranylacetone), an anti-ulcer agent, has been reported to inhibit amyloid-beta increase, senile plaque formation, and neuronal degeneration, and improve memory in mouse models of Alzheimer’s disease (AD). Objective: We conducted a randomized, double-blind, placebo-controlled study to ascertain teprenone’s therapeutic ability for AD. Methods: Patients with mild to moderate AD, with a Mini-Mental State Examination (MMSE) score of 13 to 26, were randomly allocated into two groups depending on the administered drug: donepezil + placebo (placebo group) and donepezil + teprenone (teprenone group). The primary and secondary endpoints included changes in scores of the Japanese version of the AD Assessment Scale-cognitive subscale (ADAS-J cog) and other evaluations, respectively, including MMSE scores, during a 12-month period after the first administration. Results: Forty-two and thirty-seven patients were allocated to the teprenone and placebo groups, respectively. ADAS-J cog score changes were not different between groups (placebo, 0.6 ± 0.8; teprenone, 0.4 ± 0.8; p = 0.861). However, MMSE scores significantly improved in the teprenone group (placebo, -1.2 ± 0.5; teprenone, 0.2 ± 0.5; p = 0.044).Subgroup analysis considering the severity of medial temporal area atrophy revealed that this improvement by teprenone was significant in patients with mild (p = 0.013) but not with severe atrophy (p = 0.611). Adverse events were observed in 17.8 and 10.4% of patients in the placebo and teprenone group, respectively. Conclusion: Teprenone may be effective for AD when administered before atrophy progression in the medial temporal areas. Trial Registration: UMIN ID: UMIN000016843

Paraskevi Iliadou*, Anastasia Kladi*, Christos A. Frantzidis, Sotiria Gilou, Ioanna Tepelena, Moses Gialaouzidis, Vasileios Papaliagkas, Vasilis Nigdelis, Christiane M. Nday, Grigorios Kiosseoglou, Georgia Papantoniou, Panagiotis D. Bamidis, Magda Tsolaki, Despina Moraitou *These authors contributed equally to this work.
The Pattern of Mu Rhythm Modulation During Emotional Destination Memory: Comparison Between Mild Cognitive Impairment Patients and Healthy Controls
Abstract: Leading theories of affect development and empirical studies suggest that emotion can enhance memory in older adults. Destination memory which is defined as the ability to remember to whom we told a piece of information is being found to be compromised in aging. In the present study, we sought to assess destination memory using emotional stimuli (Emotional Destination Memory, EDM) in 16 older adults with mild cognitive impairment (MCI) and 16 healthy controls and shed light onto its potential neurophysiological aspects. We measured Mu suppression in frontal and temporal regions via EEG in real time while participants performed the task of EDM. Results showed no group differences in task performance but significant differences in fronto-temporal activations, specifically in electrodes F7 and F8. Differential Mu rhythm pattern was observed between healthy controls and MCI with the first exhibiting Mu suppression and the last Mu enhancement. Furthermore, Mu enhancement in temporal electrodes within the MCI group was associated with lower scores on EDM. The absence of group differences in the task can be explained by the fact that even if there are underlying structural or functional deficits in the MCI group, these deficits are manifested only at neurophysiological level and not at a behavioral level, which is a common pattern in the process of cognitive decline in its initial phases. The overall findings reveal that, even if there are not any behavioral decrements in MCI patients, they show reduced activations in fronto-temporal regions and this can be attributed to general impairment in emotional destination memory due to possible mirror neuron deficiency.

Kalicharan Patra*, Andreas Giannisis*, Anna K. Edlund, Sigrid Botne Sando, Camilla Lauridsen, Guro Berge, Gøril Rolfseng Grøntvedt, Geir Bråthen, Linda R. White, Henrietta M. Nielsen (Handling Associate Editor: Benedatta Nacmias) *These authors contributed equally to this work.
Plasma Apolipoprotein E Monomer and Dimer Profile and Relevance to Alzheimer’s Disease
Abstract: The APOE ε4 gene variant is the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE ε3 conventionally is considered as ‘risk neutral’ although APOE ε3-carriers also develop AD. Previous studies have shown that the apolipoprotein E3 (apoE3) isoform occurs as monomers, homodimers, and heterodimers with apolipoprotein A-II in human body fluids and brain tissue, but the relevance of a plasma apoE3 monomer/dimer profile to AD is unknown. Here we assessed the distribution of monomers, homodimers, and heterodimers in plasma from control subjects and patients with mild cognitive impairment (MCI) and AD with either a homozygous APOE ε3 (n=31 control subjects, and n=14 MCI versus n=5 AD patients) or APOE ε4 genotype (n=1 control subject, n=21 MCI and n=7 AD patients). Total plasma apoE levels were lower in APOE ε4-carriers and overall correlated significantly to CSF Aβ42, p(Thr181)-tau, and t-tau levels. Apolipoprotein E dimers were only observed in the APOE ε3-carriers and associated with total plasma apoE levels, negatively correlated to apoE monomers, but unrelated to plasma homocysteine levels. Importantly, the APOE ε3-carrying AD patients versus controls exhibited a significant decrease in apoE homodimers (17.8±9.6% versus 26.7±6.3%, p=0.025) paralleled by an increase in apoE monomers (67.8±18.3% versus 48.5±11.2%, p=0.008). In the controls, apoE monomers and heterodimers were significantly associated with plasma triglycerides; the apoE heterodimers were also associated with levels of high-density lipoprotein cholesterol. The physiological relevance of apoE dimer formation needs to be further investigated, though the distribution of apoE in monomers and dimers appears to be of relevance to AD in APOE ε3 subjects.

Antti J. Luikku, Anette Halla, Ossi Nerg, Anne M. Koivisto, Mikko Hiltunen, Seppo Helisalmi, Sanna-Kaisa Herukka, Antti Junkkari, Anna Sutela, Maria Kojoukhova, Ville Korhonen, Jussi Mattila, Jyrki Lötjönen, Jaana Rummukainen, Irina Alafuzoff, Juha E. Jääskeläinen, Anne M. Remes, Alina Solomon, Miia Kivipelto, Hilkka Soininen, Tuomas Rauramaa*, Ville Leinonen* *These authors contributed equally to this work.
Predicting Development of Alzheimer’s Disease in Patients with Shunted Idiopathic Normal Pressure Hydrocephalus
Abstract: Background: Idiopathic normal pressure hydrocephalus (iNPH) patients often develop Alzheimer’s disease (AD) related brain pathology. Disease State Index (DSI) is a method to combine data from various sources for differential diagnosis and progression of neurodegenerative disorders. Objective: To apply DSI to predict clinical AD in shunted iNPH-patients in a defined population. Methods: 335 shunted iNPH-patients (median 74 years) were followed until death (n=185) or 6/2015 (n=150). DSI model (including symptom profile, onset age of NPH symptoms, atrophy of medial temporal lobe in CT/MRI, cortical brain biopsy finding, and APOE genotype) was applied. Performance of DSI model was evaluated with receiver operating characteristic (ROC) curve analysis. Results: A total of 70 (21%) patients developed clinical AD during median follow-up of 5.3 years. DSI-model predicted clinical AD with moderate effectiveness (AUC = 0.75). Significant factors were cortical biopsy (0.69), clinical symptoms (0.66), and medial temporal lobe atrophy (0.66). Conclusion: We found increased occurrence of clinical AD in previously shunted iNPH patients as compared with general population. DSI supported the prediction of AD. Cortical biopsy during shunt insertion seems indicated for earlier diagnosis of comorbid AD.

Aurélie Ledreux, Krister Håkansson, Roger Carlsson, Mhretab Kidane, Laura Columbo, Yvonne Terjestam, Eliza Ryan, Erich Tusch, Bengt Winblad, Kirk Daffner, Ann-Charlotte Granholm*, Abdul Kadir H. Mohammed* * ACG and AKHM share co-senior authorship on the study.
Differential Effects of Physical Exercise, Cognitive Training, and Mindfulness Practice on Serum BDNF Levels in Healthy Older Adults: A Randomized Controlled Intervention Study
Abstract: Previous studies have indicated that an active lifestyle is associated with better brain health and a longer life, compared to a more sedentary lifestyle. These studies, both on human and animal subjects, have typically focused on a single activity, usually physical exercise, but other activities have received an increasing interest. One proposed mechanism is that physical exercise increases levels of brain-derived neurotrophic factor (BDNF) in the brain. For the first time, the long-term effects on serum BDNF levels were compared in persons who engaged in either physical exercise training, cognitive training, or mindfulness practice during 5 weeks, and compared with an active control group. Two cohorts of healthy older individuals, one from the Boston area in the US and one from the Växjö area in Sweden, participated. A total of 146 participants were randomly assigned to one of the four groups. All interventions were structurally similar, using interactive, computer-based software that directed participants to carry out specified activities for 35 minutes/day, 5 days per week for 5 weeks. Blood samples were obtained at baseline and soon after the completion of the 5-week long intervention program, and serum BDNF levels were measured using a commercially available ELISA. Only the group that underwent cognitive training increased their serum BDNF levels after 5 weeks of training (F1,74 = 4.22, p = 0.044, partial η2 = 0.054), corresponding to an average 10% increase. These results strongly suggest that cognitive training can exert beneficial effects on brain health in an older adult population.

Gäetan Chanteloup*, Marine Cordonnier*, Teresa Moreno-Ramos, Vanesa Pytel, Jorge Matías-Guiu, Jessica Gobbo, María Nieves Cabrera-Martín, Ulises Gómez-Pinedo, Carmen Garrido, Jordi A Matías-Guiu *These authors contributed equally to this work.
Exosomal HSP70 for Monitoring of Frontotemporal Dementia and Alzheimer’s Disease: Clinical and FDG-PET Correlation
Abstract: We aimed to study the expression of circulating heat-shock protein HSP70 and exosomes in plasma of a cohort of patients with Alzheimer’s disease (AD) and frontotemporal dementia (FTD) at different stages. We performed correlations with clinical scales and FDG-PET. HSP70 levels were higher within exosomes than free in plasma. Moderate correlations were found between exosomal HSP70 and CDR, FTLD-CDR, and extension of hypometabolism. Our results suggest modifications in the level of exosomal HSP70 during the course of neurodegeneration, regardless of AD or FTD, and therefore HSP70 could have a potential role in the follow-up of these disorders.

Melissa Lamar, Adeline Leόn, Karina Romo, Ramon A. Durazo-Arvizu, Shruti Sachdeva, Richard B. Lipton, Krista M. Perreira, Linda C. Gallo, Jianwen Cai, Tasneem Khambaty, Jessica Carrasco, Maria M. Llabre, Lisa T. Eyler, Martha L. Daviglus, Hector M. González (Handling Associate Editor: Gali Weissberger)
The Independent and Interactive Associations of Bilingualism and Sex on Cognitive Performance in Hispanics/Latinos of the Hispanic Community Health Study/Study of Latinos
Abstract: Sixty percent of Hispanics/Latinos are bilingual which research suggests may confer certain cognitive advantages. Female sex confers cognitive advantages in verbal learning and memory compared to male sex, regardless of race or ethnicity. Understanding the independent and interactive associations of bilingualism and sex with cognition may aid in predicting cognitive aging in Hispanics/Latinos. We examined baseline (2008-2011) data from the Hispanic Community Health Study/Study of Latinos, a multicenter, prospective community-based study. Our analyses included 6,110 males and females ≥45 years old who self-reported birth and parents’ origin outside of the continental US, Spanish as their first language, and were evaluated in Spanish. Bilingualism was assessed along a Likert scale (1=only Spanish to 4=English>Spanish) for language proficiency (reading/spoken) and patterns of use (thinking/socializing). Cognitive testing included verbal learning, memory, fluency, and Digit Symbol Substitution (DSS). Linear regression models adjusted for relevant confounders, the complex survey design, and sampling weights. Participants’ self-reported language proficiency was Spanish better than English, while patterns of use suggested more Spanish than English. Higher language proficiency was associated with higher performance on all cognitive indices while higher patterns of use associated with higher fluency and DSS scores (p-values<0.01). Female sex was associated with higher performance on all cognitive indices (p-values<0.05). There were no significant interactions with bilingualism (regardless of metric) by sex on cognition. For Hispanics/Latinos residing in the continental US and reporting birth and parents’ origin elsewhere, bilingualism and female sex have independent cognitive benefits that are important to consider when evaluating cognitive performance.

Aida Suarez-Gonzalez, Dilek Ocal, Ivanna Pavisic, Ashley Peacock, Michelle Naessens, Samrah Ahmed, Christopher R. Butler, Alexander P. Leff, Keir X.X. Yong, Sebastian J. Crutch
ReadClear: An Assistive Reading Tool for People Living with Posterior Cortical Atrophy
Abstract: Background: Progressive reading impairment is an early and debilitating symptom of posterior cortical atrophy (PCA) arising from the progressive deterioration of visual processing skills. Objective: The goal of this study was to test the effectiveness of a purpose-built reading app (ReadClear) co-produced with people living with PCA and designed to reduce the reading difficulties experienced by this population (e.g., getting lost in the page and missing words when reading). Methods: Twenty subjects with PCA were included in a cross-over design home-based study aimed at determining whether ReadClear could 1) enhance the subjective reading experience (reading pleasantness) and 2) improve reading accuracy (reducing the number of reading errors) compared with a sham condition (a standard e-reader). Results: Reading using ReadClear provided a better subjective reading experience than sham (p = 0.018, d = 0.5) and significantly reduced the percentage of reading errors (p < 0.0001, r = 0.82), particularly errors due to omissions (p = 0.01, r = 0.50), repeated words (p = 0.002, r = 0.69), and regressions in the text (p = 0.003, r = 0.69). We found that different kinds of reading errors were related to specific neuropsychological profiles. Conclusion: ReadClear can assist reading in people living with PCA by reducing the number of reading errors and improving the subjective reading experience of users.

Miika Linna, Sauli Vuoti, Katariina Silander, Iiris Hörhammer, Olli Halminen, Teija Mikkola, Päivi Koivuranta-Vaara, Lauri J. Virta, Mirkka Koivusalo, Tero Ylisaukko-oja
Impact of Anti-Dementia Medication on the Risk of Death and Causes of Death in Alzheimer’s Disease
Abstract: Background: The Finnish population offers many advantages for evaluating the impact of anti-dementia medication on mortality in Alzheimer’s disease (AD) due to broad range of individual-level data collected in national health and social care registries and the fact that Finland has one of the highest mortality rates for dementia globally. Objective: The aim of this study was to investigate the association of anti-dementia medication with 2-year risk of death and all-cause mortality in patients with AD. Methods: This was a retrospective, non-interventional registry study based on individual-level data using Finnish national health and social care registries. An incident cohort of 9,204 AD patients (first AD diagnosis in 2012) was formed from a population of 316,470 individuals ≥74 years of age. The main outcome measure was overall 2-year risk of death. Statistical modelling was used to assess mortality (Kaplan-Meier) and adjusted hazard ratios (HR) (Cox proportional hazard model). Results: Early start of anti-dementia medication (treatment started ≤3 months from AD diagnosis) reduced significantly the risk of all-cause death compared to AD patients who had late medication initiation (defined as treatment started >3 months from AD diagnosis/no medication); HR, 0.51; 95% confidence interval (CI), 0.46–0.57). Dementia was the most common recorded cause of death in both groups. Conclusion: This study places importance on early diagnosis of AD and subsequent early initiation of drug treatment in decreasing 2-year risk of death.

Bibek Gyanwali*, Muhammad Amin Shaik*, Narayanaswamy Venketasubramanian, Christopher Chen, Saima Hilal *These authors contributed equally to this work.
Mixed-Location Cerebral Microbleeds: An Imaging Biomarker for Cerebrovascular Pathology in Cognitive Impairment and Dementia in a Memory Clinic Population
Abstract: Background: Cerebral microbleeds (CMBs) in the lobar and deep locations have been associated with two distinct pathologies namely cerebral amyloid angiopathy (CAA) and hypertensive arteriopathy. However, the role of mixed-location CMBs in cerebrovascular disease and cognitive impairment remain unexplored. Objective: The present study aims to investigate the association of strictly lobar, strictly deep and mixed-location CMBs with cognitive impairment and dementia as well as functional decline. Methods: A prospective case-control study, where 520 patients underwent 3T brain MRI to assess region and lobe-specific CMBs, and other cerebrovascular diseases (CeVD) markers such as cortical infarcts, lacunes, and white matter hyperintensities. Patients were classified as no cognitive Impairment, cognitive impairment no dementia (CIND), and dementia [Alzheimer’s disease (AD) and vascular dementia (VaD)]. Severity of cognitive impairment was assessed using Clinical Dementia Rating scale. Results: Mixed-location CMBs were associated with dementia [Odds ratio (OR):1.23; 95% confidence interval (CI):1.04, 1.47]. When stratified by the presence of CeVD, mixed-location CMBs were associated with CIND [OR:1.20;95% CI:1.02, 1.42], AD [OR:1.22;95% CI:1.02, 1.46], and VaD [OR:1.33;95% CI:1.08, 1.62]. Furthermore, CMBs in frontal, parietal, and temporal regions were associated with CIND whereas those in parietal, temporal, and occipital regions were associated with AD. Mixed-location CMBs were also associated with increased severity of cognitive impairment [OR:1.02; 95% CI:1.00, 1.05]. Conclusion: Mixed-location CMBs are associated with cognitive impairment and dementia in the presence of CeVD. Furthermore mixed-location CMBs were linked with increased severity of cognitive impairment, suggesting severe parenchymal damage as well as microangiopathy to be common underlying mechanisms in the elderly.

Maurizio Gallucci, Claudia Pallucca, Maria Elena Di Battista, Bertrand Fougère, Enzo Grossi (Handling Associate Editor: Beatrice Arosio)
Artificial Neural Networks Help to Better Understand the Interplay Between Cognition, Mediterranean Diet, and Physical Performance: Clues from TRELONG Study
Abstract: Background: Nutrition plays an important role in the aging process. Adherence to the Mediterranean diet (MedDiet) has been shown to be associated with lower rates of diseases. Cognitive status seems to be strongly interrelated with physical well-being, so that one influences the other. Physical performance measures are not only associated with clinical and subclinical age-related modifications, but are also able to predict disability, institutionalization, and mortality. Objective: To evaluate prospectively the associations between Mediterranean-Style Dietary Pattern Score (MSDPS), clinical characteristics, and cognition of the population sample of The TREVISO LONGEVA (TRELONG) Study, in Treviso, Italy. Methods: Global cognition, physical performance measures, MSDPS, and other clinical features were detected in 2010 in 82 men and 108 women. These characteristics were evaluated in relation to the physical performance measures identified 3.8 years later in 2013 in the same subjects, using a semantic connectivity map, through Auto-CM system, to grasp further and non-linear associations between variables which might remain, otherwise, undetected. Results: The Auto-CM system’s map shows a close association between better levels of global cognition and MSDPS in 2010 and higher physical performance in 2013. On the other hand, worse levels of global cognition and MSDPS in 2010 are associated with lower physical performance in 2013. Conclusion: The prevention models for successful aging may benefit from integrated programs that include cognitive, physical, and dietary interventions, since these aspects are mutually interrelated.

Heng Xu, Chengjin Yue, Lin Chen (Handling Associate Editor: Yong Guo)
Post-Transcriptional Regulation of Soluble Guanylate Cyclase that Governs Neuropathic Pain in Alzheimer’s Disease
Abstract: Many patients with Alzheimer’s disease suffer from severe neuropathic pain. Soluble guanylate cyclase (sGC) is a critical enzyme of the nitric oxide (NO) signaling pathway. Binding of NO to a group of prosthetic heme on sGC initiates the second messenger cGMP synthesis, resulting in increases in the mechanical threshold for neuropathic pain. Nevertheless, the regulation of sGC remains unclear. Here, we aimed to figure out a strategy to reduce sGC levels by microRNA (miRNA) intervention. Bioinformatical studies were then performed to predict sGC-targeting miRNAs; additionally, an assay of dual luciferase reporter was used for evaluating the functional binding of miRNAs to sGC. Among all sGC-targeting miRNAs, in particularly we found that miR-142-5p markedly inhibited sGC protein translation by pairing to the 3’-UTR of the sGC mRNA. Orthotopic injection of adeno-associated virus carrying miR-142-5p significantly decreased sGC and sGMP levels, resulting in reduction of the neuropathic pain in rats with the left hind leg sciatic nerve injured in the tibia and peroneal branches. In summary, these data show that miR-142-5p induction in injured neurons may be an effective treatment for neuropathic pain and worthy of further investigation as a treatment for those patients with Alzheimer’s disease and neuropathic pain.

Eric Frison, Carole Dufouil, Catherine Helmer, Claudine Berr, Sophie Auriacombe, Geneviève Chêne (Handling Associate Editor: Ramit Ravona-Springer)
Diabetes-Associated Dementia Risk and Competing Risk of Death in the Three-City Study
Abstract: Diabetes is associated with a higher dementia and mortality risk. However, few studies have accounted for death when estimating the association between diabetes and dementia. We estimated absolute and relative risks of all-cause dementia according to diabetes exposure status in older adults while accounting for competing risk of death using illness-death models. Effect modification by specific characteristics (age, gender, education, cardiovascular risk factors, body mass index, cardiovascular history, depressive symptomatology, impaired renal function, and APOE ε4 genotype) was also investigated. We analyzed the Three-City study data, a French population-based cohort of adults aged 65 years and above who were followed up for 12 years from 1999-2001. Among 8,328 participants selected in the analytical sample (median age, 73.3 years; 60.3% women), 809 (9.3%) presented with diabetes at baseline. Over a median follow-up period of 8.3 years, 836 participants developed incident dementia. Baseline diabetes was associated with a higher risk of dementia: hazard ratio, 1.79 [95% confidence interval, 1.46-2.19]. No effect modification was shown. Diabetes was associated with a higher 12-year absolute risk of dementia and a lower dementia-free life expectancy (e.g., 14.5% [11.2-18.1] versus 8.7% [7.6-10.2], and 13.4 [12.7-14.1] years versus 16.5 [16.0-17.1] years, respectively, for a 70-year-old woman with the highest level of education). These findings support the potential impact of preventing diabetes on reducing dementia risk in older adults, with a 2-3-year higher dementia-free life expectancy for individuals without diabetes, and inform the design of future interventional trials.

Nicole M. Ralbovsky, Lenka Halámková, Kathryn Wall, Cay Anderson-Hanley, Igor K. Lednev
Screening for Alzheimer’s Disease Using Saliva: A New Approach Based on Machine Learning and Raman Hyperspectroscopy
Abstract: Background: Alzheimer’s disease and related dementias (ADRDs) are being diagnosed at epidemic rates, with incidence to triple from 35 to 115 million cases worldwide. Most ADRDs are characterized by progressive neurodegeneration, and Alzheimer’s disease (AD) is the sixth leading cause of death in the United States. The ideal moment for diagnosing ADRDs is during the earliest stages of its progression; however, current diagnostic methods are inefficient, expensive, and unsuccessful at making diagnoses during the earliest stages of the disease. Objective: The aim of this project was to utilize Raman hyperspectroscopy in combination with machine learning to develop a novel method for the diagnosis of AD based on the analysis of saliva. Methods: Raman hyperspectroscopy was used to analyze saliva samples collected from normative, AD, and mild cognitive impairment (MCI) individuals. Genetic Algorithm and Artificial Neural Networks machine learning techniques were applied to the spectral dataset to build a diagnostic algorithm. Results: Internal cross-validation showed 99% accuracy for differentiating the three classes; blind external validation was conducted using an independent dataset to further verify the results, achieving 100% accuracy. Conclusion: Raman hyperspectroscopic analysis of saliva has a remarkable potential for use as a non-invasive, efficient, and accurate method for diagnosing AD.

Elizabeth M. Rhea, Surabhi Nirkhe, Steven Nguyen, Sarah Pemberton, Theo K. Bammler, Richard Beyer, Michael L. Niehoff, John E. Morley, Susan A. Farr, William A. Banks
Molecular Mechanisms of Intranasal Insulin in SAMP8 Mice
Abstract: Research on intranasal delivery of drugs, peptides, and proteins has grown over the past decade as an alternate way to deliver substrates to the brain. Recent work has shown intranasal (INL) delivery of insulin improves memory and cognition in healthy subjects as well as patients with Alzheimer’s disease (AD) and in AD mouse models. However, the molecular mechanism(s) for the beneficial effect of insulin on memory are still unclear. Using the SAMP8 mouse model of AD, we investigated the impact of INL insulin on protein and gene expression in brain regions including the olfactory bulb, hypothalamus, and hippocampus. We found genes and proteins in the insulin receptor signaling pathway were not activated by the doses tested. However, we did find the expression of genes present in the hippocampus involved in other pathways, especially those related to inflammation, were altered due to age and with a dose of INL insulin previously shown to improve cognition. These alternate pathways could be targets of insulin when delivered via the INL route to aid in memory improvement.