Volume 70, Number 1, 2019

Pages 1-10

Ewa M. Guzik-Makaruk, Emil W. Pływaczewski, Katarzyna Laskowska, Wojciech Filipkowski, Emilia Jurgielewicz-Delegacz, Piotr Mroczko (Handling Associate Editor: Piotr Lewczuk)
A Comparative Analysis of the Treatment of Decision-Making by or for Patients with Neurodegenerative Diseases in Four Legal Jurisdictions
Abstract: Dementia is associated with the gradual impairment of mental ability. The population of people suffering from dementia is as large as 50 million. Most dementia cases result from various neurodegenerative diseases (NDs) linked by a progressive degeneration of neurons. Among NDs, Alzheimer’s disease (AD) is the most frequent cause of dementia and accounts for 60-80% of cases. Certain pathological changes on the cellular and subcellular level occur even 15 years before the manifestation of clinical symptoms of AD. This first asymptomatic phase of AD is considered a preclinical stage, whereas mild cognitive impairment (MCI) is the symptomatic pre-dementia stage. The third, fully symptomatic phase of AD is dementia due to AD. The presence of specific proteins in the cerebrospinal fluid (CSF) may be considered as a characteristic feature of some NDs. The measurement of their CSF concentrations, together with neuropsychological examination and neuroimaging, may be useful for diagnosing AD. The collection of CSF samples is performed by lumbar puncture, which is a medical procedure that requires obtaining informed consent from patients. While asymptomatic AD patients have full legal capacity, those with dementia require a legal guardian who will represent them. Thus, the objective of this study is to compare the legal systems regulating the legal capacity issue in the USA, U.K. (England and Wales), Germany, and Poland. These countries have been chosen as examples of three different types of legal orders, according to the sources of law, i.e., civil law, common law, and case law.

Pages 11-15
Short Communication

Fiammetta Monacelli, Lucia Martella, Maria Nives Parodi, Patrizio Odetti, Francesca Fanelli, Massimo Tabaton
Frontal Variant of Alzheimer’s Disease: A Report of a Novel PSEN1 Mutation
Abstract: Alzheimer’s disease may mimic frontotemporal dementia. We describe a case of presenile dementia who presented with peudo-psychotic symptoms carrying a PSEN1 mutation (P355S), which was not known to be pathogenic. PET-FDG showed bilateral frontotemporal hypometabolism, but at MRI, multiple microbleeds were detected, suggestive of amyloid angiopathy.

Pages 17-23
Short Communication

Li Dong Niu*, Rui Yin*, Jie-Qiong Li, Xi-Peng Cao, Jin-Tai Yu, Lan Tan, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu) *These authors contributed equally to this work.
Common Variants in ABI3 Influence Cerebrospinal Fluid Total Tau Levels and Cognitive Decline in Progressive Mild Cognitive Impairment Patients
Abstract: A potential role for ABI3 gene has been suggested in the risk of Alzheimer’s disease (AD), but the detailed mechanism before typical AD onset was unclear. In this study, we investigated the associations of ABI3 common variants with cerebrospinal fluid biomarkers and cognitive function scores among non-demented elderly from the ADNI database. We found that, in the progressive mild cognitive impairment group, rs5978930 was associated with total tau levels and rs16947151 was associated with cognitive function scores at baseline and over time, suggesting that ABI3 variants may be associated with cognitive decline and may influence AD onset through tau pathology.

Pages 25-34
Simon Dietlin, Maria Soto, Vera Kiyasova, Maria Pueyo, Adelaïde de Mauleon, Julien Delrieu, Pierre Jean Ousset, Bruno Vellas
Neuropsychiatric Symptoms and Risk of Progression to Alzheimer’s Disease among Mild Cognitive Impairment Subjects
Abstract: Background: Neuropsychiatric symptoms (NPS) are prevalent in mild cognitive impairment (MCI), but we do not know much about their role in progression to dementia. Objective: To investigate NPS and the risk of progression to probable Alzheimer’s disease dementia (AD) among subjects with MCI. Methods: 96 MCI participants were followed for 4 years. Progression to probable AD was defined by the change of CDR total score from 0.5 to ≥1, reviewed by an expert consensus panel. NPS were determined using the Neuropsychiatric Inventory (NPI) 12-items. This study analyzed prognostic value of each NPI item and 5 sub-syndromes of NPS (apathy, psychosis, affective, hyperactivity, and vegetative) for prediction of progression to probable AD. A Cox proportional hazard model was used; hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with time dependent variable to compare the incidence of progression considering presence/absence of any NPS or sub-syndromes throughout the study. Results: The presence of symptoms “agitation/aggression”, “delusions”, and “aberrant motor behavior” significantly increased the risk of probable AD (HR= 3.9; 95%CI= 1.9-8.2; HR= 13.9; 95%CI= 4.1-48.9; HR= 4.3; 95%CI= 1.7-10.3, respectively). The presence of sub-syndromes “psychosis” and “hyperactivity” were also predictors of progression (HR= 14.0; 95%CI= 4.4-44.5; HR= 2.0; 95%CI= 1.1-3.7, respectively). These results did not change after adjusting by potential confounders. Conclusion: Presence of delusions, agitation/aggression, and aberrant motor behavior is predictor of progression to probable AD.

Pages 35-49
Jirayu Tanprasertsuk, Elizabeth J. Johnson, Mary Ann Johnson, Leonard W. Poon, Peter T. Nelson, Adam Davey, Peter Martin, Aron K. Barbey, Kathryn Barger, Xiang-Dong Wang, Tammy M. Scott (Handling Associate Editor: Sid O'Bryant)
Clinico-Neuropathological Findings in the Oldest Old from the Georgia Centenarian Study
Abstract: Background: Centenarian studies are important sources for understanding of factors that contribute to longevity and healthy aging. Clinico-neuropathological finding is a key in identifying pathology and factors contributing to age-related cognitive decline and dementia in the oldest old. Objective: To characterize the cross-sectional relationship between neuropathologies and measures of premortem cognitive performance in centenarians. Methods: Data were acquired from 49 centenarians (≥98 years) from the Georgia Centenarian Study. Cognitive assessment from the time point closest to mortality was used (<1 year for all subjects) and scores for cognitive domains were established. Neuropathologies [cerebral atrophy, ventricular dilation, atherosclerosis, cerebral amyloid angiopathy (CAA), Lewy bodies, hippocampal sclerosis (HS), hippocampal TDP-43 proteinopathy, neuritic plaque (NP) and neurofibrillary tangle (NFT) counts, Braak staging, and National Institute on Aging-Reagan Institute (NIARI) criteria for the neuropathological diagnosis of Alzheimer’s disease (AD)] were compared among subjects with different ratings of dementia. Linear regression was applied to evaluate the association between cognitive domain scores and neuropathologies. Results: Wide ranges of AD-type neuropathological changes were observed in both non-demented and demented subjects. Neocortical NFT and Braak staging were related to clinical dementia rating. Neocortical NFT and NP, Braak and NIARI staging, cerebral and ventricular atrophy, HS, CAA, and TDP-43 proteinopathy were differentially associated with poor performance in multiple cognitive domains and activities of daily living. Conclusion: AD-type pathology was associated with severe dementia and poor cognition but was not the only variable that explained cognitive impairment, indicating the complexity and heterogeneity of pathophysiology of dementia in the oldest old.

Pages 51-60
Jee Eun Park, So Yeon Jeon, Se An Kim, Jin Ha Kim, Sun Hwa Kim, Kyung Won Lee, Yun Jung Hwang, Gijung Jung, Hye Won Suk, Saejong Park, Dong Young Lee
A Multidomain Intervention for Modifying Lifestyle Habits Reduces the Dementia Risk in Community-Dwelling Older Adults: A Single-Blinded Randomized Controlled Pilot Study
Abstract: We aimed to examine the feasibility and effectiveness of a multidomain intervention including intensive and maintenance programs for reducing the risk of dementia in at-risk older adults. Community-dwelling older adults (aged ≥60 years) without dementia but having several risk factors for dementia (N = 32; 89% female; mean age ± standard deviation, 76.8 ± 4.7 years) were assigned to three parallel programs: intensive plus maintenance (INT+MNT), intensive only (INT-only), and active control. Subjects in INT+MNT and INT-only groups participated in a 4-week intensive group-based lifestyle modification program that focused on physical activity, vascular risk factors, dietary habits, cognitive activities, and social engagement. INT+MNT participants underwent an additional 20-week maintenance program to consolidate modified habits. The modified Australian National University-Alzheimer’s Disease Risk Index (ANU-ADRI) score was used as the primary outcome measure for dementia risk. The changes in ANU-ADRI scores exhibited a significant group-by-time interaction: the INT+MNT group showed significant improvement at 24 weeks (β = -6.05; SE = 1.86; p = 0.002), while the INT-only group did not. Additional exploratory analyses showed that the reduction in ANU-ADRI scores was caused by changes in protective factors rather than in risk factors. The INT+MNT group also showed greater improvement in executive function at 4 and 24 weeks (both p = 0.044), whereas changes in global cognitive function did not reach significance (p = 0.055). A 24-week multidomain dementia prevention involving a maintenance strategy for sustaining modified lifestyle habits reduced the risk of dementia and improved executive function in at-risk older adults.

Pages 61-73
Hana Markova, Tomas Nikolai, Adela Fendrych Mazancova, Katerina Cechova, Katerina Sheardova, Hana Georgi, Miloslav Kopecek, Jan Laczó, Jakub Hort, Martin Vyhnalek (Handling Associate Editor: Katherine Gifford)
Differences in Subjective Cognitive Complaints Between Non-Demented Older Adults from a Memory Clinic and the Community
Abstract: Background: Subjective cognitive complaints (SCCs) may represent an early cognitive marker of Alzheimer's disease (AD). There is a need to identify specific SCCs associated with an increased likelihood of underlying AD. Objective: Using the Questionnaire of Cognitive Complaints (QPC), we evaluated the pattern of SCCs in a clinical sample of non-demented older adults in comparison to cognitively healthy community-dwelling volunteers (HV). Methods: In total, 142 non-demented older adults from the Czech Brain Aging Study referred to two memory clinics for their SCCs were classified as having subjective cognitive decline (SCD, n=85) or amnestic mild cognitive impairment (aMCI, n=57) based on a neuropsychological evaluation. Furthermore, 82 age-, education-, and gender-matched HV were recruited. All subjects completed the QPC assessing the presence of specific SCCs in the last six months. Results: Both SCD and aMCI groups reported almost two times more SCCs than HV, but they did not differ from each other in the total QPC score. Impression of memory change and Impression of worse memory in comparison to peers were significantly more prevalent in both SCD and aMCI groups in comparison to HV; however, only the latter one was associated with lower cognitive performance. Conclusion: The pattern of QPC-SCCs reported by SCD individuals was more similar to aMCI individuals than to HV. A complaint about memory change seems unspecific to pathological aging whereas a complaint about worse memory in comparison to peers might be one of the promising items from QPC questionnaire potentially reflecting subtle cognitive changes.

Pages 75-89
Elena Y. Zakirova*, Inna B. Chastukhina*, Lia R. Valeeva, Viacheslav V. Vorobev, Albert A. Rizvanov, András Palotás, Eugene V. Shakirov *These authors contributed equally to this work.
Stable Co-Cultivation of the Moss Physcomitrella patens with Human Cells in vitro as a New Approach to Support Metabolism of Diseased Alzheimer Cells
Abstract: Alzheimer’s disease (AD) is a devastating slowly progressive neurodegenerative disorder with no cure. While there are many hypotheses, the exact mechanism causing this pathology is still unknown. Among many other features, AD is characterized by brain hypometabolism and decreased sugar availability, to which neurons eventually succumb. In light of this aspect of the disease, we hypothesized that boosting fuel supply to neurons may help them survive or at least alleviate some of the symptoms. Here we demonstrate that live moss Physcomitrella patens cells can be safely co-cultured with human fibroblasts in vitro and thus have a potential for providing human cells with energy and other vital biomolecules. These data may form the foundation for the development of novel approaches to metabolic bioengineering and treatment of diseased cells based on live plants. In addition, by providing alternative energy sources to human tissues, the biotechnological potential of this interkingdom setup could also serve as a springboard to foster innovative dietary processes addressing current challenges of mankind such as famine or supporting long-haul space flight.

Pages 91-97
Jens Bohlken, Louis Jacob, Karel Kostev
The Relationship Between the Use of Antihypertensive Drugs and the Incidence of Dementia in General Practices in Germany
Abstract: Background: In recent years, there has been a growing interest in the association between the use of antihypertensive drugs and the incidence of dementia. Objective: The goal of this retrospective study was to investigate the relationship between antihypertensive drug use and dementia in elderly persons followed in general practices in Germany.Methods: This study included patients ≥60 years with documented blood pressure values who were diagnosed with dementia in general practices in Germany for the first time between 2013 and 2017 (index date). Dementia cases were matched to non-dementia controls using propensity scores based on age, sex, index year, and co-diagnoses. The main outcome of the study was the incidence of dementia as a function of the use of antihypertensive drugs. Results: The present study included 12,405 patients with dementia and 12,405 patients without dementia. The use of angiotensin II receptor blockers (odds ratios [ORs] ranging from 0.74 to 0.79), angiotensin-converting enzyme inhibitors (ORs ranging from 0.85 to 0.88), calcium channel blockers (ORs ranging from 0.82 to 0.89), and beta blockers (OR=0.88) was associated with a decrease in dementia incidence. Conclusion: Antihypertensive drug use is negatively associated with dementia in elderly persons followed in general practices in Germany.

Pages 99-106
Benjamin Yi Xin Wong, Ting Ting Yong, Levinia Lim, Jayne Yi Tan, Adeline Su Lyn Ng, Simon Kang Seng Ting, Shahul Hameed, Kok Pin Ng, Juan Helen Zhou, Nagaendran Kandiah
Medial Temporal Atrophy in Amyloid-Negative Amnestic Type Dementia Is Associated with High Cerebral White Matter Hyperintensity
Abstract: Background: Non-amyloid mechanisms behind neurodegeneration and cognition impairment are unclear. Cerebrovascular disease (CVD) may play an important role in suspected non-Alzheimer’s pathophysiology (SNAP), especially in Asia. Objective: To examine the association between CVD and medial temporal lobe atrophy (MTA) in amyloid-β negative patients with mild amnestic type dementia. Methods: Thirty-six mild dementia patients with complete neuropsychological, cerebrospinal fluid (CSF) biomarker, and neuroimaging information were included. Only patients with clinically significant MTA were recruited. Patients were categorized based on their CSF Aβ levels. Neuroimaging and neuropsychological variables were analyzed. Results: Despite comparable MTA between Aβ positive and negative patients, Aβ-negative patients had significantly greater white matter hyperintensities (WMH; Total Fazekas Rating) than their Aβ-positive counterparts (6.42 versus 4.19, p=0.03). A larger proportion of Aβ-negative patients also had severe and confluent WMH. Regression analyses controlling for baseline characteristics yielded consistent results. Conclusion: Our findings demonstrate that MTA is associated with greater CVD burden among Aβ-negative patients with amnestic type dementia. CVD may be an important mechanism behind hippocampal atrophy. This has implications on clinical management strategies, where measures to reduce CVD may slow neurodegeneration and disease progression.

Pages 107-120
Lisa T. Eyler, Jeremy A. Elman, Sean N. Hatton, Sarah Gough, Anna K. Mischel, Donald J. Hagler, Jr., Carol E. Franz, Anna Docherty, Christine Fennema-Notestine, Nathan Gillespie, Daniel Gustavson, Michael J. Lyons, Michael C. Neale, Matthew S. Panizzon, Anders M. Dale, William S. Kremen (Handling Associate Editor: Robert Perneczky)
Resting State Abnormalities of the Default Mode Network in Mild Cognitive Impairment: A Systematic Review and Meta-Analysis
Abstract: Background: Large-scale brain networks such as the default mode network (DMN) are often disrupted in Alzheimer’s disease (AD). Numerous studies have examined DMN functional connectivity in those with mild cognitive impairments (MCI), a presumed AD precursor, to discover a biomarker of AD risk. Prior reviews were qualitative or limited in scope or approach. Objective: We aimed to systematically and quantitatively review DMN resting state fMRI studies comparing MCI and healthy comparison (HC) groups. Methods: PubMed was searched for relevant articles. Study characteristics were abstracted and the number of studies showing no difference in hyper- versus hypo-connectivity in MCI was tallied. A voxel-wise (ES-SDM) meta-analysis was conducted to identify regional group differences. Results: Qualitatively, our review of 57 MCI versus HC comparisons suggests substantial inconsistency; 9 showed no group difference, 8 showed MCI>HC and 22 showed HC>MCI across the brain, and 18 showed regionally-mixed directions of effect. The meta-analysis of 31 studies revealed areas of significant hypo- and hyper-connectivity in MCI, including hypoconnectivity in the posterior cingulate cortex/precuneus (z = -3.1, p<0.0001). Very few individual studies, however, showed patterns resembling the meta-analytic results. Methodological differences did not appear to explain inconsistencies. Conclusions: The pattern of altered resting DMN function or connectivity in MCI is complex and variable across studies. To date, no index of DMN connectivity qualifies as a useful biomarker of MCI or risk for AD. Refinements to MCI diagnosis, including other biological markers, or longitudinal studies of progression to AD, might identify DMN alterations predictive of AD risk.

Pages 121-129
Yahui Wu, Yuhua Zhao, Tong Xu, LiWen You, Hao Zhang, Fang Liu (Handling Associate Editor: Yong Guo)
Alzheimer’s Disease Affects Severity of Asthma through Methylation Control of Foxp3 Promoter
Abstract: Recent studies suggest that severity of asthma can be modulated by neuropsychiatric conditions, while the underlying mechanisms are not clear. Here, we used ovalbumin (OVA) to induce asthma in APP/PS1 mice, a mouse model of Alzheimer's disease (AD), or in their wildtype control C57BL/6J mice. We found that all hallmarks of asthma by OVA were significantly attenuated in APP/PS1 mice, compared to age- and gender-matched C57BL/6J mice. Interestingly, significantly higher number of regulatory T cells (Treg) was detected in the APP/PS1 mouse lung, compared to those in the C57BL/6J mouse lung. Since Foxp3 is crucial for differentiation of naive T cells into Treg and is the most important marker for Treg, we examined the Foxp3 levels in the T cells from the lung of these mice. We found that the Foxp3 levels in the APP/PS1 mouse lung were significantly higher than those in the C57BL/6J mouse lung, likely resulting from reduced Foxp3 promoter methylation. Thus, our study suggests that AD may affect severity of asthma through methylation control of Foxp3 promoter in T cells.

Pages 131-138
Michael S. Rafii, Michael C. Donohue, Dawn C. Matthews, Gabriela Muranevici, Seth Ness, Sid E. O’Bryant, Robert A. Rissman
Plasma Neurofilament Light and Alzheimer’s Disease Biomarkers in Down Syndrome: Results from the Down Syndrome Biomarker Initiative (DSBI)
Abstract: Background: Adults with Down syndrome (DS) are at very high risk for Alzheimer’s disease (AD). Neurofilament light (NF-L) has emerged as a potential blood-based biomarker of neurodegeneration due to AD. Objective: To understand the relationship between plasma NF-L with age, brain amyloid, and tau pathology, neurodegeneration as well as cognitive and functional performance. Methods: We analyzed imaging data as well as cognitive measures in relation to plasma NF-L in adults with DS, ages 30 to 60 who were enrolled in the Down Syndrome Biomarker Initiative. Results: We found significant correlations between NF-L plasma concentrations and amyloid pathology (r = 0.73, p = 0.007, pa=0.041) and significant inverse correlations with regional glucose metabolism in 5 of 6 regions examined, which were Anterior cingulate (r= -0.55, p=0.067, pa =0.067), Posterior cingulate r= -0.90, p<0.001, pa <0.001), Lateral Temporal (r= -0.78, p=0.004, pa =0.012), Frontal cortex (r= - 0.90, p<0.001, p pa <0.001), Parietal cortex (r= -0.82, p=0.002, pa =0.008), Precuneus (r= -0.73, pa=0.010, pa =0.020), and with hippocampal volume (r = -0.52, p = 0.084, pa=0.084); and an inverse correlation with direct measures of cognition: CAMCOG (r = -0.66 p=0.022, pa=0.066) and positive correlation with CANTAB Paired Associates Learning (PAL) error rate (r= 0.68, p = 0.015, pa=0.060). Finally, we found inverse relationships with informant-based functional measures (r = -0.57, p = 0.059, pa=0.084) and OMQ-PF (r= -0.74, p=0.008, pa=0.041). Conclusion: Plasma NF-L is associated with progressive neurodegeneration as well as with declines in cognitive and functional measures in adults with DS.

Pages 139-151
John Z. Cavendish, Saumyendra N. Sarkar, Mark A. Colantonio, Dominic D. Quintana, Nadia Ahmed, Brishti A. White, Elizabeth B. Engler-Chiurazzi, James W. Simpkins
Mitochondrial Movement and Number Deficits in Embryonic Cortical Neurons from 3xTg-AD Mice
Abstract: Mitochondrial dysfunction is often found in Alzheimer’s disease (AD) patients and animal models. Clinical severity of AD is linked to early deficiencies in cognitive function and brain metabolism, indicating that pathological changes may begin early in life. Previous studies showed decreased mitochondrial function in primary hippocampal neurons from triple-transgenic Alzheimer’s disease (3xTg-AD) mice and mitochondrial movement and structure deficits in primary neurons exposed to amyloid-β oligomers. The present study characterized mitochondrial movement, number, and structure in 3xTg-AD primary cortical neurons and non-transgenic (nonTg) controls. We found a significant reduction in mitochondrial number and movement in 3xTg-AD primary cortical neurons with modest structural changes. Additionally, application of the sigma-1 receptor agonist, (+)SKF-10,047, markedly increased mitochondrial movement in both 3xTg-AD and nonTg primary cortical cultures after one hour of treatment. (+)SKF-10,047 also led to a trend of increased mitochondrial number in 3xTg-AD cultures. Embryonic mitochondrial movement and number deficits could be among the key steps in the early pathogenesis of AD that compromise cognitive or metabolic reserve, and amelioration of these deficits could be a promising area for further preclinical and clinical study.

Pages 153-161
Whitney Wharton, Liping Zhao, Kyle Steenland, Felicia C. Goldstein, Julie A. Schneider, Lisa L. Barnes, Marla Gearing, Sevil Yasar
Neurofibrillary Tangles and Conversion to Mild Cognitive Impairment with Certain Antihypertensives
Abstract: Background: Individuals taking renin angiotensin system (RAS) acting antihypertensives exhibit slower cognitive decline and are less likely to progress from mild cognitive impairment (MCI) to Alzheimer’s disease (AD), but the mechanism remains unclear. Objective: We tested the hypothesis that individuals taking RAS acting antihypertensives exhibit less AD-related neuropathology and slower disease progression than individuals taking non-RAS acting antihypertensives. Method: Participants included 83 individuals with MCI who were taking an antihypertensive at baseline, had at least two follow-up visits, and had postmortem neuropathological data. Participants were old (M=83.1 years), 32% male, well educated (M=15.7 years), and 9.2% Black. Results: RAS medication users (N=38) were less likely to progress to AD than non-RAS users (N=45). RAS users exhibited fewer neurofibrillary tangles than non-RAS users in the hippocampal CA1 region (p<0.01), entorhinal cortex (p=0.03), and the angular gyrus, inferior temporal, mid-frontal cortex, and superior frontal (p=0.01). Conclusion: Prevention or clearance of neurofibrillary tangles represents a mechanism by which RAS medications may slow disease progression.

Pages 163-170
Niyatee Samudra, Michael Motes, Hanzhang Lu, Min Sheng, Ramon Diaz-Arrastia, Michael Devous, John Hart, Kyle B. Womack
A Pilot Study of Changes in Medial Temporal Lobe Fractional Amplitude of Low Frequency Fluctuations after Sildenafil Administration in Patients with Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common cause of neurodegenerative cognitive impairment, defined by abnormal accumulations of amyloid-β and tau. Approaches directly targeting these proteins have not resulted in a disease modifying therapy. Neurovascular unit dysfunction is a feature of AD offering an alternative target for intervention. Sildenafil, a phosphodiesterase 5 (PDE5) inhibitor, improves cognitive functioning in mouse models of AD. Recent work in AD patients has demonstrated increased cerebral blood flow, as well as brain oxygen utilization after a single dose of sildenafil. Its effect on nitric oxide-cGMP signaling may have downstream effects on neuroplasticity, amyloid-β processing, and improved neurovascular unit function. Fractional amplitude of low frequency fluctuations (fALFF) assesses spontaneous neural activity via resting state fMRI BOLD signal (0.01–0.08 or 0.10 Hz). In AD, other assessments have revealed increased fALFF in hippocampi and parahippocampal gyri. Here, we examined the effects of a single dose of sildenafil on fALFF in a cohort of 10 AD patients. We found a decrease (p < 0.03, α = 0.05) in fALFF an hour after sildenafil administration in the right hippocampus. Additionally, cerebral vascular reactivity in response to carbon dioxide inhalation, a measure of neural vascular reserve previously collected on most of these participants, was not significantly correlated with this decrease, implying that change in fALFF may not have been solely due to altered vascular reactivity to CO2. We demonstrate that in patients with AD, hippocampal fALFF decreases in response to sildenafil, suggesting a normalization. These findings support further investigation into the effects of sildenafil in AD.

Pages 171-185
Marggie Jones, Barry McDermott, Bárbara Luz Oliveira, Aoife O’Brien, Declan Coogan, Mark Lang, Niamh Moriarty, Eilis Dowd, Leo Quinlan, Brian Mc Ginley, Eoghan Dunne, David Newell, Emily Porter, Muhammad Adnan Elahi, Martin O’ Halloran, Atif Shahzad (Handling Associate Editor: Amy Clements-Cortes)
Gamma Band Light Stimulation in Human Case Studies: Groundwork for Potential Alzheimer’s Disease Treatment
Abstract: Background: It is known that proteins associated with Alzheimer’s disease (AD) pathogenesis are significantly reduced by 40 Hz entrainment in mice. If this were to translate to humans, verifying that such a light stimulus can induce a 40 Hz entrainment response in humans and harnessing insights from these case studies could be one step in the development of a multisensory device to prevent and treat AD. Objective: Verify the inducement of a 40 Hz response in the human brain by a 40 Hz light stimulus and obtain insights that could potentially aid in the development of a multisensory device for the prevention and treatment of AD. Methods: Electroencephalographic brain activity was recorded simultaneously with application of stimulus at different frequencies and intensities. Power spectral densities were analyzed. Results: Entrainment to visual stimuli occurred with the largest response at 40 Hz. The high intensity 40 Hz stimulus caused widespread entrainment. The number of electrodes demonstrating entrainment increased with increasing light intensity. Largest amplitudes for the high intensity 40 Hz stimulus were consistently found at the primary visual cortex. There was a harmonic effect at double the frequency for the 40 Hz stimulus. An eyes-open protocol caused more entrainment than an eyes-closed protocol. Conclusion: It was possible to induce widespread entrainment using a 40 Hz light stimulus in this sample cohort. Insights gleaned from these case studies could potentially aid in the development of a multisensory medical device to prevent and treat AD.

Pages 187-197
Richard McClure, Rey Redha, Paige Vinson, Wellington Pham
A Robust and Scalable High-Throughput Compatible Assay for Screening Amyloid-β-Binding Compounds
Abstract: A robust fluorescent readout assay using topologically-sensitive dyes improves the screening of novel amyloid-binding molecules. One of the key components that make this assay more realistic is the use of endogenous amyloid obtained from 5XFAD mouse brains. The assay conditions were optimized for high throughput screening operation with Z-prime values >0.6. Using a combination of library of 3,500 compounds including known drugs, natural-derived molecules and random organic molecules, 8 unique molecules were identified as potential amyloid-binding agents.

Pages 199-210
Donald R. Royall, Raymond F. Palmer
δ Scores Identify Subsets of “Mild Cognitive Impairment” with Variable Conversion Risks
Abstract: Background: The latent variable “δ” (for “dementia) is a transdiagnostic measure of dementia severity. δ can be reified and applied to individuals as a composite “d-score”. Like Spearman’s general intelligence factor “g”, δ can be constructed from almost any cognitive battery. So many are available that we must further distinguish each composite as a δ “homolog”. Fourteen have been validated. All are strongly associated with dementia severity and potentially with mild cognitive impairment (MCI) conversion. Objectives: To assess δ’s impact on MCI conversion risk. Methods: A new δ homolog (dDx) was constructed in 1,230 Mexican-American (MA) and 2,215 non-Hispanic White (NHW) participants in the Texas Alzheimer’s Research and Care Consortium (TARCC). 1,445 normal controls (NC) and 723 MCI were followed annually for up to 6 years. Results: Each SD decrease in the dDx score increased the risk of conversion sixteen-fold [OR = 16.39 (CI: 5.0-52.6)]. Cases below the optimal diagnostic threshold for Alzheimer’s disease (AD) versus NC were labeled as having a functionally salient cognitive impairment (FSCI). Such cases were at a 73-fold increase risk of a diagnosis of AD [OR = 73.19 (95% CI: 58.3-92.0)]. However, 25.6% of MCI cases were also FSCI(+). They accounted disproportionately for prospective conversions. Age <80 years, the absence of an ε4 allele, <12 years of education, and MA ethnicity independently increased the risk of diagnosing FSCI as MCI. Conclusion: A sizable minority of MCI cases may be misdiagnosed and they account disproportionately for AD conversions.

Pages 211-225
Adrià Tort-Merino, Jaume Olives, María León, Claudia Peñaloza Natalia Valecha, Miguel A. Santos-Santos, Estela Càmara, Petra Grönholm-Nyman, Pablo Martínez-Lage, Juan Fortea, José L. Molinuevo, Raquel Sánchez-Valle, Matti Laine, Antoni Rodríguez-Fornells, Lorena Rami (Handling Associate Editor: Montse Alegret)
Tau Protein Is Associated with Longitudinal Memory Decline in Cognitively Healthy Subjects with Normal Alzheimer’s Disease Cerebrospinal Fluid Biomarker Levels
Abstract: Background: We investigated a sample of cognitively healthy subjects with normal Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker levels to identify the earliest variables related to longitudinal memory changes. Objective: Employing a new highly demanding learning and memory test (the Ancient Farming Equipment Test; AFE-T), we aimed to investigate whether a biomarker related to neurodegeneration (i.e., CSF tau) was associated with longitudinal memory decline. Methods: Thirty-two cognitively and biologically normal (CBN) subjects underwent MRI, neuropsychological assessment, and the AFE-T at baseline and 18 months later. To explore the relationship between cognitive performance and relevant factors, a linear model was set up. For a secondary analysis that further explore the effect of tau, the subjects were divided into CBN-Tau↓ (tau<228.64 pg/ml; n=16) and CBN-Tau↑ (tau>228.64 pg/ml; n=16). We also performed voxel-based morphometry (VBM) to identify regions of grey matter volume that would predict both baseline and longitudinal cognitive performance. Results: Our main finding was an association between CSF tau and longitudinal memory decline measured with AFE-T (B=-0.17, p<0.05; r=-0.414; p<0.01), and further analyses showed different evolvement between subgroups, with an accelerated decline in individuals with higher tau (F(1,31)=8.37; p<0.01). VBM results suggested that AFE-T performance is related to grey matter volume in a medial temporal, middle frontal, and posterior cerebellar network at baseline, and that there are strategic brain areas driving the longitudinal cognitive changes. Conclusions: The present findings provide evidence for structural and biological markers linked to cognitive aging by highlighting the role of tau, a marker of neurodegeneration, which can be related with the earliest memory changes in healthy subjects.

Pages 227-239
Anna E. Blanken, Shubir Dutt, Yanrong Li, Daniel A. Nation, for the Alzheimer’s Disease Neuroimaging Initiative
Disentangling Heterogeneity in Alzheimer’s Disease: Two Empirically-Derived Subtypes
Abstract: Background: Clinical-pathological Alzheimer’s disease (AD) subtypes may help distill heterogeneity in patient presentation. To date, no studies have utilized neuropsychological and biological markers to identify preclinical subtypes with longitudinal stability. Objective: The objective of this study was to empirically derive AD endophenotypes using a combination of cognitive and biological markers. Methods: Hierarchical cluster analysis grouped dementia-free older adults using memory, executive and language abilities, and cerebrospinal fluid amyloid-β and phosphorylated tau. Brain volume differences, neuropsychological trajectory, and progression to dementia were compared, controlling for age, gender, education, and apolipoprotein E4 (ApoE4). Results: Subgroups included asymptomatic-normal (n=653) with unimpaired cognition and subthreshold biomarkers, typical AD (TAD; n=191) showing marked memory decline, high ApoE4 rates and abnormal biomarkers, and atypical AD (AAD; n=132) with widespread cognitive decline, intermediate biomarker levels, older age, less education and more white matter lesions. Cognitive profiles showed longitudinal stability with corresponding patterns of cortical atrophy, despite nearly identical rates of progression to AD dementia. Conclusion: Two clinical-pathological AD subtypes are identified with potential implications for preventative efforts.

Pages 241-256
Vasily Vorobyov, Boris Bakharev, Natalia Medvinskaya, Inna Nesterova, Alexander Samokhin, Alexander Deev, Olga Tatarnikova, Aleksey A. Ustyugov, Frank Sengpiel, Natalia Bobkova
Loss of Midbrain Dopamine Neurons and Altered Apomorphine EEG Effects in the 5xFAD Mouse Model of Alzheimer's Disease
Abstract: Cognitive malfunction, synaptic dysfunction, and disconnections in neural networks are core deficits in Alzheimer’s disease (AD). 5xFAD mice, a transgenic model of AD, are characterized by an enhanced level of amyloid-β and abnormal neurotransmission. The dopaminergic (DA) system has been shown to be involved in amyloid-β transformations and neuronal plasticity; however, its role in functional network changes in familial AD still remains unclear. In 5xFAD and non-transgenic freely moving mice, electroencephalograms (EEGs) were simultaneously recorded from the secondary motor cortex (MC), superficial layers of the hippocampal CA1 area (HPC), substantia nigra (SN), and ventral tegmental area (VTA). EEGs and their frequency spectra were analyzed before and after systemic injection of a DA receptor agonist, apomorphine (APO). In the baseline EEG from MC and HPC of 5xFAD mice, delta and alpha oscillations were enhanced and beta activity was attenuated, compared to control mice. In VTA and SN of 5xFAD mice, delta-theta activity was decreased and beta oscillations dominated. In control mice, APO suppressed delta activity in VTA to a higher extent than in MC, whereas in 5xFAD mice, this difference was eliminated due to attenuation of the delta suppression in VTA. APO increased beta activity in MC of mice from both groups while significant beta suppression was observed in VTA of 5xFAD mice. These mice were characterized by significant decrease of tyrosine hydroxylase immunopositive cells in both VTA and SN and of DA transporter in MC and hippocampal dentate gyrus. We suggest that the EEG modifications observed in 5xFAD mice are associated with alterations in dopaminergic transmission, resulting in adaptive changes in the cerebral networks in the course of familial AD development.

Pages 257-275
Agnieszka Niedźwieńska, Lia Kvavilashvili (Handling Associate Editor: Michael Hornberger)
Everyday Memory Failures in Older Adults with Amnestic Mild Cognitive Impairment
Abstract: Identifying people with amnestic mild cognitive impairment (aMCI), who are at increased risk of developing Alzheimer’s disease, is important for improving early disease management and care. Although self- or informant-reported memory problems constitute one of the diagnostic criteria of aMCI, there is currently little empirical knowledge about the frequency and nature of everyday memory failures in aMCI compared to age-matched healthy controls. Consequently, clinicians rely on their personal judgements when assessing the seriousness of reported memory failures. To address this gap in our knowledge, 32 aMCI participants and 38 healthy controls recorded their everyday memory failures as and when they occurred during a 7-day period, in a portable diary-booklet, by filling in a short questionnaire on a diary page. Descriptions of memory failures were coded into several subcategories of retrospective memory, prospective memory, and absent-minded failures. Results showed that a total number of recorded failures was significantly higher in participants with aMCI than controls. This group difference was mainly due to aMCI participants recording a higher number of retrospective memory failures, while groups did not differ in the number of prospective memory and absent-minded failures. Additionally, while certain types of failures (i.e., forgetting appointments and well-learned procedures) were recorded by a proportion of aMCI patients, they were never reported in a control group. Overall compliance rates were high and did not differ across the groups, suggesting that a structured diary method is feasible to use with aMCI patients, and can provide useful information about everyday memory functioning in this population.

Pages 277-286
Michael F. Bergeron, Sara Landset, Franck Tarpin-Bernard, Curtis B. Ashford, Taghi M. Khoshgoftaar, J. Wesson Ashford (Handling Associate Editor: David Loewenstein)
Episodic-Memory Performance in Machine Learning Modeling for Predicting Cognitive Health Status Classification
Abstract: Background: Memory dysfunction is characteristic of aging and often attributed to Alzheimer’s disease (AD). An easily administered tool for preliminary assessment of memory function and early AD detection would be integral in improving patient management. Objective: Our primary aim was to utilize machine learning in determining initial viable models to serve as complementary instruments in demonstrating efficacy of the MemTrax online Continuous Recognition Tasks (M-CRT) test for episodic-memory screening and assessing cognitive impairment. Methods: We used an existing dataset subset (n=18,395) of demographic information, general health screening questions (addressing memory, sleep quality, medications, and medical conditions affecting thinking), and test results from a convenience sample of adults who took the M-CRT test. M-CRT performance and participant features were used as independent attributes: true positive/negative, percent responses/correct, response time, age, sex, and recent alcohol consumption. For predictive modeling, we used demographic information and test scores to predict binary classification of the health-related questions (yes/no) and general health status (healthy/unhealthy), based on the screening questions. Results: ANOVA revealed significant differences among HealthQScore groups for response time true positive (p=0.000) and true positive (p=0.020), but none for true negative (p=0.0551). Both %responses and %correct had significant differences (p=0.026 and p=0.037, respectively). Logistic regression was generally the top-performing learner with moderately robust prediction performance (AUC) for HealthQScore (0.648-0.680) and selected general health questions (0.713-0.769). Conclusion: Our novel application of supervised machine learning and predictive modeling helps to demonstrate and validate cross-sectional utility of MemTrax in assessing early-stage cognitive impairment and general screening for AD.

Pages 287-302
Thomas J. Anastasio
Exploring the Correlation between the Cognitive Benefits of Drug Combinations in a Clinical Database and the Efficacies of the Same Drug Combinations Predicted from a Computational Model
Abstract: Identification of drug combinations that could be effective in Alzheimer’s disease treatment is made difficult by the sheer number of possible combinations. This analysis identifies as potentially therapeutic those drug combinations that rank highest when their efficacy is determined jointly from two independent data sources. Estimates of the efficacy of the same drug combinations were derived from a clinical dataset on cognitively impaired elderly participants and from pre-clinical data, in the form of a computational model of neuroinflammation. Linear regression was used to show that the two sets of estimates were correlated, and to rule out confounds. The ten highest ranking, jointly determined drug combinations most frequently consisted of COX2 inhibitors and aspirin, along with various antihypertensive medications. Ten combinations of from five to nine drugs, and the three-drug combination of a COX2 inhibitor, aspirin, and a calcium-channel blocker, are discussed as candidates for consideration in future pre-clinical and clinical studies.

Pages 303-314
Xi Huang, Chenchen Wang, Sai Tian, Rong Huang, Dan Guo, Haoqiang Zhang, Jijing Shi, Shaohua Wang
Higher Plasma Level of Nampt Presaging Memory Dysfunction in Chinese Type 2 Diabetes Patients with Mild Cognitive Impairment
Abstract: Background: In addition to glucose metabolism, adipocytokine Nicotinamide phosphoribosyltransferase (Nampt) has been proposed as a multifunctional protein involved in insulin resistance. Insulin resistance always occurs before the onset of type 2 diabetes mellitus (T2DM) and damages the cognition of T2DM patients very early. Objective: We aimed to investigate the role and potential clinical value of Nampt in early cognitive decline of T2DM. Methods: A total of 195 Chinese T2DM patients were enrolled and divided into a mild cognition impairment (MCI) group and a healthy cognition group according to Montreal Cognitive Assessment (MoCA) score. Their cognitive function was extensively assessed. The plasma level of Nampt was measured via enzyme-linked immunosorbent assay. Results: In the MCI group (n=78, MoCA<26), the plasma level of Nampt was significantly higher than the controls (p<0.01). After adjusting for age, sex, and level of education, Nampt levels were negatively associated with most of the cognitive domains forecasting hypomnesia (all p<0.007). Nevertheless, hierarchical regression analysis further revealed that Nampt was an independent risk factor of MCI in Chinese T2DM patients (all p<0.05), including Logic Memory Test (β=-0.31, p<0.01), Auditory Verbal Learning Test delayed recall (β=-0.26, p<0.01), and so on, which represent memory function. Correlation analysis showed that Nampt related to insulin resistance (HOMA-IR), glycosylated hemoglobin (HbA1c), and lipid levels (all p<0.05). Conclusions: We found that higher plasma level of Nampt presages memory dysfunction in MCI in Chinese T2DM patients. Further studies are necessary to confirm its scanning and prognosis prediction value of the disease clinically.