Volume 69, Number 3, IN PRESS

Review
Errol M. Thomson
Air Pollution, Stress, and Allostatic Load: Linking Systemic and Central Nervous System Impacts
Abstract: Air pollution is a risk factor for cardiovascular and respiratory morbidity and mortality. A growing literature also links exposure to diverse air pollutants (e.g., nanoparticles, particulate matter, ozone, traffic-related air pollution) with brain health, including increased incidence of neurological and psychiatric disorders such as cognitive decline, dementia (including Alzheimer’s disease), anxiety, depression, and suicide. A critical gap in our understanding of adverse impacts of pollutants on the central nervous system (CNS) is the early initiating events triggered by pollutant inhalation that contribute to disease progression. Recent experimental evidence has shown that particulate matter and ozone, two common pollutants with differing characteristics and reactivity, can activate the hypothalamic-pituitary-adrenal (HPA) axis and release glucocorticoid stress hormones (cortisol in humans, corticosterone in rodents) as part of a neuroendocrine stress response. The brain is highly sensitive to stress: stress hormones affect cognition and mental health, and chronic stress can produce profound biochemical and structural changes in the brain. Chronic activation and/or dysfunction of the HPA axis also increases the burden on physiological stress response systems, conceptualized as allostatic load, and is a common pathway implicated in many diseases. The present paper provides an overview of how systemic stress-dependent biological responses common to particulate matter and ozone may provide insight into early CNS effects of pollutants, including links with oxidative, inflammatory, and metabolic processes. Evidence of pollutant effect modification by non-chemical stressors (e.g., socioeconomic position, psychosocial, noise), age (prenatal to elderly), and sex will also be reviewed in the context of susceptibility across the lifespan.

Review
Harald Hampel, Simone Lista, Dalila Mango, Robert Nisticò, George Perry, Jesus Avila, Felix Hernandez, Hugo Geerts, Andrea Vergallo for the Alzheimer Precision Medicine Initiative (APMI)
Lithium as a Treatment for Alzheimer’s Disease: The Systems Pharmacology Perspective
Abstract: Systems pharmacology is a novel framework for drug research that models traditional and innovative pharmacological parameters and provides the overall efficacy and safety profile of a drug across body systems and complex, non-linear, molecular interactions. Lithium chloride, a pharmacological compound approved for the therapy of psychiatric disorders, represents a poorly explored compound for the treatment of Alzheimer's disease (AD). Lithium has been shown to reduce downstream effects associated with the aberrant overactivation of certain molecular pathways, such as glycogen synthase kinase 3 subunit β (GSK3-β)-related pathways, involved in AD-related pathophysiology. It seems that overactivation and overexpression of GSK3-β lead to an impairment of long-term potentiation and amyloid-β induced neurotoxicity that can be normalized using lithium. Moreover, a growing body of evidence has demonstrated that lithium’s GSK3-β inhibitory effect prevents tau phosphorylation in mouse models of tauopathies. Clinical data have been inconclusive, partly due to methodological limitations. The lack of studies exploring the dynamics of protein misfolding in AD and investigating the specific tau-isoforms appearing prior to the accumulation of neurofibrillary tangles calls for new and optimized clinical trials. Advanced computer modeling based on a formal implementation of quantitative parameters and basic enzymatic insights into a mechanism-based model would present a good start to tackle these non-linear interactions. This innovative approach will pave the way for developing “molecularly” biomarker-guided targeted therapies, i.e., treatments specifically adapted (“tailored”) to the individual, consistently with the primary objectives and key conceptual points of precision medicine and precision pharmacology.

Review
Caleb Vegh, Kyle Stokes, Dennis Ma, Darcy Wear, Jerome Cohen, Sidhartha D. Ray, Siyaram Pandey
A Bird’s-Eye View of the Multiple Biochemical Mechanisms that Propel Pathology of Alzheimer’s Disease: Recent Advances and Mechanistic Perspectives on How to Halt the Disease Progression Targeting Multiple Pathways
Abstract: Neurons consume the highest amount of oxygen, depend on oxidative metabolism for energy, and survive for the lifetime of an individual. Therefore, neurons are vulnerable to death caused by oxidative-stress, accumulation of damaged and dysfunctional proteins and organelles. There is an exponential increase in the number of patients diagnosed with neurodegenerative diseases such as Alzheimer’s (AD) as the number of elderly increases exponentially. Development of AD pathology is a complex phenomenon characterized by neuronal death, accumulation of extracellular amyloid-β plaques and neurofibrillary tangles, and most importantly loss of memory and cognition. These pathologies are most likely caused by mechanisms including oxidative stress, mitochondrial dysfunction/stress, accumulation of misfolded proteins, and defective organelles due to impaired proteasome and autophagy mechanisms. Currently, there are no effective treatments to halt the progression of this disease. In order to treat this complex disease with multiple biochemical pathways involved, a complex treatment regimen targeting different mechanisms should be investigated. Furthermore, as AD is a progressive disease-causing morbidity over many years, any chemo-modulator for treatment must be used over long period of time. Therefore, treatments must be safe and non-interfering with other processes. Ideally, a treatment like medicinal food or a supplement that can be taken regularly without any side effect capable of reducing oxidative stress, stabilizing mitochondria, activating autophagy or proteasome, and increasing energy levels of neurons would be the best solution. This review summarizes progress in research on different mechanisms of AD development and some of the potential therapeutic development strategies targeting the aforementioned pathologies.

Review
Richard J. Elsworthy, Sarah Aldred (Handling Associate Editor: Madia Lozupone)
Depression in Alzheimer’s Disease: An Alternative Role for Selective Serotonin Reuptake Inhibitors?
Abstract: Depression is a common co-morbidity seen in people with Alzheimer’s disease (AD). However, the successful treatment of depressive symptoms in people with AD is rarely seen. In fact, multiple randomized controlled trials have shown selective serotonin reuptake inhibitors (SSRIs), the current best recommended treatment for depression, to be ineffective in treating depressive symptoms in people with AD. One explanation for this lack of treatment effect may be that depressive symptoms can reflect the progression of AD, rather than clinical depression and are a consequence of more severe neurodegeneration. This raises several questions regarding not only the efficacy of SSRIs in the treatment of depression in people with AD but also regarding the accuracy of diagnosis of depression in AD. However, there may be a rationale for the prescription of SSRIs in early AD. Even in the absence of depression, SSRIs have been shown to slow the conversion from mild cognitive impairment to AD. This may be attributed to the effect of SSRIs on the processing of amyloid-β precursor protein, which may cause a reduction in the accumulation of amyloid-β. Thus, although SSRIs may lack efficacy in treating depression in people with AD, they may hold therapeutic potential for treating and delaying the progression of AD especially if treatment begins in the early stages of AD. This article reviews the current consensus for SSRI treatment of depression in people with AD and highlights the possibility of SSRIs being a treatment option for delaying the progression of AD.

Short Communication
Andrea Arighi, Andrea Di Cristofori, Chiara Fenoglio, Stefano Borsa, Marianna D’Anca, Giorgio Giulio Fumagalli, Marco Locatelli, Giorgio Carrabba, Anna Margherita Pietroboni, Laura Ghezzi, Tiziana Carandini, Annalisa Colombi, Marta Scarioni, Milena Alessandra De Riz, Maria Serpente, Paolo Maria Rampini, Elio Scarpini, Daniela Galimberti (Handling Associate Editor: Marco Bozzalli)
Cerebrospinal Fluid Level of Aquaporin4: A New Window on Glymphatic System Involvement in Neurodegenerative Disease?
Abstract: Aquaporin4 (AQP4) is a water channel protein located at astrocyte foot processes that plays a role in glymphatic system, a highly organized fluid transport pathway which seems to be involved in Alzheimer’s disease (AD) and normal pressure hydrocephalus (NPH) pathophysiology. Cerebrospinal fluid (CSF) AQP4 levels were determined in 11 patients with AD, 10 patients with NPH, and 9 controls. We found significantly reduced AQP4 in AD patients, a trend in reduction in NPH patients, and a correlation between AQP4 and amyloid-β CSF levels. This study indicates the potential role of AQP4 and glymphatic system in neurodegenerative diseases pathophysiology.

Soroor Sadegh Malvajerd, Zhila Izadi, Amir Azadi, Masoumeh Kurd, Hossein Derakhshankhah, Mohammad Sharif Zadeh, Hamid Akbari Javar, Mehrdad Hamidi
Neuroprotective Potential of Curcumin-Loaded Nanostructured Lipid Carrier in an Animal Model of Alzheimer’s Disease: Behavioral and Biochemical Evidence
Abstract: Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is caused by accumulation of amyloid-β (Aβ) peptide and is associated with neurological abnormalities in learning and memory. The protective role of curcumin on nerve cells, along with a potent antioxidant and free radical scavenging activity, has been widely studied. However, its low bioavailability and limited transport ability across the blood-brain barrier are two major drawbacks of its application in the treatment of different neurodegenerative diseases. The present study was designed to improve the effectiveness of curcumin in the treatment of Aβ-induced cognitive deficiencies in a rat model of AD by loading it into nanostructured lipid carriers (NLCs). The accumulation rate of curcumin (505.76±38.4 ng g-1 h) in rat brain, as well as its serum levels, were significantly increased by using curcumin-loaded NLCs. The effective role of NLCs for brain delivery of curcumin was confirmed by reduced oxidative stress parameters (ROS formation, lipid peroxidation, and ADP/ATP ratio) in the hippocampal tissue and improvement of spatial memory. Also, histopathological studies revealed the potential of Cur‒NLCs in decreasing the hallmarks of Aβ in AD in the animal model. The result of studying the neuroprotective potential of Cur-NLC in both pre-treatment and treatment modes showed that loading curcumin in NLCs is an effective strategy for increasing curcumin delivery to the brain and reducing Aβ-induced neurological abnormalities and memory defects and that it can be the basis for further studies in the area of AD prevention and treatment.

Nobuya Kitaguchi, Harutsugu Tatebe, Kazuyoshi Sakai, Kazunori Kawaguchi, Shinji Matsunaga, Tomoko Kitajima, Hiroshi Tomizawa, Masao Kato, Satoshi Sugiyama, Nobuo Suzuki, Masao Mizuno, Hajime Takechi, Shigeru Nakai, Yoshiyuki Hiki, Hiroko Kushimoto, Midori Hasegawa, Yukio Yuzawa, Takahiko Tokuda
Influx of Tau and Amyloid-β Proteins into the Blood During Hemodialysis as a Therapeutic Extracorporeal Blood Amyloid-β Removal System for Alzheimer’s Disease
Abstract: The accumulation of amyloid-β protein (Aβ) and tau in the brain is a major pathological change related to Alzheimer’s disease. We have continued to develop Extracorporeal Blood Aβ Removal Systems (E-BARS) as a method for enhancing Aβ clearance from the brain. Our previous report revealed that dialyzers effectively remove blood Aβ and evoke large Aβ influxes into the blood, resulting in a decrease in brain Aβ accumulation after initiating hemodialysis, and that patients who underwent hemodialysis had lower brain Aβ accumulation than those who did not. Here, plasma total tau concentrations from 30 patients undergoing hemodialysis were measured using an ultrasensitive immunoassay and compared to those from 11 age-matched controls. Plasma total tau concentrations were higher in patients with renal failure regardless of whether they underwent hemodialysis, suggesting the involvement of the kidneys in tau degradation and excretion. Hemodialyzers effectively removed blood Aβ but not extracorporeal blood tau. The influx of tau into the blood was observed at around the 1 h period during hemodialysis sessions. However, the influx amount of tau was far smaller than that of Aβ. Furthermore, histopathological analysis revealed similar, not significantly less, cerebral cortex phosphorylated tau accumulation between the 17 patients who underwent hemodialysis and the 16 age-matched subjects who did not, although both groups showed sparse accumulation. These findings suggest that hemodialysis may induce both tau and Aβ migration into the blood. However, as a therapeutic strategy for Alzheimer’s disease, it may only be effective for removing Aβ from the brain.

Xinchun Mei*, Yupeng Chen*, Hailin Zheng, Zhongyong Shi, Edward R. Marcantonio, Zhongcong Xie, Yuan Shen (Handling Associate Editor: Xuemen Xu) *These authors contributed equally to this work.
The Reliability and Validity of the Chinese Version of Confusion Assessment Method Based Scoring System for Delirium Severity (CAM-S)
Abstract: Previous studies showed that the Confusion Assessment Method based delirium severity evaluation tool (CAM-S) had good reliability and validity. However, there is no Chinese version of the CAM-S. Therefore, we set out to perform a prospective investigation in older Chinese patients who had total joint replacement surgery under general anesthesia in Tenth People’s Hospital in Shanghai, P.R. China. A total of 576 participants, aged 60 years or older, were screened, 179 participants were enrolled, and 125 of them were included for the final analysis. Pre-operative evaluations were conducted one day before the surgery. Postoperative evaluations were conducted twice daily from postoperative day 1 to day 3. The incidence of postoperative delirium was 24.8%. The Chinese version of CAM-S [including a Short Form (CAM-S Short Form) and a Long Form (CAM-S Long Form)] had an optimal reliability reflected by internal consistency (Cronbach’s α = 0.748 and 0.839 for CAM-S Short Form and CAM-S Long Form respectively), split-halves reliability (Pearson correlation coefficient = 0.372 and 0.384 for CAM-S Short Form and CAM-S Long Form respectively), and inter-rater reliability (intra-class correlation coefficients = 0.629 and 0.945 for CAM-S Short Form and CAM-S Long Form respectively). Additionally, the Chinese version of CAM-S also showed a good discriminate validity. The domain scores of CAM-S were inversely correlated with corresponding domain scores of the MMSE. Finally, a receiver operating characteristic (ROC) analysis obtained an optimal cutoff point of 2.5 for CAM-S Short Form and 3.5 for CAM-S Long Form in recognizing delirium diagnosed by CAM. The areas under the ROC were 0.989 (95% CI 0.972–1.000, p<0.001) and 0.964 (95% CI 0.946-0.982, p<0.001), respectively. These data suggest that the Chinese version of CAM-S has good reliability and validity in evaluating postoperative delirium in geriatric Chinese patients and may be a useful tool to assess the severity of delirium.

Kelsey A. Eakin*, Mahwesh Saleem*, Nathan Herrmannc, Hugo Cogo-Moreira, Michelle M. Mielke, Paul I. Oh, Norman J. Haughey, Swarajya L.V. Venkata, Krista L. Lanctôt, Walter Swardfager (Handling Associate Editor: Suzanne de la Monte) *These authors contributed equally to this work.
Plasma Sphingolipids Mediate a Relationship Between Type 2 Diabetes and Memory Outcomes in Patients with Coronary Artery Disease Undertaking Exercise
Abstract:
Background: Exercise may combat cognitive decline and prevent recurrent cardiovascular events in coronary artery disease (CAD); however, evidence in type 2 diabetes (T2DM) has been mixed. T2DM and memory decline have been associated with differences in the plasma sphingolipidome. Objective: Here, we will investigate whether T2DM-related sphingolipids predict less memory improvement over an exercise intervention for CAD. Methods: Among participants with CAD entering a 6-month exercise intervention, we matched 20 with T2DM to 40 without T2DM for age, sex, and body mass index. We assessed 45 sphingolipid species using high-performance liquid chromatography coupled electrospray ionization tandem mass spectrometry with multiple reaction monitoring. We assessed memory using the California Verbal Learning Test, 2nd Ed, and the revised Brief Visuospatial Learning Test. Results: Partial least squares discriminant analysis identified 8 species that distinguished T2DM from non-T2DM groups with 83% (95% confidence interval [70%, 95%]) accuracy in a receiver operator characteristic curve (validated by internal resampling, 1000 permutations, p=0.003). At baseline, T2DM-associated sphingolipids (ceramide C22:0, monohexylceramide C16:1, and lactosylceramide C24:0) were associated with poorer memory, attention, and psychomotor processing speed performance. Among 50 completers, an indirect effect of T2DM on less improvement in verbal memory was mediated by monohexylceramide C16:1 (0.86 fewer words recalled, 95% bootstrap confidence interval [-2.32, -0.24]), and an indirect effect of T2DM on less visuospatial memory improvement was mediated by ceramide C22:0 concentrations (0.42 fewer points, 95% bootstrap confidence interval [-1.17, -0.05]). Conclusions: Ceramide species associated with T2DM predicted poorer cognitive responses to exercise in patients with CAD.

Monique J. Bignoux, Katelyn Cuttler, Tyrone C. Otgaar, Eloise Ferreira, Boitelo T. Letsolo, Stefan F.T. Weiss
LRP::FLAG Rescues Cells from Amyloid-β-Mediated Cytotoxicity Through Increased TERT Levels and Telomerase Activity
Abstract: Alzheimer’s disease (AD) represents the most common form of neurodegenerative disorders with only palliative treatments currently available. Amyloid plaque formation caused by amyloid-β (Aβ) aggregation and neurofibrillary tangle formation caused by hyperphosphorylated tau are hallmarks for the development of AD. The 37 kDa/67 kDa laminin receptor (LRP/LR) has been implicated in AD and tools blocking or downregulating LRP/LR impede amyloid plaque formation in vitro and in vivo. We have recently shown that LRP::FLAG enhances telomerase activity with a concomitant reduction of senescent markers. Here, we overexpressed LRP::FLAG in HEK293 and SH-SY5Y cells, which resulted in an increase in hTERT levels as well as increased telomerase activity and increased cell viability in the presence of cytotoxic levels of exogenous Aβ. LRP::FLAG overexpression decreased Aβ shedding and intracellular Aβ levels in HEK293 cells. This suggests that LRP::FLAG rescues cells from Aβ-induced cytotoxicity through increased telomerase activity. This study recommends LRP::FLAG as a novel alternative therapeutic for AD treatment through activation of telomerase activity.

Hong-Bin Cai, Zhen-Zhen Fan, Ting Tian, Chon-Chon Zhao, Zhao-Ming Ge (Handling Associate Editor: Yong Guo)
Epigenetic Control of CDK5 Promoter Regulates Diabetes-Associated Development of Alzheimer’s Disease
Abstract: Cyclin-dependent kinase-5 (CDK5) is activated by p35 and then binds to both p35 and its truncated form p25 to promote hyperphosphorylation of tau protein, thereby facilitating the pathological progression of Alzheimer’s disease (AD). However, it is unknown whether a patient’s diabetic status promotes the later onset of AD in a CDK5-dependent manner. Here, we induced pro-diabetic insulin resistance and glucose intolerance in rats using a combined high fat and high glucose diet. Compared to normal diet-fed rats, these pro-diabetic rats exhibited poorer behavioral performance in the Morris water maze test and the novel object recognition test. Increased phosphorylation of tau protein was detected in the hippocampal CA1 region of the rat brain, suggesting neurodegeneration. Moreover, CDK5 transcriptional activity was significantly increased in the HFGD-rat brain, likely resulting from an increase in acetylation and a decrease in methylation of the CDK5 promoter. Together, these data suggest that epigenetic control of the CDK5 promoter by acetylation and methylation may regulate the diabetes-associated development of AD.

Mohamed Haddad, Morgane Perrotte, Sarra Landri, Aurelie Lepage, Tamás Fülöp, Charles Ramassamy (Handling Associate Editor: Slavica Krantic)
Circulating and Extracellular Vesicles Levels of N-(1-carboxymethyl)-L-lysine (CML) Differentiate Early to Moderate Alzheimer’s Disease
Abstract: Background: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in AD brain and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs. Objective: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs. Methods: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined. Results: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture. Conclusion: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs.

João Figueira, Rolf Adolfsson, Annelie Nordin Adolfsson, Lars Nyberg, Anders Öhman (Handling Associate Editor: M. Paul Murphy)
Serum Metabolite Markers of Dementia Through Quantitative NMR Analysis: The Importance of Threonine-Linked Metabolic Pathways
Abstract: There is a great need for diagnostic biomarkers of impending dementia. Metabolite markers in blood have been investigated in several studies, but inconclusive findings encourage further investigation, particularly in the pre-diagnostic phase. In the present study, the serum metabolomes of 110 dementia or pre-diagnostic dementia individuals and 201 healthy individuals matched for age, gender, and education were analyzed by nuclear magnetic resonance spectroscopy in combination with multivariate data analysis. 58 metabolites were quantified in each of the 311 samples. Individuals with dementia were discriminated from controls using a panel of seven metabolites, while the pre-diagnostic dementia subjects were distinguished from controls using a separate set of seven metabolites, where threonine was a common significant metabolite in both panels. Metabolite and pathway alterations specific for dementia and pre-diagnostic dementia were identified, in particular a disturbed threonine catabolism at the pre-diagnostic stage that extends to several threonine-linked pathways at the dementia stage.

Laura Luukkainen, Seppo Helisalmi, Laura Kytövuori, Riitta Ahmasalo, Eino Solje, Annakaisa Haapasalo, Mikko Hiltunen, Anne M. Remes, Johanna Krüger
Mutation Analysis of the Genes Linked to Early Onset Alzheimer’s Disease and Frontotemporal Lobar Degeneration
Abstract: A lot of effort has been done to unravel the genetics underlying early-onset Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD). However, many familial early-onset dementia (EOD) cases still show an unclear genetic background. The aim of this study was to evaluate the role of the known causative mutations and possible pathogenic variants associated with AD and FTLD in a Finnish EOD cohort. The cohort consisted of 39 patients (mean age at onset 54.8 years, range 39-65) with a positive family history of dementia or an atypical or rapidly progressive course of the disease. None of the patients carried the C9orf72 hexanucleotide repeat expansion. Mutations and variants in APP, PSEN1, PSEN2, MAPT, GRN, VCP, CHMP2B, FUS, TARDBP, TREM2, TMEM106B, UBQLN2, SOD1, PRNP, UBQLN1, and BIN1 were screened by using a targeted next generation sequencing panel. Two previously reported pathogenic mutations (PSEN1 p.His163Arg and MAPT p.Arg406Trp) were identified in the cohort. Both patients had familial dementia with an atypical early onset phenotype. In addition, a heterozygous p.Arg71Trp mutation in PSEN2 with an uncertain pathogenic nature was identified in a patient with neuropathologically confirmed AD. In conclusion, targeted investigation of the known dementia-linked genes is worthwhile in patients with onset age under 55 and a positive family history, as well as in patients with atypical features.

Jon B. Toledo*, Mohamad Habes*, Aristeidis Sotiras, Maria Bjerke, Yong Fan, Michael W. Weiner, Leslie M. Shaw, Christos Davatzikos, John Q. Trojanowski, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
APOE Effect on Amyloid-β PET Spatial Distribution, Deposition Rate, and Cut-Points
Abstract: There are conflicting results regarding how APOE genotype, the strongest genetic risk factor for Alzheimer’s disease (AD), influences spatial and longitudinal amyloid-β (Aβ) deposition and its impact on the selection of biomarker cut-points. In our study, we sought to determine the impact of APOE genotype on cross-sectional and longitudinal florbetapir positron emission tomography (PET) amyloid measures and its impact in classification of patients and interpretation of clinical cohort results. We included 1,019 and 1,072 Alzheimer’s Disease Neuroimaging Initiative participants with cerebrospinal fluid Aβ1-42 and florbetapir PET values, respectively. 623 of these subjects had a second florbetapir PET scans two years after the baseline visit. We evaluated the effect of APOE genotype on Aβ distribution pattern, pathological biomarker cut-points, cross-sectional clinical associations with Aβ load, and longitudinal Aβ deposition rate measured using florbetapir PET scans. 1) APOE ε4 genotype influences brain amyloid deposition pattern; 2) APOE ε4 genotype does not modify Aβ biomarker cut-points estimated using unsupervised mixture modeling methods if white matter and brainstem references are used (but not when cerebellum is used as a reference); 3) findings of large differences in Aβ biomarker value differences based on APOE genotype are due to increased probability of having AD neuropathology and are most significant in mild cognitive impairment subjects; and 4) APOE genotype and age (but not gender) were associated with increased Aβ deposition rate. APOE ε4 carrier status affects rate and location of brain Aβ deposition but does not affect choice of biomarker cut-points if adequate references are selected for florbetapir PET processing.

Xin Yan, Fangyu Li, Shuoqi Chen, Jianping Jia (Handling Associate Editor: Yanjiang Wang)
Associated Factors of Total Costs of Alzheimer’s Disease: A Cluster-Randomized Observational Study in China
Abstract: Background: Alzheimer’s disease (AD) exerts a heavy burden on China. Substantial factors are found associated with high expenditure of AD in high-income countries. To date, few studies have been conducted in China. Objective: This study aimed to analyze the associated factors of the total annual costs of AD in China. Methods: Data were drawn from a multi-center, cross-sectional, socioeconomic study on the costs of AD conducted in China from October 2015 to March 2016. Generalized linear model (GLM) using gamma distribution with a log-link function was employed to examine the associated factors of the total cost. Results: Univariate analysis showed that the demographic and clinical characteristics of AD patients and their caregivers had a substantial impact on the total cost. In GLM analysis, age, monthly household income, AD severity, number of comorbidities, and treatment with memantine were associated with higher expenditure, while the use of a nursing home/care facility was associated with lower expenditure. The mean annual costs for patients with severe dementia were almost twice as high as those for patients with mild dementia (US$ 25,601 versus US$ 13,387, p < 0.001). The mean total cost of AD patients with at least five comorbidities (US$ 38,348) was almost three times than those with no comorbidities (US$ 13,744). Conclusion: In China, AD severity and comorbidities were the most critical factors impacting the total cost. Optimizing care patterns, delaying disease progression, and managing comorbidities comprehensively could decrease the heavy burden of AD.

Aleksi Hamina, Heidi Taipale, Niina Karttunen, Antti Tanskanen, Jari Tiihonen, Anna-Maija Tolppanen, Sirpa Hartikainen
Hospital-Treated Pneumonia Associated with Opioid Use Among Community Dwellers with Alzheimer’s Disease
Abstract: Background: Pneumonia is a common cause for hospitalization and excess mortality among persons with Alzheimer’s disease (AD), but little research exists evaluating drug use as its risk factor. Objective: We investigated the association between opioid use and hospital-treated pneumonia among community dwellers with AD. Methods: This study was part of the Medication use and Alzheimer’s (MEDALZ) cohort. We included all community dwellers newly diagnosed with AD during 2010–2011 in Finland with incident prescription opioid use (n=5,623) and age-, sex-, and time since AD diagnosis-matched nonusers (n=5,623). Data on opioid use, modelled from pharmacy dispensing data, and hospital-treated pneumonia were retrieved from nationwide registers. Patients with active cancer treatment were excluded. Hazard models compared opioid users to nonusers, adjusting for comorbidities, socioeconomic position. and other drug use. Results: Incident opioid use was associated with an increased risk of hospital-treated pneumonia compared to nonuse (adjusted HR, aHR 1.34, 95% CI 1.14–1.57). Highest risk was observed during the first two months of use (aHR 2.58, 95% CI 1.87–3.55). Compared to weak opioids, buprenorphine was not associated with a higher risk of pneumonia (aHR 1.20, 95% CI 0.83–1.76), but strong opioids were (aHR 1.84, 95% CI 1.15–2.97). The risk was higher for those using ≥50 morphine milligram equivalents (MME)/day (aHR 2.03, 95% CI 1.24–3.31), compared to using <50 MME/day. Conclusions: Opioid use was associated with a risk of hospital-treated pneumonia in a dose-dependent manner among persons with AD. Risk-minimization strategies should be considered if opioid therapy is needed.

Vineeth Thirunavu, Austin McCullough, Yi Su, Shaney Flores, Aylin Dincer, John C. Morris, Carlos Cruchaga, Tammie L.S. Benzinger, Brian A. Gordon (Handling Associate Editor: Jeffrey Burns)
Higher Body Mass Index Is Associated with Lower Cortical Amyloid-β Burden in Cognitively Normal Individuals in Late-Life
Abstract: Background: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer’s disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology. Objective: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45-60 years) or late-life (> 60). Methods: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n=96 and n=277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex. Results: Higher BMI was associated with lower cortical Aβ burden in late-life (β = -0.81, p=0.0066), but no relationship was found in mid-life (β=0.04, p > 0.5). The BMI × APOE4+ and BMI × male interaction terms were not significant in the mid-life (β=0.28, p = 0.41; β=0.64, p = 0.13) or the late-life (β=0.17, p > 0.5; β=0.50, p = 0.43) groups. Conclusion: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals.

Deborah Oliveira, Katy A. Jones, Reuben Ogollah, Semanur Ozupek, Eef Hogervorst, Martin Orrell
Willingness to Adhere to Current UK Low-Risk Alcohol Guidelines to Potentially Reduce Dementia Risk: A National Survey of People Aged 50 and Over
Abstract: Background: People over 50 are increasing their alcohol intake, potentially increasing their risk of dementia. Objective: This study investigates whether people would be willing to adhere to current United Kingdom (UK, “low-risk”) alcohol guidelines to reduce dementia risk. Methods: A national cross-sectional online survey recruited a non-probabilistic sample of 3,948 individuals aged 50 and over without dementia in the UK. Self-reported willingness to comply with low-risk guidelines was predicted using multivariate logistic regression. Other relevant self-reported variables included physical health, lifestyle, and current alcohol intake. Results: Majority of the sample (90%, n=3,527) reported drinking alcohol at least once a month with 23% (n=795) exceeding the low-risk guidelines (>14 units per week). A larger proportion of men, those who were overweight, and people without a partner reported drinking above the recommended level. Most people who consumed alcohol (n=2,934; 74.3%) appeared willing to adhere to low-risk guidelines if they were told that their risk of having dementia could be reduced. Increased willingness was found in women (OR 1.81; CI 1.47-2.23), in people who had at least one child (OR 1.36; CI 1.09-1.70), and those who slept well (OR 1.45; CI 1.06-2.00). People who were obese (OR 0.72; CI 0.54-0.95), those who drank alcohol above limits (OR 0.13; CI 0.11-0.16), and those who were smokers (OR 0.56; CI 0.36-0.88) were less willing to adhere to current guidelines. Conclusion: Men and people with more lifestyle risk factors for common chronic diseases (e.g., smoking, obesity, and excess alcohol consumption) are less willing to adhere to current alcohol low-risk guidelines to reduce dementia risk.

Maurizio Gallucci, Carola Dell’Acqua, Franco Boccaletto, Chiara Fenoglio, Daniela Galimberti, Maria Elena Di Battista (Handling Associate Editor: Beatrice Arosio)
Overlap Between Frontotemporal Dementia and Dementia with Lewy Bodies: A Treviso Dementia (TREDEM) Registry Case Report
Abstract: In the present work, we report the case of a patient presenting signs of Lewy body dementia (DLB) and frontotemporal dementia (FTD) throughout different phases of the disease. In January 2017, a 79-year-old right-handed living man was admitted to our Memory Clinic for the presence of behavioral disturbances and progressive cognitive decline. For the previous six years, he was monitored by other Neurological Clinics for the onset of extrapyramidal features. Indeed, through the first phase of the disease (2011-2014), the patient predominantly showed: extrapyramidal features, initial cognitive decline, sleep disturbances, and visual hallucinations, together with a reduced dopamine transporter uptake in basal ganglia at the DATscan, suggesting a diagnosis of DLB. In a second phase (2015-2017), while his extrapyramidal features remained substantially stable, his cognitive profile deteriorated, with an additional development of severe behavioral and neuropsychiatric disturbances. Again, a subsequent DATscan study was positive and slightly worse than the preceding one; however, the 18F-FDG PET showed reduced metabolic activity in the frontal and temporal lobes, with the occipital regions left spared. Genetic analysis revealed a hexanucleotide expansion in C9ORF72 (6//38 repeats; ITALSGEN NV<30). In conclusion, we report the case of a patient presenting, firstly, with probable DLB and, in a second phase, with predominant bvFTD features with stable parkinsonism. Even though some clinical and neuropsychological aspects can co-exist in different neurodegenerative diseases, we find such a significant intersection of clinical features to be fairly atypical. Moreover, what is challenging to define is whether the two clinical phenotypes are somehow lying on a continuum, or if they are two individual entities.

Mario F. Mendez, Lorena H. Monserratt, Li-Jung Liang, Diana Chavez, Elvira E. Jimenez, Joseph J. Maurer, Megan Laffey
Neuropsychological Similarities and Differences between Amnestic Alzheimer’s Disease and its Non-Amnestic Variants
Abstract: Background: The neuropsychological recognition of early-onset Alzheimer’s disease (AD) can be difficult because of non-amnestic variants such as logopenic variant primary progressive aphasia (lvPPA) and posterior cortical atrophy (PCA). Objective: This study evaluated the similarities and differences between typical amnestic AD (tAD) and lvPPA and PCA on a screening neuropsychological battery. Methods: We enrolled 51 patients meeting NIA-AA criteria for biomarker-supported AD (amnestic or non-amnestic) and having an age of onset of < 65 years of age. Based on additional recommended clinical criteria for lvPPA and PCA, the early-onset AD patients were divided into three groups (28 tAD, 9 lvPPA, 14 PCA) of comparable age and dementia severity. We then analyzed their profiles on a focused, screening neuropsychological battery for early-onset AD. Results: In addition to greater variance on the Mini-Mental State Examination, the lvPPA and PCA variants had episodic memory impairment that did not significantly differ from the memory impairment in the tAD patients. Despite differences on language and visuospatial tasks, they did not significantly distinguish the lvPPA and PCA from tAD. The lvPPA group, however, was distinguishable by worse performance on measures reflecting working memory (digit span forward, memory registration). Conclusions: On neuropsychological screening, all clinical early-onset AD subtypes may have memory impairments. Screening batteries for early-onset AD should also include measures of working memory, which is disproportionately decreased in lvPPA.

Johannes Golchert, Susanne Roehr, Tobias Luck, Michael Wagner, Angela Fuchs, Birgitt Wiese, Hendrik van den Bussche, Christian Brettschneider, Jochen Werle, Horst Bickel, Michael Pentzek, Anke Oey, Marion Eisele, Hans-Helmut König, Siegfried Weyerer, Edelgard Mösch, Wolfgang Maier, Martin Scherer, Kathrin Heser, Steffi G. Riedel-Heller (Handling Associate Editor: Martha Jokisch)
Women Outperform Men in Verbal Episodic Memory Even in Oldest-Old Age: 13-Year Longitudinal Results of the AgeCoDe/AgeQualiDe Study
Abstract: Background: Sex differences in verbal episodic memory function have been widely reported. However, sex-specific effects on rates of episodic memory decline remain controversial, and evidence is particularly scarce in the oldest-old population. Objective: We aimed to investigate sex differences in trajectories of episodic memory performance in oldest-old individuals. Methods: Based on 13-year longitudinal data with 9 follow-up assessments of a large sample of cognitively unimpaired old (75+) primary care patients (n = 3,254) participating in the German AgeCoDe/AgeQualiDe study, we used linear mixed effect analyses to model sex-specific trajectories of change in verbal episodic memory while accounting for covarying factors. Results: We found that even in the highest age group women outperformed men in immediate (b= -1.71, p < 0.001) and delayed (b = -0.85, p < 0.001) free recall conditions. Associated late-life trajectories, however, did not differ significantly between the sexes. We further demonstrated that younger age, higher education, and an absence of depressive symptoms predicted better performance in both sexes. In contrast, past occurrences of stroke and APOE ε4 carrier status showed a negative relation to test scores. Conclusion: Our findings confirm previous research suggesting that women perform better in verbal episodic memory tests. We add that this advantage is still present in the oldest-old age groups. Our results indicate that sociodemographic and health related factors are as important as genetically based APOE ε4 carrier status in the prediction of normal cognitive development in advanced old age.

Jianyuan Li, Weidong Liu, Weicheng Yao (Handling Associate Editor: Yong Guo)
Immortalized Human Bone Marrow Derived Stromal Cells in Treatment of Transient Cerebral Ischemia in Rats
Abstract: Cerebral ischemic stroke may cause a number of adverse neurological complications or behavioral disorders. Moreover, cerebral ischemic stroke is a prevalent disease with limited treatment strategies and may increase chances of developing neurodegenerative diseases, e.g., Alzheimer’s disease, in the future. Therefore, alternative strategies are highly needed for improving the therapy for ischemic stroke. Human bone marrow stroma stem cells, also known as mesenchymal stem cells (hMSC), have a demonstrative role in treating transient cerebral ischemia, yet whether immortalized hMSC may have a better effect than hMSC is unknown. Here, we addressed this question. A rat cerebral ischemia reperfusion (IR) model was used to compare the effects of hMSC and an immortalized hMSC by human telomerase reverse transcriptase (hMSC-TERT). We found that both hMSC and hMSC-TERT similarly attenuated the elevation of serum neuron specific enolase levels after IR. Transplantation with hMSC alleviated cerebral infarction, alleviated brain edema, improved neural function, and reduced brain cell apoptosis, in a significantly better degree than transplantation with hMSC. Thus, these data suggest that immortalized hMSC may have an advantage over hMSC in treatment of transient cerebral ischemia.

Yanfang Guo, Haining Yu (Handling Associate Editor: Wenjie Yang)
Leukocyte Telomere Length Shortening and Alzheimer’s Disease Etiology
Abstract: Background: Several observational studies have found leukocyte telomere length (TL) to be associated with Alzheimer’s diseases (AD) or dementia. However, these findings were based on small sample sizes and cannot clarify whether this relationship was causal. Genome-wide association studies (GWAS) have identified common variants associated with TL, providing a valuable resource for examining the causal effect of TL on AD using Mendelian Randomization (MR) methods. Objective: To examine if TL was causally associated with AD using GWAS summary statistics. Methods: Using a genetic risk score comprised of seven variants associated with leukocyte TL as an instrumental variable, we tested whether shorter TL was associated with a higher risk of AD by applying an MR approach to the summarized genome-wide association study data. Results: The genetic risk score for TL was associated with higher risk of AD [log-odds ratio (OR)=0.003 for per TL-decreasing allele; 95% confidence interval (CI): 0.001, 0.005, p=0.005]. Moreover, the MR analysis provided support for shorter TL to be causally associated with a higher risk of AD (log-OR=0.04 per SD-decrease of TL; 95% CI: 0.01, 0.08, p=0.01). Conclusion: We suggest that TL has a causal effect on the risk of AD.

Marc Teichmann*, Chloé Daigmorte*, Aurélie Funkiewiez, Clara Sanches, Maeva Camus, Thomas Mauras, Isabelle Le Ber, Bruno Dubois, Richard Levy, Carole Azuar *These authors contributed equally to this work.
Moral Emotions in Frontotemporal Dementia
Abstract: Background: Emotions, with or without moral valence, appear to be altered in the behavioral variant of frontotemporal dementia (bvFTD) but the relative degree of moral emotion breakdown, which could be a marker of bvFTD diagnosis, remains unexplored. Objective: To assess moral emotions in bvFTD, to differentiate bvFTD from typical Alzheimer’s disease (AD) based on moral emotion processing, and to provide a sensitive and specific assessment tool contributing to bvFTD diagnosis. Methods: We investigated moral emotions in 22 bvFTD patients, 15 patients with typical AD having positive CSF AD biomarkers, and 45 healthy controls. The ‘Moral Emotions Assessment’ task consisted in 42 scenarios exploring positive and negative moral emotions. To control for moral-specificity, we contrasted the 42 moral scenarios with 18 extra-moral scenarios eliciting the emotions without involving any inter-human moral context. Results: bvFTD patients were more impaired in emotion processing than AD patients and healthy controls and had significantly poorer performance in the processing of moral emotions than of emotions without moral valence. ROC analyses of data on moral scenarios showed a high area under the curve (83%), and indicated a cut-off score (<37/42) for differentiating bvFTD from AD with a sensitivity of 82% and specificity of 73%. Conclusion: Our findings demonstrate that bvFTD patients have disorders in emotion processing which is mainly related to failure regarding moral emotions. They also show that this deficit is reliably detected by the ‘Moral Emotions Assessment’ which represents a sensitive and specific diagnostic tool detecting bvFTD and differentiating it from AD.