Volume 77, Number 1, 2020

Pages 1-14

Jieun Kim*, Yujeong Lee*, Seulah Lee, Kipom Kim, Minjung Song, Jaewon Lee *These authors contributed equally to this work.
Mesenchymal Stem Cell Therapy and Alzheimer’s Disease: Current Status and Future Perspectives
Abstract: Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease worldwide, but its cause remains unclear. Although a few drugs can provide temporary and partial relief of symptoms in some patients, no curative treatment is available. Therefore, attention has been focused on research using stem cells to treat AD. Among stem cells, mesenchymal stem cells (MSCs) have been used to treat the related pathologies in animal models of AD, and other neurodegenerative disease. This review describes latest research trends on the use of MSC-based therapies in AD and its action of mechanism. MSCs have several beneficial effects. They would be specified as the reduction of neuroinflammation, the elimination of amyloid-β, neurofibrillary tangles, and abnormal protein degradation, the promotion of autophagy-associated and blood-brain barrier recoveries, the upregulation of acetylcholine levels, improved cognition, and the recovery of mitochondrial transport. Therefore, this review describes the latest research trends in MSC-based therapy for AD by demonstrating the importance of MSC-based therapy and understanding of its mechanisms in AD and discusses the limitations and perspectives of stem cell therapy in AD.

Pages 15-31

Li-na Zhang, Meng-jie Li, Ying-hui Shang, Fan-fan Zhao, Han-chang Huang, Feng-xue Lao
Independent and Correlated Role of Apolipoprotein E ε4 Genotype and Herpes Simplex Virus Type 1 in Alzheimer’s Disease
Abstract: The ε4 allele of the Apolipoprotein E (APOE) gene in individuals infected by Herpes simplex virus type 1 (HSV-1) has been demonstrated to be a risk factor in Alzheimer's disease (AD). APOE-ε4 reduces the levels of neuronal cholesterol, interferes with the transportation of cholesterol, impairs repair of synapses, decreases the clearance of neurotoxic peptide amyloid-β (Aβ), and promotes the deposition of amyloid plaque, and eventually may cause development of AD. HSV-1 enters host cells and can infect the olfactory system, trigeminal ganglia, entorhinal cortex, and hippocampus, and may cause AD-like pathological changes. The lifecycle of HSV-1 goes through a long latent phase. HSV-1 induces neurotropic cytokine expression with pro-inflammatory action and inhibits antiviral cytokine production in AD. It should be noted that interferons display antiviral activity in HSV-1-infected AD patients. Reactivated HSV-1 is associated with infectious burden in cognitive decline and AD. Finally, HSV-1 DNA has been confirmed as present in human brains and is associated with APOE ε4 in AD. HSV-1 and APOE ε4 increase the risk of AD and relate to abnormal autophagy, higher concentrations of HSV-1 DNA in AD, and formation of Aβ plaques and neurofibrillary tangles.

Pages 33-51

Camila Calfio, Andrea Gonzalez, Sandeep Kumar Singh, Leonel E. Rojo, Ricardo B. Maccioni
The Emerging Role of Nutraceuticals and Phytochemicals in the Prevention and Treatment of Alzheimer’s Disease
Abstract: One of the major challenges of medical sciences has been finding a reliable compound for the pharmacological treatment of Alzheimer’s disease (AD). As most of the drugs directed to a variety of targets have failed in finding a medical solution, natural products from Ayurvedic medicine or nutraceutical compounds emerge as a viable preventive therapeutics’ pathway. Considering that AD is a multifactorial disease, nutraceutical compounds offer the advantage of a multitarget approach, tagging different molecular sites in the human brain, as compared with the single-target activity of most of the drugs used for AD treatment. We review in-depth important medicinal plants that have been already investigated for therapeutic uses against AD, focusing on a diversity of pharmacological actions. These targets include inhibition of acetylcholinesterase, β-amyloid senile plaques, oxidation products, inflammatory pathways, specific brain receptors, etc., and pharmacological actions so diverse as anti-inflammatory, memory enhancement, nootropic effects, glutamate excitotoxicity, anti-depressants, and antioxidants. In addition, we also discuss the activity of nutraceutical compounds and phytopharmaceuticals formulae, mainly directed to tau protein aggregates mechanisms of action. These include compounds such as curcumin, resveratrol, epigallocatechin-3-gallate, morin, delphinidins, quercetin, luteolin, oleocanthal, and meganatural-az and other phytochemicals such as huperzine A, limonoids, azaphilones, and aged garlic extract. Finally, we revise the nutraceutical formulae BrainUp-10 composed of Andean shilajit and B-complex vitamins, with memory enhancement activity and the control of neuropsychiatric distress in AD patients. This integrated view on nutraceutical opens a new pathway for future investigations and clinical trials that are likely to render some results based on medical evidence.

Pages 53-58
Short Communication

Sydney Y. Schaefer, Andrew Hooyman, Kevin Duff (Handling Associate Editor: Madeleine Hackney)
Using a Timed Motor Task to Predict One-Year Functional Decline in Amnestic Mild Cognitive Impairment
Abstract: Affordable, noninvasive methods of predicting functional decline are needed for individuals at risk for Alzheimer’s disease. This study tested whether a timed upper-extremity motor task predicted functional decline over one year in 79 adults diagnosed with amnestic mild cognitive impairment. Participants completed subjective and objective measures of daily functioning at baseline and one year later. Motor task performance and delayed memory were also evaluated at baseline. Motor task performance was a significant predictor of one-year follow-up daily functioning, improving model fits by 18-35%. Thus, motor behavior has potential to be an affordable enrichment strategy that is sensitive to functional decline.

Pages 59-65
Short Communication

Pradeep K. Singh, Zu-Lin Chen, Sidney Strickland, Erin H. Norris
Increased Contact System Activation in Mild Cognitive Impairment Patients with Impaired Short-Term Memory
Abstract: An activated plasma contact system is an abnormality observed in many Alzheimer’s disease (AD) patients. Since mild cognitive impairment (MCI) patients often develop AD, we analyzed the status of contact system activation in MCI patients. We found that kallikrein activity, high molecular weight kininogen cleavage, and bradykinin levels—measures of contact system activation—were significantly elevated in MCI patient plasma compared to plasma from age- and education-matched healthy individuals. Changes were more pronounced in MCI patients with impaired short-term recall memory, indicating the possible role of the contact system in early cognitive changes.

Pages 67-73
Jingwen Li*, Xi Long*, Heqing Huang*, Jine Tang*, Chunli Zhu, Shaoping Hu, Jing Wu, Jinghong Li, Zhicheng Lin, Nian Xiong *These authors contributed equally to this work.
Resilience of Alzheimer’s Disease to COVID-19
Abstract: Background: Facing the novel coronavirus disease 2019 (COVID-19), most vulnerable individuals are seniors, especially those with comorbidities. More attention needs to been paid to the COVID-19 patients with Alzheimer’s disease, which is the top age-related neurodegenerative disease. Objective: Since it is unclear whether AD patients are prone to infection with COVID-19 and advance to severe stages, we report for the first time a retrospective analysis of the clinical characteristics of AD patients with COVID-19 pneumonia. Methods: We conducted a retrospective cohort study of the clinical data of 19 AD patients with COVID-19 pneumonia, compared with 23 non-AD COVID-19 patients admitted at the same time to our hospital. Demographic, clinical, laboratory, radiological, and treatment data were collected and analyzed. Results: Between AD patients and non-AD with COVID-19 pneumonia, the pneumonia severity was not significantly different. AD patients had a higher clustering onset than non-AD patients. The median duration from symptom onset to hospitalization were shorter in AD patients than non-AD patients, indicating the former were sent to the hospital by their family or from nursing home earlier than the later. The median duration from hospitalization to discharge seemed shorter in AD patients than non-AD patients. Dementia patients seemed less likely to report fatigue. It is noticed that more AD patients might have pericardial effusion than the non-AD patients. Conclusion: AD patients with COVID-19 were in milder conditions with a better prognosis than non-AD patients. AD patients had adequate access to healthcare, leading to earlier diagnosis and treatment for shorter hospital stays.

Pages 75-84
Hong-Bin Cai, Zhen-Zhen Fan, Ting Tian, Zi-Chao Li, Chon-Chon Zhao, Wen-Ting Guo, Zhao-Ming Ge (Handling Associate Editor: Yong Guo)
Diabetes-Induced H3K9 Hyperacetylation Promotes Development of Alzheimer’s Disease Through CDK5
Abstract: The connection between diabetes and Alzheimer’s disease (AD) is not fully determined. Hyperphosphorylation of tau protein is mediated by binding and stabilization of truncated p25 with cyclin-dependent kinase-5 (CDK5) in AD. We recently showed that diabetes-associated hyperglycemia increased the CDK5 levels to promote development of AD. Here, we examined the underlying mechanisms. Hyperglycemia and glucose intolerance were induced in rats that had received a low dose of streptozotocin (STZ) and a high fat diet (HFD). Compared to the control rats that received no STZ and were fed a normal diet, the STZ+HFD rats exhibited poorer performance in the behavioral test and showed hyperacetylation of H3K9 histone on the CDK5 promoter, likely resulting from upregulation of a histone acetyltransferase, GCN5. Inhibition of acetylation of H3K9 histone by a specific GCN5 inhibitor, MB3, attenuated activation of CDK5, resulting in decreased tau phosphorylation in rat brain and improved performance of the rats in the behavior test. Thus, these data suggest that diabetes may promote future development of AD through hyperacetylation of H3K9 histone on CDK5 promoter.

Pages 85-98
Yiwen Gao*, Nan Zhang*, Chunmei Lv, Na Li, Xueqin Li, Weiwei Li *These authors contributed equally to this work.
lncRNA SNHG1 Knockdown Alleviates Amyloid-β-Induced Neuronal Injury by Regulating ZNF217 via Sponging miR-361-3p in Alzheimer’s Disease
Abstract: Background: Long noncoding RNAs have been proven to play an important role in the progression of Alzheimer’s disease (AD). However, the function of small nucleolar RNA host gene 1 (SNHG1) in AD progression remains to be studied. Objective: To explore the role of SNHG1 in AD progression and clarify its potential mechanism. Methods: Amyloid β-protein (Aβ) was used to construct an AD cell model in vitro. The expression levels of SNHG1 and miR-361-3p were determined by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were measured by cell counting kit 8 assay and flow cytometry. The levels of apoptosis-related proteins and zinc finger gene 217 (ZNF217) protein were evaluated by western blot analysis. Additionally, the contents of inflammatory cytokines and oxidative stress markers were tested by enzyme-linked immunosorbent assay. Furthermore, dual-luciferase reporter and RNA immunoprecipitation assays were used to verify the interaction between miR-361-3p and SNHG1 or ZNF217. Results: Aβ could induce cell injury, while resveratrol could reverse this effect. SNHG1 expression was positively regulated by Aβ and negatively regulated by resveratrol. SNHG1 knockdown could reverse the promotion effect of Aβ on cell injury. Moreover, SNHG1 sponged miR-361-3p, and miR-361-3p targeted ZNF217. Additionally, miR-361-3p overexpression reversed the promotion effect of SNHG1 overexpression on cell injury, and ZNF217 silencing also reversed the promotion effect of miR-361-3p inhibitor on cell injury. Conclusion: SNHG1 promoted cell injury by regulating the miR-361-3p/ZNF217 axis, which might provide a theoretical basis for molecular therapy of AD.

Pages 99-112
Luka Rejc, Vanessa Gómez-Vallejo, Xabier Rios, Unai Cossío, Zuriñe Baz, Edurne Mujica, Tiago Gião, Ellen Y. Cotrina, Jesús Jiménez-Barbero, Jordi Quintana, Gemma Arsequell, Isabel Cardoso, Jordi Llop
Oral Treatment with Iododiflunisal Delays Hippocampal Amyloid-β Formation in a Transgenic Mouse Model of Alzheimer’s Disease: A Longitudinal in vivo Molecular Imaging Study
Abstract: Background: Transthyretin (TTR) is a tetrameric, amyloid-β (Aβ)-binding protein which reduces Aβ toxicity. The TTR/Aβ interaction can be enhanced by a series of small molecules that stabilize its tetrameric form. Hence, TTR stabilizers might act as disease-modifying drugs in Alzheimer’s disease. Objective: We monitored the therapeutic efficacy of two TTR stabilizers, iododiflunisal (IDIF), which acts as small-molecule chaperone of the TTR/Aβ interaction, and tolcapone, which does not behave as a small-molecule chaperone, in an animal model of Alzheimer’s disease using positron emission tomography (PET). Methods: Female mice (AβPPswe/PS1A246E/TTR+/-) were divided into 3 groups (n=7 per group): IDIF-treated, tolcapone-treated, and non-treated. The oral treatment (100 mg/Kg/day) was started at 5 months of age. Treatment efficacy assessment was based on changes in longitudinal deposition of Aβ in the hippocampus (HIP) and the cortex (CTX) and determined using PET-[18F]florbetaben. Immunohistochemical analysis was performed at age=14 months. Results: Standard uptake values relative to the cerebellum (SUVr) of [18F]florbetaben in CTX and HIP of non-treated animals progressively increased from age=5 to 11 months and stabilized afterwards. In contrast, [18F]florbetaben uptake in HIP of IDIF-treated animals remained constant between ages=5 and 11 months and significantly increased at 14 months. In the tolcapone-treated group, SUVr progressively increased with time, but at lower rate than in the non-treated group. No significant treatment effect was observed in CTX. Results from immunohistochemistry matched the in vivo data at age=14 months. Conclusion: Our work provides encouraging preliminary results on the ability of small-molecule chaperones to ameliorate Aβ deposition in certain brain regions.

Pages 113-125
Ilaria Roccaro, Daniela Smirni
Fiat Lux: The Light Became Therapy. An Overview on the Bright Light Therapy in Alzheimer’s Disease Sleep Disorders
Abstract: Background: A system of photosensitive retinal ganglion cells provides ‘non-visual’ information on the circadian sequences of light to the suprachiasmatic nucleus (SCN), which, as the ‘master clock’, synchronizes the chronobiological mechanisms of all the biological clocks. Damage to SCN structure alters circadian behavioral and hormonal rhythms and interferes with a regular sleep-wake pattern. Several studies have shown that, in aging and in Alzheimer’s disease (AD), circadian rhythms change their synchronization with the environment and behavior loses sync with light. Objective: The current overview aims to examine research studies showing the effect of bright light therapy (BLT) on sleep disorders and sleep-wake patterns in AD. Methods: A literature search was conducted, taking into consideration the relevant studies over the last 20 years. Fifteen studies have been thorough: seven followed an environmental-architectural approach and eight followed a treatment devices approach. Results: Studies agree in considering BLT as a promising non-pharmacological intervention to compensate for circadian rhythm alterations and they support the need for standardized protocols that allow a comparison between multicenter studies.Conclusion: Interestingly, in an attempt to contain the spread of the COVID-19 pandemic, health authorities have forced the population to stay home. Therefore, AD people are not currently able to enjoy exposure to sunlight. It is predictable that they may experience an exacerbation of circadian disturbances and that the BLT can be an effective response to prevent such exacerbation.

Pages 127-138
Linda Clare, Anthony Martyr, Robin G. Morris, Lynette J. Tippett
Discontinuity in the Subjective Experience of Self Among People with Mild-To-Moderate Dementia Is Associated with Poorer Psychological Health: Findings from the IDEAL Cohort
Abstract: Background: The onset and progression of dementia can result in changes in the subjective experience of self, impacting on psychological health. Objective: We aimed to explore the extent to which people with mild-to-moderate dementia experience discontinuity in the subjective experience of self, and the factors associated with this experience for people with dementia and their family caregivers. Methods: We used data from the baseline assessment of the IDEAL cohort. Discontinuity in the subjective experience of self was assessed by asking participants about their agreement with the statement ‘I feel I am the same person that I have always been’. Participants were divided into those who did and did not experience discontinuity, and the two groups were compared in terms of demographic and disease-related characteristics, psychological well-being, measures of ‘living well’, and caregiver stress. Results: Responses to the continuity question were available for 1,465 participants with dementia, of whom 312 (21%) reported experiencing discontinuity. The discontinuity group experienced significantly poorer psychological well-being and had significantly lower scores on measures of ‘living well’. There was no clear association with demographic or disease-related characteristics, but some indication of increased caregiver stress. Conclusion: A significant proportion of people with mild-to-moderate dementia describe experiencing discontinuity in the subjective sense of self, and this is associated with poorer psychological health and reduced ability to ‘live well’ with the condition. Sensitively asking individuals with dementia about the subjective experience of self may offer a simple means of identifying individuals who are at increased risk of poor well-being.

Pages 139-147
Jinzhong Xiao, Noriko Katsumata, Francois Bernier, Kazuya Ohno, Yuki Yamauchi, Toshitaka Odamaki, Kenji Yoshikawa, Kumie Ito, Toshiyuki Kaneko
Probiotic Bifidobacterium breve in Improving Cognitive Functions of Older Adults with Suspected Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial
Abstract: Background: Probiotics use has been associated with modulation of inflammation and considered as a possible intervention for CNS diseases such as mild cognitive impairment (MCI) and dementia. Objective: We aimed to test the effect of the probiotic strain, Bifidobacterium breve A1 (MCC1274), to restore cognition in a physically healthy, suspected MCI population. Methods: In this randomized, double-blind, placebo-controlled trial, 80 healthy older adults suffering from MCI were divided into two even groups to receive once daily either probiotic (B. breve A1, 2 × 1010 CFU) or placebo for 16 weeks using a computer-generated algorithm. Cognitive functions were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Japanese version of the MCI Screen (JMCIS) tests before and after the study as primary and secondary endpoints, respectively. Results: 79 participants completed the study, and no adverse events were observed. RBANS total score was significantly improved in probiotic group compared with placebo (mean between-group difference 11.3 [95% CI 6.7 to 15.8]; p < 0.0001) after 16 weeks of consumption, in particular with significant improvement in domain scores of immediate memory, visuospatial/constructional, and delayed memory (p < 0.0001), in both intention-to-treat (ITT) analysis and per-protocol (PP) analysis. JMCIS score was also improved versus placebo in ITT analysis (p = 0.052) and PP analysis (p = 0.036). Conclusion: Study results indicate B. breve A1 is a safe and effective approach for improving memory functions of suspected MCI subjects.

Pages 149-163
Ian W. Weidling, Heather M. Wilkins, Scott J. Koppel, Lewis Hutfles, Xiaowan Wang, Anuradha Kalani, Blaise W. Menta, Benjamin Ryan, Judit Perez-Ortiz, T. Chris Gamblin, Russell H. Swerdlow
Mitochondrial DNA Manipulations Affect Tau Oligomerization
Abstract: Background: Mitochondrial dysfunction and tau aggregation occur in Alzheimer’s disease (AD), and exposing cells or rodents to mitochondrial toxins alters their tau. Objective: To further explore how mitochondria influence tau, we measured tau oligomer levels in human neuronal SH-SY5Y cells with different mitochondrial DNA (mtDNA) manipulations. Methods: Specifically, we analyzed cells undergoing ethidium bromide-induced acute mtDNA depletion, ρ0 cells with chronic mtDNA depletion, and cytoplasmic hybrid (cybrid) cell lines containing mtDNA from AD subjects. Results: We found cytochrome oxidase activity was particularly sensitive to acute mtDNA depletion, evidence of metabolic re-programming in the ρ0 cells, and a relatively reduced mtDNA content in cybrids generated through AD subject mitochondrial transfer. In each case tau oligomer levels increased, and acutely depleted and AD cybrid cells also showed a monomer to oligomer shift. Conclusion: We conclude a cell’s mtDNA affects tau oligomerization. Overlapping tau changes across three mtDNA-manipulated models establishes the reproducibility of the phenomenon, and its presence in AD cybrids supports its AD-relevance.

Pages 165-174
Andrea M. Kurasz, Glenn E. Smith, Maria G. McFarland, Melissa J. Armstrong (Handling Associate Editor: Sid O'Bryant)
Ethnoracial Differences in Lewy Body Diseases with Cognitive Impairment
Abstract: Background: Increasing research focuses on ethnic differences in Alzheimer’s disease, but such efforts in other neurodegenerative dementias are lacking. Currently, data on the ethnic profile of cognitive impaired persons with Lewy body disease (LBD) is limited, despite Lewy body dementia being the second most common neurodegenerative dementia. Objective: The study aimed to investigate presenting characteristics among ethnoracially diverse individuals with cognitive impairment secondary to LBD using the National Alzheimer’s Coordinating Center database. Methods: Participants self-identified as African American, Hispanic, or White. We used Kruskal-Wallis and Pearson χ2 analyses to investigate group differences in presenting characteristics and linear regression to compare neuropsychological test performance. Results: Presentation age was similar between groups (median 74-75 years). Compared to Whites (n=1782), African Americans (n=130) and Hispanics (n=122) were more likely to be female and single, have less educational attainment, report more cardiovascular risk factors, describe less medication use, and perform worse on select cognitive tests. Hispanics reported more depressive symptoms. Conclusion: Cohorts differences highlight the need for population-based LBD studies with racial-ethnic diversity. Culturally-sensitive neuropsychological tests are needed to determine whether observed differences relate to cultural, social, testing, or disease-related factors. More research is needed regarding how social and biological factors impact LBD care among diverse populations.

Pages 175-182
Eric D. Vidoni, Ashwini Kamat, William P. Gahan, Victoria Ourso, Kaylee Woodard, Diana R. Kerwin, Ellen F. Binder, Jeffrey M. Burns, Munro Cullum, Linda S. Hynan, Wanpen Vongpatanasin, David C. Zhu, Rong Zhang, Jeffrey N. Keller
Baseline Prevalence of Polypharmacy in Older Hypertensive Study Subjects with Elevated Dementia Risk: Findings from the Risk Reduction for Alzheimer’s Disease Study (rrAD)
Abstract: Background: Little is known about the prevalence of polypharmacy, the taking of five or more medications a day, in older adults with specific dementia risk factors. Objective: To examine the prevalence of polypharmacy in participants at baseline in a vascular risk reduction focused Alzheimer’s disease (rrAD) trial targeting older patients with hypertension and elevated dementia risk. Methods: We conducted a detailed review of medications in a cross-sectional study of community-dwelling older adults with hypertension and elevated dementia risk. Medications were identified in a structured interview process with an onsite pharmacist or qualified designee. Polypharmacy was defined as use of five or more medications on a regular basis. Descriptive analyses were conducted on the sample as well as direct comparisons of subgroups of individuals with hypertension, diabetes, and hyperlipidemia. Results: The 514 rrAD participants, mean age 68.8 (standard deviation [sd] 6), reported taking different combinations of 472 unique medications at their baseline visit. The median number of medications taken by participants was eight [Range 0–21], with 79.2% exhibiting polypharmacy (n=407). Sites differed in their prevalence of polypharmacy, χ2(3)=56.0, p < 0.001. A nearly identical percentage of the 2,077 prescribed (51.8%) and over the counter (48.2%) medications were present in the overall medication profile. The presence of diabetes (87.5%), hyperlipidemia (88.2%), or both (97.7%) was associated with a higher prevalence of polypharmacy than participants who exhibited hypertension in the absence of either of these conditions (63.2%), χ2(3)=35.8, p < 0.001. Conclusion: Participants in a dementia risk study had high levels of polypharmacy, with the co-existence of diabetes or hyperlipidemia associated with a greater prevalence of polypharmacy as compared to having hypertension alone.

Pages 183-190
Bjørn Erik Neerland, Nathalie Bodd Halaas, Ane Victoria Idland, Kristi Henjum, Kaj Blennow, Henrik Zetterberg, Leiv Otto Watne
Fatty Acid-Binding Protein 3 in Cerebrospinal Fluid of Hip Fracture Patients with Delirium
Abstract: Background: Delirium is associated with dementia and thus biomarkers reflecting neurodegeneration are of interest. Fatty acid-binding protein 3 (FABP3) is a cytoplasmic neuronal protein that has been isolated from the brain. It is released following brain injury and concentrations in cerebrospinal fluid (CSF) are also higher in neurodegenerative disorders such as Alzheimer’s disease (AD). Objective: To examine the relationship between CSF FABP3 concentration and delirium in hip fracture patients compared to a group of cognitively normal controls. Methods: CFS FABP3 concentration was measured in 128 hip fracture patients with (n=71) and without (n=57) delirium, and in cognitively unimpaired adults ≥64 years (n= 124) undergoing elective surgery. Results: CSF FABP3 (pg/ml) concentration (median (IQR)) was higher in hip-fracture patients compared to cognitively normal controls (5.7 (4.2-7.7) versus 4.5 (3.4-6.1), p < 0.001). There was a significant weak correlation between age and CSF FABP3 (ρ=0.3, p < 0.001). After adjustment for age, the association between CSF FABP3 and hip-fracture was no longer statistically significant (β=0.05, p=0.5). There were no significant differences in CSF FABP3 concentration between hip fracture patients with (5.4 (4.1-8.2)) and without (5.8 (4.2-7.2)) delirium. CSF FABP3 concentration correlated positively with CSF AD biomarkers p-tau (ρ=0.7, p < 0.01) and t-tau (ρ=0.7, p < 0.01). Conclusion: CSF FABP3 concentrations were higher in hip fracture patients compared with cognitively normal older adults, indicating ongoing age-related neurodegeneration in these patients. There were no differences of CSF FABP3 concentrations across delirium groups, suggesting that neuronal damage or degeneration reflected by FABP3 may not be directly linked to delirium pathophysiology.

Pages 191-202
Tsubasa Tomoto, Takashi Tarumi, Jason Chen, Evan P. Pasha, C. Munro Cullum, Rong Zhang (Handling Associate Editor: Jack de la Torre)
Cerebral Vasomotor Reactivity in Amnestic Mild Cognitive Impairment
Abstract: Background: Cerebral blood flow (CBF) is sensitive to changes in arterial CO2, referred to as cerebral vasomotor reactivity (CVMR). Whether CVMR is altered in patients with amnestic mild cognitive impairment (aMCI), a prodromal stage of Alzheimer disease (AD), is unclear. Objective: To determine whether CVMR is altered in aMCI and is associated with cognitive performance. Methods: Fifty-three aMCI patients aged 55 to 80 and 22 cognitively normal subjects (CN) of similar age, sex, and education underwent measurements of CBF velocity (CBFV) with transcranial Doppler and end-tidal CO2 (EtCO2) with capnography during hypocapnia (hyperventilation) and hypercapnia (rebreathing). Arterial pressure (BP) was measured to calculate cerebrovascular conductance (CVCi) to normalize the effect of changes in BP on CVMR assessment. Cognitive function was assessed with Mini-Mental State Examination (MMSE) and neuropsychological tests focused on memory (Logical Memory, California Verbal Learning Test) and executive function (Delis-Kaplan Executive Function Scale; DKEFS). Results: At rest, CBFV and MMSE did not differ between groups. CVMR was reduced by 13% in CBFV% and 21% in CVCi% during hypocapnia and increased by 22% in CBFV% and 20% in CVCi% during hypercapnia in aMCI when compared to CN (all p<0.05). Logical Memory recall scores were positively correlated with hypocapnia (r=0.283, r=0.322, p<0.05) and negatively correlated with hypercapnic CVMR measured in CVCi% (r=-0.347, r=-0.446, p<0.01). Similar correlations were observed in D-KEFS Trail Making scores. Conclusion: Altered CVMR in aMCI and its associations with cognitive performance suggests the presence of cerebrovascular dysfunction in older adults who have high risks for AD.

Pages 203-217
Gemma Lombardi, Alberto Pupi, Valentina Bessi, Cristina Polito, Sonia Padiglioni, Camilla Ferrari, Giulia Lucidi, Valentina Berti, Maria Teresa De Cristofaro, Irene Piaceri, Silvia Bagnoli, Benedetta Nacmias, Sandro Sorbi
Challenges in Alzheimer’s Disease Diagnostic Work-Up: Amyloid Biomarker Incongruences
Abstract: Background: Discordance among amyloid biomarkers is a challenge to overcome in order to increase diagnostic accuracy in dementia. Objectives: 1) To verify that cerebrospinal fluid (CSF) Aβ42/Aβ40 ratio (AβR) better agrees with Amyloid PET (Amy-PET) results compared to CSF Aβ42; 2) to detect differences among concordant positive, concordant negative, and discordant cases, basing the concordance definition on the agreement between CSF AβR and Amy-PET results; 3) to define the suspected underlying pathology of discordant cases using in vivo biomarkers. Method: We retrospectively enrolled 39 cognitively impaired participants in which neuropsychological tests, apolipoprotein E genotype determination, TC/MRI, FDG-PET, Amy-PET, and CSF analysis had been performed. In all cases, CSF analysis was repeated using the automated Lumipulse method. In discordant cases, FDG-PET scans were evaluated visually and using automated classifiers. Results: CSF AβR better agreed with Amy-PET compared to CSF Aβ42 (Cohen’s K 0.431 versus 0.05). Comparisons among groups did not show any difference in clinical characteristics except for age at symptoms onset that was higher in the 6 discordant cases with abnormal CSF AβR values and negative Amy-PET (CSF AβR+/AmyPET-). FDG-PET and all CSF markers (Aβ42, AβR, p-Tau, t-Tau) were suggestive of Alzheimer’s disease (AD) in 5 of these 6 cases. Conclusion: 1) CSF AβR is the CSF amyloid marker that shows the better level of agreement with Amy-PET results; 2) The use of FDG-PET and CSF-Tau markers in CSFAβR+/Amy-PET- discordant cases can support AD diagnosis; 3) Disagreement between positive CSF AβR and negative Amy-PET in symptomatic aged AD patients could be due to the variability in plaques conformation and a negative Amy-PET scan cannot be always sufficient to rule out AD.

Pages 219-226
Sandra Garrido, Laura Dunne, Catherine J. Stevens, Esther Chang (Handling Associate Editor: Amy Clements-Cortes)
Music Playlists for People with Dementia: Trialing A Guide for Caregivers
Abstract: Background: Music programs have the potential to provide an effective non-pharmacological tool for caregivers to reduce depression and agitation and increase quality of life in people with dementia. However, where such programs are not facilitated by a trained music therapist, caregivers need greater access to information about how to use music most effectively in response to key challenges to care, and how to pre-empt and manage adverse responses. Objective: This study reports on the trial of a Guide for use of music with 45 people with dementia and their caregivers in residential care facilities and home-based care. Methods: The study used a pre-post experimental design in which participants were randomly allocated to a treatment group or a waitlist control group. Results: Improvements to quality of life were found in the experimental group over the 6-week period. Significant increases in Interest, Responsiveness, Initiation, Involvement, and Enjoyment were reported for individual listening sessions. Conclusion: The Guide can provide an effective protocol for caregivers to follow in selecting music to manage particular challenges to care, confirming the need for caregivers to be prepared to monitor and manage potential negative responses.

Pages 227-239
Bruno Remígio Cavalcante, Mariana Ferreira de Souza, Ryan Stanley Falck, Teresa Liu-Ambrose, David G. Behm, Ana Carolina Rodarti Pitangui, Rodrigo Cappato de Araújo
Effects of Resistance Exercise with Instability on Cognitive Function (REI Study): A Proof-Of-Concept Randomized Controlled Trial in Older Adults with Cognitive Complaints
Abstract: Background: Activities which simultaneously challenge both physical and cognitive function are promising strategies for promoting cognitive function. Objective: To examine the effects of resistance exercise with instability and traditional resistance exercise compared with a health education control on cognitive function in older adults with cognitive complaints. Methods: Sixty-seven participants were randomized to either 12 weeks of thrice-weekly resistance exercise (RE=23), RE with instability (REI=22), or a weekly health education control (CON=22). At each training session, RE and REI participants performed seven exercises for three sets and 10-15 repetitions. REI participants performed each exercise using instability devices. The primary outcome was a composite score of global cognitive function. Secondary outcomes included composite scores for cognitive sub-domains and physical function. Results: Most participants were women (REI: 77%; RE= 78%; CON=77%; mean age of 71 years), and did not need transport to the intervention site. At completion, compared with CON, REI and RE did not significantly improve on global cognition or each cognitive sub-domain. Both exercise groups improved on the timed up and go (REI - CON: -1.6 s, 95% CI: [-2.6, -0.5]; RE - CON: -1.4 s, 95% CI: [-2.4, -0.5) and 1-RM (REI - CON: 24 kg, 95% CI: [11, 36]; RE - CON: 25 kg, 95% CI: [12, 37]). An exploratory contrast showed that compared with RE, REI promote greater gains on global cognition (2.20, 95% CI: [0.10, 4.31]) and memory (1.34; 95% CI: [0.15, 2.54]). Conclusion: REI did not substantially improve cognitive function but did promote physical function among older adults with cognitive complaints. However, compared with RE, REI improved global cognition and memory.

Pages 241-255
Xin Wang, En-Jie Liu, Qian Liu, Shi-Hong Li, Ting Li, Qiu-Zhi Zhou, Yan-Chao Liu, Huaqiu Zhang, Jian-Zhi Wang
Tau Acetylation in Entorhinal Cortex Induces Its Chronic Hippocampal Propagation and Cognitive Deficits in Mice
Abstract: Background: Increased tau acetylation at K174, K274, K280, and K281 has been observed in the brains of Alzheimer’s disease (AD) patients or in transgenic mice, but the role of acetylation in tau propagation is elusive. Objective: To study the effect of tau acetylation in entorhinal cortex on tau transmission and learning and memory. Methods: Stereotactic brain injection, behavioral test, electrophysiological recording, immunohistochemistry, and immunofluorescence were used. Results: We constructed the hyperacetylation mimics of tau (AAV-Tau-4Q), the non-acetylation tau mutant (AAV-Tau-4R), and the wild-type tau (AAV-Tau-WT). By overexpressing these different tau proteins in the entorhinal cortex (EC) of 2-month-old mice, we found that overexpressing Tau-4Q in EC for 3 or 6 months (to 5 or 8 months of age) neither induces tau propagation to dentate gyrus (DG) nor glial activation in DG, nor spatial memory deficit. However, overexpressing Tau-WT and Tau-4Q in EC for 13.5 months (15.5 months of age) at 2 months promoted tau propagation respectively to granulosa and hilus of DG with glial activation, synaptic dysfunction, and memory deficit, while overexpressing Tau-4R abolished tau propagation with improved cellular pathologies and cognitive functions. Furthermore, overexpressing Tau-4Q in unilateral DG of 2-month-old mice for 8 weeks also promoted its contralateral transmission with glial activation, and mice with tau (Tau-WT, Tau-4Q, and Tau-4R) overexpression in DG showed cognitive deficits compared with the empty vector controls. Conclusion: Tau acetylation induces a time-dependent propagation from EC to DG, and only hippocampus but not EC tau accumulation induces cognitive deficits.

Pages 257-273
Lionel Breuza, Cecilia N. Arighi, Ghislaine Argoud-Puy, Cristina Casals-Casas, Anne Estreicher, Maria Livia Famiglietti, George Georghiou, Arnaud Gos, Nadine Gruaz-Gumowski, Ursula Hinz, Nevila Hyka-Nouspikel, Barbara Kramarz, Ruth C. Lovering, Yvonne Lussi, Michele Magrane, Patrick Masson, Livia Perfetto, Sylvain Poux, Milagros Rodriguez-Lopez, Christian Stoeckert, Shyamala Sundaram, Li-San Wang, Elizabeth Wu, Sandra Orchard, IMEx Consortium, UniProt Consortium
A Coordinated Approach by Public Domain Bioinformatics Resources to Aid the Fight Against Alzheimer’s Disease Through Expert Curation of Key Protein Targets
Abstract: Background: The analysis and interpretation of data generated from patient-derived clinical samples relies on access to high-quality bioinformatics resources. These are maintained and updated by expert curators extracting knowledge from unstructured biological data described in free-text journal articles and converting this into more structured, computationally-accessible forms. This enables analyses such as functional enrichment of sets of genes/proteins using the Gene Ontology, and makes the searching of data more productive by managing issues such as gene/protein name synonyms, identifier mapping, and data quality. Objective: To undertake a coordinated annotation update of key public-domain resources to better support Alzheimer’s disease research. Methods: We have systematically identified target proteins critical to disease process, in part by accessing informed input from the clinical research community. Results: Data from 954 papers have been added to the UniProtKB, Gene Ontology, and the International Molecular Exchange Consortium (IMEx) databases, with 299 human proteins and 279 orthologs updated in UniProtKB. 745 binary interactions were added to the IMEx human molecular interaction dataset. Conclusion: This represents a significant enhancement in the expert curated data pertinent to Alzheimer’s disease available in a number of biomedical databases. Relevant protein entries have been updated in UniProtKB and concomitantly in the Gene Ontology. Molecular interaction networks have been significantly extended in the IMEx Consortium dataset and a set of reference protein complexes created. All the resources described are open-source and freely available to the research community and we provide examples of how these data could be exploited by researchers.

Pages 275-290
Daniele Caligiore, Massimo Silvetti, Marcello D’Amelio, Stefano Puglisi-Allegra, Gianluca Baldassarre (Handling Associate Editor: Gholamreza Anbarjafari)
Computational Modeling of Catecholamines Dysfunction in Alzheimer’s Disease at Pre-Plaque Stage
Abstract: Background: Alzheimer’s disease (AD) etiopathogenesis remains partially unexplained. The main conceptual framework used to study AD is the Amyloid Cascade Hypothesis, although the failure of recent clinical experimentation seems to reduce its potential in AD research. Objective: A possible explanation for the failure of clinical trials is that they are set too late in AD progression. Recent studies suggest that the ventral tegmental area (VTA) degeneration could be one of the first events occurring in AD progression (pre-plaque stage). Methods: Here we investigate this hypothesis through a computational model and computer simulations validated with behavioral and neural data from patients. Results: We show that VTA degeneration might lead to system-level adjustments of catecholamine release, triggering a sequence of events leading to relevant clinical and pathological signs of AD. These changes consist first in a midfrontal-driven compensatory hyperactivation of both VTA and locus coeruleus (norepinephrine) followed, with the progression of the VTA impairment, by a downregulation of catecholamine release. These processes could then trigger the neural degeneration at the cortical and hippocampal levels, due to the chronic loss of the neuroprotective role of norepinephrine. Conclusion: Our novel hypothesis might contribute to the formulation of a wider system-level view of AD which might help to devise early diagnostic and therapeutic interventions.

Pages 291-300
Sandrine Brice, Aude Jabouley, Sonia Reyes, Carla Machado, Christina Rogan, Nathalie Dias-Gastellier, Hugues Chabriat, Sophie Tezenas du Montcel (Handling Associate Editor: Erin Abner)
Modeling the Cognitive Trajectory in CADASIL
Abstract: Background: For developing future clinical trials in Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it seems crucial to study the long-term changes of cognition. Objective: We aimed to study the global trajectory of cognition, measured by the Mini-Mental State Examination (MMSE) and the Mattis Dementia Rating Scale (MDRS), along the course of CADASIL. Methods: Follow-up data of 185 CADASIL patients, investigated at the French National Referral center CERVCO from 2003, were considered for analysis based on strict inclusion criteria. Assuming that the MMSE and the MDRS provide imprecise measures of cognition, the trajectory of a common cognitive latent process during follow-up was delineated using a multivariate latent process mixed model. After adjustment of this model for sex and education, the sensitivities of the two scales to cognitive change were compared. Results: Analysis of the cognitive trajectory over a time frame of 60 years of age showed a decrease of performances with aging, especially after age of 50 years. This decline was not altered by sex or education but patients who graduated from high school had a higher mean cognitive level at baseline. The sensitivities of MMSE and MDRS scales were similar and the two scales suffered from a ceiling effect and curvilinearity. Conclusion: These data support that cognitive decline is not linear and mainly occurs after the age of 50 years during the course of CADASIL. They also showed that MMSE and MDRS scales are hampered by major limitations for longitudinal studies.

Pages 301-311
Bianca Maria Ciminelli, Giovanna Menduti, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Rosanna Squitti, Mauro Rongioletti, Sabrina Nica, Andrea Novelletto, Luisa Rossi, Patrizia Malaspina
Polymorphic Genetic Markers of the GABA Catabolism Pathway in Alzheimer’s Disease
Abstract: Background: The compilation of a list of genetic modifiers in Alzheimer’s disease (AD) is an open research field. The GABAergic system is affected in several neurological disorders but its role in AD is largely understudied. Objective/Methods: As an explorative study, we considered variants in genes of GABA catabolism (ABAT, ALDH5A1, AKR7A2), and APOE in 300 Italian patients and 299 controls. We introduce a multivariate method to take into account the individual APOE genotype, thus controlling for the effect of the discrepant allele distributions in cases versus controls. We add a genotype-phenotype analysis based on age at onset and the Mini-Mental State Evaluation score. Results: On the background of strongly divergent APOE allele distributions in AD versus controls, two genotypic interactions that represented a subtle but significant peculiarity of the AD cohort emerged. The first is between ABAT and APOE, and the second between some ALDH5A1 genotypes and APOE. Decreased SSADH activity is predicted in AD carriers of APOE ε4, representing an additional suggestion for increased oxidative damage. Conclusion: We identified a difference between AD and controls, not in a shift of the allele frequencies at genes of the GABA catabolism pathway, but rather in gene interactions peculiar of the AD cohort. The emerging view is that of a multifactorial contribution to the disease, with a main risk factor (APOE), and additional contributions by the variants here considered. We consider genes of the GABA degradation pathway good candidates as modifiers of AD, contributing to energy impairment in AD brain.

Pages 313-322
Min Zhang, Xiaomei Zhong, Haishan Shi, Eugeen Vanmechelen, Ann De Vos, Sen Liu, Ben Chen, Naikeng Mai, Qi Peng, Xinru Chen, Zhangying Wu, Le Hou, Huarong Zhou, Cong Ouyang, Weiru Zhang, Wanyuan Liang, Chunying Dai, Yuping Ning
BACE1 and Other Alzheimer’s-Related Biomarkers in Cerebrospinal Fluid and Plasma Distinguish Alzheimer’s Disease Patients from Cognitively-Impaired Neurosyphilis Patients
Abstract: Background: Patients with spirochetal infection, which causes neurosyphilis (NS) and at a later stage general paresis of the insane (GPI), present with brain pathology features of Alzheimer’s disease (AD). However, the relationships among these illnesses regarding biomarker levels are still unclear. Objective: To explore biomarker levels in NS and GPI compared with those in AD and the relationship between biomarker levels and cognitive function in NS and GPI. Methods: Levels of neurogranin (NGRN) and β-amyloid precursor protein cleaving enzyme (BACE1) in cerebrospinal fluid (CSF)/plasma, together with amyloid-β 1-40 (Aβ40), Aβ42, and total tau in the CSF of 23 AD patients, 55 GPI patients, and 13 NS patients were measured. Patients were classified into none-to-mild, moderate, and severe stages of cognitive impairment. Results: Levels of CSF NGRN, BACE1, and tau as well as plasma BACE1 levels were significantly different among groups. In the none-to-mild stage, plasma BACE1 levels correlated with the protein levels in CSF and were significantly increased in AD patients versus GPI patients. The CSF tau levels in AD patients were significantly increased versus GPI patients in the moderate and severe stages. Pooling data from GPI and NS patients, both CSF tau and plasma NGRN levels correlated with cognitive scale scores. Conclusion: GPI and NS patients might have different biomarker level patterns than AD patients. While plasma BACE1 could be a promising early biomarker for to distinguish AD from GPI, CSF tau and plasma NGRN levels might be valuable in indications of cognitive function in pooled NS populations.

Pages 323-337
Can Sheng*, Yu Sun*, Min Wang*, Xiaoni Wang, Yi Liu, Dongqing Pang, Jiaqi Liu, Xiaoxia Bi, Wenying Du, Mingyan Zhao, Yuxia Li, Xiaobo Li, Jiehui Jiang, Ying Han (Handling Associate Editor: Lan Tan) *These authors contributed equally to this work.
Combining Visual Rating Scales for Medial Temporal Lobe Atrophy and Posterior Atrophy to Identify Amnestic Mild Cognitive Impairment from Cognitively Normal Older Adults: Evidence Based on Two Cohorts
Abstract: Background: Visual rating scales for medial temporal lobe atrophy (MTA) and posterior atrophy (PA) have been reported to be useful for Alzheimer’s disease diagnosis in routine clinical practice. Objective: To investigate the efficacy of combined MTA and PA visual rating scales to discriminate amnestic mild cognitive impairment (aMCI) patients from healthy controls. Methods: This study included T1-weighted MRI images from two different cohorts. In the first cohort, we recruited 73 patients with aMCI and 48 group-matched cognitively normal controls for training and validation. Visual assessments of MTA and PA were carried out for each participant. Global gray matter volume and density were estimated using voxel-based morphometry analysis as the objective reference. We investigated the discriminative power of a single visual rating scale and the combination of the MTA and PA rating scales for identifying aMCI. The second cohort, consisting of 33 aMCI patients and 45 controls, was used to verify the reliability of the visual assessments. Results: Compared with the single visual rating scale, the combination of the MTA and PA exhibited the best discriminative power, with an AUC of 0.818 ± 0.041, which was similar to the diagnostic accuracy of the gray matter volumetric measures. The discriminative power of the combined MTA and PA was verified in the second cohort (AUC 0.824 ± 0.058). Conclusion: The combined MTA and PA rating scales demonstrated practical diagnostic value for distinguishing aMCI patients from controls, suggesting its potential to serve as a convenient and reproducible method to assess the degree of atrophy in clinical settings.

Pages 339-353
Alex McKeown, Andrew Turner, Zuzanna Angehrn, Dianne Gove, Amanda Ly, Clementine Nordon, Mia Nelson, Claire Tochel, Brent Mittelstadt, Alex Keenan, Michael Smith, Ilina Singh
Health Outcome Prioritization in Alzheimer’s Disease: Understanding the Ethical Landscape
Abstract: Background: Dementia has been described as the greatest global health challenge in the 21st century on account of longevity gains increasing its incidence, escalating health and social care pressures. These pressures highlight ethical, social, and political challenges about healthcare resource allocation, what health improvements matter to patients, and how they are measured. This study highlights the complexity of the ethical landscape, relating particularly to the balances that need to be struck when allocating resources; when measuring and prioritizing outcomes; and when individual preferences are sought. Objective: Health outcome prioritization is the ranking in order of desirability or importance of a set of disease-related objectives and their associated cost or risk. We analyze the complex ethical landscape in which this takes place in the most common dementia, Alzheimer’s disease. Methods: Narrative review of literature published since 2007, incorporating snowball sampling where necessary. We identified, thematized, and discussed key issues of ethical salience. Results: Eight areas of ethical salience for outcome prioritization emerged: 1) Public health and distributive justice, 2) Scarcity of resources, 3) Heterogeneity and changing circumstances, 4) Knowledge of treatment, 5) Values and circumstances, 6) Conflicting priorities, 7) Communication, autonomy and caregiver issues, and 8) Disclosure of risk. Conclusion: These areas highlight the difficult balance to be struck when allocating resources, when measuring and prioritizing outcomes, and when individual preferences are sought. We conclude by reflecting on how tools in social sciences and ethics can help address challenges posed by resource allocation, measuring and prioritizing outcomes, and eliciting stakeholder preferences.

Pages 355-365
Julia Schneider, Anton Schönstein, Winfried Teschauer, Andreas Kruse, Birgit Teichmann
Hospital Staff’s Attitudes Toward and Knowledge About Dementia Before and After a Two-Day Dementia Training Program
Abstract: Background: The outcomes of hospitalized People with Dementia (PwD) are likely to be negative due to, among other key causes, negative staff attitudes and limited staff knowledge regarding dementia. Targeted interventions have been shown to positively change the attitudes of the hospital staff while also increasing their overall knowledge of dementia. However, training effects are often short-lived and frequently long-term effects are not examined in studies. Objective: To examine whether attending a dementia training program changes the attitudes of hospital staff toward PwD and/or increases their knowledge levels about dementia, and whether or not these changes are stable. Methods: The training program lasted two days and N = 60 attending hospital staff members agreed to participate in the study. Data were assessed with questionnaires prior to the training, 3 months, and 6 months after the training. German versions of the Dementia Attitude Scale (DAS-D) and the Knowledge in Dementia (KIDE) scale were used. Additionally, data about perception of PwD and confidence in dealing with challenging behavior were collected and analyzed. Results: After the training program, participants showed a significantly better attitude toward PwD as measured by DAS-D. These time-effects occurred in both DAS-D subscales (“dementia knowledge” and “social comfort”). Although a positive trend could be seen in the KIDE scale, no statistically significant increase occurred over time. Conclusion: Specialist training programs seem to be promising in positively changing attitudes toward and increasing knowledge about PwD with long-term effects. Further research should address the effects of attitude change in patient care.

Pages 367-374
Zi-Wei Yu, Xin Li, Ying Wang, Yu-Hong Fu, Xin-Yuan Gao
Association Between Lipid Accumulation Product and Mild Cognitive Impairment in Patients with Type 2 Diabetes
Abstract: Background: Diabetes may increase the risk of conversion of mild cognitive impairment (MCI) to dementia. Lipid accumulation product (LAP), an index of visceral obesity, has been shown to be a powerful predictor of insulin resistance and type 2 diabetes (T2D). However, little attention has been paid to the relationship between LAP and MCI in T2D. Objective: We aimed to investigate the association between the LAP index and MCI in patients with T2D. Methods: In total, 220 hospitalized patients with T2D, including 113 MCI patients and 107 patients with normal cognition, were enrolled in this cross-sectional study. We collected demographic, anthropometric, and biochemical data on each subject. The LAP index was calculated according to the following formulas: [waist circumference (WC) (cm) - 65] × triglyceride (TG) (mmol/L) for males and [WC (cm) - 58] ×TG (mmol/L) for females. Results: Compared with patients with normal cognition, MCI patients were older and had a higher LAP index, WC, body mass index, and glycosylated hemoglobin A1c level, as well as a lower Montreal Cognitive Assessment score and education level (p<0.05). After adjusting for confounding factors, LAP index was associated with MCI (OR=1.047, 95%CI=1.031-1.063, p<0.01). The area under the ROC curve (AUC) for the LAP index was higher than that for WC and BMI. Conclusion: A high LAP index is associated with an increased risk of MCI in T2D patients. The LAP index appears to be a good indicator of risk of MCI in patients with T2D.

Pages 375-386
Edin Begic*, Suncica Hadzidedic*, Slobodan Obradovic, Zijo Begic, Mirsada Causevic *These authors contributed equally to this work.
Increased Levels of Coagulation Factor XI in Plasma Are Related to Alzheimer's Disease Diagnosis
Abstract: Background: Alzheimer's disease is a complex disorder of unclear etiology that develops in the elderly population. It is a debilitating, progressive neurodegeneration for which disease-modifying therapies do not exist. Previous studies have suggested that, for a subset of patients, dysregulation in hemostasis might be one of the molecular mechanisms that ultimately leads to the development of neurodegeneration resulting in cognitive decline that represents the most prominent symptomatic characteristic of Alzheimer's disease. Objective: To examine a relationship between factors that are part of coagulation and anticoagulation pathways with cognitive decline that develops during Alzheimer's disease. Methods: SOMAscan assay was used to measure levels of coagulation/anticoagulation factors V, VII, IX, X, Xa, XI, antithrombin III, protein S, protein C, and activated protein C in plasma samples obtained from three groups of subjects: 1) subjects with stable cognitively healthy function, 2) subjects with stable mild cognitive impairment, and 3) subjects diagnosed with probable Alzheimer's disease. Results: Our results show that protein levels of coagulation factor XI are significantly increased in patients who are diagnosed with probable Alzheimer's disease compared with cognitively healthy subjects or patients diagnosed with mild cognitive impairment. Furthermore, our results demonstrate that significant predictors of Alzheimer's-type diagnosis are factors IX and XI—an increase in both factors is associated with a reduction in cognitive function. Conclusion: Our study justifies further investigations of biological pathways involving coagulation/anticoagulation factors in relation to dementia, including dementia resulting from Alzheimer's-type neurodegeneration.

Pages 387-400
Anping Xu, Yinshan Tang, Qingtao Zeng, Xin Wang, Huiling Tian, You Zhou, Zhigang Li
Electroacupuncture Enhances Cognition by Promoting Brain Glucose Metabolism and Inhibiting Inflammation in the APP/PS1 Mouse Model of Alzheimer’s Disease: A Pilot Study
Abstract: Background: Alzheimer's disease (AD) is a neurodegenerative disease, yet there is no effective treatment. Electroacupuncture (EA) is a complementary alternative medicine approach. In clinical and animal studies, EA promotes cognition in AD and vascular dementia. It has been previously reported that cognitive decline in AD might be closely related to reduced glucose intake in the brain. It is worth mentioning that the regions of glucose hypometabolism are usually found to be associated with neuroinflammation. Objective: This study is to explore whether the protective mechanism of EA on cognition is related to the regulation of glucose metabolism and neuroinflammation. Methods: APP/PS1 mice were randomly divided into AD group and the treatment (AD+EA) group. In the AD+EA group, EA was applied on Baihui (GV20) and Yintang (GV29) for 20 min and then pricked at Shuigou (GV26), once every alternate day for 4 weeks. Morris water maze (MWM) tests were performed to evaluate the effects of EA treatment on cognitive functions. 18F-FDG PET, immunofluorescence, and western blot were used to examine the mechanisms underlying EA effects. Results: From MWM tests, EA treatment significantly improved cognition of APP/PS1 mice. From the 18F-FDG PET, the levels of uptake rate of glucose in frontal lobe were higher than the AD group after EA. From immunofluorescence and western blot, amyloid-β (Aβ) and neuroinflammation were reduced after EA. Conclusion: These results suggest that EA may prevent cognitive decline in AD mouse models by enhancing glucose metabolism and inhibiting inflammation-mediated Aβ deposition in the frontal lobe.

Pages 401-409
Rong-Ze Wang, Yu-Xiang Yang, Hong-Qi Li, Xue-Ning Shen, Shi-Dong Chen, Qiang Dong, Yi Wang, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative
Genome-Wide Association Study of Brain Alzheimer’s Disease-Related Metabolic Decline as Measured by [18F] FDG-PET Imaging
Abstract: Background: Hypometabolism detected by fluorodeoxyglucose F18 positron emission tomography ([18F] FDG PET) is an early neuropathologic changes in Alzheimer’s disease (AD) and provides important pathologic staging information. Objective: This study aimed to discover genetic interactions that regulate longitudinal glucose metabolic decline in AD-related brain regions. Methods: A total of 586 non-Hispanic white individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) 1/GO/2 cohorts that met all quality control criteria were included in this study. Genome-wide association study of glucose metabolic decline in region of interests (ROIs) was performed with linear regression under the additive genetic model. Results: We identified two novel variants that had a strong association with longitudinal metabolic decline in different ROI. Rs4819351-A in gene 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3) demonstrated reduced metabolic decline in right temporal gyrus (p=3.97 × 10-8, β=-0.016), while rs13387360-T in gene LOC101928196 demonstrated reduced metabolic decline in left angular gyrus (p=1.69 × 10-8, β=-0.027). Conclusion: Our results suggest two genome-wide significant SNPs (rs4819351, rs13387360) in AGPAT3 and LOC101928196 as protective loci that modulate glucose metabolic decline. These two genes should be further investigated as potential therapeutic target for neurodegeneration diseases.

Pages 411-421
Ya-Hui Ma*, Jia-Huan Wu*, Wei Xu, Xue-Ning Shen, Hui-Fu Wang, Xiao-He Hou, Xi-Peng Cao, Yan-Lin Bi, Qiang Dong, Lei Feng, Lan Tan, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer’s Disease Pathology in Cognitively Intact Older Adults: The CABLE study
Abstract: Background: Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer’s disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. Objective: This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of ADs pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. Methods: Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer’s Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOE ε4 status and gender using a two-way analysis of covariance. Results: Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p=0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p=0.007) and CSF t-tau/Aβ42 (p=0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOE ε4 and gender. Conclusion: Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.

Pages 423-435
Nidhi Sharda, Thomas Pengo, Zengtao Wang, Karunya K. Kandimalla (Handling Associate Editor: Ottavio Arancio)
Amyloid-β Peptides Disrupt Interactions Between VAMP-2 and SNAP-25 in Neuronal Cells as Determined by FRET/FLIM
Abstract: Background: Synaptic dysfunction prevalent in Alzheimer’s disease (AD) brain is closely associated with increased accumulation of amyloid-β (Aβ) peptides in the brain parenchyma. It is widely believed that Aβ peptides trigger synaptic dysfunction by interfering with the synaptic vesicular fusion and the release of neurotransmitters, primarily facilitated by the SNARE protein complexes formed by VAMP-2, SNAP-25, and syntaxin-1. However, Aβ interactions with SNARE proteins to ultimately disrupt synaptic vesicular fusion are not well understood. Objective: Our objective is to elucidate mechanisms by which Aβ peptides perturb SNARE complexes. Methods: Intensity (qualitative) and lifetime (quantitative) based measurements involving Forster (fluorescence) resonance energy transfer (FRET) followed by fluorescence lifetime imaging microscopy (FLIM) were employed to investigate the effect of Aβ peptides on dynamic interactions between VAMP-2, labeled with cerulean (Cer) at the N-terminus (FRET donor), and SNAP-25 labeled with citrine (Cit) on the N-terminus (FRET acceptor). The FRET and FLIM interactions at the exocytosis locations on the pre-synaptic membrane were recorded under spontaneous and high potassium evoked conditions. Moreover, cellular accumulation of fluorescein labeled Aβ (F-Aβ) peptides and their co-localization with Cer-VAMP2 was investigated by confocal microscopy. Results: The F-Aβ40 and F-Aβ42 are internalized by differentiated N2A cells, where they colocalize with Cer-VAMP2. Both Aβ40 and Aβ42 decrease interactions between the N-termini of Cer-VAMP2 and Cit-SNAP25 in N2A cells, as determined by FRET/FLIM. Conclusion: By perturbing the N-terminal interactions between VAMP-2 and SNAP-25, Aβ40 and Aβ42, can directly interfere with the SNARE complex formation, which is critical for the docking and fusion of synaptic vesicles.

Pages 437-447
Kristen R. Hollinger, Xiaolei Zhu, Elizabeth S. Khoury, Ajit G. Thomas, Kevin Liaw, Carolyn Tallon, Ying Wu, Eva Prchalova, Atsushi Kamiya, Camilo Rojas, Sujatha Kannan, Barbara S. Slusher (Handling Associate Editor: Anne Schmöle)
Glutamine Antagonist JHU-083 Normalizes Aberrant Hippocampal Glutaminase Activity and Improves Cognition in APOE4 Mice
Abstract: Background: Given the emergent aging population, the identification of effective treatments for Alzheimer’s disease (AD) is critical. Objective: We investigated the therapeutic efficacy of JHU-083, a brain-penetrable glutamine antagonist, in treating AD using the humanized APOE4 knock-in mouse model. Methods: Cell culture studies were performed using BV2 cells and primary microglia isolated from hippocampi of adult APOE4 knock-in mice to evaluate the effect of JHU-083 treatment on LPS-induced glutaminase (GLS) activity and inflammatory markers. Six-month-old APOE4 knock-in mice were administered JHU-083 or vehicle via oral gavage 3x/week for 4-5 months and cognitive performance was assessed using the Barnes maze. Target engagement in the brain was confirmed using a radiolabeled GLS enzymatic activity assay, and electrophysiology, gastrointestinal histology, blood chemistry, and CBC analyses were conducted to evaluate the tolerability of JHU-083. Results: JHU-083 inhibited the LPS-mediated increases in GLS activity, nitic oxide release, and pro-inflammatory cytokine production in cultured BV2 cells and primary microglia isolated from APOE4 knock-in AD mice. Chronic treatment with JHU-083 in APOE4 mice improved hippocampal-dependent Barnes maze performance. Consistent with the cell culture findings, postmortem analyses of APOE4 mice showed increased GLS activity in hippocampal CD11b+ enriched cells versus age-matched controls, which was completely normalized by JHU-083 treatment. JHU-083 was well-tolerated, showing no weight loss effect or overt behavioral changes. Peripheral nerve function, gastrointestinal histopathology, and CBC/clinical chemistry parameters were all unaffected by chronic JHU-083 treatment. Conclusion: These results suggest that the attenuation of upregulated hippocampal glutaminase by JHU-083 represents a new therapeutic strategy for AD.

Pages 449-456
Wei Xu, Fu-Rong Sun, Chen-Chen Tan, Lan Tan, for the Alzheimer’s Disease Neuroimaging Initiative
Weight Loss Is a Preclinical Signal of Cerebral Amyloid Deposition and Could Predict Cognitive Impairment in Elderly Adults
Abstract: Background: Higher late-life body mass index (BMI) was associated with reduced risk of Alzheimer’s disease (AD), which might be explained by a reverse causal relationship. Objective: To investigate whether weight loss was a preclinical manifestation of AD pathologies and could be a predictor of cognitive impairment. Methods: A total of 1,194 participants (mean age = 73.2 [range: 54 to 91] years, female = 44.5%) from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped according to AD biomarker profile as indicated by amyloid (A) and tau (TN) status and clinical stage by clinical dementia rating (CDR). BMI across the biomarker-defined clinical stages was compared with Bonferroni correction. Pearson correlation analysis was performed to test the relationship between the amyloid change by PET and the BMI change. Multiple regression models were used to explore the influences of amyloid pathologies on BMI change as well as the effects of weight loss on longitudinal changes of global cognitive function. Results: BMI was significantly decreased in AD preclinical stage (amyloid positive [A+] and CDR = 0) and dementia stage (A+/TN+ and CDR = 0.5 or 1), compared with the healthy controls (A-/TN- and CDR = 0, p < 0.005), while no significant differences were observed between preclinical AD and AD dementia. Amyloid PET change was inversely correlated with BMI change (p = 0.023, β = -14). Individuals in amyloid positive group exhibited faster weight loss (time × group interaction p = 0.019, β = -0.20) compared to the amyloid negative group. Greater weight loss predicted higher risk of developing cognitive disorders. Conclusion: Elders who experienced greater weight loss might belong to preclinical stage of AD and could be targeted for primary prevention of the disease.