Volume 74, Number 1, 2020

Pages 1-28

Teodor T. Postolache , Abhishek Wadhawan , Adem Can, Christopher A. Lowry, Margaret Woodbury, Hina Makkar, Andrew J. Hoisington, Alison J. Scott, Eileen Potocki, Michael E. Benros, John W. Stiller
Inflammation in Traumatic Brain Injury
Abstract: There is increasing evidence that inflammation contributes to clinical and functional outcomes in traumatic brain injury (TBI). Many successful target-engaging, lesion-reducing, symptom-alleviating, and function-improving interventions in animal models of TBI have failed to show efficacy in clinical trials. Timing and immunological context are paramount for the direction, quality, and intensity of immune responses to TBI and the resulting neuroanatomical, clinical, and functional course. We present components of the immune system implicated in TBI, potential immune targets, and target-engaging interventions. The main objective of our article is to point toward modifiable molecular and cellular mechanisms that may modify the outcomes in TBI, and contribute to increasing the translational value of interventions that have been identified in animal models of TBI.

Pages 29-41

Xiaoran Li, Chunyan Liu, Rong Wang
Light Modulation of Brain and Development of Relevant Equipment
Abstract: Light modulation plays an important role in understanding the pathology of brain disorders and improving brain function. Optogenetic techniques can activate or silence targeted neurons with high temporal and spatial accuracy and provide precise control, and have recently become a method for quick manipulation of genetically identified types of neurons. Photobiomodulation (PBM) is light therapy that utilizes non-ionizing light sources, including lasers, light emitting diodes, or broadband light. It provides a safe means of modulating brain activity without any irreversible damage and has established optimal treatment parameters in clinical practice. This manuscript reviews 1) how optogenetic approaches have been used to dissect neural circuits in animal models of Alzheimer’s disease, Parkinson’s disease, and depression, and 2) how low level transcranial lasers and LED stimulation in humans improves brain activity patterns in these diseases. State-of-the-art brain machine interfaces that can record neural activity and stimulate neurons with light have good prospects in the future.

Pages 43-53

Ariel J. Kuhn, Jevgenij Raskatov (Handling Associate Editor: Annelise Barron)
Is the p3 (Aβ17-40, Aβ17-42) Peptide Relevant to the Pathology of Alzheimer’s Disease?
Abstract: Despite the vast heterogeneity of amyloid plaques isolated from the brains of those with Alzheimer’s disease (AD), the basis of the Amyloid Cascade Hypothesis targets a single peptide, the amyloid-β (Aβ) peptide. The countless therapeutic efforts targeting the production and aggregation of this specific peptide have been met with disappointment, leaving many to question the role of Aβ in AD. An alternative cleavage product of the amyloid-β protein precursor, called the p3 peptide, which has also been isolated from the brains of AD patients, has been largely absent from most Aβ-related studies. Typically referred to as non-amyloidogenic and even suggested as neuroprotective, the p3 peptide has garnered little attention aside from some conflicting findings on cytotoxicity and potential self-assembly to form higher order aggregates. Herein, we report an extensive analysis of the findings surrounding p3 and offer some evidence as to why it may not be as innocuous as previously suggested.

Pages 55-63
Ali Ezzati, Richard B. Lipton
Machine Learning Predictive Models Can Improve Efficacy of Clinical Trials for Alzheimer’s Disease
Abstract: Background: The ideal participants for Alzheimer’s disease (AD) clinical trials would show cognitive decline in the absence of treatment (i.e., placebo arm) and also would be responsive to the therapeutic intervention being studied (i.e., drug arm). One strategy to boost the power of trials is to enroll individuals who are more likely to progress targeted using data-driven predictive models. Objective: To investigate if machine learning (ML) models can effectively predict clinical disease progression (cognitive decline) in mild-to-moderate AD patients during the timeframe of a phase III clinical trial. Methods: Data from 202 participants with a diagnosis of AD at baseline from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) was used to train ML classifiers that can differentiate between individuals who had declining cognitive function (DC) and individuals with stable cognitive function (SC). DC was defined as any downward change in the Alzheimer’s Disease Assessment Scale cognitive subscale (ADAS-cog) score over 12 months of follow-up. SC was defined by the absence of decline in ADAS-cog. Trained models were applied to data from 77 participants from the placebo arm of the phase III trial of Semagacestat (LFAN study) to identify subgroups of SC versus DC. Results: Only 74.8% of ADNI participants and 63.6% of LFAN participants had cognitive decline after one year of follow up. K-nearest neighbors (kNN) classifier had an accuracy of 68.3%, sensitivity of 80.1%, and specificity of 33.3% for identifying decliners in ADNI (training sample). In LFAN (validation sample), the model showed an overall accuracy of 61.3%, sensitivity of 65.5%, and specificity of 47.0% in identifying decliners at the 12 months of follow-up. The model had a positive predictive value of 80.8%, which was 17.2% more than the base prevalence of decliners. Conclusions: Machine learning predictive models can be effectively used to boost the power of clinical trials by reducing the sample size.

Pages 65-77
Lynne Shinto, David Lahna, Charles F. Murchison, Hiroko Dodge, Kirsten Hagen, Jason David, Jeffrey Kaye, Joseph F. Quinn, Rachel Wall, Lisa C. Silbert (Handling Associate Editor: Michelle Mielke)
Oxidized Products of Omega-6 and Omega-3 Long Chain Fatty Acids Are Associated with Increased White Matter Hyperintensity and Poorer Executive Function Performance in a Cohort of Cognitively Normal Hypertensive Older Adults
Abstract: Background: Cerebrovascular disease is a common cause of dementia in older adults, and potentially preventable with early intervention. Oxylipins are produced from the oxidation of long-chain polyunsaturated fatty acids (PUFA) possessing potent vascular effects. Oxylipins generated from the cytochrome P450 pathway are enzymatically converted to diols by soluble epoxide hydrolase (sEH); sEH products have been associated with small vessel ischemic disease. Little is known about oxylipins’ impact on markers of dementia risk. Objective: An exploratory examination of the association between omega-6 and omega-3 derived oxylipins, brain MRI, and cognition. Methods: Thirty-seven non-demented participants with controlled hypertension (mean age 65.6 years) were enrolled in a dementia prevention study investigating fish oil and lipoic acid on preserving cognitive function. Baseline associations between plasma oxylipins, white matter hyperintensity (WMH), and Trails-B were examined using linear regression. P450-derived diol/epoxide ratio was an indirect measure of sEH activity. Results: Omega-6 derived 9-HODE was associated with increased WMH (p=0.017) and reduced grey matter volume (p=0.02). Omega-6 P450-derived diol/epoxide ratio 9,10-DiHOME/9,10-EpOME was associated with increased WMH (p=0.035) and poorer performance on Trails-B (p=0.05); ratio14,15-DHET/14,15-EET was associated with increased WMH (p=0.045). Omega-3 P450-derived diol/epoxide ratio 19,20-DiHDPE/19,20-EpDPE was associated with increased WMH (p=0.04) and poorer performance on Trails-B (p=0.04). Arachidonic acid was associated with better performance on Trails-B (p=0.012); Omega-3 derived 16,17-EpDPE was associated with decreased WMH (p=0.005). Conclusions: With the exception of arachidonic acid, it was specific oxylipin products, not their parent PUFAs, that were associated with unfavorable and favorable MRI and cognitive markers of dementia risk.

Pages 79-89
Jean-Michel Dorey, Isabelle Rouch, Catherine Padovan, Nawèle Boublay, Elodie Pongan, Bernard Laurent, PACO group, Armin von Gunten, Pierre Krolak-Salmon
Neuroticism-Withdrawal and Neuroticism-Volatility Differently Influence the Risk of Neuropsychiatric Symptoms in Alzheimer’s Disease
Abstract:Background: Neuroticism is recognized as the personality domain that is most strongly associated with behavioral and psychological symptoms (BPS) of Alzheimer’s disease (AD). Two sub-components of neuroticism have been recently isolated. Neuroticism-withdrawal (N-withdrawal) refers to the tendency to internalize negative emotion, whereas neuroticism-volatility (N-volatility) reflect the predisposition to externalize negative emotions. Objective: The objective of the current study was to investigate the specific influence of these two sub-components of neuroticism on BPS. Methods: One hundred eighty-seven patients with prodromal or mild AD were drawn from the PACO study (Personalité Alzheimer COmportement). Neuroticism and its facets were assessed at baseline using the NEO-PI-R inventory. N-withdrawal and N-volatility were isolated using a principal component analysis led on the six facets composing neuroticism. BPS were measured with the short version of Neuropsychiatric Inventory (NPI-Q) and collected at baseline, then every 6 months over an 18-month follow-up. Linear mixed-effect analyses were conducted to investigate the association between N-withdrawal, N-volatility, and the severity of BPS over the follow-up. Results: Mean age of the participant was 79.2 ± 6.5; 59% were female; mean MMSE was 24.5± 2.5. Both N-volatility and N-withdrawal were related with the NPI-Q (p<0.001; p=0,004). N-withdrawal was positively associated with anxiety (p=0.001) and depression (p=0.002), while N-volatility was positively related to delusions (p=0.004), agitation/aggression (p<0.001), irritability/volatility (p=0.037), and apathy (p=0.021). Conclusion: The present study demonstrates that N-volatility and N-withdrawal influence the risk of developing BPS in a different way. These results highlight the relevance of considering sub-components of neuroticism when studying links between personality and BPS.

Pages 91-99
W.M.A.D. Binosha Fernando, Ian J. Martins, Michael Morici, Prashant Bharadwaj, Stephanie R. Rainey-Smith, Wei Ling Florence Lim, Ralph N. Martins
Sodium Butyrate Reduces Brain Amyloid-β Levels and Improves Cognitive Memory Performance in an Alzheimer’s Disease Transgenic Mouse Model at an Early Disease Stage
Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline and neuropathological features, including abnormal deposition of amyloid-β (Aβ) peptides, intracellular neurofibrillary tangles, and neuronal death. Identifying therapeutics which can reduce memory deficits at an early stage of the disease has the advantage of slowing or even reversing disease progression before irreversible brain damage has occurred. Consequently, in this study, we investigated the ability of the histone deacetylase inhibitor sodium butyrate (NaB) to attenuate memory deficits in the 5xFAD mouse model of AD following a 12-week feeding regimen. 5xFAD mice demonstrate a unique time course of Aβ pathology, developing Aβ plaques as early as 2 months. Male mice were assigned to either a control diet or a NaB-supplemented diet which was administered at either 5 mg/kg/day, or 15 mg/kg/day for 12 weeks (each group, N=15). Supplementation commenced at an early disease stage (8-10 weeks of age). Behavioral testing (contextual and cued fear conditioning) was undertaken, and brain Aβ levels measured, at the end of the 12-week intervention. NaB had profound effects on Aβ levels and on associative learning and cognitive functioning. A 40% reduction in brain Aβ levels and a 25% increase in fear response in both the cued and contextual testing was observed in the NaB-treated animals compared to the control group. These findings suggest that NaB warrants further investigation as a potential therapeutic agent in the treatment of cognitive deficits associated with early stages of AD.

Pages 101-112
Leonie Beyer, Matthias Brendel, Franziska Scheiwein, Julia Sauerbeck, Chisa Hosakawa, Ian Alberts, Kuangyu Shi, Peter Bartenstein, Kazunari Ishii, John Seibyl, Paul Cumming, Axel Rominger for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Valentina Bessi)
Improved Risk Stratification for Progression from Mild Cognitive Impairment to Alzheimer’s Disease with a Multi-Analytical Evaluation of Amyloid-β Positron Emission Tomography
Abstract: Background: Amyloid-β (Aβ) accumulation in brain of patients with suspected Alzheimer’s disease (AD) can be assessed by positron emission tomography (PET) in vivo. While visual classification prevails in the clinical routine, semiquantitative PET analyses may enable more reliable evaluation of cases with a visually uncertain, borderline Aβ accumulation. Objective: We evaluated different analysis approaches (visual/semiquantitative) to find the most accurate and sensitive interpretation of Aβ-PET for predicting risk of progression from mild cognitive impairment (MCI) to AD. Methods: Based on standard uptake value (SUV) ratios of a cortical-composite volume of interest of 18F-AV45-PET from MCI subjects (n = 396, ADNI database), we compared three different reference region (cerebellar grey matter, CBL; brainstem, BST; white matter, WM) normalizations and the visual read by receiver operator characteristics for calculating a hazard ratio (HR) for progression to Alzheimer’s disease dementia (ADD). Results: During a mean follow-up time of 45.6 ± 13.0 months, 28% of the MCI cases (110/396) converted to ADD. Among the tested methods, the WM reference showed best discriminatory power and progression-risk stratification (HRWM of 4.4 [2.6-7.6]), but the combined results of the visual and semiquantitative analysis with all three reference regions showed an even higher discriminatory power. Conclusion: A multi-analytical composite of visual and semiquantitative reference tissue analyses of 18F-AV45-PET gave improved risk stratification for progression from MCI to ADD relative to performance of single read-outs. This optimized approach is of special interest for prospective treatment trials, which demand a high accuracy.

Pages 113-126
Opeyemi S. Ademowo, Irundika H.K. Dias, Lorena Diaz-Sanchez, Lissette Sanchez-Aranguren, Wilhelm Stahl, Helen R. Griffiths
Partial Mitigation of Oxidized Phospholipid-Mediated Mitochondrial Dysfunction in Neuronal Cells by Oxocarotenoids
Abstract: Mitochondria are important (patho)physiological sources of reactive oxygen species (ROS) that mediate mitochondrial dysfunction and phospholipid oxidation; an increase in mitochondrial content of oxidized phospholipid (OxPL) associates with cell death. Previously we showed that the circulating OxPL 1-palmitoyl-2-(5'-oxo-valeroyl)-sn-glycero-3-phosphocholine (POVPC) increases in patients with Alzheimer’s disease (AD), and associates with lower plasma antioxidant oxocarotenoids, zeaxanthin, and lutein. Since oxocarotenoids are metabolized in mitochondria, we propose that during AD, lower concentrations of mitochondrial zeaxanthin and lutein may result in greater phospholipid oxidation and predispose to neurodegeneration. Here, we have investigated whether non-toxic POVPC concentrations impair mitochondrial metabolism in differentiated (d)SH-SY5Y neuronal cells and whether there is any protective role for oxocarotenoids against mitochondrial dysfunction. After 24 hours, glutathione (GSH) concentration was lower in neuronal cells exposed to POVPC (1-20 µM) compared with vehicle control without loss of viability compared to control. However, mitochondrial ROS production (determined by MitoSOX oxidation) was increased by 50% only after 20 µM POVPC. Following delivery of lutein (0.1-1 µM) and zeaxanthin (0.5-5 µM) over 24 hours in vitro, oxocarotenoid recovery from dSH-SY5Y cells was >50%. Co-incubation with oxocarotenoids prevented loss of GSH after 1 µM but not 20 µM POVPC, whereas the increase in ROS production induced by 20 µM POVPC was prevented by lutein and zeaxanthin. Mitochondrial uncoupling increases and ATP production is inhibited by 20 µM but not 1 µM POVPC; carotenoids protected against uncoupling although did not restore ATP production. In summary, 20 µM POVPC induced loss of GSH and a mitochondrial bioenergetic deficit in neuronal cells that was not mitigated by oxocarotenoids.

Pages 127-138
Miharu Nakanishi, Ataru Igarashi, Kaname Ueda, Alan J.M. Brnabic, Tamas Treuer, Masayo Sato, Kristin Kahle-Wrobleski, Kenichi Meguro, Masahito Yamada, Masaru Mimura, Heii Arai (Handling Associate Editor: Sophie Vandepitte)
Costs and Resource Use Associated with Community-Dwelling Patients with Alzheimer’s Disease in Japan: Baseline Results from the Prospective Observational GERAS-J Study
Abstract: Background: As the Japanese population ages, caring for people with Alzheimer’s disease (AD) dementia is becoming a major socioeconomic issue. Objective: To determine the contribution of patient and caregiver costs to total societal costs associated with AD dementia. Methods: Baseline data was used from the longitudinal, observational GERAS-J study. Using the Mini-Mental State Examination (MMSE) score, patients routinely visiting memory clinics were stratified into three groups based on AD severity. Health care resource utilization was recorded using the Resource Utilization in Dementia questionnaire. Total monthly societal costs were estimated using Japan-specific unit costs of services and products (patient direct health care use, patient social care use, and informal caregiving time). Uncertainty around mean costs was estimated using bootstrapping methods. Results: Overall, 553 community-dwelling patients with AD dementia (28.3% mild [MMSE 21-26], 37.8% moderate [MMSE 15-20], and 34.0% moderately severe/severe [MMSE < 14]) and their caregivers were enrolled. Patient characteristics were: mean age 80.3 years, 72.7% female, and 13.6% living alone. Caregiver characteristics were: mean age 62.1 years, 70.7% female, 78.8% living with patient, 49.0% child of patient, and 39.2% sole caregiver. Total monthly societal costs of AD dementia (Japanese yen) were: 158,454 (mild), 211,301 (moderate), and 294,224 (moderately severe/severe). Informal caregiving costs comprised over 50% of total costs. Conclusion: Baseline results of GERAS-J showed that total monthly societal costs associated with AD dementia increased with AD severity. Caregiver-related costs were the largest cost component. Interventions are needed to decrease informal costs and decrease caregiver burden.

Pages 139-149
Shi-Dong Chen, Hong-Qi Li, Xue-Ning Shen, Jie-Qiong Li, Wei Xu, Yu-Yuan Huang, Lan Tan, Qiang Dong, Jin-Tai Yu, on behalf of Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ling-Qiang Zhu)
Genome-Wide Association Study Identifies SLAMF1 Affecting the Rate of Memory Decline
Abstract: Background: As cognitive function declines with age, identifying factors affecting the trajectory of cognitive decline is an indispensable step toward developing intervention strategies to improve the quality of the elderly life. Objective: We performed a genome-wide association study (GWAS) focusing on memory function to explore single nucleotide polymorphisms (SNPs) associated with the rate of memory decline. Methods: Seven hundred and nine eligible non-Hispanic Caucasians from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were included for analysis after quality control. GWAS was performed with linear regression. We subsequently tested whether the associations remained significant in subgroup analysis and also examined the impact of SNPs on the longitudinal changes in other neuropsychological measures and amyloid pathology. Results: We identified rs13374761-A in SLAMF1 gene associated with less memory decline (MAF= 0.071, β = 0.0103, p = 4.14 x 10-8). Subgroup analysis showed stability of results across groups with different diagnosis at baseline. Rs13374761-A also had protective effects on global cognition (p = 0.024), episodic memory (p = 0.024), and semantic memory (p = 0.042), and exerts protection against a decrease in CSF Aβ42 concentration (p = 0.0463) and an increase in Aβ loading in cerebral cortex (p = 0.00666) among minor allele carriers. Conclusion: A novel variant in gene SLAMF1 affects the rate of memory decline in the aged population. Given the protective effect of this variant, SLAMF1 should be further investigated as a potential preventive and therapeutic target for monitoring cognition trajectories.

Pages 151-161
Kathrin Heser, Luca Kleineidam, Alexander Pabst, Birgitt Wiese, Susanne Roehr, Margrit Löbner, André Hajek, Carolin van der Leeden, Matthias C. Angermeyer, Martin Scherer, Hans-Helmut König, Wolfgang Maier, Steffi G. Riedel-Heller, Michael Wagner (Handling Associate Editor: Jessica Kirkland Caldwell)
Sex-Specific Associations Between Depressive Symptoms and Risk for Subsequent Dementia
Abstract: Background: An association between depression and an increased risk for subsequent dementia is well-established. Sex-specific associations are understudied yet. Objective: We aimed to investigate sex-specific associations between depressive symptoms and dementia risk. Methods: Longitudinal analyses were conducted in a pooled data set (n = 4,255, mean age = 80 years) of two prospective cohort studies (LEILA 75+, AgeCoDe). Depressive symptoms were harmonized by dichotomized scores of two different depression screening scales using established cutoffs. Transition to dementia was used as outcome in Cox proportional hazards models. Results: Depressive symptoms at baseline were associated with an increased risk for subsequent dementia, and this association was more pronounced in males (interaction of depressive symptoms x sex: HR = 1.64, 95% CI: 1.02-2.64, p = 0.042) in a model adjusted for study, age, and education. After additional adjustment for subjective and objective cognition, depressive symptoms and their interaction with sex (HR = 1.38, 95% CI: 0.85-2.23, p = 0.188) were no longer significantly associated with the risk for subsequent dementia. Sex-stratified analyses showed stronger and significant associations between depressive symptoms and subsequent dementia in men (e.g., HR = 2.10, 95% CI: 1.36-3.23, p = 0.001, compared to HR = 1.28, 95% CI: 1.04-1.58, p = 0.020, in women). Conclusion: Overall, we provide evidence for a stronger association between depression and dementia in men compared to women. Depressive symptoms should be diagnosed, monitored, and treated, not only due to depression, but also with respect to the risk for subsequent dementia, especially in elderly men.

Pages 163-171
Michelle M.Y. Lai, Matthew J. Sharman, David J. Ames, Kathryn A. Ellis, Kay L. Cox, Graham Hepworth, Patricia Desmond, Elizabeth V. Cyarto, Ralph N. Martins, Colin L. Masters, Nicola T. Lautenschlager (Handling Associate Editor: Simon Laws)
Relationship of Established Cardiovascular Risk Factors and Peripheral Biomarkers on Cognitive Function in Adults at Risk of Cognitive Deterioration
Abstract: Background: There is a paucity of information on the role of microvascular and inflammatory biomarkers in cognitive dysfunction. Objective: This study sought to evaluate the relationships between established and a number of peripheral biomarkers on cognitive patterns in 108 older adults with memory complaints. Methods: Participants in the AIBL Active study aged 60 years and older with at least one vascular risk factor and memory complaints completed a neuropsychological test battery and provided cross-sectional health data. Linear regression models adjusted for covariates examined associations between cognitive performance and a panel of vascular risk factors (Framingham cardiovascular scores, hs-CRP, homocysteine, fasting glucose, LDL-cholesterol) and peripheral biomarkers (TNF-α, BDNF, VCAM-1, ICAM-1, PAI-1, CD40L). Results: Higher fasting glucose and homocysteine levels were independent factors associated with poorer performance in Trail Making Test (TMT) B (adjusted β=0.40 ± 0.10 and 0.43 ± 0.09, respectively). Increasing homocysteine levels were weakly associated with poorer global cognition and delayed recall (adjusted β=0.23 ± 0.10 and -0.20 ± 0.10 respectively). Increasing Framingham cardiovascular scores were related to poorer performance in TMT B (β=0.42 ± 0.19). There was early evidence of associations between increasing plasma TNF-α and poorer TMT B (adjusted β=0.21 ± 0.10) and between increasing BDNF and better global cognition (β=-0.20 ± 0.09). Conclusion: This study provides evidence to support the associations between vascular risk factors (Framingham scores, fasting glucose, and homocysteine) and poorer cognitive functions. Additionally, we measured several peripheral biomarkers to further investigate their associations with cognition. The relationship between TNF-α, BDNF, and cognitive performance in various domains may offer new insights into potential mechanisms in vascular cognitive impairment.

Pages 173-187
Fúlvio R. Mendes*, Jenna L. Leclerc*, Lei Liu, Pradip K. Kamat, Arash Naziripour, Damian Hernandez, Chris Li, Abdullah S. Ahmad, Sylvain Doré (Handling Associate Editor: Tauheed Ishrat) *These authors contributed equally to this work.
Effect of Experimental Ischemic Stroke and PGE2 EP1 Selective Antagonism in Alzheimer’s Disease Mouse Models
Abstract: Background: Neuroinflammation has been recognized as an important factor in the pathogenesis of Alzheimer’s disease (AD). One of the most recognized pathways in mediating neuroinflammation is the prostaglandin E2-EP1 receptor pathway. Objective: Here, we examined the efficacy of the selective EP1 antagonist ONO-8713 in limiting amyloid-β (Aβ), lesion volumes, and behavioral indexes in AD mouse models after ischemic stroke. Methods: Transgenic APP/PS1, 3xTgAD, and wildtype (WT) mice were subjected to permanent distal middle cerebral artery occlusion (pdMCAO) and sham surgeries. Functional outcomes, memory, anatomical outcomes, and Aβ concentrations were assessed 14 days after surgery. Results: pdMCAO resulted in significant deterioration in functional and anatomical outcomes in the transgenic mice compared with the WT mice. No relevant differences were observed in the behavioral tests when comparing the ONO-8713 and vehicle-treated groups. Significantly lower cavitation (p=0.0373) and percent tissue loss (p=0.0247) were observed in APP/PS1+ONO-8713 mice compared with the WT+ONO-8713 mice. However, the percent tissue injury was significantly higher in APP/PS1+ONO-8713 mice compared with WT+ONO-8713 group (p=0.0373). Percent tissue loss was also significantly lower in the 3xTgAD+ONO-8713 mice than in the WT+ONO-8713 mice (p=0.0185). ONO-8713 treatment also attenuated cortical microgliosis in APP/PS1 mice as compared with the vehicle (p=0.0079); however, no differences were observed in astrogliosis across the groups. Finally, APP/PS1 mice presented characteristic Aβ load in the cortex while 3xTgAD mice exhibited very low Aβ levels. Conclusion: In conclusion, under the experimental conditions, EP1 receptor antagonist ONO-8713 showed modest benefits on anatomical outcomes after stroke, mainly in APP/PS1 mice.

Pages 189-197
Michael Malek-Ahmadi, Sylvia E. Perez, Kewei Chen, Elliott J. Mufson
Braak Stage, Cerebral Amyloid Angiopathy, and Cognitive Decline in Early Alzheimer’s Disease
Abstract: The aim of this study was to determine the interaction between cerebral amyloid angiopathy (CAA) and Braak staging on cognition in the elderly. 141 [72 non-cognitively impaired (NCI), 33 mild cognitive impairment (MCI), 36 Alzheimer’s disease (AD)] cases consisting of Braak stages 0-II and III from the Rush Religious Order Study cohort were used. The association between Braak stage and CAA status and cognition was evaluated using a series of regression models that adjusted for age at death, sex, education, APOE ε4 status, and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) neuropathological diagnosis. Individuals with CAA were more likely to be classified as Braak stage III relative to those without CAA [OR = 2.33, 95% CI (1.06, 5.14), p = 0.04]. A significant interaction was found between Braak stage and CAA status on a global cognitive score (β = -0.58, SE = 0.25, p = 0.02). Episodic memory also showed a significant association between Braak stage and CAA (β = -0.75, SE = 0.35, p = 0.03). These data suggest that there is a significant interaction between tau pathology and cerebrovascular lesions on cognition within the AD clinical spectrum. These findings show that CAA plays a key role in the early stages of tau pathology and cognitive decline in AD.

Pages 199-211
Jianping Jia, Cuibai Wei, Wei Chen, Longfei Jia, Aihong Zhou, Fen Wang, Yi Tang, Luoyi Xu (Handling Associate Editor: Jin-Tai Yu)
Safety and Efficacy of Donepezil 10 mg/day in Patients with Mild to Moderate Alzheimer’s Disease
Abstract: Background: Efficacy and dose-effect relationship of donepezil for treating patients with Alzheimer’s disease (AD) have been proven. However, few studies focused on the safety of donepezil, particularly in Chinese patients. Objective: To assess the safety of donepezil 10 mg/day in Chinese patients with mild-to-moderate AD. Methods: In this single-arm, prospective, multicenter trial, 241 patients with mild to moderate AD who had been treated with donepezil 5 mg/day for at least 4 weeks were enrolled. All patients received donepezil 10 mg/day for 20 weeks. Primary outcome was the incidence of adverse events (AEs). Safety profile was evaluated by physical examinations including vital signs and weight, clinical laboratory tests and electrocardiograms, and also correlation analysis between AEs and APOE genotypes. Results: 241 patients were enrolled. Of which, 38.59% patients experienced at least one AE and 17.43% discontinued due to AEs. Most AEs were mild to moderate, with diarrhea, vomiting, and nausea the most frequently reported. Risk of AEs was significantly increased by concomitant use of drugs for cardiovascular and cerebrovascular diseases. Mean changes in heart rate and corrected QT relative to baseline were -1.08 ± 6.02 beat/min (p=0.009) and -3.91 ± 18.68 ms (p=0.0062) at week 4 and -1.48 beat/min ± 7.18 (p=0.0028) and -0.66 ms ± 19.66 (p=0.6561) at week 20, respectively. There were no significant changes in other vital sign parameters. Patients' MMSE scores improved significantly after treatment (p=0.0038), especially for non-APOE ε4 allele carriers and patients ≤75 years. Conclusion: Donepezil 10 mg/day can be tolerated and is effective in Chinese patients with mild-to-moderate AD.

Pages 213-225
Sarah Westwood, Alison L. Baird, Sneha N. Anand, Alejo J. Nevado-Holgado, Andrey Kormilitzin, Liu Shi, Abdul Hye, Nicholas J. Ashton, Angharad R. Morgan, Isabelle Bos, Stephanie J.B. Vos, Susan Baker, Noel J. Buckley, Mara ten Kate, Philip Scheltens, Charlotte E. Teunissen, Rik Vandenberghe, Silvy Gabel, Karen Meersmans, Sebastiaan Engelborghs, Ellen E. De Roeck, Kristel Sleegers, Giovanni B. Frisoni, Olivier Blin, Jill C. Richardson, Régis Bordet, José L. Molinuevo, Lorena Rami, Anders Wallin, Petronella Kettunen, Magda Tsolaki, Frans Verhey, Alberto Lléo, Isabel Sala, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Peter Johannsen, Yvonne Freund-Levi, Lutz Frölich, Valerija Dobricic, Cristina Legido-Quigley, Lars Bertram, Frederik Barkhof, Henrik Zetterberg, B. Paul Morgan, Johannes Streffer, Pieter Jelle Visser, Simon Lovestone (Handling Associate Editor: Robert Rissman)
Validation of Plasma Proteomic Biomarkers Relating to Brain Amyloid Burden in the EMIF-Alzheimer’s Disease Multimodal Biomarker Discovery Cohort
Abstract: We have previously investigated, discovered, and replicated plasma protein biomarkers for use to triage potential trials participants for PET or cerebrospinal fluid measures of Alzheimer’s disease (AD) pathology. This study sought to undertake validation of these candidate plasma biomarkers in a large, multi-center sample collection. Targeted plasma analyses of 34 proteins with prior evidence for prediction of in vivo pathology were conducted in up to 1,000 samples from cognitively healthy elderly individuals, people with mild cognitive impairment, and in patients with AD-type dementia, selected from the EMIF-AD catalogue. Proteins were measured using Luminex xMAP, ELISA, and Meso Scale Discovery assays. Seven proteins replicated in their ability to predict in vivo amyloid pathology. These proteins form a biomarker panel that, along with age, could significantly discriminate between individuals with high and low amyloid pathology with an area under the curve of 0.74. The performance of this biomarker panel remained consistent when tested in apolipoprotein E ε4 non-carrier individuals only. This blood-based panel is biologically relevant, measurable using practical immunocapture arrays, and could significantly reduce the cost incurred to clinical trials through screen failure.

Pages 227-235
Areti Triantafyllou*, João Pedro Ferreira*, Masatake Kobayashi, Emilien Micard, Yu Xie, Anna Kearney-Schwartz, Gabriela Hossu, Patrick Rossignol, Serge Bracard, Athanase Benetos *These authors contributed equally to this work.
Longer Duration of Hypertension and MRI Microvascular Brain Alterations Are Associated with Lower Hippocampal Volumes in Older Individuals with Hypertension
Abstract: Background: Hippocampal atrophy is associated with cognitive decline. Determining the clinical features associated with hippocampal volume (HV)/atrophy may help in tailoring preventive strategies. Objective: This study was aimed to investigate the association between HV (at visit 2) and vascular status (both at visit 1 and visit 2) in a cohort of individuals aged 60+ with hypertension and without overt cognitive impairment at visit 1 (visit 1 and visit 2 were separated by approximately 8 years). Methods: Hippocampal volume was estimated in brain MRIs as HV both clinically with the Scheltens' Medial Temporal Atrophy score, and automatically with the Free Surfer Software application. A detailed medical history, somatometric measurements, cognitive tests, leukoaraiosis severity (Fazekas score), vascular parameters including pulse wave velocity, central blood pressure, and carotid artery plaques, as well as several biochemical parameters were also measured. Results: 113 hypertensive patients, 47% male, aged 75.1±5.6 years, participated in both visit 1 and visit 2 of the ADELAHYDE study. Age (β=-0.30) and hypertension duration (β=-0.20) at visit 1 were independently associated with smaller HV at visit 2 (p<0.05 for all). In addition to these variables, body mass index (β=0.18), MRI Fazekas score (β=-0.20), and Gröber-Buschke total recall (β=0.27) were associated with smaller HV at visit 2 (p<0.05 for all). Conclusion: In a cohort of older individuals without cognitive impairment at baseline, we described several factors associated with lower HV, of which hypertension duration and obesity (high body mass index) can potentially be modified.

Pages 237-244
Yaxin Zhang, Yun Li, Rong Wang, Guiming Sha, He Jin, Lina Ma
Elevated Urinary AD7c-NTP Levels in Older Adults with Hypertension and Cognitive Impairment
Abstract: Background: Hypertension, a common chronic disease, is associated with cognitive impairment. Cognitive impairment, especially Alzheimer's disease (AD), seriously affects older adults' quality of life and aggravates the burden of disease on society and families. Elevated Alzheimer-associated neuronal thread protein (AD7c-NTP) has been observed in the urine of patients with AD and mild cognitive impairment; however, it is not clear whether this protein can be used as a biomarker for cognitive impairment in older hypertensive patients. Objective: To explore the value of urinary AD7c-NTP, and the association of urinary AD7c-NTP with cognitive function in older hypertensive patients. Methods: This was a cross-sectional study. In total, 134 hypertensive patients aged ≥60 years were divided into two groups: Lower Cognitive Function group (LCF group, n=89) and a Normal Control group (NC group, n=45) based on the Montreal Cognitive Assessment (MoCA). Urinary AD7c-NTP, blood glucose, serum insulin, superoxide dismutase (SOD) and malondialdehyde (MDA) levels were measured. Results: Urinary AD7c-NTP level was significantly higher in the LCF group than in the NC group [0.48 (0.21-1.00) versus 0.25 (0.04-0.44) ng/ml, p < 0.001]. SOD level [(43.07±23.74) versus (53.12±25.80) U/ml, p = 0.026] and higher homeostasis model assessment of insulin resistance (HOMA-IR) [7.17 (3.74-13.94) versus 6.01 (3.78-7.43), p = 0.033] was lower in the older hypertensive patients than in the NC group. Urinary AD7c-NTP level was associated with MoCA score and HOMA-IR but not with SOD, MDA, blood glucose, and insulin. Conclusion: The level of urinary AD7c-NTP is elevated in older hypertensive patients with lower cognitive function, and insulin resistance may be involved in the process.

Pages 245-259
Mona Abdelhamid, Cha-Gyun Jung, Chunyu Zhou, Mohammad Abdullah, Manabu Nakano, Hiroyuki Wakabayashi, Fumiaki Abe, Makoto Michikawa
Dietary Lactoferrin Supplementation Prevents Memory Impairment and Reduces Amyloid-β Generation in J20 Mice
Abstract: Lactoferrin (LF) is present in senile plaques and neurofibrillary tangles in the brains of Alzheimer’s disease (AD) patients and amyloid-β protein precursor transgenic (AβPP-Tg) mice. LF has anti-inflammatory and antioxidant functions, which exert neuroprotective effects against AD. However, its effects on memory impairment and AD pathogenesis have not been fully examined. In this study, we examined the effects of LF on memory impairment and AD pathogenesis in AβPP-Tg mice (J20 mice). Nine-month-old J20 mice were fed with control, 2% lactoferrin-containing (LF), and 0.5% pepsin-hydrolyzed lactoferrin-containing (LF-hyd) diets for 3 months. We found that both the LF and LF-hyd diets attenuated memory impairment in J20 mice and decreased brain Aβ40 and Aβ42 levels through the inhibition of amyloidogenic processing of AβPP, as it decreased β-site amyloid protein precursor cleaving enzyme 1 (BACE1) levels. Furthermore, we found for the first time that LF and LF-hyd treatments increased both ApoE secretion and ATP-binding cassette A1 (ABCA1) protein levels in the brains of J20 mice and in primary astrocyte cultures. Moreover, LF and LF-hyd promoted extracellular degradation of Aβ in primary astrocyte cultures. These findings indicate that the reduction in Aβ levels in the brains of mice fed with both the LF and LF-hyd diets may also be mediated by increased ApoE secretion and ABCA1 protein levels, which in turn leads to the enhanced degradation of Aβ in the brains of J20 mice. Our findings suggest that LF and LF-hyd can be used for the treatment and/or prevention of the development of AD.

Pages 261-275
Heyun Yang, Wei Wang, Longfei Jia, Wei Qin, Tingting Hou, Qiaoqi Wu, Haitao Li, Yuanruhua Tian, Jianping Jia
The Effect of Chronic Cerebral Hypoperfusion on Blood-Brain Barrier Permeability in a Transgenic Alzheimer’s Disease Mouse Model (PS1V97L)
Abstract: The blood-brain barrier (BBB) can restrict the therapeutic effects of Alzheimer's disease (AD) medications. While a large number of AD drug treatment trials targeting BBB dynamics have emerged, most have failed due to insufficient permeability. Furthermore, a subset of AD cases, which also feature chronic hypoperfusion are complicated by BBB deficits. We used a mouse model of AD with chronic hypoperfusion—transgenic mice (PS1V97L) with right common carotid artery ligation. In this model, we assessed how chronic cerebral hypoperfusion changed the pathophysiological processes that increase BBB permeability. Compared with control mice, AD mice with chronic hypoperfusion revealed significantly upregulated expression of the receptor for advanced glycation end products (RAGE) on the BBB. Upregulated RAGE caused increased accumulation of amyloid-β (Aβ) in the brain in these mice. Upregulation of RAGE (or binding to Aβ) can promote activation of the NF-κB pathway and enhance oxidative stress and increase the release of pro-inflammatory factors. These factors promoted the reduction of tight junction proteins between the endothelial cells in the BBB and increased its permeability. These findings suggest that the transporter RAGE dysregulation on the BBB initiates a series of pathophysiological processes which lead to increased BBB permeability. Taken together, we have shown that chronic hypoperfusion can serve to enhance and aggravate the BBB impairment in AD.

Pages 277-286
Olli Jääskeläinen*, Anette Hall*, Mika Tiainen, Mark van Gils, Jyrki Lötjönen, Antti J. Kangas, Seppo Helisalmi, Maria Pikkarainen, Merja Hallikainen, Anne Koivisto, Päivi Hartikainen, Mikko Hiltunen, Mika Ala-Korpela, Pasi Soininen, Hilkka Soininen, Sanna-Kaisa Herukka (Handling Associate Editor: Alberto Lleó) *These authors contributed equally to this work.
Metabolic Profiles Help Discriminate Mild Cognitive Impairment from Dementia Stage in Alzheimer’s Disease
Abstract: Accurate differentiation between neurodegenerative diseases is developing quickly and has reached an effective level in disease recognition. However, there has been less focus on effectively distinguishing the prodromal state from later dementia stages due to a lack of suitable biomarkers. We utilized the Disease State Index (DSI) machine learning classifier to see how well quantified metabolomics data compares to clinically used cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease (AD). The metabolic profiles were quantified for 498 serum and CSF samples using proton nuclear magnetic resonance spectroscopy. The patient cohorts in this study were dementia (with a clinical AD diagnosis) (N=359), mild cognitive impairment (MCI) (N=96), and control patients with subjective memory complaints (N=43). DSI classification was conducted for MCI (N=51) and dementia (N=214) patients with low CSF amyloid-β levels indicating AD pathology and controls without such amyloid pathology (N=36). We saw that the conventional CSF markers of AD were better at classifying controls from both dementia and MCI patients. However, quantified metabolic subclasses were more effective in classifying MCI from dementia. Our results show the consistent effectiveness of traditional CSF biomarkers in AD diagnostics. However, these markers are relatively ineffective in differentiating between MCI and the dementia stage, where the quantified metabolomics data provided significant benefit.

Pages 287-307
Duygu Gezen-Ak, Merve Alaylıoğlu, Gençer Genç, Büşra Şengül, Ebru Keskin, Pelin Sordu, Zeynep Ece Kaya Güleç, Hülya Apaydın, Çiğdem Bayram-Gürel, Turgut Ulutin, Selma Yılmazer, Sibel Ertan, Erdinç Dursun (Handling Associate Editor: Benedict Albensi)
Altered Transcriptional Profile of Mitochondrial DNA-Encoded OXPHOS Subunits, Mitochondria Quality Control Genes, and Intracellular ATP Levels in Blood Samples of Patients with Parkinson’s Disease
Abstract: Mitochondrial dysfunctions are significant contributors to neurodegeneration. One result or a cause of mitochondrial dysfunction might be the disruption of mtDNA transcription. Limited data indicated an altered expression of mtDNA encoded transcripts in Alzheimer’s disease (AD) or Parkinson’s disease (PD). The number of mitochondria is high in cells with a high energy demand, such as muscle or nerve cells. AD or PD involves increased risk of cardiomyopathy, suggesting that mitochondrial dysfunction might be systemic. If it is systemic, we should observe it in different cell types. Given that, we wanted to investigate any disruption in the regulation of mtDNA encoded gene expression in addition to PINK1, PARKIN, and ATP levels in peripheral mononuclear blood cells of PD cases who are affected by a neurodegenerative disorder that is very well known by its mitochondrial aspects. Our results showed for the first time that: 1) age of onset > 50 PD sporadic (PDS) cases: mtDNA transcription and quality control genes were affected; 2) age of onset < 50 PDS cases: only mtDNA transcription was affected; and 3) PD cases with familial background: only quality control genes were affected. mtDNA copy number was not a confounder. Intracellular ATP levels of PD case subgroups were significantly higher than those of healthy subjects. We suggest that a systemic dysregulation of transcription of mtDNA or mitochondrial quality control genes might result in the development of a sporadic form of the disease. Additionally, ATP elevation might be an independent compensatory and response mechanism. Hyperactive cells in AD and PD require further investigation.

Pages 309-318
Neha Sinha, Chelsie N. Berg, Ashlee Shaw, Mark A. Gluck
ABCA7 Genotype Moderates the Effect of Aerobic Exercise Intervention on Generalization of Prior Learning in Healthy Older African Americans
Abstract: African Americans are at elevated risk for age-related cognitive decline, with double the prevalence of Alzheimer’s disease (AD) compared to Caucasians Americans. Various behavioral, biological, and lifestyle factors may underlie this health disparity, but little is known about the relative importance and interactions among these different risk factors in African Americans. While the neuroprotective effects of aerobic exercise on biomarkers are well established, few studies have examined the differential benefits of exercise based on genetic risk for AD. Furthermore, evidence is limited regarding the potential moderating effects of ABCA7, a gene known to confer significantly greater AD risk in African Americans. In a case-control matched sample of 56 healthy older African Americans, we investigated the effect of an aerobic exercise intervention on a hippocampus-related assessment of generalization following rule learning, in individuals who were carriers of the ABCA7 rs3764650 non-risk (TT) or high-risk (GG) genotypes. Following the exercise-intervention, the non-risk group made significantly fewer generalization errors, while there was no improvement in generalization for the high-risk group. For the controls, no changes in generalization scores were observed regardless of genotype status. Our results indicate that the ongoing adverse effects of ABCA7 high-risk genotype may diminish the benefits associated with aerobic exercise. As such, the potential disease-modifying effects of aerobic exercise on AD-related neuropathology may be limited to carriers of the ABCA7 rs3764650 non-risk genotype.

Pages 319-329
Mohammad Talaei, Lei Feng, Jon Barrenetxea, Jian-Min Yuan, An Pan, Woon-Puay Koh
Adiposity, Weight Change, and Risk of Cognitive Impairment: The Singapore Chinese Health Study
Abstract: Background: Few prospective studies with long duration of follow-up have assessed the relations of body mass index (BMI) and weight change with cognitive function, especially in Asian populations. Objective: To investigate whether BMI and weight change in midlife are associated with cognitive impairment in old age. Methods: We used data from 14,691 participants in the Singapore Chinese Health Study and computed weight change as the difference between weight reported at baseline (1993-1998) at mean age of 53.0 years and follow-up 1 (1999-2004) at mean age of 58.6 years. Cognitive impairment was determined using education-specific cut-offs of the Singapore Modified Mini-Mental State Examination at follow-up 3 (2014-2016) at mean age of 72.9 years. We used multivariable logistic regression models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the associations. Results: Obesity (as defined BMI ≥27.5 kg/m2) was associated with a higher risk of cognitive impairment at baseline (OR 1.33, 95% CI 1.12-1.58) and follow-up 1 (OR 1.30, 95% CI 1.10-1.54) compared to BMI of 18.5-22.9 kg/m2. Underweight (BMI < 18.5 kg/m2) was not associated with a significant risk either at baseline (OR 0.91, 95% CI 0.73-1.13) or follow-up 1 (OR 1.05, 95% CI 0.85-1.28). Compared to participants with <5% weight change, the ORs (95% CIs) of cognitive impairment were 1.20 (1.03-1.41) for those with 5-9.9% weight loss, 1.53 (1.29-1.81) for ≥10% weight loss, 1.00 (0.85-1.17) for 5-9.9% weight gain, and 1.50 (1.28-1.75) for ≥10% weight gain. Conclusion: Obesity, weight loss, and excessive weight gain at midlife were associated with an increased risk of cognitive impairment at old age.

Pages 331-343
Agnès Benvenutto, Eric Guedj, Olivier Felician, Alexandre Eusebio, Jean-Philippe Azulay, Mathieu Ceccaldi, Lejla Koric
Clinical Phenotypes in Corticobasal Syndrome with or without Amyloidosis Biomarkers
Abstract: Corticobasal syndrome (CBS) is a neuropathologically heterogeneous entity. The use of cerebrospinal fluid and amyloid biomarkers enables detection of underlying Alzheimer's disease (AD) pathology. We thus compared clinical, eye movement, and 18FDG-PET imaging characteristics in CBS in two groups of patients divided according to their amyloid biomarkers profile. Fourteen patients presenting with CBS and amyloidosis (CBS-A+) were compared with 16 CBS patients without amyloidosis (CBS-A-). The two groups showed similar motor abnormalities (parkinsonism, dystonia) and global cognitive functions. Unlike CBS-A+ patients who displayed more posterior cortical abnormalities, CBS-A- patients demonstrated more anterior cortical and brain stem dysfunctions on the basis of neuropsychological testing, study of saccade velocities and brain hypometabolism areas on 18FDG-PET. Interestingly, Dopamine Transporter SPECT imaging showed similar levels of dopaminergic degeneration in both groups. These findings confirm common and distinct brain abnormalities between the different neurodegenerative diseases that result in CBS. We demonstrate the importance of a multidisciplinary approach to improve diagnosis in vivo in particular on oculomotor examination.

Pages 345-361
Eric L. Goldwaser*, Nimish K. Acharya*, Hao Wu, George A. Godsey, Abhirup Sarkar, Cassandra A. DeMarshall, Mary C. Kosciuk, Robert G. Nagele (Handling Associate Editor: Thomas Shea) *These authors contributed equally to this work.
Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer’s Disease Pathogenesis
Abstract: Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-β1-42 (Aβ42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (α7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of Aβ42, IgG, GluR2/3, and α7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble Aβ42 peptide and serum from AD and control subjects. The rate and extent of Aβ42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for α7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM Aβ42. Initial co-localization of IgG, α7nAChR, and Aβ42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). Aβ42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then rescued by coupling F(ab) fragments with divalent human anti-Fab. Overall, results suggest that cross-linking of neuron-binding autoantibodies targeting cell surface proteins can accelerate intraneuronal Aβ42 deposition in AD.

Pages 363-376
Kaitlin B. Casaletto, Miguel Arce Rentería, Judy Pa, Sarah E. Tom, Amal Harrati, Nicole M. Armstrong, K. Bharat Rajan, Dan Mungas, Samantha Walters, Joel Kramer, Laura B. Zahodne
Late-Life Physical and Cognitive Activities Independently Contribute to Brain and Cognitive Resilience
Abstract: Background: Active lifestyles are related to better cognitive aging outcomes, yet the unique role of different types of activity are unknown. Objective: To examine the independent contributions of physical (PA) versus cognitive (CA) leisure activities to brain and cognitive aging. Methods: Independent samples of non-demented older adults from University of California, San Francisco Hillblom Aging Network (UCSF; n=344 typically aging) and University of California, Davis Diversity cohort (UCD; n=485 normal to MCI) completed: 1) self-reported engagement in current PA and CA (UCSF: Physical Activity Scale for the Elderly and Cognitive Activity Scale; UCD: Life Experiences Assessment Form); 2) neuropsychological batteries; and 3) neuroimaging total gray matter volume, white matter hyperintensities, and/or global fractional anisotropy. PA and CA were simultaneously entered into multivariable linear regression models, adjusting for demographic characteristics and functional impairment severity. Results: Brain outcomes: In UCSF, only PA was positively associated with gray matter volume and attenuated the relationship between age and fractional anisotropy. In UCD, only CA was associated with less white matter hyperintensities and attenuated the relationship between age and gray matter volume. Cognitive outcomes: In both cohorts, greater CA, but not PA, related to better cognition, independent of age and brain structure. In UCSF, CA attenuated the relationship between fractional anisotropy and cognition. In UCD, PA attenuated the association between white matter hyperintensities and cognition. Conclusions: Although their specificity was not easily teased apart, both PA and CA are clearly related to better brain and cognitive resilience markers across cohorts with differing educational, racial, and disease statuses. PA and CA may independently contribute to converging neuroprotective pathways for brain and cognitive aging.

Pages 377-389
Jennifer L. Whitwell, Nirubol Tosakulwong, Stephen D. Weigand, Jonathan Graff-Radford, Joseph R. Duffy, Heather M. Clark, Mary M. Machulda, Hugo Botha, Rene L. Utianski, Christopher G. Schwarz, Matthew L. Senjem, Edythe A. Strand, Nilufer Ertekin-Taner, Clifford R. Jack, Jr, Val J. Lowe, Keith A. Josephs
Longitudinal Amyloid-β PET in Atypical Alzheimer’s Disease and Frontotemporal Lobar Degeneration
Abstract: Background: Rates of amyloid-β (Aβ) accumulation have been characterized across the cognitively normal to typical Alzheimer’s dementia spectrum, but little is known about Aβ accumulation in atypical Alzheimer’s disease (AD) and other neurodegenerative diseases, such as frontotemporal lobar degeneration (FTLD). Objective: We aimed to characterize longitudinal Aβ accumulation and determine the influence of age, apolipoprotein E genotype, disease duration, and sex in atypical AD and FTLD. Methods: 322 patients (138 atypical AD, 184 FTLD) underwent Pittsburgh compound B PET scanning, with 73 having serial PiB-PET scans (42 atypical AD, 31 FTLD). Global Aβ standard uptake value ratios were calculated for every scan. Mixed effects models were used to assess the effect of age, APOE genotype, disease duration, and sex on baseline and change measures of Aβ. Results: Atypical AD showed higher baseline Aβ than FTLD. Rate of Aβ accumulation was not associated with baseline Aβ in either group. Older age was associated with greater baseline Aβ and faster rates of accumulation in FTLD. In patients under age 70, atypical AD showed faster rates of accumulation than FTLD. APOE ε4 genotype was associated with greater baseline Aβ in FTLD but did not influence rates of accumulation. Rates of Aβ accumulation were faster in FTLD patents with time from onset-to-PET ≤4 years. Female sex was associated with faster rates of accumulation in atypical AD. Conclusion: Accumulation of Aβ is observed in atypical AD and FTLD, although different demographic factors influence accumulation in these diseases providing insight into different biological mechanisms of Aβ deposition.

Pages 391-405
Tânia Soares Martins, Sandra Magalhães, Ilka Martins Rosa, Jonathan Vogelgsang, Jens Wiltfang, Ivonne Delgadillo, José Catita, Odete A.B. da Cruz e Silva, Alexandra Nunes, Ana Gabriela Henriques
Potential of FTIR Spectroscopy Applied to Exosomes for Alzheimer’s Disease Discrimination: A Pilot Study
Abstract: Alzheimer’s disease (AD) diagnosis is based on psychological and imaging tests but can also include monitoring cerebrospinal fluid (CSF) biomarkers. However, CSF based-neurochemical approaches are expensive and invasive, limiting their use to well-equipped settings. In contrast, blood-based biomarkers are minimally invasive, cost-effective, and a widely accessible alternative. Blood-derived exosomes have recently emerged as a reliable AD biomarker source, carrying disease-specific cargo. Fourier-transformed infrared (FTIR) spectroscopy meets the criteria for an ideal diagnostic methodology since it is rapid, easy to implement, and has high reproducibility. This metabolome-based technique is useful for diagnosing a broad range of diseases, although to our knowledge, no reports for FTIR spectroscopy applied to exosomes in AD exist. In this ground-breaking pilot study, FTIR spectra of serum and serum-derived exosomes from two independent cohorts were acquired and analyzed using multivariate analysis. The regional UA-cohort includes 9 individuals, clinically diagnosed with AD, mean age of 78.7 years old; and the UMG-cohort comprises 12 individuals, clinically diagnosed with AD (based on molecular and/or imaging data), mean age of 73.2 years old. Unsupervised principal component analysis of FTIR spectra of serum-derived exosomes revealed higher discriminatory value for AD cases when compared to serum as a whole. Consistently, the partial least-squares analysis revealed that serum-derived exosomes present higher correlations than serum. In addition, the second derivative peak area calculation also revealed significant differences among Controls and AD cases. The results obtained suggest that this methodology can discriminate cases from Controls and thus be potential useful to assist in AD clinical diagnosis.