Volume 73, Number 1, 2020

Pages 1-21

Mahraz Parvand, Catharine H. Rankin (Handling Associate Editor: Lori Beason-Held)
Is There a Shared Etiology of Olfactory Impairments in Normal Aging and Neurodegenerative Disease?
Abstract: As we age, our olfactory function declines. In addition to occurring in normal aging, more rapid decrement of olfactory decline has been associated with several neurodegenerative diseases including Alzheimer’s disease (AD) and Parkinson’s disease (PD). It has been argued that since olfactory deficits occur less frequently or are absent in diseases such as progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy, olfactory deficits can be used for differential diagnoses of AD and PD. The purpose of this review is to provide a survey of current knowledge about the molecular bases and differential patterns of olfactory deficits present in normal aging, AD, and PD. As substantial research has been conducted in this area, the majority of the content of this review focuses on articles published in the past decade. We hypothesize that olfactory deficits in normal aging, AD, and PD may have different underlying causes, and propose the use of model organisms with small, tractable nervous systems and/or easy to manipulate genomes to further investigate the cellular mechanisms responsible for these deficits.

Pages 23-37

Katrine Yare, Michael Woodward
Hormone Therapy and Effects on Sporadic Alzheimer’s Disease in Postmenopausal Women: Importance of Nomenclature
Abstract: Numerous observational studies have suggested that hormone therapy (HT) might protect postmenopausal women against cognitive decline and Alzheimer’s disease (AD). However, because of the significant disparity between results, especially those between observational and randomized controlled trials (RCT), this postulate remains unproven. A significant contributing factor to these inconsistencies is the loose use of the generic definitions of estrogens and progestogens with most studies not delineating the clear differences between non-endogenous and endogenously identical (bioidentical) hormones, their molecular binding affinities and actions, and resultant metabolites. This is highlighted by the generalized terminological use of HT, which is often used to encompass significantly disparate hormonal formulations without clear demarcation. This has impacted and continues to significantly influence interpretations of data, meta-analyses, observational studies, etc., relevant to AD. To progress forward and allow unbiased interpretation, it is no longer acceptable to group HT formulations together as a homogenous group. This will also allow differentiation between compounds that exhibit beneficial actions and those that do not and whether these effects are specific or generalized. The role of the endogenous hormones, 17 beta-oestradiol (E2) and progesterone (P4), in the development of sporadic AD in postmenopausal women is also examined.

Pages 39-58

Jin-Ting He, Xin Zhao, Lei Xu, Cui-Ying Mao
Vascular Risk Factors and Alzheimer’s Disease: Blood-Brain Barrier Disruption, Metabolic Syndromes, and Molecular Links
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder, marked by cortical and hippocampal deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles and cognitive impairment. Studies indicate a prominent link between cerebrovascular abnormalities and the onset and progression of AD, where blood-brain barrier (BBB) dysfunction and metabolic disorders play key risk factors. Pericyte degeneration, endothelial cell damage, astrocyte depolarization, diminished tight junction integrity, and basement membrane disarray trigger BBB damage. Subsequently, the altered expression of low-density lipoprotein receptor-related protein 1 and receptor for advanced glycation end products at the microvascular endothelial cells dysregulate Aβ transport across the BBB. White matter lesions and microhemorrhages, dyslipidemia, altered brain insulin signaling, and insulin resistance contribute to tau and Aβ pathogenesis, and oxidative stress, mitochondrial damage, inflammation, and hypoperfusion serve as mechanistic links between pathophysiological features of AD and ischemia. Deregulated calcium homeostasis, voltage gated calcium channel functioning, and protein kinase C signaling are also common mechanisms for both AD pathogenesis and cerebrovascular abnormalities. Additionally, APOE polymorphic alleles that characterize impaired cerebrovascular integrity function as primary genetic determinants of AD. Overall, the current review enlightens key vascular risk factors for AD and underscores pathophysiologic relationship between AD and vascular dysfunction.

Pages 59-62

Lee Schnaider, Zohar Arnon, Ehud Gazit
Reevaluating the Microbial Infection Link to Alzheimer's Disease
Abstract: Alzheimer's disease (AD) is the most common cause of dementia. Despite substantial investment in research, there are no current effective treatments to prevent or delay the onset and development of AD and the exact molecular mechanism of AD pathogenesis is still not fully understood. Researchers have long suspected that microbial infections may play a role in AD; however, this hypothesis has been greatly overlooked for decades, only recently gaining a traction and recognition within the broad scientific community due to new overwhelming evidence on the association of various pathogenic microbes and AD. Here, we provide our perspective on the significance of these findings, which shed light on the interplay between molecular self-assembly, neurodegeneration, and antimicrobial peptides, as well as propose an amendment to the amyloid cascade hypothesis. It is important to note that this association does not yet prove a causal link, but these reports warrant a thorough investigation into the microbial infection-AD hypothesis which might in turn deliver the elusive therapeutic target the scientific community has been so desperately searching for.

Pages 63-71

Sheina Emrani, Melissa Lamar, Catherine C. Price, Victor Wasserman, Emily Matusz, Rhoda Au, Rodney Swenson, Robert Nagele, Kenneth M. Heilman, David J. Libon
Alzheimer’s/Vascular Spectrum Dementia: Classification in Addition to Diagnosis
Abstract: Alzheimer’s disease (AD) and vascular dementia (VaD) are the two most common types of dementia. Although the combination of these disorders, called ‘mixed’ dementia, is recognized, the prevailing clinical and research perspective continues to consider AD and VaD as independent disorders. A review of recent neuropathological and neuropsychological literature reveals that these two disorders frequently co-occur and so-called ‘pure’ AD or VaD is comparatively rare. In addition, recent research shows that vascular dysfunction not only potentiates AD pathology, but that pathological changes in AD may subsequently induce vascular disorders. On the basis of these data, we propose that the neurobiological underpinnings underlying AD/VaD dementia and their neuropsychological phenotypes are best understood as existing along a clinical/pathological continuum or spectrum. We further propose that in conjunction with current diagnostic criteria, statistical modeling techniques using neuropsychological test performance should be leveraged to construct a system to classify AD/VaD spectrum dementia in order to test hypotheses regarding how mechanisms related to AD and VaD pathology interact and influence each other.

Pages 73-76
Short Communication

Gabriella Marcon, Paolo Manganotti, Mauro Tettamanti
Is Parkinson’s Disease a Very Rare Pathology in Centenarians? A Clinical Study in a Cohort of Subjects
Abstract: The number of people reaching old age is growing dramatically and centenarians are among the fastest growing age groups. Since no epidemiological study on Parkinson’s disease (PD) in this age class is present in the medical literature, we estimated PD prevalence in the Centenari a Trieste (CaT) study. Participating centenarians were examined by a neurologist, who also retrieved their remote and pharmacological anamnesis. Ninety centenarians received a neurological examination. No subject had PD clinical signs. Moreover, none had a previous diagnosis of PD or had taken or was taking anti-Parkinson treatment. This simple but consistent clinical observation permits some physio-pathological hypotheses.

Pages 77-86
Lori A. Newkirk, Virginia L. Dao, Joshua T. Jordan, Loren I. Alving, Helen D. Davies, Linda Hewett, Sherry A. Beaudreau, Logan D. Schneider, Christine E. Gould, Christina F. Chick, Rayna B. Hirst, Sophia Miryam Schüssler-Fiorenza Rose, Lauren A. Anker, Jared R. Tinklenberg, Ruth O’Hara *These authors contributed equally to this work.
Factors Associated with Supportive Care Service Use Among California Alzheimer’s Disease Patients and Their Caregivers
Abstract: Background: Existing literature on factors associated with supportive care service (SCS) use is limited. A better understanding of these factors could help tailor SCS to the needs of frequent users, as well as facilitate targeted outreach to populations that underutilize available services. Objective: To investigate the prevalence of SCS use and to identify factors associated with, and barriers to, service use. Methods: California Alzheimer’s Disease Center patients with AD (n=220) participated in the study from 2006-2009. Patients and their caregivers completed assessments to determine SCS use. Cognitive, functional, and behavioral status of the patients were also assessed. A two-part hurdle analysis identified 1) factors associated with any service use and 2) service use frequency among users. Results: Forty percent of participants reported using at least one SCS. Patients with more impaired cognition and activities of daily living and more of the following: total number of medications, comorbid medical conditions, and years of education were more likely to use any SCS (p<0.05). Factors associated with more frequent SCS use included younger age, more years of education, older age of AD onset, female gender, and having a spouse or relative for a caregiver (p<0.05). Caregivers frequently indicated insufficient time as a reason for not receiving enough services. Conclusion: Factors associated with any SCS use mostly differed from those associated with SCS frequency, suggesting different characteristics between those who initiate versus those who continue SCS use. Our findings highlight the importance of targeted education on services and identifying barriers to long-term SCS use.

Pages 87-101
Chelsea C. Hays, Zvinka Z. Zlatar, M.J. Meloy, Jessica Osuna, Thomas T. Liu, Douglas R. Galasko, Christina E. Wierenga (Handling Associate Editor: Moira Marizzoni)
Anterior Cingulate Structure and Perfusion Is Associated with Cerebrospinal Fluid Tau Among Cognitively Normal Older Adult APOE ε4 Carriers
Abstract: Evidence suggests the ε4 allele of the apolipoprotein E gene (APOE) may accelerate an age-related process of cortical thickening and cerebral blood flow (CBF) reduction in the anterior cingulate cortex (ACC). Although the neural basis of this association remains unclear, evidence suggests it might reflect early neurodegenerative processes. However, to date, associations between cerebrospinal fluid (CSF) biomarkers of neurodegeneration, such as CSF tau, and APOE-related alterations in ACC cortical thickness (CTH) and CBF have yet to be explored. The current study explored the interaction of CSF tau and APOE genotype (ε4+, ε4-) on FreeSurfer-derived CTH and arterial spin labeling MRI-measured resting CBF in the ACC (caudal ACC [cACC] and rostral ACC [rACC]) among a sample of 45 cognitively normal older adults. Secondary analyses also examined associations between APOE, CTH/CBF, and cognitive performance. In the cACC, higher CSF tau was associated with higher CTH and lower CBF in ε4+, whereas these relationships were not evident in ε4-. In the rACC, higher CSF tau was associated with higher CTH for both ε4+ and ε4-, and with lower CBF only in ε4+. Significant interactions of CSF tau and APOE on CTH/CBF were not observed in two posterior reference regions implicated in Alzheimer’s disease. Secondary analyses revealed a negative relationship between cACC CTH and executive functioning in ε4+ and a positive relationship in ε4-. Findings suggest the presence of an ε4-related pattern of increased CTH and CBF reduction in the ACC that is associated with biomarkers of neurodegeneration and subtle decrements in cognition.

Pages 103-116
Wassim Tarraf, Robert Kaplan, Martha Daviglus, Linda C. Gallo, Neil Schneiderman, Frank J. Penedo, Krista M. Perreira, Melissa Lamar, Albert Chai, Priscilla M. Vásquez, Hector M. González (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Cardiovascular Risk and Cognitive Function in Middle-Aged and Older Hispanics/Latinos: Results from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)
Abstract: Background: Cardiovascular disease is linked to cognitive decline and disorders (e.g., dementia). The evidence is based largely on older non-Latino White cohorts. Objective: Examine the association between global vascular risk and cognitive function among Hispanics/Latinos in the United States. Methods: We used data from a large sample of stroke- and cardiovascular disease-free, middle-aged and older Hispanics/Latinos with diverse backgrounds (n=7,650) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL). We compared associations between two measures of cardiovascular risk (CVR), the Framingham Cardiovascular Risk Score (FCRS) and the multiethnic Global Vascular Risk Score (GVRS), and cognitive performance using measures of global and domain specific cognitive function, and tested for modification by sex and age. Results: Higher FCRS and GVRS were associated with lower global cognition and higher probability of low mental status, after covariates adjustment. Both CVR indices were associated with lower performances in learning and memory, verbal fluency, and psychomotor speed. Higher GVRS presented stronger associations with lower cognitive function compared to the FCRS. Women and younger age (45-64 years) exhibited more pronounced associations between higher CVR and worse cognition, particularly so with the GVRS. Discussion: CVR is also a risk for compromised cognitive function and evident in middle-age among Hispanics/Latinos. The multiethnic GVRS, tailored to specific risks based on racial/ethnic background, is feasible to use in primary care settings and can provide important insight on cognitive risk. Even modest shifts in population toward cardiovascular health in the high-risk Hispanic/Latino population can have important positive impacts on healthy cognitive aging.

Pages 117-123
Soichiro Shimizu, Naoto Takenoshita, Yuta Inagawa, Akito Tsugawa, Daisuke Hirose, Yoshitsugu Kaneko, Yusuke Ogawa, Shuntaro Serisawa, Shu Sakurai, Kentaro Hirao, Hidekazu Kanetaka, Takashi Kanbayashi, Aya Imanishi, Hirofumi Sakurai, Haruo Hanyu
Positive Association Between Cognitive Function and Cerebrospinal Fluid Orexin A Levels in Alzheimer’s Disease
Abstract: Background: Recently, many studies have investigated the association between orexin A and Alzheimer’s disease (AD). However, it remains to be determined whether the observed changes in orexin A levels are associated with pathological changes underlying AD, or cognitive function. In particular, a direct association between cerebrospinal fluid (CSF) orexin A levels and cognitive function has not been reported to date. Objective: The aim of this study was to identify whether there is a direct association between the orexinergic system and cognitive function in AD. Methods: For this study, we included 22 patients with AD and 25 control subjects who underwent general physical, neurological, and psychiatric examinations, neuroimaging, and CSF collection by lumbar puncture were enrolled. Correlations between CSF orexin A levels and CSF AD biomarker levels (i.e., levels of phosphorylated tau [p-tau], Aβ42, and Aβ42/Aβ40) were assessed to confirm the results of previous studies. Moreover, the correlation between CSF orexin A levels and Mini-Mental State Examination (MMSE) and Japanese version of the Montreal Cognitive Assessment (MoCA-J) scores were analyzed. Results: There was a significant positive correlation between CSF orexin-A levels and cognitive function (MMSE scores: r = 0.591, p = 0.04, MoCA score: r = 0.571, p = 0.006) in AD patients. Conclusion: This is the first study to our knowledge demonstrating an association between cognitive function and CSF orexin A levels in AD. Our results suggest the possibility that orexinergic system overexpression is not always a negative factor for cognitive function In AD.

Pages 125-133
Michaela Defrancesco, Josef Marksteiner, Georg Kemmler, Peter Dal-Bianco, Gerhard Ransmayr, Thomas Benke, Jochen Mosbacher, Yvonne Höller, Reinhold Schmidt
Specific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer’s Disease: Results of the Prospective Dementia Registry (PRODEM-Austria)
Abstract: Background: Neuropsychiatric symptoms (NPS) occur frequently in the course of Alzheimer’s disease (AD) and are suspected to be associated with a faster dementia progression. Numerous reports have defined specific subsyndromes, summarized in clusters of items of the Neuropsychiatric Inventory (NPI). Objective: This study investigated the influence of specific NPI subsyndromes and clinical patient characteristics on dementia progression. Methods: Data of the prospective registry on dementia in Austria (PRODEM) were retrospectively analyzed. Cognitive functioning was determined at baseline and 2 yearly follow-up visits using the Mini-Mental State Examination (MMSE) and the Consortium to Establish a Registry for Alzheimer’s dementia neuropsychological test battery (CERAD). To assess NPS, the NPI was used: NPI items were classified in three subsyndromes (psychotic cluster, behavioral cluster, emotional cluster). Results: Out of the 662 included patients (mean age 76.4 ± 8.4 years), 43% completed follow-up visits for two years. Significant correlation between higher scores in all three subsyndromes and worse cognitive performance were found for MMSE score, naming, and verbal fluency. Results of linear mixed model analysis revealed lower age and higher scores in the psychotic cluster as significant predictors of changes in MMSE with time. Conclusion: In this study, we report the influence of psychotic subsyndromes and lower age on faster MMSE decline in early AD. These results emphasize the importance of not only assessing but also differentiating neuropsychiatric symptoms in subsyndromes in the early stages of AD as a possible predictor of disease progression.

Pages 135-145
Mirjana Babić Leko, Matea Nikolac Perković, Nataša Klepac, Dubravka Švob Štrac, Fran Borovečki, Nela Pivac, Patrick R. Hof, Goran Šimić
Relationships of Cerebrospinal Fluid Alzheimer’s Disease Biomarkers and COMT, DBH, and MAOB Single Nucleotide Polymorphisms
Abstract: The noradrenergic and dopaminergic systems are affected in Alzheimer’s disease (AD). Polymorphisms in genes encoding enzymes and proteins that are components of these systems can affect products of transcription and translation and lead to altered enzymatic activity and alterations in overall dopamine and noradrenaline levels. Catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAOB) are the enzymes that regulate degradation of dopamine, while dopamine β-hydroxylase (DBH) is involved in synthesis of noradrenaline. COMT Val158Met (rs4680), DBH rs1611115 (also called -1021C/T or -970C/T), and MAOB rs1799836 (also called A644G) polymorphisms have been previously associated with AD. We assessed whether these polymorphisms are associated with cerebrospinal fluid AD biomarkers including total tau (t‐tau), phosphorylated tau proteins (p‐tau181, p‐tau199, and p‐tau231), amyloid-β42 (Aβ42), and visinin‐like protein 1 (VILIP‐1) to test possible relationships of specific genotypes and pathological levels of CSF AD biomarkers. The study included 233 subjects: 115 AD, 53 mild cognitive impairment, 54 subjects with other primary causes of dementia, and 11 healthy controls. Significant decrease in Aβ42 levels was found in patients with GG compared to AG COMT Val158Met genotype, while t-tau and p-tau181 levels were increased in patients with AA compared to AG COMT Val158Met genotype. Aβ42 levels were also decreased in carriers of A allele in MAO-B rs1799836 polymorphism, while p-tau181 levels were increased in carriers of T allele in DBH rs1611115 polymorphism. These results indicate that COMT Val158Met, DBH rs1611115, and MAOB rs1799836 polymorphisms deserve further investigation as genetic markers of AD.

Pages 147-161
Eliot J. Davidowitz, Pavan K. Krishnamurthy, Patricia Lopez, Heidy Jimenez, Leslie Adrien, Peter Davies, James G. Moe
In Vivo Validation of a Small Molecule Inhibitor of Tau Self-Association in htau Mice
Abstract: Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer’s disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.

Pages 163-173
Alby Elias, Tia Cummins, Fiona Lamb, Regan Tyrrell, Vincent Dore, Rob Williams, Jeffrey V. Rosenfeld, Malcolm Hopwood, Victor L. Villemagne, Christopher C. Rowe
Amyloid-β, Tau, and 18F-Fluorodeoxyglucose Positron Emission Tomography in Posttraumatic Stress Disorder
Abstract: Background: Epidemiological studies suggest a relationship between posttraumatic stress disorder (PTSD) and dementia. Objective: This study assessed whether Alzheimer’s disease (AD) imaging biomarkers were elevated in Vietnam veterans with PTSD. Methods: The study compared cognition, amyloid-β, tau, regional brain metabolism and volumes, and the effect of APOE in 83 veterans with and without PTSD defined by the Clinician-Administered PTSD Scale. Results: The PTSD group had significantly lower education, predicted premorbid IQ, total intracranial volume, and Montreal Cognitive Assessment score compared with the controls. There was no difference between the two groups in the imaging or genetic biomarkers for AD. Conclusion: Our findings do not support an association between AD pathology and PTSD of up to 50 years duration. Measures to assess cognitive reserve, a factor that may delay the onset of dementia, were lower in the PTSD group compared with the controls and this may account for the previously observed higher incidence of dementia with PTSD.

Pages 175-183
Michael Nerius*, Britta Haenisch*,¬ Willy Gomm, Gabriele Doblhammer, Anja Schneider (Handling Associate Editor: Raymond Lo) *These authors contributed equally to this work.
Glucocorticoid Therapy Is Associated with a Lower Risk of Dementia
Abstract: Background: Recent evidence indicates an important role for neuroinflammation in the pathological cascade of Alzheimer’s disease (AD), and neuroinflammation is increasingly being recognized as a potential therapeutic target. Objective: To assess the impact of glucocorticoids on the risk of developing dementia. Methods: We used health insurance data of the largest German health insurer from 2004–2013 with a baseline sample of 176,485 persons aged 50 years and older to study the association of glucocorticoid treatment and incidence of dementia. Cox proportional-hazard models were calculated adjusting for sex, age, and comorbidities known to be major risk factors for dementia and were given as hazard ratios (HR) with 95% confidence intervals (CI). We further stratified glucocorticoid treatment by route of application and treatment duration. Results: Of the 176,485 dementia-free persons, 19,938 were diagnosed with dementia by the end of 2013. The risk of suffering from dementia was significantly lower for glucocorticoid users compared to non-users (HR=0.81, CI=0.78–0.84). The lowest risk was found among users of inhaled glucocorticoid (HR=0.65, CI=0.57–0.75), followed by nasal (HR=0.76, CI=0.66–0.87), other (HR=0.84, CI=0.80–0.88), and oral users (HR=0.83, CI=0.78–0.88). We found no difference in risk reduction between long- and short-term-users. Conclusion: Longitudinal German health insurance data indicate that the use of glucocorticoids is associated with a lower risk of dementia. Prospective clinical trials will be necessary to determine whether glucocorticoids can have a positive impact on neuroinflammation and thus protect persons against dementia.

Pages 185-196
Emily M. Briceño, Roshanak Mehdipanah, Xavier Gonzales, Steven Heeringa, Deborah A. Levine, Kenneth M. Langa, Nelda Garcia, Ruth Longoria, Lewis B. Morgenstern
Methods and Early Recruitment of a Community-Based Study of Cognitive Impairment Among Mexican Americans and Non-Hispanic Whites: The BASIC-Cognitive Study
Abstract: Background: As the Mexican American (MA) population grows and ages, there is an urgent need to estimate the prevalence of cognitive impairment or dementia (CID), cognitive trajectories, and identify community resource needs. The Brain Attack Surveillance in Corpus Christi (BASIC)-Cognitive project is a population-based study to address these issues among older MAs and non-Hispanic whites (NHW) and their informal care providers. Objective: Present the methodology and initial recruitment findings for the BASIC-Cognitive project. Method: Random, door-to-door case ascertainment is used in Nueces County, Texas, to recruit community-dwelling and nursing home residents ≥ 65 and informal care providers. Households are identified from a two-stage area probability sample, using Census data to aim for equal balance of MAs and NHWs. Individuals with cognitive screens indicative of possible CID complete neuropsychological assessment (Harmonized Cognitive Assessment Protocol from the Health and Retirement Study). Informal care providers complete comprehensive interview and needs assessment. Study pairs repeat procedures at 2-year follow-up. Asset and concept mapping are performed to identify community resources and study care providers’ perceptions of needs for individuals with CID. Results: 1,030 age-eligible households were identified, or 27% of households for whom age could be determined. 1,320 individuals were age-eligible, corresponding to 1.3 adults per eligible household. Initial recruitment yielded robust participation in the MA eligible population (60% of 689 individuals that completed cognitive screening). Conclusion: The BASIC-Cognitive study will provide critical information regarding the prevalence of CID in MAs, the impact of caregiving, and allocation of community resources to meet the needs of this population.

Pages 197-207
Masamichi Imai, Mika Tanaka, Muneyuki Sakata, Kei Wagatsuma, Tetsuro Tago, Jun Toyohara, Renpei Sengoku, Yuji Nishina, Kazutomi Kanemaru, Kenji Ishibashi, Shigeo Murayama, Kenji Ishii
Metabolic Network Topology of Alzheimer’s Disease and Dementia with Lewy Bodies Generated Using Fluorodeoxyglucose Positron Emission Tomography
Abstract: Background: Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) are often misdiagnosed with each other because of similar symptoms including progressive memory loss. The metabolic network topology that describes inter-regional metabolic connections can be generated using fluorodeoxyglucose positron emission tomography (FDG-PET) data with the graph-theoretical method. We hypothesized that different metabolic connectivity underlies the symptoms of AD patients, DLB patients, and cognitively normal (CN) individuals. Objective: This study aimed to generate metabolic connectivity using FDG-PET data and assess the network topology to differentiate AD patients, DLB patients, and CN individuals. Methods: This study included 45 AD patients, 18 DLB patients, and 142 CN controls. We analyzed FDG-PET data using the graph-theoretical method and generated the network topology in AD patients, DLB patients, and CN individuals. We statistically assessed the topology with global and nodal parameters. Results: The whole metabolic network was preserved in CN; however, diffusely decreased connection was found in AD and partially but more deeply decreased connection was observed in DLB. The metabolic topology revealed that the right posterior cingulate and the left transverse temporal gyrus were significantly different between AD and DLB. Conclusion: The present findings indicate that metabolic connectivity decreased in both AD and DLB, compared with CN. DLB was characterized restricted but deeper stereotyped network disruption compared with AD. The right posterior cingulate and the left transverse temporal gyrus are significant regions in the metabolic connectivity for differentiating AD from DLB.

Pages 209-215
Keiichiro Tsunoda, Toru Yamashita, Yosuke Osakada, Ryo Sasaki, Koh Tadokoro, Namiko Matsumoto, Emi Nomura, Ryuta Morihara, Yumiko Nakano, Yoshiaki Takahashi, Noriko Hatanaka, Jingwei Shang, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe
Early Emergence of Neuropsychiatric Symptoms in Cognitively Normal Subjects and Mild Cognitive Impairment
Abstract: The world is rapidly aging and facing an increase in the number of dementia patients, so it is important to detect the preclinical stage of dementia in such countries. We examined both cognitive and affective functions among cognitively normal control (n=218), mild cognitive impairment (MCI, n=146), and Alzheimer’s disease (AD, n=305) subjects using two evaluation tools for behavioral and psychological symptoms of dementia (BPSD) [Abe’s BPSD score (ABS) and mild behavioral impairment (MBI)]. BPSD were present in 12.4% (ABS) and 9.6% (MBI) of cognitively normal people, 34.9% and 32.2% in MCI subjects, and 66.2% and 51.1% in AD patients. Both ABS (§p < 0.05) and MBI (§§p < 0.01) score showed worse score with cognitive decline of the Mini-Mental State Examination in the AD group in BPSD-positive participants. Similar correlations were found in all participants in AD group (||||p < 0.01 versus ABS and MBI). Among the subscales in BPSD-positive participants, an apathy/indifference score of ABS and a decreased motivation of MBI showed significant differences in AD patients compared to the control and MCI subjects (**p < 0.01). In addition, subscale analyses further showed a downward trend from the control to MCI and AD subjects in four ABS subscales and three MBI subscales. The present study showed the preclinical presence of BPSD in cognitively normal people, more so in MCI subjects, and ABS detected BPSD more sensitively than MBI in all three groups.

Pages 217-227
Koji Abe, Jinwei Shang, Xiaowen Shi, Toru Yamashita, Nozomi Hishikawa, Mami Takemoto, Ryuta Morihara, Yumiko Nakano, Yasuyuki Ohta, Kentaro Deguchi, Masaki Ikeda, Yoshio Ikeda, Koichi Okamoto, Mikio Shoji, Masamitsu Takatama, Motohisa Kojo, Takeshi Kuroda, Kenjiro Ono, Noriyuki Kimura, Etsuro Matsubara, Yosuke Osakada, Yosuke Wakutani, Yoshiki Takao, Yasuto Higashi, Kyoichi Asada, Takehito Senga, Liang-Ja Lee, Kenji Tanaka
A New Serum Biomarker Set to Detect Mild Cognitive Impairment and Alzheimer’s Disease by Peptidome Technology
Abstract: Background: Because dementia is an emerging problem in the world, biochemical markers of cerebrospinal fluid (CSF) and radio-isotopic analyses are helpful for diagnosing Alzheimer’s disease (AD). Although blood sample is more feasible and plausible than CSF or radiological biomarkers for screening potential AD, measurements of serum amyloid- β (Aβ), plasma tau, and serum antibodies for Aβ1-42 are not yet well established. Objective: We aimed to identify a new serum biomarker to detect mild cognitive impairment (MCI) and AD in comparison to cognitively healthy control by a new peptidome technology. Methods: With only 1.5 µl of serum, we examined a new target plate “BLOTCHIP®” plus a matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS) to discriminate control (n=100), MCI (n=60), and AD (n=99). In some subjects, cognitive Mini-Mental State Examination (MMSE) were compared to positron emission tomography (PET) with Pittsburgh compound B (PiB) and the serum probability of dementia (SPD). The mother proteins of candidate serum peptides were examined in autopsied AD brains. Results: Apart from Aβ or tau, the present study discovered a new diagnostic 4-peptides-set biomarker for discriminating control, MCI, and AD with 87% of sensitivity and 65% of specificity between control and AD (***p<0.001). MMSE score was well correlated to brain Aβ deposition and to SPD of AD. The mother proteins of the four peptides were upregulated for coagulation, complement, and plasticity (three proteins), and was downregulated for anti-inflammation (one protein) in AD brains. Conclusion: The present serum biomarker set provides a new, rapid, non-invasive, highly quantitative and low-cost clinical application for dementia screening, and also suggests an alternative pathomechanism of AD for neuroinflammation and neurovascular unit damage.

Pages 229-246
Gregory J. Brewer, Robert A. Herrera, Stephan Philipp, Justyna Sosna, Jorge Mauricio Reyes-Ruiz, Charles G. Glabe
Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes
Abstract: This work provides new insight into the age-related basis of Alzheimer's disease (AD), the composition of intraneuronal amyloid (iAβ), and the mechanism of an age-related increase in iAβ in adult AD-model mouse neurons. A new end-specific antibody for Aβ45 and another for aggregated forms of Aβ provide new insight into the composition of iAβ and the mechanism of accumulation in old adult neurons from the 3xTg-AD model mouse. iAβ levels containing aggregates of Aβ45 increased 30-50-fold in neurons from young to old age and were further stimulated upon glutamate treatment. iAβ was 8 times more abundant in 3xTg-AD than non-transgenic neurons with imaged particle sizes following the same log-log distribution, suggesting a similar snow-ball mechanism of intracellular biogenesis. Pathologically misfolded and mislocalized Alz50 tau colocalized with iAβ and rapidly increased following a brief metabolic stress with glutamate. AβPP-CTF, Aβ45, and aggregated Aβ colocalized most strongly with mitochondria and endosomes and less with lysosomes and autophagosomes. Differences in iAβ by sex were minor. These results suggest that incomplete carboxyl-terminal trimming of long Aβs by gamma-secretase produced large intracellular deposits which limited completion of autophagy in aged neurons. Understanding the mechanism of age-related changes in iAβ processing may lead to application of countermeasures to prolong dementia-free health span.

Pages 247-257
Katerina Cechova, Ross Andel, Francesco Angelucci, Zuzana Chmatalova, Hana Markova, Jan Laczó, Martin Vyhnalek, Vaclav Matoska, Vojtech Kaplan, Zuzana Nedelska, David Ward, Jakub Hort (Handling Associate Editor: Yen Ying Lim)
Impact of APOE and BDNF Val66Met Gene Polymorphisms on Cognitive Functions in Patients with Amnestic Mild Cognitive Impairment
Abstract: Apolipoprotein (APOE) ε4 is a well-known risk factor for late-onset Alzheimer’s disease (AD), but other AD-related gene polymorphisms might also be important, such as the polymorphism within the brain-derived neurotrophic factor (BDNF) gene. Carriage of BDNF Val66Met has been associated with faster cognitive decline and greater hippocampal atrophy in cognitively normal elderly. Thus, we examined the effects of the concurrent presence of APOE and BDNF polymorphisms on cognitive functions and brain morphometry in amnestic mild cognitive impairment (aMCI) patients. 107 aMCI patients (mean age=72.2) were recruited from the Czech Brain Aging Study and, based on APOE and BDNF genes polymorphisms, were divided into four groups: ε4-BDNFVal/Val (n=37), ε4-BDNFMet (n=19), ε4+BDNFVal/Val (n=35), and ε4+BDNFMet (n=16). All patients underwent clinical examination, magnetic resonance imaging, and complex neuropsychological battery. The combination of APOE ε4+ and BDNF Met was associated with significantly worse memory performance in immediate and delayed recall compared to other polymorphism groups. We did not observe increased atrophy in areas related to memory function in the ε4+BDNFMet group. Our findings suggest that carriage of ε4+BDNFMet is associated with more pronounced memory dysfunction, a typical feature of early AD, but not with structural brain changes in aMCI patients. These findings suggest that in APOE ε4/BDNF Met carriers, synaptic dysfunction affecting memory may precede pronounced structural changes.

Pages 259-267
Christina Jensen-Dahm, Ane Nørgaard Christensen, Christiane Gasse, Gunhild Waldemar (Handling Associate Editor: Alba Malara)
The Use of Opioids and Antipsychotics in Elderly with Dementia: Have Opioids Replaced Antipsychotics in Treating Behavioral Symptoms in Dementia?
Abstract: Background: Opioids are used with increasing frequency. Elderly with dementia are prescribed opioids more frequent than elderly without. One possible explanation is that opioids may be used not only to treat pain but also behavioral symptoms. Objective: To test the hypothesis that strong opioid use, especially transdermal formulations, had increased, especially in elderly with dementia, in parallel with a decrease in antipsychotic use. Methods: Population-based cross-sectional study conducted using nationwide Danish registers with data on Denmark’s entire elderly population age ≥65 (2000: n=802,106; 2015: n=1,056,476). The registers were used to identify elderly with and without dementia and filled prescriptions for opioids and antipsychotics. Annual prevalence of opioid and antipsychotic use from 2000-2015 was calculated. Results: Prevalence of opioid use increased by 35% (24.2 to 32.5%) among elderly with dementia and by 13% among elderly without (14.9 to 16.8%) from 2000-2015. The disproportionate increase in opioid use among elderly with dementia was mainly driven by an increase in strong opioids (dementia: 11.7 to 23.1%; without dementia: 5.9 to 7.4%). Use of antipsychotics decreased during the same period (dementia: 31.3 to 19.3%; no dementia: 4.5 to 2.7%). Conclusion: From 2000-2015, use of opioids among the elderly increased with a disproportionately higher increase among elderly with dementia. The parallel decrease in the use of antipsychotics may suggest that opioids to some extent have replaced antipsychotics in managing behavioral symptoms, despite safety concerns and lack of evidence for effect of opioids. Future research should focus on potential risks associated with increased opioid use.

Pages 269-275
Leonie J.M. Vergouw*, Brechje Bosman*, Marleen van de Beek, Mariet Salomé, Susanne E. Hoogers, Inger van Steenoven, Gerwin Roks, Vincenzo Bonifati, John C. van Swieten, Afina W. Lemstra, Frank Jan de Jong *These authors contributed equally to this work.
Family History Is Associated with Phenotype in Dementia with Lewy Bodies
Abstract: It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson’s disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer’s disease (AD) biomarkers in patients with familial DLB (n=154) and sporadic DLB (n=137), using among others linear mixed model analysis and Cox regression analysis. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p≤0.001; 30%, p=0.037). Our findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis.

Pages 277-295
Haoyu Chen*, Lu Liang*, Hua Xu*, Jia Xu, Leyi Yao, Yanling Li, Yufan Tan, Xiaofen Li, Qingtian Huang, Zhenjun Yang, Jiawen Wu, Jinghong Chen, Hongbiao Huang, Xuejun Wang, Chang-E Zhang, Jinbao Liu *These authors contributed equally to this work.
Short Term Exposure to Bilirubin Induces Encephalopathy Similar to Alzheimer’s Disease in Late Life
Abstract: Hyperbilirubinemia may increase the risk of Alzheimer’s disease (AD) but its mechanistic role in AD pathogenesis remains obscure. Here, we used animal models to investigate the short- and long-term effects of neonatal systemic exposure to bilirubin on brain histology and function as well as the acute effect of lateral ventricle injection of bilirubin in adult rats. We found that three days exposure to bilirubin in newborn rats could induce AD-like pathological changes in late life, including tau protein hyperphosphorylation at multiple sites, increased Aβ production in brain tissues, and spatial learning and memory injury. Bilirubin activated the activities of several protein kinases (GSK-3β, CDK5, and JNK), which were positively correlated with hyperphosphorylated tau; simultaneously increased the expression of AβPP γ-secretase PS2 and decreased the expression of α-secretase ADAM17, which were positively correlated with Aβ production. The above results were well replicated in primary hippocampal cell cultures. These data demonstrate that bilirubin encephalopathy is an AD-like disease, suggesting a potent role of bilirubin in AD.

Pages 297-306
Tsung-Lin Lee, Chi-Hung Liu, Yu-Ming Chang, Tien-Yu Lin, Chung-Yao Chien, Chih-Hung Chen, Kuen-Jer Tsai, Sheng-Hsiang Lin, Pi-Shan Sung
The Impact of Antiplatelet Use on the Risk of Intracerebral Hemorrhage in Patients with Alzheimer’s Disease: A Nationwide Cohort Study
Abstract: Background: Antiplatelet use on the risk of intracerebral hemorrhage (ICH) in patients with Alzheimer’s disease (AD) has not yet been completely elucidated. Objective: This large epidemiologic study aims to estimate the risk of ICH in AD patients treated with antiplatelet therapy (APT). Methods: Using data from Taiwan’s National Health Insurance Research Database, ICH risk in APT-treated AD patients with a validated diagnosis (N=824) was determined. AD without APT and non-AD with and without APT comparison cohorts were selected. To adjust for confounders and competing risk of death, inverse probability of treatment weighting using propensity scores and competing risks regression (CRR) were applied. Cox proportional hazards regression analysis estimated ICH risk in all cohorts comparing with non-AD without APT. Results: Among the 824 AD patients with APT, 79.6% were prescribed aspirin. ICH incidence rates in the AD (with/without APT) and non-AD (with/without APT) cohorts were 2.88/2.70 and 2.24/1.20 per 1,000 person-years, respectively. Overall, AD with (adjusted hazards ratio (aHR), 2.29; 95% CI, 1.19-4.38) and without (aHR, 1.97; 95% CI, 1.08-3.61) APT and non-AD with APT (aHR, 1.80; 95% CI, 1.34-2.42) were at a higher risk and had elevated subdistribution HR obtained from CRR than non-AD without APT controls. However, the risk was comparable between the AD cohorts with and without APT (HR, 1.16; 95% CI, 0.51-2.66). Conclusions: Our study indicated both the APT and non-APT users in AD population yielded higher ICH risks. However, whether APT use potentiate the risk of ICH in AD patients may warrant further evaluation.

Pages 307-315
Tian-Shin Yeh, Jung-Der Wang, Li-Jung Ku (Handling Associate Editor: Takeshi Tabira)
Estimating Life Expectancy and Lifetime Healthcare Costs for Alzheimer’s Disease in Taiwan: Does the Age of Disease Onset Matter?
Abstract: Background: People with early onset Alzheimer’s disease (EOAD) seem to suffer greater impact. But there is a lack of population-based studies on loss of life expectancy (LE) and lifetime healthcare costs. Objectives: We conducted this study to estimate LE, expected years of life lost (EYLL), and lifetime healthcare costs for Alzheimer’s disease (AD) in Taiwan stratified by onset age and gender, using a method which integrates the product of the survival function and the mean cost function over a lifetime horizon. Methods: We linked the National Health Insurance datasets with the National Mortality Registry and extrapolated the survival to lifetime to estimate the mean cumulative costs since the date of the first AD diagnosis using medical claims between 2001 and 2012. Results: A total of 21,615 mild to moderate severe AD patients (including 20,358 late-onset (LOAD) and 1,257 EOAD) were recruited. The average onset age for EOAD was 61 years old, while that of LOAD was 78. Although the LE of EOAD was 4.8 years longer than that of LOAD due to younger age, the EYLL for the former was 8.7 years versus 1.7 years for the latter. EOAD also had higher lifetime healthcare costs than the LOAD group (USD$37,957±2,403 versus 33,809±786). Conclusions: Since EOAD patients had both higher EYLL and lifetime healthcare costs than LOAD, future studies should pay more attention to the needs of EOAD patients.

Pages 317-325
E. Julia Chosy, Noele Gross, Marnie Meyer, Catherine Liu, Steven D. Edland, Lenore J Launer, Lon R. White
Brain Injury and Later-Life Cognitive Impairment and Neuropathology: The Honolulu-Asia Aging Study
Abstract: Background: Findings are inconsistent regarding the role of traumatic head injury in the subsequent development of neurologic outcomes. Objective: Examine the relationship between head injury and later cognitive impairment. Methods: A sample of 3,123 Japanese-American men was assessed for history of head injury and evaluated for cognitive impairment using the Cognitive Abilities Screening Instrument (CASI). For a subsample of 676 respondents, neuropathologic results from those with and without head injury were compared. Results: Although the crude model showed an association between history of head injury and later severe cognitive impairment, the relationship lost significance in the adjusted model (OR=1.320, CI: 0.90-1.93), regardless of time between injury and impairment. Similar to cognitive impairment, hippocampal sclerosis was observed significantly more in the brains of respondents with a history of head injury in the crude model, but the relationship weakened in the adjusted model (OR=1.462, CI: 0.68-3.12). After adjustment, decedents with a head injury demonstrated marginally higher brain weight (OR=1.003, CI: 1.00-1.01). Conclusion: We did not find a relationship between head injury and subsequent cognitive decline in this cohort. The neuropathology results also displayed no strong association between history of head injury and specific brain lesions and characteristics. These results support other findings in prospective cohorts. However, they could be influenced by the demographic make-up of the sample (male Japanese-Americans) or by the observation that the majority reported only a single head injury.

Pages 327-332
Puja Agarwal, John D. Brockman, Yamin Wang, Julie A. Schneider, Martha C. Morris (Handling Associate Editor: Rosanna Squitti)
Brain Bromine Levels Associated with Alzheimer’s Disease Neuropathology
Abstract: Background: Bromine is a naturally occurring element that is widely present in the human environment in various chemical forms primarily as flame retardants, pesticides, and water treatments. Objective: In this exploratory study, we investigated the association of brain bromine concentrations on Alzheimer’s disease (AD) neuropathology, cerebral infarcts, and Lewy bodies. Methods: The study was conducted in 215 deceased participants of the Memory and Aging Project, a clinical-pathologic cohort study. Brain bromine levels were measured using instrumental neutron activation analysis. Multiple brain regions were assessed for diffuse and neuritic plaques, neurofibrillary tangles, cerebral macro-and microinfarcts, and Lewy bodies. Standardized measures of AD pathology (Braak, CERAD, NIA-Reagan, global AD pathology) were computed. Results: In linear regression models, the higher brain bromine levels were associated with more AD neuropathology (Braak (p trend=0.01); CERAD (p trend=0.02); NIA-Reagan (p trend=0.02). Conclusion: Bromine accumulation in the brain is associated with higher level of AD neuropathology. The potential deleterious effects of this element on AD need further exploration.

Pages 333-345
Konstantinos Arfanakis, Arnold M. Evia, Sue E. Leurgans, Luis F.C. Cardoso, Arman Kulkarni, Nabil Alqam, Lucas F. Lopes, Diego Vieira, David A. Bennett, Julie A. Schneider (Handling Associate Editor: Margaret Flanagan)
Neuropathologic Correlates of White Matter Hyperintensities in a Community-Based Cohort of Older Adults
Abstract: Background: The association of white matter hyperintensities (WMH) with age-related vascular and neurodegenerative pathologies remains incompletely understood. Objective: The objective of this work was to elucidate the neuropathologic correlates of WMH in a large community-based cohort of older adults. Methods: Cerebral hemispheres from 603 community-based older adults were imaged with MRI ex vivo. All participants underwent annual clinical evaluation, cognitive assessment, and neuropathologic examination. WMH burden was assessed using a modified Fazekas rating scale. Multiple ordinal logistic regression was used to test the association of WMH burden with an array of age-related neuropathologies, adjusting for demographics. Mixed effects models of cognition controlling for neuropathologies and demographics were used to determine whether WMH burden contributes to cognitive decline beyond measured pathologies. Results: WMH burden in the whole group was associated with both vascular and Alzheimer’s disease (AD) pathologies: arteriolosclerosis (p<10-4), gross (p<10-4), and microscopic infarcts (p=0.04), and amyloid-β plaques (p=0.028). In non-demented participants (mild or no cognitive impairment) (N=332), WMH burden was related to gross infarcts (p=10-4) and arteriolosclerosis (p<10-4), but not to AD pathology. Similarly, in those with no cognitive impairment (N=178), WMH burden was related to gross infarcts (p=8x10-4) and arteriolosclerosis (p=0.014). WMH burden was associated with faster decline in perceptual speed in both the whole (p=0.038) and non-demented (p=0.006) groups. Conclusion: WMH burden has independent associations with vascular pathologies in older adults regardless of clinical status, and with AD pathology later in the progression of AD. Moreover, WMH burden may reflect additional tissue injury not captured with traditional neuropathologic indices.

Pages 347-357
Emilie T. Reas, Donald J. Hagler Jr., Joshua M. Kuperman, Christina E. Wierenga, Douglas Galasko, Nathan S. White, Anders M. Dale, Sarah J. Banks, Linda K. McEvoy, James B. Brewer
Associations Between Microstructure, Amyloid, and Cognition in Amnestic Mild Cognitive Impairment and Dementia
Abstract: Background: Although amyloid-β (Aβ) and microstructural brain changes are both effective biomarkers of Alzheimer’s disease, their independent or synergistic effects on cognitive decline are unclear. Objective: To examine associations of Aβ and brain microstructure with cognitive decline in amnestic mild cognitive impairment and dementia. Methods: Restriction spectrum imaging, cerebrospinal fluid Aβ, and longitudinal cognitive data were collected on 23 healthy controls and 13 individuals with mild cognitive impairment or mild to moderate Alzheimer's disease. Neurite density (ND) and isotropic free water diffusion (IF) were computed in fiber tracts and cortical regions of interest. We examined associations of Aβ with regional and whole-brain microstructure, and assessed whether microstructure mediates effects of Aβ on cognitive decline. Results: Lower ND in limbic and association fibers and higher medial temporal lobe IF predicted baseline impairment and longitudinal decline across multiple cognitive domains. ND and IF predicted cognitive outcomes after adjustment for Aβ or whole-brain microstructure. Correlations between microstructure and cognition were present for both amyloid-positive and amyloid-negative individuals. Aβ correlated with whole-brain, rather than regional, ND and IF. Conclusion: Aβ correlates with widespread microstructural brain changes, whereas regional microstructure correlates with cognitive decline. Microstructural abnormalities predict cognitive decline regardless of amyloid, and may inform about neural injury leading to cognitive decline beyond that attributable to amyloid.

Pages 359-374
Nikita Francis, Lisa S. Robison, Dominique L. Popescu, Michalis Michaelos, Joshua Hatfield, Feng Xu, Xiaoyue Zhu, Judianne Davis, Maria E. Anderson, Brenda J. Anderson, William E. Van Nostrand, John K. Robinson
Voluntary Wheel Running Reduces Amyloid-β42 and Rescues Behavior in Aged Tg2576 Mouse Model of Alzheimer’s Disease
Abstract: Exercise has been shown to be protective against the risk of dementias, including Alzheimer’s disease (AD). Intervention studies have demonstrated its ability to mitigate cognitive and behavioral impairments and reduce disease in both humans and animals. However, information is lacking in regard to the volume and intensity, as well as timing of exercise onset with respect to disease stage, which produces optimal benefits. Here, utilizing the Tg2576 mouse, a model of AD-like parenchymal amyloid pathology and cognitive impairment, we sought to understand the effects of different lengths of daily access to a running wheel on advanced stage disease. This study is the first to determine the benefits of long-term exercise (4 months of voluntary running) and different periods of daily access to a running wheel (0h, 1h, 3h, and 12h running wheel access) beginning in 14-month-old Tg2576 mice, an age with significant amyloid pathology. We found that exercising Tg2576 animals showed lower levels of some aspects of AD pathology and reduced behavioral dysfunction compared to sedentary Tg2576 animals. High intensity exercise, rather than high volume exercise, was generally most beneficial in reducing amyloid pathology. Our results suggest that engaging in vigorous exercise programs, even after living a sedentary life, may lead to a measurable reduction in AD pathology and preservation of some cognitive abilities.

Pages 375-382
Shasha Song*, Jingjiong Chen*, Pinpin Xiao, Hao Duan, Yajun Zhou, Feng Wang, Hongmei Wang, Yuwu Zhao, Zhi Geng (Handling Associate Editor: Yong Guo) *These authors contributed equally to this work.
Role of Macrophages in Status Epilepticus Predisposing to Alzheimer’s Disease
Abstract: Continuous epileptic seizures hallmark status epilepticus, leading to preferential neuronal cell loss in the hippocampus that can progress into Alzheimer’s disease. Previous studies have shown that status epilepticus prompts an overproduction of nitric oxide (NO) by upregulation of NO synthase II (NOS II) to induce apoptosis of neuronal cells in the hippocampus, in a nuclear factor-kappaB (NF-κB) signaling dependent manner. Here, in an experimental rat model for status epilepticus, elicitation of sustained seizure activity was achieved by microinjection of kainic acid (KA) into the hippocampal CA3 subfield. We found that KA induced features of status epilepticus, which could be attenuated by blocking NF-κB signaling through a specific inhibitor. Interestingly, infiltration of macrophages of primarily pro-inflammatory subtype was detected in the hippocampal CA3 region immediately after KA injection. Experimental elimination of macrophages by an anti-CD115 antibody significantly attenuated the features of status epilepticus, likely through suppressing activation of NF-κB signaling. Together, these data suggest that macrophages play a critical role in NF-κB signaling-mediated status epilepticus that predisposes to Alzheimer’s disease.

Pages 383-392
Kenji Wada-Isoe, Takashi Kikuchi, Yumi Umeda-Kameyama, Takahiro Mori, Masahiro Akishita, Yu Nakamura; on behalf of the ABC Dementia Scale Research Group
ABC Dementia Scale Classifies Alzheimer’s Disease Patients into Subgroups Characterized by Activities of Daily Living, Behavioral and Psychological Symptoms of Dementia, and Cognitive Function
Abstract: The course of Alzheimer’s disease (AD) varies between individuals, and the relationship between cognitive and functional decline and the deterioration of behavioral and psychological symptoms of dementia (BPSD) is still poorly understood. Until recently, it was challenging to monitor subsequent changes in these symptoms because there was no single composite scale available that could simultaneously evaluate activities of daily living (ADL), BPSD, and cognitive function (CF) states. The present authors developed a new, brief assessment scale, the “ABC Dementia Scale” (ABC-DS), which is based on item response theory and facilitates concurrent measurement of ADL, BPSD, and CF states. We previously presented the reliability, construct validity, concurrent validity, and responsiveness of the ABC-DS. We obtained the evidence through three clinical trials featuring 1,400 subjects in total. In the present study, we performed a secondary analysis of the data obtained in the previous study. We conducted hierarchical cluster analyses that allowed us to classify 197 AD patients in terms of similarities regarding ADL, BPSD, and CF domain scores, as measured by the ABC-DS. Consequently, the scale identified subgroups of patients with global clinical dementia ratings of 1, 2, and 3. Considering our results in conjunction with the clinical experiences of the AD expert among the present authors regarding longitudinal changes in ADL, BPSD, and CF, we were able to propose potential progression pathways of AD in the form of a hypothetical roadmap.

Pages 393-411
Joakim Bastrup, Kenneth Kastaniegaard, Ayodeji A. Asuni, Christiane Volbracht*, Allan Stensballe* (Handling Associate Editor: Henrietta Nielsen) *Shared senior authorship
Proteomic and Unbiased Post-Translational Modification Profiling of Amyloid Plaques and Surrounding Tissue in a Transgenic Mouse Model of Alzheimer’s Disease
Abstract: Amyloid plaques are one of the hallmarks of Alzheimer’s disease (AD). The main constituent of amyloid plaques is amyloid-β peptides, but a complex interplay of other infiltrating proteins also co-localizes. We hypothesized that proteomic analysis could reveal differences between amyloid plaques and adjacent control tissue in the transgenic mouse model of AD (APPPS1-21) and in similar regions from non-transgenic littermates. Our microproteomic strategy included isolation of regions of interest by laser capture microdissection and analysis by liquid chromatography mass spectrometry-based label-free relative quantification. We consistently identified 183, 224, and 307 proteins from amyloid plaques, adjacent control and non-tg samples, respectively. Pathway analysis revealed 27 proteins that were significantly regulated when comparing amyloid plaques and corresponding adjacent control regions. We further elucidated that co-localized proteins were subjected to post-translational modifications and are the first to report 193 and 117 unique modifications associated to amyloid plaques and adjacent control extracts, respectively. The three most common modifications detected in proteins from the amyloid plaques were oxidation, deamidation, and pyroglutamylation. Together, our data provide novel information about the biological processes occurring within and around amyloid plaques in the APPPS1-21 mouse model of AD.

Pages 413-429
Eriko Kuroda, Kazuyuki Takata, Kaneyasu Nishimura, Hikaru Oka, Mari Sueyoshi, Mayu Aitani, Atsushi Kouda, Shiho Satake, Chiaki Shima, Yuki Toda, Susumu Nakata, Yoshihisa Kitamura*, Eishi Ashihara* *These authors both served as senior authors.
Peripheral Blood-Derived Microglia-Like Cells Decrease Amyloid-β Burden and Ameliorate Cognitive Impairment in a Mouse Model of Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) accumulation in the brain triggers the onset of Alzheimer's disease (AD), and its prevention and elimination are high priorities for anti-AD therapeutic strategies. Microglia, the resident immune cells in the brain, promote Aβ clearance by phagocytosis. Previously, we demonstrated that injection of primary cultured rat microglia and mouse bone marrow-derived microglia-like cells into the brain decreases the level of Aβ and that intrahippocampal injection of these cells ameliorates cognitive impairment in a mouse model of AD. To advance this cell therapeutic strategy to the clinical stage, less invasive ways of preparing autologous microglia-like cells from elderly patients are required. In this study, we demonstrated that hematopoietic stem cells mobilized from the bone marrow to peripheral blood by administering granulocyte colony-stimulating factor and a CXCR4 antagonist to mice differentiated into microglia-like cells upon stimulation with colony-stimulating factor 1 and interleukin-34. The peripheral blood-derived microglia-like (PBDML) cells expressed microglial markers and engaged in Aβ phagocytosis. Although PBDML cells were in an anti-inflammatory state under nonstimulated conditions, they expressed mRNAs encoding proinflammatory cytokines following lipopolysaccharide treatment. PBDML cells injected into the hippocampi of a mouse AD model survived for at least 36 days while phagocytosing Aβ, contributed to a reduction in brain Aβ burden, and ameliorated cognitive impairment in the mice. These results strongly suggest that PBDML cells are a promising source for the development of a novel cell therapy against AD.