Volume 77, Number 3, 2020

Pages 923-934

Jian-Quan Shi, Bian-Rong Wang, Teng Jiang, Li Gao, Ying-Dong Zhang, Jun Xu
NLRP3 Inflammasome: A Potential Therapeutic Target in Fine Particulate Matter-Induced Neuroinflammation in Alzheimer’s Disease
Abstract: As one of the most harmful air pollutants, fine particulate matter (PM2.5) has been implicated as a risk factor for multiple diseases, which has generated widespread public concern. Accordingly, a growing literature links PM2.5 exposure with Alzheimer’s disease (AD). A critical gap in our understanding of the adverse effects of PM2.5 on AD is the mechanism triggered by PM2.5 that contributes to disease progression. Recent evidence has demonstrated that PM2.5 can activate NLRP3 inflammasome-mediated neuroinflammation. In this review, we highlight the novel evidence between PM2.5 exposure and AD incidence, which is collected and summarized from neuropathological, epidemiological, and neuroimaging studies to in-depth deciphering molecular mechanisms. First, neuropathological, epidemiological, and neuroimaging studies will be summarized. Then, the transport pathway for central nervous system delivery of PM2.5 will be presented. Finally, the role of NLRP3 inflammasome-mediated neuroinflammation in PM2.5 induced-effects on AD will be recapitulated.

Pages 935-947

Cyrus A. Raji*, Nare Torosyan*, Daniel H. S. Silverman *These authors contributed equally to this work.
Optimizing Use of Neuroimaging Tools in Evaluation of Prodromal Alzheimer’s Disease and Related Disorders
Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disease and is characterized by preclinical, pre-dementia, and dementia phases. Progression of the disease leads to cognitive decline and is associated with loss of functional independence, personality changes, and behavioral disturbances. Current guidelines for AD diagnosis include the use of neuroimaging tools as biomarkers for identifying and monitoring pathological changes. Various imaging modalities, namely magnetic resonance imaging (MRI), fluorodeoxyglucose-positron emission tomography (FDG-PET) and PET with amyloid-beta tracers are available to facilitate early accurate diagnoses. Enhancing diagnosis in the early stages of the disease can allow for timely interventions that can delay progression of the disease. This paper will discuss the characteristic findings associated with each of the imaging tools for patients with AD, with a focus on FDG-PET due to its established accuracy in assisting with the differential diagnosis of dementia and discussion of other methods including MRI. Diagnostically-relevant features to aid clinicians in making a differential diagnosis will also be pointed out and multimodal imaging will be reviewed. We also discuss the role of quantification software in interpretation of brain imaging. Lastly, to guide evaluation of patients presenting with cognitive deficits, an algorithm for optimal integration of these imaging tools will be shared. Molecular imaging modalities used in dementia evaluations hold promise toward identifying AD-related pathology before symptoms are fully in evidence. The work describes state of the art functional and molecular imaging methods for AD. It will also overview a clinically applicable quantitative method for reproducible assessments of such scans in the early identification of AD.

Pages 949-960

Tam T. Quach, Aubin Moutal, Rajesh Khanna, Nicholas P. Deems, Anne-Marie Duchemin, Ruth M. Barrientos
Collapsin Response Mediator Proteins: Novel Targets for Alzheimer’s Disease
Abstract: Numerous experimental and postmortem studies have increasingly reported dystrophic axons and dendrites, and alterations of dendritic spine morphology and density in the hippocampus as prominent changes in the early stages of Alzheimer’s disease (AD). Furthermore, these alterations tend to correlate well with the progressive cognitive decline observed in AD. For these reasons, and because these neurite structures have a capacity to re-grow, re-establish lost connections, and are critical for learning and memory, there is compelling evidence to suggest that therapeutic interventions aimed at preventing their degradation or promoting their regrowth may hold tremendous promise in preventing the progression of AD. In this regard, collapsin response mediator proteins (CRMPs), a family of phosphoproteins playing a major role in axon guidance and dendritic growth, are especially interesting. The roles these proteins play in neurons and immune cells are reviewed here.

Pages 961-977

Carol A. Deaton, Gail V.W. Johnson
Presenilin 1 Regulates Membrane Homeostatic Pathways that are Dysregulated in Alzheimer’s Disease
Abstract: Mutations in the PSEN1 gene, encoding presenilin 1 (PS1), are the most common cause of familial Alzheimer’s disease (fAD). Since the first mutations in the PSEN1 gene were discovered more than 25 years ago, many postulated functions of PS1 have been investigated. The majority of earlier studies focused on its role as the catalytic component of the γ-secretase complex, which in concert with β site amyloid precursor protein cleaving enzyme 1 (BACE1), mediates the formation of Aβ from amyloid-β protein precursor (AβPP). Though mutant PS1 was originally considered to cause AD by promoting Aβ pathology through its protease function, it is now becoming clear that PS1 is a multifunctional protein involved in regulating membrane dynamics and protein trafficking. Therefore, through loss of these abilities, mutant PS1 has the potential to impair numerous cellular functions such as calcium flux, organization of proteins in different compartments, and protein turnover via vacuolar metabolism. Impaired calcium signaling, vacuolar dysfunction, mitochondrial dysfunction, and increased ER stress, among other related membrane-dependent disturbances, have been considered critical to the development and progression of AD. Given that PS1 plays a key regulatory role in all these processes, this review will describe the role of PS1 in different cellular compartments and provide an integrated view of how PS1 dysregulation (due to mutations or other causes) could result in impairment of various cellular processes and result in a “multi-hit”, integrated pathological outcome that could contribute to the etiology of AD.

Pages 979-984
Short Communication

Massimo Marano, Angelo Pompucci, Francesco Motolese, Mariagrazia Rossi, Ernesto Coletta, Vincenzo Di Lazzaro, Alfonso Fasano, Gianpaolo Petrella (Handling Associate Editor: Tommaso Schirinzi)
Normal Pressure Hydrocephalus in Down Syndrome: The Report of Two Cases
Abstract: Down syndrome (DS) is the most common cause of intellectual disability in infants and has a well-known relationship with the Alzheimer’s disease. The association between DS and the other pathologies of senescence, such as normal pressure hydrocephalus (NPH), has been poorly investigated. This series included two DS patients with NPH. In both cases, NPH symptoms were initially misdiagnosed as DS associated senescence. Patients were treated with ventricular-peritoneal shunt, showing a sustained improvement (1 and 4 years of follow-up). To our knowledge, this is the first description of the occurrence of NPH in adult patients with DS and surgical outcomes.

Pages 985-991
Short Communication

Adrián Valls-Carbó, Vicente Gajate, María Romeral, Álvaro Gutiérrez-Viedma, Beatriz Parejo-Carbonell, María Nieves Cabrera-Martín, Jorge Matías-Guiu, Jordi A Matías-Guiu*, Irene García-Morales* *These authors contributed equally to this work.
Non-Convulsive Status Epilepticus in Behavioral Variant Frontotemporal Dementia
Abstract: Epilepsy in frontotemporal dementia is considered to be less frequent than in Alzheimer’s disease. We report two cases of patients with non-convulsive status epilepticus associated with behavioral variant frontotemporal dementia. In the first case, status epilepticus was the first symptom of the disease, and consisted of loss of consciousness and mutism. In the second case, status epilepticus led to a clinical worsening one year after the diagnosis. Our study highlights the importance of suspecting non-convulsive status epilepticus in patients with frontotemporal dementia, and including frontotemporal dementia within the differential diagnosis of new-onset seizures.

Pages 993-1003
Poomarin Surinkaew*, Nattayaporn Apaijai*, Passakorn Sawaddiruk, Thidarat Jaiwongkam, Sasiwan Kerdphoo, Nipon Chattipakorn, Siriporn C. Chattipakorn *These authors contributed equally to this work.
Mitochondrial Fusion Promoter Alleviates Brain Damage in Rats with Cardiac Ischemia/Reperfusion Injury
Abstract: Background: Cardiac ischemia/reperfusion (I/R) injury induces brain damage through increased blood-brain barrier (BBB) breakdown, microglial hyperactivity, pro-inflammatory cytokines, amyloid-β deposition, loss of dendritic spines, brain mitochondrial dysfunction, and imbalanced mitochondrial dynamics. Previous studies demonstrated that mitochondrial fusion promoter reduced cardiac damage from cardiac I/R injury; however, following cardiac I/R injury, the roles of mitochondrial dynamics on the brain have not been investigated. Objective: To investigate the effects of pharmacological modulation using mitochondrial fusion promoter (M1) in the brain of rats following cardiac I/R injury. Methods: Twenty-four male Wistar rats were separated into two groups; 1) sham-operation (n=8) and 2) cardiac I/R injury (n=16). Rats in the cardiac I/R injury group were randomly received either normal saline solution as a vehicle or a mitochondrial fusion promoter (M1, 2 mg/kg) intravenously. Both treatments were given to the rats 15 minutes before cardiac I/R injury. At the end of the reperfusion protocol, the brain was rapidly removed to investigate brain mitochondrial function, mitochondrial dynamics proteins, microglial activity, and Alzheimer’s disease (AD) related proteins. Results: Cardiac I/R injury induced brain mitochondrial dynamics imbalance as indicated by reduced mitochondrial fusion proteins expression without alteration in mitochondrial fission, brain mitochondrial dysfunction, BBB breakdown, increased macrophage infiltration, apoptosis, and AD-related proteins. Pretreatment with M1 effectively increased the expression of mitofusin 2, a mitochondrial outer membrane fusion protein, reduced brain mitochondrial dysfunction, BBB breakdown, macrophage infiltration, apoptosis, and AD-related proteins in rats following cardiac I/R injury. Conclusion: This mitochondrial fusion promoter significantly protected rats with cardiac I/R injury against brain damage.

Pages 1005-1015
Andrew C. Robinson, Federico Roncaroli, Stephen Chew-Graham, Yvonne S. Davidson, James Minshull, Michael A. Horan, Antony Payton, Neil Pendleton*, David M.A. Mann* (Handling Associate Editor: Margaret Flanagan) *These authors contributed equally to this work.
The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology
Abstract: Background: The pathological features of Alzheimer’s disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer’s type pathology.

Pages 1017-1024
SeongHee Ho, Dong-Won Yang
Risk Factors Predicting Amyloid PET Positivity in Patients with Mild Cognitive Impairment and Apolipoprotein E ε3/ε3 Genotypes
Abstract: Background: The apolipoprotein E (APOE) ε4 allele is a well-known risk factor for AD and is associated with higher amyloid deposition and earlier dementia onset. However, the relationship between amyloid pathology and the most common APOE allele, ε3, has not been well studied. Objective: In this study, we aimed to identify the risk factors predicting amyloid PET positivity in patients with mild cognitive impairment (MCI) and APOE ε3/ε3 genotypes. Methods: We retrospectively reviewed the medical records of MCI patients with APOE ε3/ε3 genotypes who underwent amyloid PET scanning. Demographics, neuropsychological tests, and brain MRI were obtained. We analyzed which risk factors could affect amyloid PET positivity in MCI patients with APOE ε3/ε3 genotypes using logistic regression models. Results: We recruited 171 MCI patients with APOE ε3/ε3 genotypes in this study. Out of 171 patients, 49 patients (28.65%) showed positive results in the amyloid PET scans. In a multivariate logistic regression model, amyloid positivity was associated with frontal atrophy (OR = 2.63, p = 0.009), and CDR-SOB scores (OR = 2.46, p = 0.013). The odds ratio for amyloid PET positivity in patients older than and equal to 75 years with both frontal atrophy and CDR-SOB scores > 1.0 was 3.63. Conclusion: Our study demonstrated that frontal atrophy, high CDR-SOB scores, and old age were risk factors associated with amyloid PET positivity in MCI with APOE ε3/ε3 genotypes.

Pages 1025-1042
Jie Huang, Paul Beach, Andrea Bozoki, David C. Zhu (Handling Associate Editor: Roser Sala Llonch)
Alzheimer’s Disease Progressively Alters the Face-Evoked Visual-Processing Network
Abstract: Background: Postmortem studies of Alzheimer’s disease (AD) brains not only find amyloid-β (Aβ) and neurofibrillary tangles (NFT) in the primary and associative visual cortical areas, but also reveal a temporally successive sequence of AD pathology beginning in higher-order visual association areas, followed by involvement of lower-order visual processing regions with disease progression, and extending to primary visual cortex in late-stage disease. These findings suggest that neuronal loss associated with Aβ and NFT aggregation in these areas may alter not only the local neuronal activation but also visual neural network activity. Objective: Applying a novel method to identify the visual functional network and investigate the association of the network changes with disease progression. Methods: To investigate the effect of AD on the face-evoked visual-processing network, 8 severe AD (SAD) patients, 11 mild/moderate AD (MAD), and 26 healthy senior (HS) controls undertook a task-fMRI study of viewing face photos. Results: For the HS, the identified group-mean visual-processing network in the ventral pathway started from V1 and ended within the fusiform gyrus. In contrast, this network was disrupted and reduced in the AD patients in a disease-severity dependent manner: for the MAD patients, the network was disrupted and reduced mainly in the higher-order visual association areas; for the SAD patients, the network was nearly absent in the higher-order association areas, and disrupted and reduced in the lower-order areas. Conclusion: This finding is consistent with the current canonical view of the temporally successive sequence of AD pathology through visual cortical areas.

Pages 1043-1056
Benjamin B. Tournier, Stergios Tsartsalis, Kelly Ceyzériat, Ben H. Fraser, Marie-Claude Grégoire, Enikö Kövari, Philippe Millet
Astrocytic TSPO Upregulation Appears Before Microglial TSPO in Alzheimer’s Disease
Abstract: Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-translocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes.

Pages 1057-1065
Yen Ying Lim, Paul Maruff, Naoki Kaneko, James Doecke, Christopher Fowler, Victor L. Villemagne, Takashi Kato, Christopher C. Rowe, Yutaka Arahata, Shinichi Iwamoto, Kengo Ito, Koichi Tanaka, Katsuhiko Yanagisawa, Colin L Masters, Akinori Nakamura
Plasma Amyloid-β Biomarker Associated with Cognitive Decline in Preclinical Alzheimer’s Disease
Abstract: Background: Using immunoprecipitation-mass spectrometry, we recently developed and validated a plasma composite biomarker for the assessment of amyloid-β (Aβ) levels. However, as yet, its relationship with clinical outcomes remains unclear. Objective: We aimed to examine the relationship between this plasma Aβ composite biomarker and cognitive function in cognitively normal older adults in two independent cohorts. Methods: Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study and the National Centre for Geriatrics and Gerontology (NCGG) study had undergone Aβ neuroimaging using positron emission tomography (PET), cognitive assessments and provided blood samples. We derived a high-performance plasma Aβ composite biomarker by immunoprecipitation with mass-spectrometry. Results: Both continuous and categorical measures of the plasma Aβ composite biomarker were significantly related to decline in episodic memory and executive function. The magnitude of effects of the plasma Aβ composite on episodic memory and executive function were comparable to that observed for the effects of PET Aβ levels on these same outcome measures. Conclusion: Several plasma Aβ biomarkers have been developed, but none have yet been applied to investigate their relationship with cognitive outcomes. Our results have important implications for the use of this biomarker in the detection of at-risk individuals.

Pages 1067-1076
Ashleigh F. Parker, Colette M. Smart, Vanessa Scarapicchia, Jodie R. Gawryluk, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Andrew Saykin)
Identification of Earlier Biomarkers for Alzheimer’s Disease: A Multimodal Neuroimaging Study of Individuals with Subjective Cognitive Decline
Abstract: Background: Individuals with subjective cognitive decline (SCD) are thought to be the earliest along the cognitive continuum between healthy aging and Alzheimer’s disease (AD). Objective: The current study used a multi-modal neuroimaging approach to examine differences in brain structure and function between individuals with SCD and healthy controls (HC). Methods: 3T high-resolution anatomical images and resting-state functional MRI scans were retrieved for 23 individuals with SCD and 23 HC from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Results: The SCD and HC groups were not significantly different in age or education level. Voxel-based morphometry results did not show significant differences in grey matter volume between the groups. Functional MRI results revealed significantly greater functional connectivity in the default mode network in regions including the bilateral precuneus cortex, bilateral thalamus, and right hippocampal regions in individuals with SCD relative to controls. Conversely, those with SCD showed decreased functional connectivity in the bilateral frontal pole, caudate, angular gyrus, and lingual gyrus, compared to HC. Conclusion: Findings revealed differences in brain function but not structure between individuals with SCD and HC. Overall, this study represents a crucial step in characterizing individuals with SCD, a group recognized to be at increased risk for AD. It is imperative to identify biomarkers of AD prior to significant decline on clinical assessment, so that disease-delaying interventions may be delivered at the earliest possible time point.

Pages 1077-1093
Na Qu*, Xiao-Ming Wang*, Teng Zhang, Shu-Fang Zhang, Yi Li, Fu-Yuan Cao, Qun Wang, Lin-Na Ning, Qing Tian *These authors contributed equally to this paper.
Estrogen Receptor α Agonist Is Beneficial for Young Female Rats Against Chronic Unpredicted Mild Stress-Induced Depressive Behavior and Cognitive Deficits
Abstract: Background: Women are reported more likely to develop depression and dementia. However, the involved mechanism is poorly understood. Objective: Here, we clarified the role of estrogen receptor α (ERα) in depression and cognitive deficit in young female rats. Methods: After being exposed to 7-weeks’ chronic unpredicted mild stress (CUMS), the depression resilient rats (Res rats) and depressed rats (Dep rats) were selected according to their records in sucrose preference test, forced swimming test, and open field test. Their cognition abilities were tested by Morris water maze. Proteomic assay, immunoprecipitation, western blotting, immunohistochemical, and Nissl staining were also used to understand the involved mechanism. Results: Compared with control rats and Res rats, Dep rats showed cognitive deficits and hippocampal impairments revealed by proteomic data, neuron losses, increased cleaved caspase-3, β-catenin phosphorylation, and glycogen synthase kinase3β (GSK3β) activation. As ERα, but not ERb, was found declined in hippocampi of Dep rats, 4,4k,4a-(4-propyl-[1H]-pyrazole-1,3,5-triyl) trisphenol (PPT, an ERα agonist, 1 mg/kg/day), was used to treat Dep rats (Dep+PPT). Twenty days later, the depressive behaviors, cognition deficits, and hippocampal neuron loss were rescued in Dep+PPT rats. Furthermore, Res and Dep+PPT rats had higher levels of β-catenin combined with ERα and lower levels of β-catenin combined with GSK3β than Dep rats in hippocampi. Conclusion: These results demonstrated hippocampal ERα is an important pro-resilient factor in CUMS-induced depressive behaviors and cognitive deficits. It was also given that the neuroprotection afforded by hippocampal ERα/Wnt interactions have significant implications for cognition and emotion in young females.

Pages 1095-1105
Stanislav Sutovsky, Robert Petrovic, Maria Fischerova, Viera Haverlikova, Barbara Ukropcova, Jozef Ukropec, Peter Turcani (Handling Associate Editor: Irena Rektorova)
Allelic Distribution of Genes for Apolipoprotein E and MTHFR in Patients with Alzheimer’s Disease and Their Epistatic Interaction
Abstract: Background: Genetic risk factors play an important role in the pathogenesis of Alzheimer’s disease (AD). However, the gene-gene interaction (epistasis) between specific allelic variants is only partially understood. Objective: In our study, we examined the presence of the ε4 allele of apolipoprotein E (APOE) and the presence of C677T and A1298C (rs1801133 and rs1801131) polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene in patients with AD and controls. We also evaluated the epistatic interaction between MTHFR and the APOE variants. Methods: A total of 564 patients with AD and 534 cognitively unimpaired age-matched controls were involved in the study. Results: The presence of the ε4 allele of APOE increases the risk of developing AD in a dose-dependent manner (OR 32.7: homozygotes, 15.6: homozygotes + heterozygotes, 14.3: heterozygotes). The combination of genotypes also increases the risk of developing AD in a dose-dependent manner: OR 18.3 (APOE 4/X and 4/4 + CT rs1801133), OR 19.4 (APOE 4/X and 4/4 + CT rs1801133+AC rs1801131), OR 22.4 (APOE 4/X and 4/4 + TT rs1801133), and OR 21.2 (APOE 4/X and 4/4 + CC rs1801131). Homozygotes for variant alleles of MTHFR as well as patients with AD had significantly higher levels of homocysteine than homozygotes for standard alleles or controls. Conclusion: Homozygotes for APOE4 and carriers of APOE4 with TT genotype of rs1801133 were found to be at the highest risk of developing AD. These findings suggest that the epistatic interaction of specific gene variants can have a significant effect on the development of AD.

Pages 1107-1115
Robin C.P. van den Kieboom, Liselore J.A.E. Snaphaan, Ruth E. Mark, Inge M.B. Bongers
The Trajectory of Caregiver Burden and Risk Factors in Dementia Progression: A Systematic Review
Abstract: Background: Caring for patients with dementia at home is often a long-term process, in which the independence of the patient declines, and more responsibility and supervision time is required from the informal caregiver. Objective: In order to minimize and reduce caregiver burden, it is important to explore its trajectory and the accompanying risk factors as dementia progresses; the objective of this systematic review. Methods: PRISMA guidelines were followed in this systematic review. Three databases, PubMed, PsycINFO, and EMbase, were systematically searched in November 2019 using specific keywords. Results: 1,506 hits emerged during the systematic search but only eleven articles actually met the inclusion criteria for this review. The trajectory of caregiver burden is highly variable and depends on multiple factors. Important risk factors included: patients’ behavioral and neuropsychiatric symptoms, and their decline in functioning in (I)ADL; the caregiver’s age, gender, and physical and mental health; and, within the dyads (patient/caregiver), cohabitation and kinship. Conclusion: There is no one-size-fits-all for predicting how caregiver burden will change over time, but specific factors (like being a spouse and increased behavioral impairment and decline in functional status in the patient) may heighten the risk. Other factors, not yet comprehensively included in the published studies, might also prove to be important risk factors. Future research in the field of reducing caregiver burden is recommended to integrate the patient, caregiver, and context characteristics in the trajectory of caregiver burden, and to assess more clearly the phase of the dementia progression and use of external resources.

Pages 1117-1127
Anne Katrine Bergland*, Petroula Proitsi*, Bjørn-Eivind Kirsebom, Hogne Soennesyn, Abdul Hye, Alf Inge Larsen, Jin Xu, Cristina Legido-Quigley, Lawrence Rajendran, Tormod Fladby, Dag Aarsland *These authors contributed equally to this work.
Exploration of Plasma Lipids in Mild Cognitive Impairment due to Alzheimer’s Disease
Abstract: Background: Lipids have important structural roles in cell membranes and changes to these membrane lipids may influence β- and γ-secretase activities and thus contribute to Alzheimer’s disease (AD) pathology. Objective: To explore baseline plasma lipid profiling in participants with mild cognitive impairment (MCI) with and without AD pathology. Methods: We analyzed 261 plasma lipid profiles using reversed phase chromatography mass spectrometry in cerebrospinal fluid amyloid positive (Aβ+) or negative (Aβ-) participants with MCI as compared to controls. Additionally, we analyzed the potential associations of plasma lipid profiles with performance on neuropsychological tests at baseline and after two years. Results: Sphingomyelin (SM) concentrations, particularly, SM(d43:2), were lower in MCI Aβ+ individuals compared to controls. Further, SM(d43:2) was also nominally reduced in MCI Aβ+ individuals compared to MCI Aβ-. No plasma lipids were associated with performance on neuropsychological tests at baseline or between the two time points after correction for multiple testing. Conclusion: Reduced plasma concentrations of SM were associated with AD.

Pages 1129-1141
Alberto Benussi, Nicholas J. Ashton, Thomas K. Karikari, Stefano Gazzina, Enrico Premi, Luisa Benussi, Roberta Ghidoni, Juan Lantero Rodriguez, Andreja Emeršič, Giuliano Binetti, Silvia Fostinelli, Marcello Giunta, Roberto Gasparotti, Henrik Zetterberg, Kaj Blennow, Barbara Borroni (Handling Associate Editor: Andrea Arighi)
Serum Glial Fibrillary Acidic Protein (GFAP) Is a Marker of Disease Severity in Frontotemporal Lobar Degeneration
Abstract: Background: It is still unknown if serum glial fibrillary acidic protein (GFAP) is a useful marker in frontotemporal lobar degeneration (FTLD). Objective: To assess the diagnostic and prognostic value of serum GFAP in a large cohort of patients with FTLD. Methods: In this retrospective study, performed on 406 participants, we measured serum GFAP concentration with an ultrasensitive Single molecule array (Simoa) method in patients with FTLD, Alzheimer’s disease (AD), and in cognitively unimpaired elderly controls. We assessed the role of GFAP as marker of disease severity by analyzing the correlation with clinical variables, neurophysiological data, and cross-sectional brain imaging. Moreover, we evaluated the role of serum GFAP as a prognostic marker of disease survival. Results: We observed significantly higher levels of serum GFAP in patients with FTLD syndromes, except progressive supranuclear palsy, compared with healthy controls, but not compared with AD patients. In FTLD, serum GFAP levels correlated with measures of cognitive dysfunction and disease severity, and were associated with indirect measures of GABAergic deficit. Serum GFAP concentration was not a significant predictor of survival. Conclusion: Serum GFAP is increased in FTLD, correlates with cognition and GABAergic deficits, and thus shows promise as a biomarker of disease severity in FTLD.

Pages 1143-1155
Daniela Enache, Joana B. Pereira, Vesna Jelic, Bengt Winblad, Per Nilsson, Dag Aarsland, Erika Bereczki
Increased Cerebrospinal Fluid Concentration of ZnT3 Is Associated with Cognitive Impairment in Alzheimer’s Disease
Abstract: Background: Cognitive deficits arising in the course of Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease with dementia (PDD) are directly linked to synaptic loss. Postmortem studies suggest that zinc transporter protein 3 (ZnT3), AMPA glutamate receptor 3 (GluA3), and Dynamin1 are associated with cognitive decline in AD and Lewy body dementia patients. Objective: We aimed to evaluate the diagnostic value of ZnT3, GluA3, and Dynamin 1 in the cerebrospinal fluid (CSF) of patients with dementia due to AD, DLB, and PDD compared to cognitively normal subjective cognitive decline (SCD) patients in a retrospective study. In addition, we assessed the relationship between synaptic markers and age, sex, cognitive impairment, and depressive symptoms as well as CSF amyloid, phosphorylated tau (p-tau), and total tau (T-tau). Methods: Commercially available ELISA immunoassay was used to measure the levels of proteins in a total of 97 CSF samples from AD (N=24), PDD (N=18), DLB (N=27), and SCD (N=28) patients. Cognitive impairment was assessed using the Mini-Mental State Examination (MMSE). Results: We found a significant increase in the concentrations of ZnT3, GluA3, and Dynamin1 in AD (p=0.002) and of ZnT3 and Dynamin 1 in DLB (p=0.001, p=0.002) when compared to SCD patients. Changes in ZnT3 concentrations correlated with MMSE scores in AD (p=0.011), and with depressive symptoms in SCD (p=0.041). Conclusion: We found alteration of CSF levels of synaptic proteins in AD, PDD, and DLB. Our results reveal distinct changes in CSF concentrations of ZnT3 that could reflect cognitive impairment in AD with implications for future prognostic and diagnostic marker development.

Pages 1157-1167
Zhirong Yang, Duncan Edwards, Stephen Burgess, Carol Brayne, Jonathan Mant
Association of Prior Atherosclerotic Cardiovascular Disease with Dementia After Stroke: A Retrospective Cohort Study
Abstract: Background: Prior atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD) and peripheral artery disease (PAD), are common among patients with stroke, a known risk factor for dementia. However, whether these conditions further increase the risk of post-stroke dementia remains uncertain. Objective: To examine whether prior ASCVD is associated with increased risk of dementia within stroke patients. Methods: A retrospective cohort study was conducted using the Clinical Practice Research Datalink with linkage to hospital data. Patients with first-ever stroke between 2006 and 2017 were followed up to 10 years. We used multi-variable Cox regression models to examine the associations of prior ASCVD with dementia and the impact of prior ASCVD onset and duration. Results: Among 63,959 patients, 7,265 cases (11.4%) developed post-stroke dementia during a median of 3.6-year follow-up. The hazard ratio (HR) of dementia adjusted for demographics and lifestyle was 1.18 (95% CI: 1.12-1.25) for ASCVD, 1.16 (1.10-1.23) for CHD, and 1.25 (1.13-1.37) for PAD. The HR additionally adjusted for multimorbidity and medications was 1.07 (1.00-1.13), 1.04 (0.98-1.11), and 1.11 (1.00-1.22), respectively. Based on the fully adjusted estimates, there was no linear relationship between the age of ASCVD onset and post-stroke dementia (all p-trend > 0.05). The adjusted risk of dementia was not increased with the duration of pre-stroke ASCVD (all p-trend > 0.05). Conclusion: Stroke patients with prior ASCVD are more likely to develop subsequent dementia. After full adjustment for confounding, however, the risk of post-stroke dementia is attenuated, with only a slight increase with prior ASCVD.

Pages 1169-1180
Marie-Paule E. van Engelen, Flora T. Gossink, Lieke S. de Vijlder, Jan R.A. Meursing, Philip Scheltens, Annemiek Dols*, Yolande A.L. Pijnenburg* (Handling Associate Editor: David Knopman) *Shared last authorship.
End Stage Clinical Features and Cause of Death of Behavioral Variant Frontotemporal Dementia and Young-Onset Alzheimer’s Disease
Abstract: Background: Limited literature exists regarding the clinical features of end stage behavioral variant frontotemporal dementia (bvFTD). This data is indispensable to inform and prepare family members as well as professional caregivers for the expected disease course and to anticipate with drug-based and non-pharmacological treatment strategies. Objective: The aim of the present study was to describe end stage bvFTD in a broad explorative manner and to subsequently evaluate similarities and dissimilarities with the end stage of the most prevalent form of young-onset dementia, Alzheimer’s disease (yoAD). Methods: We analyzed medical files on patients, using a mixed model of qualitative and quantitative approaches. Included were previously deceased patients with probable bvFTD and probable yoAD. End stage was defined as the last 6 months prior to death. Primary outcome measures comprised somatic, neurological, and psychiatric symptoms and the secondary outcome measure was cause of death. Results: Out of 89 patients, a total of 30 patients were included (bvFTD; n=12, yoAD; n=18). Overall, the end stages of bvFTD and yoAD were characterized by a broad spectrum of clinical symptoms including severe autonomic dysfunction and an increased muscle tone. Patients with bvFTD displayed more mutism compared with yoAD while compulsiveness was only present in bvFTD. Conclusion: Our study describes the full clinical spectrum of end stage bvFTD and yoAD. In this study, symptoms extend far beyond the initial behavioral and cognitive features. By taking both somatic, psychiatric, and neurological features into account, family members and professional caregivers may anticipate (non) pharmacological treatment.

Pages 1181-1194
Myrlene Sanon Aigbogun, Martin Cloutier, Marjolaine Gauthier-Loiselle, Annie Guerin, Martin Ladouceur, Ross A. Baker, Michael Grundman, Ruth A. Duffy, Ann Hartry, Keva Gwin, Howard Fillit (Handling Associate Editor: Christina Jensen-Dahm)
Real-World Treatment Patterns and Characteristics Among Patients with Agitation and Dementia in the United States: Findings from a Large, Observational, Retrospective Chart Review
Abstract: Background: Few studies have examined patient characteristics and treatment patterns among patients with dementia and agitation in the United States (US). Objective: To examine real-world treatment patterns and characteristics of patients with agitation related to dementia who were treated with antipsychotics in US residential care and community-based settings. Methods: This retrospective chart review collected US physician-level data from patients 55 to 90 years old initiated on an antipsychotic medication for the treatment of agitation related to dementia from January 2018 to May 2018. Clinical characteristics and treatment patterns were assessed overall and stratified by residential care and community-based settings. Results: A total of 313 participating physicians, 59.5% of whom were primary care physicians, abstracted 801 patient charts (residential care: n = 312; community-based: n = 489). Of patients with agitation who were initiated on an antipsychotic, most patients (74.5%) were initiated within 3 months of the onset of their studied agitation episode, and 62.8% experienced multiple agitation episodes before initiation. While non-pharmacological therapies are recommended first-line approach for agitation in dementia, use of non-pharmacological therapy before initiation of antipsychotics was reported for only 37.8% of patients in residential care and 21.3% in community-based settings. Conclusion: Most patients were initiated on an antipsychotic treatment after multiple episodes of agitation and largely without initial non-pharmacological therapy, suggesting that current treatment guideline recommendations for first-line non-pharmacological intervention may not be adequately followed in clinical practice. Understanding the clinical burden and treatment patterns among dementia patients with agitation is imperative for effective disease management.

Pages 1195-1207
Jung Yun Jang, Jean K. Ho, Anna E. Blanken, Shubir Dutt, Daniel A. Nation, the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ines Ramakers)
Affective Neuropsychiatric Symptoms as Early Signs of Dementia Risk in Older Adults
Abstract: Background: Affective neuropsychiatric symptoms (aNPS: depression, anxiety, apathy, irritability) have been linked to increased dementia risk. However, less is known whether this association is independent of Alzheimer’s disease (AD) pathophysiology. Objective: To investigate the contribution of early aNPS to dementia risk in cognitively normal (CN) older adults and mild cognitive impairment (MCI) patients, with and without AD biomarker abnormality. Methods: Participants included 763 community-dwelling, stroke-free older adults identified as CN and 617 with MCI at baseline, drawn from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database. Baseline assessments included a neuropsychological battery, the Neuropsychiatric Inventory (NPI), and apolipoprotein E ε4 (ApoE4) genotyping. A participant subset completed cerebrospinal fluid (CSF) AD biomarker assessment. Time to progression to dementia was measured based on months at follow-up when an individual was diagnosed with dementia, over the follow-up period of 48 months. Results: Latent class analysis identified 3 subgroups of older adults in CN and MCI, indicated by the baseline profiles of neuropsychiatric symptoms (NPS). Subgroups with higher aNPS were at increased risk of progression to dementia in both CN (HR = 3.65, 95% CI [1.80, 7.40]) and MCI (HR = 1.52, 95% CI [1.16, 2.00]; HR = 1.86 [1.05, 3.30]) groups, adjusting for age, sex, global cognition, and ApoE4, compared with their counterparts with minimal NPS. There was no difference between higher aNPS and minimal NPS subgroups in their CSF AD biomarker profiles. Conclusion: Findings suggest that aNPS may represent a neurobiological vulnerability that uniquely contribute to the dementia risk, independent of AD biomarker profiles.

Pages 1209-1221
Surya Prakash Rai⁠⁠, Pablo Bascuñana, Mirjam Brackhan, Markus Krohn, Luisa Möhle, Kristin Paarmann, Jens Pahnke
Detection and Prediction of Mild Cognitive Impairment in Alzheimer’s Disease Mice
Abstract: Background: The failure of all clinical trials to treat Alzheimer’s disease (AD) indicates that the current approach of modifying disease is either wrong or is too late to be efficient. Mild cognitive impairment (MCI) denotes the phase between the preclinical phase and clinical overt dementia. AD mouse models that overexpress human amyloid-β (Aβ) are used to study disease pathogenesis and to conduct drug development/testing. However, there is no direct correlation between the Aβ deposition, the age of onset and the severity of cognitive dysfunction. Objective: To detect and predict MCI when Aβ plaques start to appear in the hippocampus of an AD mouse. Methods: We trained wild-type and AD mice in a Morris water maze (WM) task with different inter-trial intervals (ITI) at 3 months of age and assessed their WM performance. Additionally, we used a classification algorithm to predict the genotype (APPtg versus wild-type) of individual mice from their respective WM data. Results: MCI can be empirically detected using a short-ITI protocol. We show that the ITI modulates the spatial learning of AD mice without affecting the formation of spatial memory. Finally, a simple classification algorithm such as logistic regression on WM data can give an accurate prediction of the cognitive dysfunction of a specific mouse. Conclusion: MCI can be detected as well predicted simultaneously with the onset of Aβ deposition in the hippocampus in AD mouse model. The mild cognitive impairment prediction can be used for assessing the efficacy of a treatment.

Pages 1223-1239
Kim Blom, Huiberdina L. Koek, Maarten H.T. Zwartbol, Rashid Ghaznawi, Hugo J. Kuijf, Theo D. Witkamp, Jeroen Hendrikse, Geert Jan Biessels, Mirjam I. Geerlings, on behalf of the UCC-SMART Study Group
Vascular Risk Factors of Hippocampal Subfield Volumes in Persons without Dementia: The Medea 7T Study
Abstract: ackground: Vascular risk factors have been associated with risk of Alzheimer’s disease (AD) and volume loss of the hippocampus, but the associations with subfields of the hippocampus are understudied. Knowing if vascular risk factors contribute to hippocampal subfield atrophy may improve our understanding of vascular contributions to neurodegenerative diseases. Objective: To investigate the associations between age, sex, and vascular risk factors with hippocampal subfields volumes on 7T MRI in older persons without dementia. Methods: From the Medea 7T study, 283 participants (67±9 years, 68% men) without dementia had 7T brain MRI and hippocampal subfield segmentation. Subfields were automatically segmented on the 3D T2-weighted 7T images with ASHS software. Using linear mixed models, we estimated adjusted associations of age, sex, and vascular risk factors with z-scores of volumes of the entorhinal cortex (ERC), subiculum (SUB), Cornu Ammonis (CA)1, CA2, CA3, CA4, and dentate gyrus (DG), and tail as multivariate correlated outcomes. Results: Increasing age was associated with smaller volumes in all subfields, except CA4/DG. Current smoking was associated with smaller ERC and SUB volumes; moderate alcohol use with smaller CA1 and CA4/DG, obesity with smaller volumes of ERC, SUB, CA2, CA3, and tail; and diabetes mellitus with smaller SUB volume. Sex, former smoking, and hypertension were not associated with subfield volumes. When formally tested, no risk factor affected the subfield volumes differentially. Conclusion: Several vascular risk factors were associated with smaller volumes of specific hippocampal subfields. However, no statistical evidence was found that subfields were differentially affected by these risk factors.

Pages 1241-1253
Jing Wang, Lily Dongxia Xiao, Kai Wang, Yan Luo, Xiaomei Li (Handling Associate Editor: Matthew Lennon)
Cognitive Impairment and Associated Factors in Rural Elderly in North China
Abstract: Background: China has the largest population living with dementia globally and urban-rural differences are significant in prevalence, risk factors, and health resources. Epidemiologic studies on cognitive impairment in rural areas are limited in China and other low- and middle-income countries. Objective: This study investigated cognitive impairment and associated factors in rural elderly aged 65 years and over in China. Methods: In total, 1,250 participants from ten villages in North China were recruited from June to September, 2017. Face-to-face structured interviews were conducted for data collection. The interviews included socio-demographic information, health status, and psychological assessments. Cognitive function was assessed using the Chinese version of the Mini-Mental State Examination. A multivariate logistic regression model with backward method was employed to identify factors associated with cognitive impairment. Results: The positive rate of cognitive impairment among rural Chinese elderly aged 65 years and older was 42.9% (95% CI, 40.1-45.6). No significant differences were found in cognitive impairment by age or gender before the age of 75 years. Older age, lack of formal school education, reliance on the basic living allowance as the only income source, poor hearing and vision function, diabetes, and activities of daily living dependence were associated with higher rate of cognitive impairment, while tea consumption and fatty liver disease were associated with lower cognitive impairment rate. Conclusion: A very high percentage of rural elderly in China had cognitive impairment. Education programs and prevention interventions targeting modifiable risk factors among high-risk populations should be developed through collective efforts involving all stakeholders.

Pages 1255-1265
Hui Xu, Jianping Jia
Immune-Related Hub Genes and the Competitive Endogenous RNA Network in Alzheimer's Disease
Abstract: Background: The pathogenesis of Alzheimer’s disease (AD) involves various immune-related phenomena; however, the mechanisms underlying these immune phenomena and the potential hub genes involved therein are unclear. An understanding of AD-related immune hub genes and regulatory mechanisms would help develop new immunotherapeutic targets. Objective: The aim of this study was to explore the hub genes and the mechanisms underlying the regulation of competitive endogenous RNA (ceRNA) in immune-related phenomena in AD pathogenesis. Methods: We used the GSE48350 data set from the Gene Expression Omnibus database and identified AD immune-related differentially expressed RNAs (DERNAs). We constructed protein–protein interaction (PPI) networks for differentially expressed mRNAs and determined the degree for screening hub genes. By determining Pearson’s correlation coefficient and using StarBase, DIANA-LncBase, and Human MicroRNA Disease Database (HMDD), the AD immune-related ceRNA network was generated. Furthermore, we assessed the upregulated and downregulated ceRNA subnetworks to identify key lncRNAs. Results: In total, 552 AD immune-related DERNAs were obtained. Twenty hub genes, including PIK3R1, B2M, HLA-DPB1, HLA-DQB1, PIK3CA, APP, CDC42, PPBP, C3AR1, HRAS, PTAFR, RAB37, FYN, PSMD1, ACTR10, HLA-E, ARRB2, GGH, ALDOA, and VAMP2 were identified on PPI network analysis. Furthermore, upon microRNAs (miRNAs) inhibition, we identified LINC00836 and DCTN1-AS1 as key lncRNAs regulating the aforementioned hub genes. Conclusion: AD-related immune hub genes include B2M, FYN, PIK3R1, and PIK3CA, and lncRNAs LINC00836 and DCTN1-AS1 potentially contribute to AD immune-related phenomena by regulating AD-related hub genes.

Pages 1267-1278
Ariana M. Stickel, Wassim Tarraf, Benson Wu, Maria J. Marquine, Priscilla M. Vásquez, Martha Daviglus, Mayra L. Estrella, Krista M. Perreira, Linda C. Gallo, Richard B. Lipton, Carmen R. Isasi, Robert Kaplan, Donglin Zeng, Neil Schneiderman, Hector M. González (Handling Associate Editor: Lilian Calderón-Garcidueñas)
Cognition and Daily Functioning: Results from the Hispanic Community Health Study/Study of Latinos (SOL) and Study of Latinos-Investigation of Neurocognitive Aging (SOL-INCA)
Abstract: Background: Among older adults, poorer cognitive functioning has been associated with impairments in instrumental activities of daily living (IADLs). However, IADL impairments among older Hispanics/Latinos is poorly understood. Objective: To characterize the relationships between cognition and risk for IADL impairment among diverse Hispanics/Latinos. Methods: Participants included 6,292 community-dwelling adults from the Study of Latinos - Investigation of Neurocognitive Aging, an ancillary study of 45+ year-olds in the Hispanic Community Health Study/Study of Latinos. Cognitive data (learning, memory, executive functioning, processing speed, and a Global cognitive composite) were collected at Visit 1. IADL functioning was self-reported 7 years later, and treated as a categorical (i.e., risk) and continuous (i.e., degree) measures of impairment. Survey two-part models (mixture of logit and generalized linear model with Gaussian distribution) and ordered logistic regression tested the associations of cognitive performance (individual tests and composite z-score) with IADL impairment. Additionally, we investigated the moderating role of age, sex, and Hispanic/Latino background on the association between cognition and IADL impairment. Results: Across all cognitive measures, poorer performance was associated with higher odds of IADL impairment 7 years later. Associations were generally stronger for the oldest group (70+ years) relative to the youngest group (50-59 years). Sex and Hispanic/Latino background did not modify the associations. Across the full sample, lower scores on learning, memory, and the Global cognitive composite were also associated with higher degree of IADL impairment. Conclusion: Across diverse Hispanics/Latinos, cognitive health is an important predictor of everyday functioning 7 years later, especially in older adulthood.

Pages 1279-1289
Victoria Sanborn*, Sarah R. Preis*, Alvin Ang, Sherral Devine, Jesse Mez, Charles DeCarli, Rhoda Au, Michael L. Alosco*, John Gunstad* (Handling Associate Editor: Lori Beason-Held) *These authors contributed equally to this work.
Association Between Leptin, Cognition, and Structural Brain Measures Among “Early” Middle-Aged Adults: Results from the Framingham Heart Study Third Generation Cohort
Abstract: Background: There is growing interest in the pathophysiological processes of preclinical Alzheimer’s disease (AD), including the potential role of leptin. Human studies have shown that both low and high levels of leptin can be associated with worse neurocognitive outcomes, suggesting this relationship may be moderated by another risk factor. Objective: We examined the association between plasma leptin levels and both neuropsychological test performance and structural neuroimaging and assessed whether body mass index (BMI) is an effect modifier of these associations. Methods: Our study sample consisted of 2,223 adults from the Framingham Heart Study Third Generation Cohort (average age = 40 years, 53% women). Results: Among the entire sample, there was no association between leptin and any of the neuropsychological domain measures or any of the MRI brain volume measures, after adjustment for BMI, APOE4, and other clinical factors. However, we did observe that BMI category was an effect modifier for the association between leptin and verbal memory (p for interaction=0.03), where higher levels of leptin were associated with better performance among normal weight participants (BMI 18.5-24.9) kg/m2 (beta=0.12, p=0.02). No association was observed between leptin level and verbal memory test performance among participants who were overweight or obese. Conclusion: These findings suggest that the association between leptin and cognitive function is moderated by BMI category. Prospective examination of individuals transitioning from middle age to older adulthood will help to clarify the contribution of leptin to AD and other neurodegenerative conditions.

Pages 1291-1304
Danielle L. Sanchez, Kelsey R. Thomas, Emily C. Edmonds, Mark W. Bondi, Katherine J. Bangen, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Jason Brandt)
Regional Hypoperfusion Predicts Decline in Everyday Functioning at Three-Year Follow-Up in Older Adults without Dementia
Abstract: Background: Increasing evidence indicates that cerebrovascular dysfunction may precede cognitive decline in aging and Alzheimer’s disease (AD). Reduced cerebral blood flow (CBF) is associated with cognitive impairment in older adults. However, less is known regarding the association between CBF and functional decline, and whether CBF predicts functional decline beyond cerebrovascular and metabolic risk factors. Objective: To examine the association between regional CBF and functional decline in nondemented older adults. Method: One hundred sixty-six (N=166) participants without dementia from the Alzheimer’s Disease Neuroimaging Initiative underwent neuropsychological testing and neuroimaging. Pulsed arterial spin labeling magnetic resonance imaging was acquired to quantify resting CBF. Everyday functioning was measured using the Functional Assessment Questionnaire at baseline and annual follow-up visit across three years. Results: Adjusting for age, education, sex, cognitive status, depression, white matter hyperintensity volume, cerebral metabolism, and reference (precentral) CBF, linear mixed effects models showed that lower resting CBF at baseline in the medial temporal, inferior temporal, and inferior parietal lobe was significantly associated with accelerated decline in everyday functioning. Results were similar after adjusting for conventional AD biomarkers, including cerebrospinal fluid (CSF) amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) and apolipoprotein E (APOE) ε4 positivity. Individuals who later converted to dementia had lower resting CBF in the inferior temporal and parietal regions compared to those who did not. Conclusion: Lower resting CBF in AD vulnerable regions including medial temporal, inferior temporal, and inferior parietal lobes predicted faster rates of decline in everyday functioning. CBF has utility as a biomarker in predicting functional declines in everyday life and conversion to dementia.

Pages 1305-1314
Chathuri Yatawara, Kok Pin Ng, Anne Cristine Guevarra, Benjamin Wong, TingTing Yong, Nagaendran Kandiah (Handling Associate Editor: Ronan O'Caoimh)
Small Vessel Disease and Associations with Cerebrospinal Fluid Amyloid, Tau, and Neurodegeneration (ATN) Biomarkers and Cognition in Young Onset Dementia
Abstract: Background: Small vessel disease (SVD) and Alzheimer’s disease (AD) frequently coexist; however, it remains unclear how they collectively affect cognition. Objective: We investigated associations between SVD and AD biomarkers, namely amyloid, tau, and neurodegeneration (ATN) in young onset dementia (YOD) and explored how SVD and ATN interact to affect cognition. Methods: 80 YOD individuals were recruited from a memory clinic. SVD burden (SVD+) was operationalized as a score >1 on the Staals scale and ATN was measured using cerebrospinal fluid (CSF). Results: SVD+ was associated with lower CSF Aβ1-42 (B = -0.20, 95%CI: -0.32 to -0.008) and greater neurodegeneration, indexed as lower grey matter (B = -0.15, 95%CI: -0.28 to 0.02) and hippocampal volume (B = -0.24, 95%CI: -0.40 to -0.04). SVD+ was not associated with tau. Cognitive impairment was associated with CSF Aβ1-42 (B = -0.35, 95%CI: -0.55 to -0.18) but not SVD. Rather, SVD was indirectly associated with cognition via reduced CSF Aβ1-42, specifically with global cognition (B = -0.03, 95%CI: -0.09 to -0.01) and memory (B = 0.08, 95%CI: -0.09 to -0.01). SVD was indirectly associated with cognition via increased neurodegeneration in grey matter (Global cognition: B = -0.06, 95%CI: -0.09 to -0.03; Memory: B = 0.05, 95%CI: 0.01 to 0.18) and the hippocampus (Global cognition: B = -0.05, 95%CI: -0.11 to -0.01; Memory: B = 0.06, 95%CI: 0.01 to 0.17). Conclusion: In YOD, SVD burden was associated with AD pathology, namely CSF Aβ1-42. SVD indirectly contributed to cognitive impairment via reducing CSF Aβ1-42 and increasing neurodegeneration.

Pages 1315-1330
Tak-Ho Chu, Karen Cummins, Peter K. Stys
Traumatic Injury Reduces Amyloid Plaque Burden in the Transgenic 5xFAD Alzheimer’s Mouse Spinal Cord
Abstract: Background: Axonal injury has been implicated in the development of amyloid-β in experimental brain injuries and clinical cases. The anatomy of the spinal cord provides a tractable model for examining the effects of trauma on amyloid deposition. Objective: Our goal was to examine the effects of axonal injury on plaque formation and clearance using wild type and 5xFAD transgenic Alzheimer's disease mice. Methods: We contused the spinal cord at the T12 spinal level at 10 weeks, an age at which no amyloid plaques spontaneously accumulate in 5xFAD mice. We then explored plaque clearance by impacting spinal cords in 27-week-old 5xFAD mice where amyloid deposition is already well established. We also examined the cellular expression of one of the most prominent amyloid-β degradation enzymes, neprilysin, at the lesion site. Results: No plaques were found in wild type animals at any time points examined. Injury in 5xFAD prevented plaque deposition rostral and caudal to the lesion when the cords were examined at 2 and 4 months after the impact, whereas age-matched naïve 5xFAD mice showed extensive amyloid plaque deposition. A massive reduction in the number of plaques around the lesion was found as early as 7 days after the impact, preceded by neprilysin upregulation in astrocytes at 3 days after injury. At 7 days after injury, the majority of amyloid was found inside microglia/macrophages. Conclusion: These observations suggest that the efficient amyloid clearance after injury in the cord may be driven by the orchestrated efforts of astroglial and immune cells.

Pages 1331-1337
Daniel G. Amen, Joseph Wu, Noble George, Andrew Newberg
Patterns of Regional Cerebral Blood Flow as a Function of Obesity in Adults
Abstract: Background: While obesity has been shown to be a risk factor for Alzheimer’s disease, the potential mechanisms underlying this risk may be clarified with better understanding of underlying physiology in obese persons. Objective: To identify patterns of cerebral perfusion abnormality in adults as a function of body mass index (BMI) defined weight categories, including overweight or obese status. Methods: A large psychiatric cohort of 35,442 brain scans across 17,721 adults (mean age 40.8 &plusmn; 16.2 years, range 18-94 years) were imaged with SPECT during baseline and concentration scans, the latter done after each participant completed the Connors Continuous Performance Test II. ANOVA was done to identify patterns of perfusion abnormality in this cohort across BMI designations of underweight (BMI < 18.5), normal weight (BMI = 18.5 to 24.9), overweight (BMI 24.9 to 29.9), obesity (BMI ≥ 30), and morbid obesity (BMI ≥ 40). This analysis was done for 128 brain regions quantifying SPECT perfusion using the automated anatomical labeling (AAL) atlas. Results: Across adulthood, higher BMI correlated with decreased perfusion on both resting and concentration brain SPECT scans. These are seen in virtually all brain regions, including those influenced by AD pathology such as the hippocampus. Conclusion: Greater BMI is associated with cerebral perfusion decreases in both resting and concentration SPECT scans across adulthood.

Pages 1339-1351
Michela Guglielmotto, Giusi Manassero, Valeria Vasciaveo, Marika Venezia, Massimo Tabaton, Elena Tamagno
Estrogens Inhibit Amyloid-β-Mediated Paired Helical Filament-Like Conformation of Tau Through Antioxidant Activity and miRNA 218 Regulation in hTau Mice
Abstract: Background: The risk of developing Alzheimer’s disease as well as its progression and severity are known to be different in men and women, and cognitive decline is greater in women than in men at the same stage of disease and could be correlated at least in part on estradiol levels. Objective: In our work we found that biological sex influences the effect of amyloid-β42 (Aβ42) monomers on pathological tau conformational change. Methods: In this study we used transgenic mice expressing the wild-type human tau (hTau) which were subjected to intraventricular (ICV) injections of Aβ peptides in nanomolar concentration. Results: We found that Aβ42 produces pathological conformational changes and hyperphosphorylation of tau protein in male or ovariectomized female mice but not in control females. The treatment of ovariectomized females with estradiol replacement protects against the pathological conformation of tau and seems to be mediated by antioxidant activity as well as the ability to modulate the expression of miRNA 218 linked to tau phosphorylation. Conclusion: Our study indicates that factors as age, reproductive stage, hormone levels, and the interplay with other risk factors should be considered in women, in order to identify the best appropriate therapeutic approach in prevention of cognitive impairment.

Pages 1353-1368
Liu Shi, Laura M. Winchester, Benjamine Y. Liu, Richard Killick, Elena M. Ribe, Sarah Westwood, Alison L. Baird, Noel J. Buckley, Shengjun Hong, Valerija Dobricic, Fabian Kilpert, Andre Franke, Steven Kiddle, Martina Sattlecker, Richard Dobson, Antonio Cuadrado, Abdul Hye, Nicholas J. Ashtonj, Angharad R. Morgan, Isabelle Bos, Stephanie J.B. Vos, Mara ten Kate, Philip Scheltens, 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 Lleó, Daniel Alcolea, Julius Popp, Gwendoline Peyratout, Pablo Martinez-Lage, Mikel Tainta, Peter Johannsen, Charlotte E. Teunissen, Yvonne Freund-Levi, Lutz Frölich, Cristina Legido-Quigley, Frederik Barkhof, Kaj Blennow, Katrine Laura Rasmussen, Børge Grønne Nordestgaard, Ruth Frikke-Schmidt, Sune Fallgaard Nielsen, Hilkka Soininen, Bruno Vellas, Iwona Kloszewska, Patrizia Mecocci, Henrik Zetterberg, B. Paul Morgan, Johannes Streffer, Pieter Jelle Visser, Lars Bertram, Alejo J. Nevado-Holgado, Simon Lovestone
Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer’s Disease Pathology
Abstract: Background: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer’s disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. Objective: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. Methods: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). Results: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ε4 genotype distinguished amyloid pathology (A+T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. Conclusion: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect the ATN framework as well as predict disease severity and progression in vivo.