Volume 85, Number 1, IN PRESS

Editorial
Pravat K. Mandal, George Perry (Handling Editor: Paula Moreira)
SWADESH: A Comprehensive Platform for Multimodal Data and Analytics for Advanced Alzheimer’s Disease and other Brain Disorders

Review
Xin Fu*, Qiantong Liu*, Xiaowei Sun*, Hui Chang, Ying Liu, Jiatong Han *These authors contributed equally to this work.
Research Advances in the Treatment of Alzheimer’s Disease with Polysaccharides of Danggui-Shaoyao-San
Abstract: Alzheimer's disease (AD) is a common progressive neurodegenerative disease. In recent years, the research on the treatment of AD with Chinese medicine is increasing and the results are optimistic, which may provide some new options for the treatment of AD. Existing animal and clinical studies have found that Danggui Shaoyao San (DSS), which has been used in gynecological diseases, is effective in the treatment of AD. As the main component of DSS, macromolecular polysaccharide plays an indispensable role in the treatment of AD. In addition to anti-inflammatory, anti-neuronal injury, and immune regulation, polysaccharides extracted from Danggui Shaoyao San (p-DSS) also have good activities in hypoglycemia, and participate in the physiological regulation of ubiquitination, iron metabolism, intestinal flora, estrogen, and autophagy. Given that there is little systematic analysis of p-DSS, this paper reviews the possible mechanism of p-DSS in the treatment of AD, so as to provide reference for further research.

Manuel Ruiz-Adame
A Systematic Review of the Indirect and Social Costs for Early and Young Onset Dementias
Abstract: Background: The World Health Organization has estimated that worldwide around 50 million people have dementia. The World Alzheimer Report estimated that between 2 and 10% of all cases of dementia begin before the age of 65. Early and young onset dementias (EYOD) provoke more working, social, family, and economic consequences than late onset dementias. All general studies about costs of dementias show that most of them are indirect or social costs. Despite that, very few studies have been performed in EYOD. Objective: To do a systematic review of literature about indirect or social costs in EYOD to know the state of knowledge and to discover gaps that should be filled. Methods: A systematic review was performed in the main database: Scopus, PsychInfo, Web of Science (Web of Science Core Collection, Medline and SciELO), and CINAHL. Additionally, we looked for reviews in Cochrane and in the International Prospective Register Of Systematic Reviews (PROSPERO). Results: Most of the studies are about costs of dementias in general, but they do no differentiate costs for the case of EYOD. Many studies highlight the increased costs for EYOD but very little included evidence of that. 135 papers were selected. Finally, only two were studies providing data. EYOD reduce the odds to get or maintain a job. Most of the care is provided by informal caregivers. The costs in EYOD are 39.26% higher among EYOD than in late onset. Conclusion: There is a lack of studies about social and indirect costs in EYOD. More evidence is needed.

Review
Valory N. Pavlik, Samantha C. Burnham, Joseph S. Kass, Catherine Helmer, Sebastian Palmqvist, Maria Vassilaki, Jean-François Dartigues, Oskar Hansson, Colin L. Masters, Karine Pérès, Ronald C. Petersen, Erik Stomrud, Lesley Butler, Preciosa M. Coloma, Xavier M. Teitsma, Rachelle Doody, Mary Sano for the CONCORD-AD investigators
Connecting Cohorts to Diminish Alzheimer’s Disease (CONCORD-AD): A Report of an International Research Collaboration Network
Abstract: Longitudinal observational cohort studies are being conducted worldwide to understand cognition, biomarkers, and the health of the aging population better. Cross-cohort comparisons and networks of registries in Alzheimer’s disease (AD) foster scientific exchange, generate insights, and contribute to the evolving clinical science in AD. A scientific working group was convened with invited investigators from established cohort studies in AD, in order to form a research collaboration network as a resource to address important research questions. The Connecting Cohorts to Diminish Alzheimer’s Disease (CONCORD-AD) collaboration network was created to bring together global resources and expertise, to generate insights and improve understanding of the natural history of AD, to inform design of clinical trials in all disease stages, and to plan for optimal patient access to disease-modifying therapies once they become available. The network brings together expertise and data insights from 7 cohorts across Australia, Europe, and North America. Notably, the network includes populations recruited through memory clinics as well as population-based cohorts, representing observations from individuals across the AD spectrum. This report aims to introduce the CONCORD-AD network, providing an overview of the cohorts involved, reporting the common assessments used, and describing the key characteristics of the cohort populations. Cohort study designs and baseline population characteristics are compared, and available cognitive, functional, and neuropsychiatric symptom data, as well as the frequency of biomarker assessments, are summarized. Finally, the challenges and opportunities of cross-cohort studies in AD are discussed.

Hypothesis
Kaneez Fatima Shad, Wissam Soubra, Dennis John Cordato
The Auditory Afferent Pathway as a Clinical Marker of Alzheimer’s Disease
Abstract: Brain stem neural tracts and nuclei may be disturbed prior to observable neuronal atrophy in AD. In this perspective, we discuss the notion of functional deficits presenting prior to structural abnormalities in Alzheimer’s disease (AD). Imaging of inferior colliculi using magnetic resonance spectroscopy (MRS) shows significant decrease in the neuronal markers, N acetyl aspartate/creatine ratio and increase in the glial marker myo-Inositol, in subjects with Mini-Mental State Examination scores greater than 24 and with no signs of atrophy in their MRI of the medial temporal lobe. Abnormalities in components of the auditory event-related potentials (ERPs) are described in cognitive impairment including AD. We observed a significant decrease in amplitude and increase in latency during the first 10 ms of auditory evoked potentials measured on electroencephalography (EEG) indicating slow auditory response of the brainstem. EEG spectral power recorded at the cortex is also associated with neural activity at the level of the inferior colliculi. We postulate that a functional examination of auditory afferent pathways, using non-invasive techniques, such as MRS, brain stem auditory evoked potentials (BAEPs) and ERPs may improve diagnostic accuracy of AD. Functional changes precede structural changes and it is important to further understand the relationship between biochemical and electrophysiological measures such as MRS, BAEPs and EEG.

Short Communication
Gustavo L. Franklin, Alex T. Meira, Maira Tonidandel Barbosa, Hélio A.G. Teive, Paulo Caramelli
When My Child Has Alzheimer’s Disease
Abstract: The significant increment in life expectancy, associated to the existence of high-performing older adults, and the appropriate diagnosis of early dementias, lead to an uncommon scenario, of healthy parents accompanying their children with Alzheimer's disease or another dementia to medical consultations. Here, we reported three peculiar clinical vignettes of patients diagnosed with a dementia, who were accompanied by healthy parents. This is a modern situation that tends to become more frequent, and must be properly discussed, since multidisciplinary care and specific training are necessary.

Short Communication
Christopher G. Schwarz, David S. Knopman, Vijay K. Ramanan, Val J. Lowe, Heather J. Wiste, Petrice M. Cogswell, Rene L. Utianski, Matthew L. Senjem, Jeffrey R. Gunter, Prashanthi Vemuri, Ronald C. Petersen, Clifford R. Jack Jr. (Handling Associate Editor: Brian Gordon)
Longitudinally Increasing Elevated Asymmetric Flortaucipir Binding in a Cognitively Unimpaired Amyloid-Negative Older Individual
Abstract: We present the case of a cognitively unimpaired 77-year-old man with elevated, asymmetric, and longitudinally increasing Flortaucipir tau PET despite normal (visually negative) amyloid PET. His atypical tau PET signal persisted and globally increased in a follow-up scan five years later. Across eight years of observations, temporoparietal atrophy was observed consistent with tau PET patterns, but he retained the cognitively unimpaired classification. Altogether, his atypical tau PET signal is not explained by any known risk factors or alternative pathologies, and other imaging findings were not remarkable. He remains enrolled for further observation.

Short Communication
Ke-Liang Chen*, Pei-Xi Li*, Yi-Min Sun*, Shu-Fen Chen, Chuan-Tao Zuo, Jian Wang, Qiang Dong, Mei Cui, Jin-Tai Yu (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Very Early-Onset Alzheimer’s Disease in the Third Decade of Life with de novo PSEN1 Mutations
Abstract: Mutations in Presenilin-1 (PSEN1) have been found to be associated with very early onset Alzheimer’s disease (VEOAD). Here, we reported two patients with VEOAD caused by de novo PSEN1 mutations. A 33-year-old man with a de novo p.F177S mutation in PSEN1 presented with progressive decline in memory and daily functioning. A 37-year-old woman with a de novo PSEN1 p.L381V mutation presented with onset memory impairment, developed cerebellar syndrome, rigidity, and spastic paraparesis. The Amyloid/Tau/Neurodegeneration (ATN) biomarker profiles of both patients were A+T+(N)+. Our finding increases the genetic knowledge of VEOAD and extends the ethnic distribution of PSEN1 mutations.

Maureen Schmitter-Edgecombe, Katelyn Brown, Catherine Luna, Reanne Chilton, Catherine A. Sumida, Lawrence Holder, Diane Cook (Handling Associate Editor: Mark Bondi)
Partnering a Compensatory Application with Activity-Aware Prompting to Improve Use in Individuals with Amnestic Mild Cognitive Impairment: A Randomized Controlled Pilot Clinical Trial
Abstract: Background: Compensatory aids can help mitigate the impact of progressive cognitive impairment on daily living. Objective: We evaluate whether the learning and sustained use of an Electronic Memory and Management Aid (EMMA) application can be augmented through a partnership with real-time, activity-aware transition-based prompting delivered by a smart home. Methods: Thirty-two adults who met criteria for amnestic mild cognitive impairment (aMCI) were randomized to learn to use the EMMA app on its own (N = 17) or when partnered with smart home prompting (N = 15). The four-week, five-session manualized EMMA training was conducted individually in participant homes by trained clinicians. Monthly questionnaires were completed by phone with trained personnel blind to study hypotheses. EMMA data metrics were collected continuously for four months. For the partnered condition, activity-aware prompting was on during training and post-training months 1 and 3, and off during post-training month 2. Results: The analyzed aMCI sample included 15 EMMA-only and 14 partnered. Compared to the EMMA-only condition, by week four of training, participants in the partnered condition were engaging with EMMA more times daily and using more basic and advanced features. These advantages were maintained throughout the post-training phase with less loss of EMMA app use over time. There was little differential impact of the intervention on self-report primary (everyday functioning, quality of life) and secondary (coping, satisfaction with life) outcomes. Conclusion: Activity-aware prompting technology enhanced acquisition, habit formation and long-term use of a digital device by individuals with aMCI. (ClinicalTrials.gov NCT03453554).

Phoebe P. Chum, Md A. Hakim, Erik J. Behringer (Handling Associate Editor: Simone Agostini)
Cerebrovascular microRNA Expression Profile During Early Development of Alzheimer’s Disease in a Mouse Model
Abstract: Background: Emerging evidence demonstrates association of Alzheimer’s disease (AD) with impaired delivery of blood oxygen and nutrients to and throughout the brain. The cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition entailing moment-to-moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment to prevent or delay the progression of AD, cerebrovascular microRNA (miRNA) markers corresponding to post-transcriptional regulation may distinguish phases of AD. Objective: We tested the hypothesis that cerebrovascular miRNA expression profiles indicate developmental stages of AD pathology. Methods: Total RNA was isolated from total brain vessel segments of male and female 3xTg-AD mice [young, 1-2 mo; cognitive impairment (CI), 4-5 mo; extracellular amyloid-β plaques (Aβ), 6-8 mo; plaques + neurofibrillary tangles (AβT), 12-15 mo]. NanoString technology nCounter miRNA Expression panel for mouse was used to screen for 599 miRNAs. Results: Significant (p<0.05) downregulation of various miRNAs indicated transitions from young to CI (e.g., let-7g & miR-1944, males; miR-133a & miR-2140, females) and CI to Aβ (e.g., miR-99a, males) but not from Aβ to AβT. In addition, altered expression of select miRNAs from overall Pre-AD (young + CI) versus AD (Aβ + AβT) were detected in both males (let-7d, let-7i, miR-23a, miR-34b-3p, miR-99a, miR-126-3p, miR-132, miR-150, miR-151-5p, miR-181a) and females (miR-150, miR-539). Altogether, at least 20 cerebrovascular miRNAs effectively delineate AD versus Pre-AD pathology. Conclusion: Using the 3xTg-AD mouse model, these data demonstrate that cerebrovascular miRNAs pertaining to endothelial function, vascular permeability, angiogenesis, inflammation, and Aβ/tau metabolism can track early development of AD.

Joël Macoir, Marie-Pier Tremblay, Maximiliano A. Wilson, Robert Laforce Jr., Carol Hudon (Handling Associate Editor: Jordi A. Matias-Guiu)
The Importance of Being Familiar: The Role of Semantic Knowledge in the Activation of Emotions and Factual Knowledge from Music in the Semantic Variant of Primary Progressive Aphasia
Abstract: Background: The role of semantic knowledge in emotion recognition remains poorly understood. The semantic variant of primary progressive aphasia (svPPA) is a degenerative disorder characterized by progressive loss of semantic knowledge, while other cognitive abilities remain spared, at least in the early stages of the disease. The syndrome is therefore a reliable clinical model of semantic impairment allowing for testing the propositions made in theoretical models of emotion recognition. Objective: The main goal of this study was to investigate the role of semantic memory in the recognition of basic emotions conveyed by music in individuals with svPPA. Methods: The performance of 9 individuals with svPPA was compared to that of 32 control participants in tasks designed to investigate the ability: a) to differentiate between familiar and non-familiar musical excerpts, b) to associate semantic concepts to musical excerpts, and c) to recognize basic emotions conveyed by music. Results: Results revealed that individuals with svPPA showed preserved abilities to recognize familiar musical excerpts but impaired performance on the two other tasks. Moreover, recognition of basic emotions and association of musical excerpts with semantic concepts was significantly better for familiar than non-familiar musical excerpts in participants with svPPA. Conclusion: Results of this study have important implications for theoretical models of emotion recognition and music processing. They suggest that impairment of semantic memory in svPPA affects both the activation of emotions and factual knowledge from music and that this impairment is modulated by familiarity with musical tunes.

Yike Li, Jiajie Guo, Peikai Yang (Handling Associate Editor: Ethan Schonfeld)
Developing an Image-Based Deep Learning Framework for Automatic Scoring of The Pentagon Drawing Test
Abstract: Background: The Pentagon Drawing Test (PDT) is a common assessment for visuospatial function. Evaluating the PDT by artificial intelligence can improve efficiency and reliability in the big data era. This study aimed to develop a deep learning (DL) framework for automatic scoring of the PDT based on image data. Methods: A total of 823 PDT photos were retrospectively collected and preprocessed into black-and-white, square-shape images. Stratified fivefold cross-validation was applied for training and testing. Two strategies based on convolutional neural networks were compared. The first strategy was to perform an image classification task using supervised transfer learning. The second strategy was designed with an object detection model for recognizing the geometric shapes in the figure, followed by a predetermined algorithm to score based on their classes and positions. Results: On average, the first framework demonstrated 62% accuracy, 62% recall, 65% precision, 63% specificity, and 0.72 area under the receiver operating characteristic curve. This performance was substantially outperformed by the second framework, with averages of 94%, 95%, 93%, 93%, and 0.95, respectively. Conclusion: An image-based DL framework based on the object detection approach may be clinically applicable for automatic scoring of the PDT with high efficiency and reliability. With a limited sample size, transfer learning should be used with caution if the new images are distinct from the previous training data. Partitioning the problem-solving workflow into multiple simple tasks should facilitate model selection, improve performance, and allow comprehensible logic of the DL framework.

Esme Fuller-Thomson, Katherine Marie Ahlin
A Decade of Decline in Serious Cognitive Problems Among Older Americans: A Population-Based Study of 5.4 Million Respondents
Abstract: Background: Numerous studies suggest the prevalence of dementia has decreased over the past several decades in Western countries. Less is known about whether these trends differ by gender or age cohort, and if generational differences in educational attainment explain these trajectories. Objective: 1) To detect temporal trends in the age-sex-race adjusted prevalence of serious cognitive problems among Americans aged 65+; 2) To establish if these temporal trends differ by gender and age cohort; 3) To examine if these temporal trends are attenuated by generational differences in educational attainment. Methods: Secondary analysis of 10 years of annual nationally representative data from the American Community Survey with 5.4 million community-dwelling and institutionalized older adults aged 65+. The question on serious cognitive problems was, “Because of a physical, mental, or emotional condition, does this person have serious difficulty concentrating, remembering, or making decisions?” Results: The prevalence of serious cognitive problems in the US population aged 65 and older declined from 12.2% to 10.0% between 2008 and 2017. Had the prevalence remained at the 2008 levels, there would have been an additional 1.13 million older Americans with serious cognitive problems in 2017. The decline in memory problems across the decade was higher for women (23%) than for men (13%). Adjusting for education substantially attenuated the decline. Conclusion: Between 2008 and 2017, the prevalence of serious cognitive impairment among older Americans declined significantly, although these declines were partially attributable to generational differences in educational attainment.

Natalie D. DiProspero, David B. Keator, Michael Phelan, Theo G.M. van Erp, Eric Doran, David K. Powell, Kathryn L. Van Pelt, Frederick A. Schmitt, Elizabeth Head, Ira T. Lott, Michael A. Yassa
Selective Impairment of Long-Range Default Mode Network Functional Connectivity as a Biomarker for Preclinical Alzheimer’s Disease in People with Down Syndrome
Abstract: Background: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN functional connectivity predict clinical onset of AD and cognitive decline in people with DS? Methods: Resting state functional MRI (rsfMRI), longitudinal neuropsychological, and clinical assessment data were collected on 15 nondemented people with DS (mean age = 51.66 years, SD = 5.34 years, range = 42-59 years) over four years, during which 4 transitioned to dementia. Amyloid-β (Aβ) PET data were acquired on 13 of the 15 participants. Resting state fMRI, neuropsychological, and clinical assessment data were also acquired on an independent, slightly younger unimpaired sample of 14 nondemented people with DS (mean age = 44.63 years, SD = 7.99 years, range = 38-61 years). Results: Lower functional connectivity between long-range but not short-range DMN regions predicts AD diagnosis and cognitive decline in people with DS. Aβ accumulation in the inferior parietal cortex is associated with lower regional DMN functional connectivity. Conclusion: Reduction of long-range DMN connectivity is a potential biomarker for AD in people with DS that precedes and predicts clinical conversion.

Yizhi Song*, Zunshu Du*, Xinyue Chen, Wanning Zhang, Guitao Zhang, Hui Li, Lirong Chang, Yan Wu *These authors contributed equally to this work.
Astrocytic N-Methyl-D-Aspartate Receptors Protect the Hippocampal Neurons Against Amyloid-β1-42-Induced Synaptotoxicity by Regulating Nerve Growth Factor
Abstract: Background: Soluble oligomeric amyloid-β (Aβ)-induced synaptic dysfunction is an early event in Alzheimer’s disease (AD) pathogenesis. Mounting evidence has suggested N-methyl-D-aspartate receptors (NMDARs) play an important role in Aβ-induced synaptotoxicity. Originally NMDARs were believed to be expressed exclusively in neurons; however, recent two decades studies have demonstrated functional NMDARs present on astrocytes. Neuronal NMDARs are modulators of neurodegeneration, while our previous initial study found that astrocytic NMDARs mediated synaptoprotection and identified nerve growth factor (NGF) secreted by astrocytes, as a likely mediator, but how astrocytic NMDARs protect neurons against Aβ-induced synaptotoxicity through regulating NGF remains unclear. Objective: To achieve further insight into the mechanism of astrocytic NMDARs oppose Aβ-induced synaptotoxicity through regulating NGF. Methods: With the primary hippocampal neuronal and astrocytic co-cultures, astrocytes were pretreated with agonist or antagonist of NMDARs before Aβ1-42 oligomers application to neuron-astrocyte co-cultures. Western blot, RT-PCR, etc., were used for the related proteins evaluation. Results: Activation of astrocytic NMDARs can significantly mitigate Aβ1-42-induced loss of PSD-95 and synaptophysin through increasing NGF release. Blockade of astrocytic NMDARs inhibited Aβ-induced compensatory protective NGF increase in protein and mRNA levels through modulating NF-κB of astrocytes. Astrocytic NMDARs activation can enhance Aβ-induced Furin increase, and blockade of astrocytic NMDARs inhibited Aβ-induced immunofluorescent intensity elevation of vesicle trafficking protein VAMP3 and NGF double-staining. Conclusion: Astrocytic NMDARs oppose Aβ-induced synaptotoxicity through modulating the synthesis, maturation, and secretion of NGF in astrocytes. This new information may contribute to the quest for specific targeted strategy of intervention to delay the onset of AD.

Jinshil Hyun, Charles B. Hall, Mindy J. Katz, Carol A. Derby, Darren M. Lipnicki, John D. Crawford, Antonio Guaita, Roberta Vaccaro, Annalisa Davin, Ki Woong Kim, Ji Won Han, Jong Bin Bae, Susanne Röhr, Steffi Riedel-Heller, Mary Ganguli, Erin Jacobsen, Tiffany F. Hughes, Henry Brodaty, Nicole A. Kochan, Julian Trollor, Antonio Lobo, Javier Santabarbara, Raul Lopez-Anton, Perminder S. Sachdev, Richard B. Lipton for Cohort Studies of Memory in an International Consortium (COSMIC) (Handling Associate Editor: Ozioma Okonkwo)
Education, Occupational Complexity, and Incident Dementia: A COSMIC Collaborative Cohort Study
Abstract: Background: Education and occupational complexity are main sources of mental engagement during early life and adulthood respectively, but research findings are not conclusive regarding protective effects of these factors against late-life dementia. Objective: This project aimed to examine the unique contributions of education and occupational complexity to incident dementia, and to assess the mediating effects of occupational complexity on the association between education and dementia across diverse cohorts. Method: We used data from 10,195 participants (median baseline age = 74.1, range = 58~103), representing 9 international datasets from 6 countries over 4 continents. Using a coordinated analysis approach, the accelerated failure time model was applied to each dataset, followed by meta-analysis. In addition, causal mediation analyses were performed. Result: The meta-analytic results indicated that both education and occupational complexity were independently associated with increased dementia-free survival time, with 28% of the effect of education mediated by occupational complexity. There was evidence of threshold effects for education, with increased dementia-free survival time associated with ‘high school completion’ or ‘above high school’ compared to ‘middle school completion or below’. Conclusion: Using datasets from a wide range of geographical regions, we found that both early life education and adulthood occupational complexity were independently predictive of dementia. Education and occupational experiences occur during early life and adulthood respectively, and dementia prevention efforts could thus be made at different stages of the life course.

Ebba Gløersen Müller*, Trine Holt Edwin*, Bjørn Heine Strand, Caroline Stokke, Mona Elisabeth Revheim, Anne-Brita Knapskog *These authors contributed equally to this work.
Is Amyloid Burden Measured by 18F-Flutemetamol PET Associated with Progression in Clinical Alzheimer’s Disease?
Abstract: Background: Patients with Alzheimer’s disease (AD) show heterogeneity in clinical progression rate, and we have limited tools to predict prognosis. Amyloid burden from 18F-Flutemetamol positron emission tomography (PET), as measured by standardized uptake value ratios (SUVR), might provide prognostic information. Objective: We investigate whether 18F-Flutemetamol PET composite or regional SUVRs are associated with trajectories of clinical progression. Methods: This observational longitudinal study included 94 patients with clinical AD. PET images were semi-quantified with normalization to pons. Group-based trajectory modeling was applied to identify trajectory groups according to change in the Clinical Dementia Rating Scale Sum of Boxes (CDR-SB) over time. Multinomial logistic regression models assessed the association of SUVRs with trajectory group membership. Results: Three trajectory groups were identified. In the regression models, neither composite nor regional SUVRs were associated with trajectory group membership. Conclusion: There were no associations between CDR progression and 18F-Flutemetamol PET-derived composite SUVRs or regional SUVRs in clinical AD.

Chinnadurai Mani, Ganesh Acharya, Sudhir Kshirsagar, Murali Vijayan, Hafiz Khan, P. Hemachandra Reddy, Komaraiah Palle (Handling Associate Editor: Debomoy Lahiri)
A Novel Role for BRIP1/FANCJ in Neuronal Cells Health and in Resolving Oxidative Stress-Induced DNA Lesions
Abstract: Background: DNA damage accumulation and mitochondrial abnormalities are elevated in neurons during aging and may contribute to neurodegenerative pathologic conditions such as Alzheimer’s disease. BRCA1 interacting protein 1 or BRIP1 is a 5’ to 3’ DNA helicase that catalyzes many abnormal DNA structures during DNA replication, gene transcription, and recombination, and contribute to genomic integrity. Objective: BRIP1 functions were reasonably well studied in DNA repair; however, there is limited data on its role and regulation during aging and neurodegenerative diseases. Methods: We used immunohistochemistry, western blot, and qRT-PCR assays to analyze the expression of BRIP1. Immunofluorescence studies were performed to study the formation of R-loops, reactive oxygen species (ROS) generation, and mitochondrial morphology. Flow cytometry and transmission electron microscopy were used to evaluate mitochondrial ROS and mitochondrial structures, respectively. Oxygen consumption rate was measured using Seahorse, and the Presto Blue™ assays were used to evaluate cell viability. Results: Our results demonstrate the expression of BRIP1 in mouse and human brain tissues and in neuronal cell lines. BRIP1 levels were elevated in the hippocampal regions of the brains, specifically in the dentate gyrus. BRIP1 downregulation in neuronal cells caused increased R-loop formation basally and in response to H2O2 treatment. Furthermore, BRIP1 deficient cells exhibited elevated levels of excitotoxicity induced by L-Glutamic acid exposure as evidenced by (mitochondrial) ROS levels, deteriorated mitochondrial health, and cell death compared to BRIP1 proficient neuronal cells. Conclusion: Overall, our results indicate an important role for BRIP1 in maintaining neuronal cell health and homeostasis by suppressing cellular oxidative stress.

Takashi Nihashi, Keita Sakurai, Takashi Kato, Kaori Iwata, Yasuyuki Kimura, Hiroshi Ikenuma, Akiko Yamaoka, Akinori Takeda, Yutaka Arahata, Yukihiko Washimi, Keisuke Suzuki, Masahiko Bundo, Takashi Sakurai, Nobuyuki Okamura, Kazuhiko Yanai, Kengo Ito, Akinori Nakamura, MULNIAD Study Group (Handling Associate Editor: Junichi Iga)
Patterns of Distribution of 18F-THK5351 Positron Emission Tomography in Alzheimer’s Disease Continuum
Abstract: Background: Alzheimer's disease (AD) is conceptualized as a biological continuum encompassing the preclinical (clinically asymptomatic but with evidence of AD pathology) and clinical (symptomatic) phases. Objective: Using 18F-THK5351 as a tracer that binds to both tau and MAO-B, we investigated the changes in 18F-THK5351 accumulation patterns in AD continuum individuals with positive amyloid PET consisting of cognitively normal individuals (CNp), amnestic mild cognitive impairment (aMCI), and AD and cognitively normal individuals (CNn) with negative amyloid PET. Methods: We studied 69 individuals (32 CNn, 11 CNp, 9 aMCI, and 17 AD) with structural magnetic resonance imaging, 11C-Pittsburgh compound-B (PIB) and 18F-THK5351 PET, and neuropsychological assessment. 18F-THK5351 accumulation was evaluated with visual analysis, voxel-based analysis and combined region of interest (ROI)-based analysis corresponding to Braak neurofibrillary tangle stage. Results: On visual analysis, 18F-THK5351 accumulation was increased with stage progression in the AD continuum. On voxel-based analysis, there was no statistical difference in 18F-THK5351 accumulation between CNp and CNn. However, a slight increase of the bilateral posterior cingulate gyrus in aMCI and definite increase of the bilateral parietal temporal association area and posterior cingulate gyrus/precuneus in AD were detected compared with CNn. On ROI-based analyses, 18F-THK5351 accumulation correlated positively with supratentorial 11C-PIB accumulation and negatively with the hippocampal volume and neuropsychological assessment. Conclusion: The AD continuum showed an increase in 18F-THK5351 with stage progression, suggesting that 18F-THK5351 has the potential to visualize the severity of tau deposition and neurodegeneration in accordance with the AD continuum.

Moeko Noguchi-Shinohara, Sohshi Yuki-Nozaki, Chiemi Abe, Ayaka Mori, Mai Horimoto, Masami Yokogawa, Natsuko Ishida, Yukio Suga, Junko Ishizaki, Mai Ishimiya, Hiroyuki Nakamura, Kiyonobu Komai, Hiroyuki Nakamura, Mao Shibata, Tomoyuki Ohara, Jun Hata, Toshiharu Ninomiya, Masahito Yamada, on behalf of the Japan Prospective Studies Collaboration for Aging and Dementia (JPSC-AD) study group (Handling Associate Editor: Robert Friedland)
Diabetes Mellitus, Elevated Hemoglobin A1c, and Glycated Albumin Are Associated with the Presence of All-Cause Dementia and Alzheimer’s Disease: The JPSC-AD Study
Abstract: Background: Glucose dysmetabolism is an important risk factor for dementia. Objective: We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. Methods: In this study, 10,214 community-dwelling participants were enrolled. Hemoglobin A1c (HbA1c), the homeostasis model assessment (HOMA) for insulin resistance (HOMA-IR), the HOMA of percent β-cell function (HOMA-β), and the glycated albumin (GA) was evaluated. The associations of each measure with Alzheimer’s disease (AD) and vascular dementia (VaD) were investigated. Results: The multivariable-adjusted odds ratios (ORs) of AD were significantly higher in participants with diabetes mellitus than in those without diabetes (1.46 [95% CI: 1.08–1.97]). Higher HbA1c levels were significantly associated with AD at diabetes (≥6.5%) and even at prediabetes (5.7 %–6.4 %) levels; multivariable-adjusted ORs for AD in participants at the diabetes level were 1.72 (95% CI: 1.19–2.49), and those in participants at the prediabetes level were 1.30 (95% CI: 1.00–1.68), compared with those in normal participants. Moreover, higher GA levels were associated with AD. No associations were observed between the diabetic status or the levels of glycemic measures and VaD. In addition, no significant relationships were observed between insulin resistance and secretion measurements and AD and VaD. Conclusion: Our findings indicate that diabetes mellitus and hyperglycemia are significantly associated with AD, even in individuals at the prediabetes level.

Shiwani Kumari*, Ambica Singh*, Abhinay Kumar Singh, Yudhishthir Yadav, Swati Bajpai, Pramod Kumar, Ashish Datt Upadhyay, Shashank Shekhar, Sadanand Dwivedi, A.B. Dey, Sharmistha Dey *These authors contributed equally to this work.
Circulatory GSK-3β: Blood-Based Biomarker and Therapeutic Target for Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is the progressive brain disorder which degenerates brain cells connection and causes memory loss. Although AD is irreversible, it is not impossible to arrest or slow down the progression of the disease. However, this would only be possible if the disease is diagnosed at an early stage, and early diagnosis requires clear understanding of the pathogenesis at molecular level. Overactivity of GSK-3β and p53 accounts for tau hyperphosphorylation and the formation of amyloid-β plaques. Objective: Here, we explored GSK-3β and p53 as blood-based biomarkers for early detection of AD. Methods: The levels of GSK-3β, p53, and their phosphorylated states were measured using surface plasmon resonance and verified using western blot in serum from AD, mild cognitive impairment (MCI), and geriatric-control (GC) subjects. The neurotoxic SH-SY5Y cell line was treated with antioxidant Emblica Officinalis (EO) for rescue effect. Results: GSK-3β, p53, and their phosphorylated states were significantly over expressed (p>0.001) in AD and MCI compared to GC and can differentiate AD and MCI from GC. The expression level of GSK-3β and p53 proteins were found to be downregulated in a dose-dependent manner after the treatment with EO in amyloid-b-induced neurotoxic cells. Conclusion: These proteins can serve as potential blood markers for the diagnosis of AD and EO can suppress their level. This work has translational value and clinical utility in the future.

Yan Tan*, Jiani Zhang*, Ke Yang*, Zihui Xu, Huawei Zhang, Weihang Chen, Tiantian Peng, Xu Wang, Zhaoheng Liu, Peng Wei, Na Li, Zhenqiang Zhang, Tonghua Liu, Qian Hua *These authors contributed equally to this work.
Anti-Stroke Chinese Herbal Medicines Inhibit Abnormal Amyloid-β Protein Precursor Processing in Alzheimer’s Disease
Abstract: Background: Chinese Herbal Medicines (CHMs), as an important and integral part of a larger system of medicine practiced in China, called Traditional Chinese Medicine (TCM), have been used in stroke therapy for centuries. A large body of studies suggest that some Chinese herbs can help reverse cognitive impairment in stroke patients, while whether these herbs also exert therapeutic benefits for Alzheimer’s disease remains to be seen. Objective: To address this issue, we selected four types of CHMs that are commonly prescribed for stroke treatment in clinical practice, namely DengZhanXiXin (D1), TongLuoJiuNao (T2), QingKaiLing (Q3), and HuangQinGan (H4), and tested their effects on amyloid-β protein precursor (AβPP) processing in vitro. Methods: AβPP, β-secretase (BACE1), and 99-amino acid C-terminal fragment of AβPP (C99) stably transfected cells were used for the tests of AβPP processing. The production of Aβ, activity of BACE1, neprilysin (NEP), and γ-secretase were assessed by ELISA, RT-PCR, and western blot. Results: By upregulating BACE1 activity, D1 increased Aβ production whereas decreased the ratio of Aβ42/Aβ40; by downregulating BACE1 activity and modulating the expression of γ-secretase, T2 decreased Aβ production and the ratio of Aβ42/Aβ40; by downregulating BACE1 activity, Q3 decreased Aβ production; H4 did not change Aβ production due to the simultaneously downregulation of BACE1 and NEP activity. Conclusion: Our study indicates that these four anti-stroke CHMs regulate AβPP processing through different mechanisms. Particularly, T2 with relatively simple components and prominent effect on AβPP processing may be a promising candidate for the treatment of AD.

Emilie M. Blair, Darin B. Zahuranec, Jane Forman, Bailey K. Reale, Kenneth M. Langa, Bruno Giordani, Angela Fagerlin, Colleen Kollman, Rachael T. Whitney, Deborah A. Levine
Physician Diagnosis and Knowledge of Mild Cognitive Impairment
Abstract: Background: Older adults with mild cognitive impairment (MCI) receive fewer guideline-concordant treatments for multiple health conditions than those with normal cognition. Reasons for this disparity are unclear. Objective: To better understand this disparity, we describe physician understanding and experience with patient MCI, particularly physician identification of MCI, ability to distinguish between MCI and dementia, and perspectives on education and training in MCI and dementia. Methods: As part of a mixed-methods study assessing the influence of patient MCI on physician recommendations for acute myocardial infraction and stroke treatments, we conducted a descriptive qualitative study using semi-structured interviews of physicians from three specialties. Key question topics included participants’ identification of MCI, impressions of MCI and dementia awareness within their practice specialty, and perspectives on training and education in MCI. Results: The study included 22 physicians (8 cardiologists, 7 neurologists, and 7 internists). We identified two primary themes: There is 1) a lack of adequate understanding of the distinction between MCI and dementia; and 2) variation in physician approaches to identifying whether an older adult has MCI. Conclusion: These findings suggest that physicians have a poor understanding of MCI. Our results suggest that interventions that improve physician knowledge of MCI are needed.

Herrer Abdulrahman, Edo Richard, Willem A. van Gool, Eric P. Moll van Charante, Jan Willem van Dalen
Sex Differences in the Relation Between Subjective Memory Complaints, Impairments in Instrumental Activities of Daily Living, and Risk of Dementia
Abstract: Background: Older people with subjective memory complaints (SMC) and Instrumental Activities of Daily Living impairments (IADL-I) have an increased risk of developing dementia. Previous reports suggest that the predictive value of SMC and IADL-I may differ between sexes, leaving possible consequences for personalized risk prediction and prognosis. However, none of these studies addressed the competing risk of death, which may substantially differ between sexes. Objective: We investigated sex-differences in the association between IADL-I, SMC, and incident dementia and mortality as competing risk. Methods: 3,409 community-dwelling older people without dementia (mean age 74.3±2.5), were followed for 6.7 years (median). Baseline SMC were assessed using the 15-item Geriatric Depression Scale memory question, and IADL-I using the Academic Medical Center Linear Disability Score. Potential sex-differences in the predictive value of SMC and IADL-I were assessed using Cox regression models with an interaction term for sex. Results: HRs for isolated SMC and SMC+IADL-I and risk of dementia were higher in women (HR: 2.02, 95%CI=0.91-4.46, p=0.08; HR:2.85, 95%CI=1.65-4.91, p<0.001) than in men (HR:1.52, 95%CI=0.86-2.69, p=0.18; HR:1.24, 95%CI=0.62-2.49, p=0.54), but these sex-differences were not significant. Conversely, HRs for isolated IADL-I and risk of mortality were higher in men (HR:1.56, 95%CI=1.18-2.05, p=0.002) than in women (HR:1.14, 95%CI=0.80-1.62, p=0.48), but again, these sex-differences were not significant. Conclusion: The predictive value of SMC and IADL-I for the risk of dementia and mortality was not significantly modified by sex. However, the competing risk of death for these factors differed considerably between men and women, suggesting it is an essential factor to consider when comparing sex-differences in IADL/dementia risk.

Rosanne Freak-Poli, Nina Wagemaker, Rui Wang, Thom S. Lysen, M. Arfan Ikram , Meike W. Vernooij, Christina S. Dintica, Myrra Vernooij-Dassen, Rene J.M. Melis, Erica J. Laukka, Laura Fratiglioni, Weili Xu, Henning Tiemeier
Loneliness, Not Social Support, Is Associated with Cognitive Decline and Dementia Across Two Longitudinal Population-Based Cohorts
Abstract: Background: Poor social health is likely associated with cognitive decline and risk of dementia; however, studies show inconsistent results. Additionally, few studies separate social health components or control for mental health. Objective: To investigate whether loneliness and social support are independently associated with cognitive decline and risk of dementia, and whether depressive symptoms confound the association. Methods: We included 4,514 participants from the population-based Rotterdam Study (RS; aged 71±7SD years) followed up to 14 years (median 10.8, interquartile range 7.4–11.6), and 2,112 participants from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K; aged 72±10SD years) followed up to 10 years (mean 5.9±1.6SD). At baseline, participants were free of major depression and scored on the Mini-Mental State Examination (MMSE) ≥26 for RS and ≥25 for SNAC-K. We investigated loneliness, perceived social support, and structural social support (specifically marital status and number of children). In both cohorts, dementia was diagnosed and cognitive function was repeatedly assessed with MMSE and a global cognitive factor (g-factor). Results: Loneliness was prospectively associated with a decline in the MMSE in both cohorts. Consistently, persons who were lonely had an increased risk of developing dementia (RS: HR 1.34, 95% CI 1.08-1.67; SNAC-K: HR 2.16, 95% CI 1.12-4.17). Adjustment for depressive symptoms and exclusion of the first 5 years of follow-up did not alter results. Neither perceived or structural social support was associated with cognitive decline or dementia risk. Conclusion: Loneliness, not social support, predicted cognitive decline and incident dementia independently of depressive symptoms.

Kate E. Hoy, Melanie R.L. Emonson*, Neil W. Bailey*, Gregory Humble, Hannah Coyle, Caitlyn Rogers, Paul B. Fitzgerald *These authors contributed equally to this work.
Investigating Neurophysiological Markers of Symptom Severity in Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is characterized by a progressive decline in cognitive functioning for which there is a stark lack of effective treatments. Investigating the neurophysiological markers of symptom severity in AD may aid in the identification of alternative treatment targets. Objective: In the current study, we used a multimodal approach to investigate the association between functional connectivity (specifically between scalp electrodes placed over frontal and parietal regions) and symptom severity in AD, and to explore the relationship between connectivity and cortical excitability. Methods: 40 people with AD (25 mild severity, 15 moderate severity) underwent neurobiological assessment (resting state electroencephalography (EEG) and prefrontal transcranial magnetic stimulation (TMS) with EEG) and cognitive assessment. Neurobiological outcomes were resting state functional connectivity and TMS-evoked potentials. Cognitive outcomes were scores on the Alzheimer's Disease Assessment Scale-Cognitive Subscale, Mini-Mental Status Examination, and a measure of episodic verbal learning. Results: Greater contralateral functional theta connectivity between frontal scalp electrodes and parietal scalp electrodes was associated with poorer cognitive performance. In addition, significant correlations were seen between the contralateral theta connectivity and the N100 and P60 TMS-evoked potentials measured from electrodes over the left dorsolateral prefrontal cortex. Conclusion: Together these findings provide initial support for the use of a multimodal neurophysiological approaches to investigate potential therapeutic targets in AD. Suggestions for future research are discussed.

Marcella Reale, Claudia Carrarini, Mirella Russo, Fedele Dono, Laura Ferri, Martina Di Pietro, Erica Costantini, Annamaria Porreca, Marta Di Nicola, Marco Onofrj, Laura Bonanni
Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer’s Disease
Abstract: Background: Central nervous system disruption of cholinergic (ACh) signaling, which plays a major role in cognitive processes, is well documented in dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). The expression of muscarinic ACh receptors type 1 and 4 (CHRM1 and CHRM4) has been reported to be altered in the brain of DLB patients. Objective: We aim to assess the peripheral gene expression of CHRM1 and 4 in DLB as a possible marker as compared to AD and healthy control (HC) subjects. Methods: Peripheral blood mononuclear cells were collected from 21 DLB, 13 AD, and 8 HC matched subjects. RT-PCR was performed to estimate gene expression of CHRM1 and CHRM4. Results: Peripheral CHRM1 expression was higher and CHRM4 was lower in DLB and AD compared to HC, whereas both CHRM1 and CHRM4 levels were higher in AD compared to DLB patients. Receiver operating characteristics curves, with logistic regression analysis, showed that combining peripheral CHRM1 and CHRM4 levels, DLB and AD subjects were classified with an accuracy of 76.0%. Conclusion: Alterations of peripheral CHRM1 and CHRM4 was found in both AD and DLB patients as compared to HC. CHRM1 and CHRM4 gene expression resulted to be lower in DLB patients compared to AD. In the future, peripheral CHRM expression could be studied as a possible marker of neurodegenerative conditions associated with cholinergic deficit and a possible marker of response to acetylcholinesterase inhibitors.

Jeanne Neuffer, Marjorie Gourru, Aline Thomas, Sophie Lefèvre-Arbogast, Alexandra Foubert-Samier, Catherine Helmer, Cécile Delcourt, Catherine Féart, Cécilia Samieri
A Biological Index to Screen Multi-Micronutrient Deficiencies Associated with the Risk to Develop Dementia in Older Persons from the Community
Abstract: Background: Low blood status in several nutritional compounds, including long-chain omega-3 fatty acids (LC n-3 PUFA), carotenoids, and vitamin D, have been associated with a higher risk to develop dementia. Nutritional deficiencies may potentiate each other regarding dementia risk; yet the association of multiple nutritional deficiencies with dementia has been little explored. Objective: To develop an index of micronutritional biological status (MNBS) for the screening of multi-micronutritional deficiencies associated with the risk of dementia in a prospective population-based cohort of older persons. Methods: We included participants from the Bordeaux Three-City study, who were free of dementia at baseline, had blood measurements of LC n-3 PUFA, carotenoids, and 25(OH)D, and who were followed for up to 18 years for dementia. We used penalized splines in Cox models to model dose-response relationships of each nutritional component with the risk of dementia and construct a risk index. Results: 629 participants with an average age of 73.1 years were included in the study. Each increase of 1 SD of the MNBS index was associated with a 46% higher risk of dementia (HR=1.46, 95% CI 1.23; 1.73). Participants with highest index ([mean+1SD; max]) had a 4-fold increased risk of dementia compared with participants with a low index ([min; mean-1SD]) (HR= 4.17, 95% CI 2.30; 7.57). Conclusion: This index of assessment of micronutritional biological status is a practical tool that may help identify populations with inadequate nutritional status, screen eligible individuals for nutritional prevention in primary care, or for supplementation in preventive trials of dementia.

Xu-Dong Yan, Xue-Song Qu, Jing Yin, Jin Qiao, Jun Zhang, Jin-Shun Qi, Mei-Na Wu
Adiponectin Ameliorates Cognitive Behaviors and in vivo Synaptic Plasticity Impairments in 3xTg-AD Mice
Abstract: Background: Cognitive deficit is mainly clinical characteristic of Alzheimer’s disease (AD). Recent reports showed adiponectin and its analogues could reverse cognitive impairments, lower amyloid-β protein (Aβ) deposition, and exert anti-inflammatory effects in different APP/PS1 AD model mice mainly exhibiting amyloid plaque pathology. However, the potential in vivo electrophysiological mechanism of adiponectin protecting against cognitive deficits in AD and the neuroprotective effects of adiponectin on 3xTg-AD mice including both plaque and tangle pathology are still unclear. Objective: To observe the effects of adiponectin treatment on cognitive deficits in 3xTg-AD mice, investigate its potential in vivo electrophysiological mechanism, and testify its anti-inflammatory effects. Methods: Barnes maze test, Morris water maze test, and fear conditioning test were used to evaluate the memory-ameliorating effects of adiponectin on 3xTg-AD mice. In vivo hippocampal electrophysiological recording was used to observe the change of basic synaptic transmission, long-term potentiation, and long-term depression. Immunohistochemistry staining and western blot were used to observe the activation of microglia and astroglia, and the expression levels of proinflammatory factors and anti-inflammtory factor IL-10. Results: Adiponectin treatment could alleviate spatial memory and conditioned fear memory deficits observed in 3xTg-AD mice, improve in vivo LTP depression and LTD facilitation, inhibit overactivation of microglia and astroglia, decrease the expression of proinflammatory factors NF-κB and IL-1β, and increase the expression level of IL-10 in the hippocampus of 3xTg-AD mice. Conclusion: Adiponectin could ameliorate cognitive deficits in 3xTg-AD mice through improving in vivo synaptic plasticity impairments and alleviating neuroinflammation in the hippocampus of 3xTg-AD mice.

Julia Z. Sarant, David C. Harris, Peter A. Busby, Christopher Fowler, Jurgen Fripp, Colin L. Masters, Paul Maruff (Handling Associate Editor: Barbara Bendlin)
No Influence of Age-Related Hearing Loss on Brain Amyloid-β
Abstract: Background: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. Objective: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. Methods: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. Results: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4) carrier status increased the risk of being Aβ positive (p = 0.002). Conclusion: Degree of HL was not associated with positive Aβ status.

Yanan Qiao*, Yu Sun*, Jing Guo, Yaojing Chen, Wenjie Hou, Junying Zhang, Dantao Peng *These authors contributed equally to this work.
Disrupted White Matter Integrity and Cognitive Functions in Amyloid-β Positive Alzheimer’s Disease with Concomitant Lobar Cerebral Microbleeds
Abstract: Background: Lobar cerebral microbleeds (CMBs), which can impair white matter (WM), are often concomitant with definite Alzheimer’s disease (AD). Objective: To explore the features of cognitive impairments and WM disruptions due to lobar CMBs in patients with AD. Methods: There were 310 participants who underwent Florbetapir F18 (AV45) amyloid PET and susceptibility-weighted imaging. Participants with cognitive impairment and amyloid-β positive (ADCI) were included into three groups: ADCI without CMBs, with strictly lobar CMBs (SL-CMBs), and with mixed CMBs (M-CMBs). Tract-based spatial statistics were performed to detect the group differences in WM integrity. Results: There were 82 patients and 29 healthy controls finally included. A decreasing tendency in memory and executive performance can be found among HCs > no CMBs (n=16) > SL-CMBs (n=41) > M-CMBs (n=25) group. Compared to no CMBs, M-CMBs group had significantly decreased fractional anisotropy in left anterior thalamic radiation (ATR), forceps major, forceps minor and inferior longitudinal fasciculus, bilateral inferior fronto-occipital fasciculus (IFOF), and superior longitudinal fasciculus. M-CMBs group also had lower fractional anisotropy in left ATR, IFOF, uncinate fasciculus, and forceps minor compared with SL-CMBs. Furthermore, analysis of Pearson correlation indicated damages in discrepant WMs were positively associated with impairment of memory, executive function, and attention. Conclusion: This study showed lobar CMBs had intensively aggravated cognitive impairments associated with extensive WM damages in definite AD. These findings highlight that lobar CMBs play an important role in AD progression and need to be taken into consideration for the early detection of AD.

Heather M. Wilkins, Benjamin R. Troutwine, Blaise W. Menta, Sharon J. Manley, Taylor A. Strope, Colton R. Lysaker, Russell H. Swerdlow
Mitochondrial Membrane Potential Influences Amyloid-β Protein Precursor Localization and Amyloid-β Secretion
Abstract: Background: Amyloid-β (Aβ), which derives from the amyloid-β protein precursor (AβPP), forms plaques and serves as a fluid biomarker in Alzheimer’s disease (AD). How Aβ forms from AβPP is known, but questions relating to AβPP and Aβ biology remain unanswered. AD patients show mitochondrial dysfunction, and an Aβ/AβPP mitochondria relationship exists. Objective: We considered how mitochondrial biology may impact AβPP and Aβ biology. Methods: SH-SY5Y cells were transfected AβPP constructs. After treatment with FCCP (uncoupler), Oligomycin (ATP synthase inhibitor), or starvation Aβ levels were measured. β-secretase (BACE1) expression was measured. Mitochondrial localized full-length AβPP was also measured. All parameters listed were measured in ρ0 cells on an SH-SY5Y background. iPSC derived neurons were also used to verify key results. Results: We showed that mitochondrial depolarization routes AβPP to, while hyperpolarization routes AβPP away from, the organelle. Mitochondrial AβPP and cell Aβ secretion inversely correlate, as cells with more mitochondrial AβPP secrete less Aβ, and cells with less mitochondrial AβPP secrete more Aβ. An inverse relationship between secreted/extracellular Aβ and intracellular Aβ was observed. Conclusion: Our findings indicate mitochondrial function alters AβPP localization and suggest enhanced mitochondrial activity promote Aβ secretion while depressed mitochondrial activity minimize Aβ secretion. Our data complement other studies that indicate a mitochondrial, AβPP, and Aβ nexus, and could help explain why cerebrospinal fluid Aβ is lower in those with AD. Our data further suggest Aβ secretion could serve as a biomarker of cell or tissue mitochondrial function.

Maurizio Bergamino, Elizabeth G. Keeling, Leslie C. Baxter, Nicholas J. Sisco, Ryan R. Walsh, Ashley M. Stokes (Handling Associate Editor: Jessica Kirkland Caldwell)
Sex Differences in Alzheimer’s Disease Revealed by Free-Water Diffusion Tensor Imaging and Voxel-Based Morphometry
Abstract: Background: Imaging biomarkers are increasingly used in Alzheimer’s disease (AD), and the identification of sex differences using neuroimaging may provide insight into disease heterogeneity, progression, and therapeutic targets. Objective: The purpose of this study was to investigate differences in grey matter (GM) volume and white matter (WM) microstructural disorganization between males and females with AD using voxel-based morphometry (VBM) and free-water-corrected diffusion tensor imaging (FW-DTI). Methods: Data were downloaded from the OASIS-3 database, including 158 healthy control (HC; 86 females) and 46 mild AD subjects (24 females). VBM and FW-DTI metrics (fractional anisotropy (FA), axial and radial diffusivities (AxD and RD, respectively), and FW index) were compared using effect size for the main effects of group, sex, and their interaction. Results: Significant group and sex differences were observed, with no significant interaction. Post-hoc comparisons showed that AD is associated with reduced GM volume, reduced FW-FA, and higher FW-RD/FW-index, consistent with neurodegeneration. Females in both groups exhibited higher GM volume than males, while FW-DTI metrics showed sex differences only in the AD group. Lower FW, lower FW-FA and higher FW-RD were observed in females relative to males in the AD group. Conclusion: The combination of VBM and DTI may reveal complementary sex-specific changes in GM and WM associated with AD and aging. Sex differences in GM volume were observed for both groups, while FW-DTI metrics only showed significant sex differences in the AD group, suggesting that WM tract disorganization may play a differential role in AD pathophysiology between females and males.

Nicolas R. Barthélemy, Balazs Toth, Paul T. Manser, Sandra Sanabria-Bohórquez, Edmond Teng, Michael Keeley, Randall J. Bateman, Robby M. Weimer, Kristin R. Wildsmith
Site-Specific Cerebrospinal Fluid Tau Hyperphosphorylation in Response to Alzheimer’s Disease Brain Pathology: Not All Tau Phospho-Sites Are Hyperphosphorylated
Abstract: Background: Understanding patterns of association between CSF phosphorylated tau (p-tau) species and clinical disease severity will aid Alzheimer’s disease (AD) diagnosis and treatment. Objective: To evaluate changes in tau phosphorylation ratios to brain imaging (amyloid PET, [18F]GTP1 PET, and MRI) and cognition across clinical stages of AD in two different cohorts. Methods: A mass spectrometry (MS)-based method was used to evaluate the relationship between p-tau/tau phosphorylation ratios on 11 sites in CSF and AD pathology measured by tau PET ([18F]GTP1) and amyloid PET ([18F]florbetapir or [18F]florbetaben). Cohort A included cognitively normal-amyloid negative (n=6) and positive (n=5) individuals, and amyloid positive prodromal (n=13), mild (n=12), and moderate AD patients (n=10); and Cohort B included amyloid positive prodromal (n=24) and mild (n=40) AD patients. Results: In this cross-sectional analysis, we identified clusters of phosphosites with different profiles of phosphorylation ratios across stages of disease. Eight of 11 investigated sites were hyperphosphorylated and associated with the SUVR measures from [18F]GTP1 and amyloid PET. Novel sites 111, 153, and 208 may be relevant biomarkers for AD diagnosis to complement tau hyperphosphorylation measures on previously established sites 181, 205, 217, and 231. Hypophosphorylation was detected on residues 175, 199, and 202, and was inversely associated with [18F]GTP1 and amyloid PET. Conclusion: Hyperphosphorylated and hypophosphorylated forms of tau are associated with AD pathologies, and due to their different site-specific profiles, they may be used in combination to assist with staging of disease.

Valeria Elisa Contarino*, Silvia Siggillino*, Andrea Arighi, Elisa Scola, Giorgio Giulio Fumagalli, Giorgio Conte, Emanuela Rotondo, Daniela Galimberti, Anna Margherita Pietroboni, Tiziana Carandini, Alexander Leemans, Anna Maria Bianchi, Fabio Maria Triulzi (Handling Associate Editor: Marco Bozzali) *These authors contributed equally to this work.
Association of Superficial White Matter Alterations with Cerebrospinal Fluid Biomarkers and Cognitive Decline in Neurodegenerative Dementia
Abstract: Background: Superficial white matter (SWM) alterations correlated with cognitive decline have been described in Alzheimer’s disease (AD). Objective: The study aims to extend the investigation of the SWM alterations to AD and non-AD neurodegenerative dementia (ND) and explore the relationship with cerebrospinal fluid (CSF) biomarkers and clinical data. Methods: From a database of 323 suspected dementia cases, we retrospectively recruited 55 ND with abnormal amyloid-β42 (AD) and 38 ND with normal amyloid-β42 (non-AD) and collected clinical data, CSF biomarkers, and magnetic resonance images. Ten healthy controls (HC) were recruited for imaging and Mini-Mental State Examination (MMSE). Diffusion tensor imaging (DTI) measurements were performed in the lobar SWM regions and Kruskal Wallis tests were used for among-group comparison. Spearman’s correlation tests were performed between DTI measures, CSF biomarkers, and clinical data. Results: AD and non-AD showed significant differences in the DTI measures across the SWM compared to HC. Significant differences between AD and non-AD were detected in the left parietal lobe. DTI measures correlated with amyloid-β42 and MMSE diffusely in the SWM, less extensively with total-tau and phosphorylated tau, and with disease duration in the parietal lobe bilaterally. Conclusion: Widespread SWM alterations occur in both AD and non-AD ND and AD shows appreciably more severe alterations in the parietal SWM. Notably, the alterations in the SWM are strongly linked not only to the cognitive decline but also to the diagnostic CSF biomarkers. Further studies are encouraged to evaluate the DTI measures in the SWM as in vivo non-invasive biomarkers in the preclinical phase.

Xiaodi Sun, Xinjun Suo, Xianyou Xia, Chunshui Yu, Yan Dou
Dimethyl Fumarate Is a Potential Therapeutic Option for Alzheimer’s Disease
Abstract: Background: Dimethyl fumarate (DMF) has been approved for clinical treatment of multiple sclerosis based on its antioxidant and anti-inflammatory effects by activating the Nrf2 pathway. Since both oxidative stress and inflammation are involved in Alzheimer's disease (AD), DMF is a potential therapeutic option for AD. Objective: This study aims to test the therapeutic effects of DMF on AD model mice and to reveal its underlying molecular mechanisms. Methods: Cell viability assay and in vitro immunofluorescence imaging were used to evaluate the antioxidant effect of DMF on embryonic mouse hippocampal neurons. Behavioral test and brain magnetic resonance imaging were used to assess the therapeutic effects of DMF on spatial learning and memory as well as hippocampal volume in AD model mice with and without Nrf2 knockdown. Western blotting was used to analyze the expression of antioxidant enzymes and molecules associated with AD-related pathological pathways. Results: DMF inhibits reactive oxygen species overproduction and protects neurons without Nrf2 knockdown from death. DMF reduces amyloid-β induced memory impairment and hippocampal atrophy in AD model mice rather than in Nrf2 knockdown AD mice. DMF delays the progression of AD by activating the Nrf2 pathway to enhance the expression of downstream antioxidant enzymes and inhibits lipid peroxidation, apoptosis, inflammation, mitochondrial dysfunction and amyloid-β deposition. Conclusion: These results indicate that DMF is a potential therapeutic option for AD through its antioxidant, anti-inflammatory, anti-apoptotic, and other anti-AD effects by activating the Nrf2 pathway.