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Volume 59, Number 1, IN PROGRESS

Ethics Review
Julie M. Robillard, Tanya L. Feng (Handling Associate Editor: Allyson Rosen)
When Patient Engagement and Research Ethics Collide: Lessons from a Dementia Forum
Abstract: The importance of patient engagement in research has been gaining recognition since the turn of the 21st century. However, little is known about the perspectives of people with dementia on the process of discovery. To fill this gap and to inform priorities in patient engagement in the context of dementia research, the Clinic for Alzheimer Disease and Related Disorders at the University of British Columbia hosted an interactive session for members of the patient community and of the general public to share their views on various ethical aspects of the research process. Results from the session indicate that several current research ethics policies and norms in dementia research are not in line with participants’ preferences. Here we discuss the importance of bridging the gap between researchers and patients and call for reforms in current standards of dementia research.

Ethics Response
Cynthia Forlini (Handling Associate Editor: Allyson Rosen)
Patient Preferences May Be Indicative of Normative Issues in Dementia Research
Abstract: Robillard and Feng highlight incongruence between patient preferences and the procedural aspects of research ethics as they relate to protocols for dementia research. Their findings break ground for a reassessment of how research ethics, researchers, and participants (including patients and caregivers) approach participation in dementia research. However, it is unclear whether patient preferences may also herald a normative gap between how dementia research is being conducted and how it should be done. This response uses one of Robillard and Feng’s findings to illustrate how descriptive empirical data might be reinterpreted into normative questions that reframe current practices in the context of dementia research.

Short Communication
Annachiara Cagnin, Sara Mariotto, Michele Fiorini, Marina Gaule, Nicola Bonetto, Matteo Tagliapietra, Emanuele Buratti, Gianluigi Zanusso, Sergio Ferrari, Salvatore Monaco
Microglial and Neuronal TDP-43 Pathology in Anti-IgLON5-Related Tauopathy
Abstract: A novel neuronal tauopathy, mainly confined to hypothalamus and brainstem tegmentum, has recently been reported in patients with autoantibodies to the neuronal cell-adhesion molecule IgLON5. We describe a patient with anti-IgLON5 syndrome, who presented with dysautonomia and sleep disorder, followed by subacute dementia. Postmortem brain examination disclosed neuronal tau pathology prevailing in the hippocampus, amygdala, and locus coeruleus, in addition to microglial/neuronal TDP-43 pathology, with overexpression of aberrantly phosphorylated forms and neurotoxic truncated fragments, in basal ganglia, nucleus basalis, thalamus, and midbrain. These findings suggest that neurodegeneration in anti-IgLON5 syndrome might also occur via a microglia-triggered non-cell autonomous pathway.

Chang-Ho Yun, Ho-Young Lee, Seung Ku Lee, Hyun Kim, Hyung Suk Seo, Seong Ae Bang, Sang Eun Kim, Douglas N. Greve, Rhoda Au, Chol Shin*, Robert J. Thomas* *These authors contributed equally to this work as senior authors.
Amyloid Burden in Obstructive Sleep Apnea
Abstract: To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer’s disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50-65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011–2012. Nineteen OSA subjects (Apnea–Hypopnea Index [AHI] ≥15/h, 21.2±5.1/h; age 58.5±4.1 years; 9 male) and 19 controls (AHI 1.8±1.3/h; age 58.5±4.2 years; 9 male) underwent 60-min dynamic 11C-PiB PET. All subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p<0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer’s disease.

Wassim Tarraf, Carlos J. Rodríguez, Martha L. Daviglus, Melissa Lamar, Neil Schneiderman, Linda Gallo, Gregory A. Talavera, Robert C. Kaplan, Myriam Fornage, Alan Conceicao, Hector M. González
Blood Pressure and Hispanic/Latino Cognitive Function: Hispanic Community Health Study/Study of Latinos Results
Abstract: Background: Hispanics/Latinos are at increased risk for cardiovascular disease and cognitive decline and dementias. High blood pressure (BP) has been implicated in both stroke and dementias. Associations between BP and cognition among diverse Latinos are still unpublished. Objective: We examined associations between cognition and four BP based measures among diverse Hispanics/Latinos. We hypothesized that higher BP, particularly systolic pressure, and increased arterial stiffness (i.e., pulse pressure), would be associated with lower cognitive function. Methods: We used baseline (2008-2011) Hispanic Community Health Study/Study of Latinos (HCHS/SOL; n=9,019; ages 45-74 years) data to examine cognition in relation to BP measures. Results: In age, sex, and education adjusted models, systolic, pulse, and mean arterial pressure were consistently negatively associated with executive function, psychomotor speed and sustained attention, verbal episodic learning and memory, speech fluency, and mental status measures. These associations were attenuated but remained statistically significant in fully adjusted models. Conclusion: Among middle-aged and older diverse Hispanics/Latinos, we found modest but consistent associations between indicators of arterial stiffness, and compromised blood flow and lower cognitive function. Clinical management and public health interventions to raise awareness and enhance BP management beginning in midlife could reduce disparities and improve population health by reducing cognitive decline burdens.

Marina Leino, Svetlana N. Popova, Irina Alafuzoff (Handling Associate Editor: Isidre Ferrer)
Transactive DNA Binding Protein 43 Rather Than Other Misfolded Proteins in the Brain is Associated with Islet Amyloid Polypeptide in Pancreas in Aged Subjects with Diabetes Mellitus
Abstract: A link between diabetes mellitus (DM) related islet amyloid polypeptide (IAPP) and Alzheimer’s disease (AD) related amyloid-β (Aβ) has been suggested in epidemiological and clinical studies. In 2017, proof for existing interaction between type 2 DM and AD on a molecular level was provided based on research carried out in experimental animal models. We assessed aging-related neurodegenerative lesions, i.e., misfolded proteins, associated with dementia such as hyperphosphorylated (HP), Aβ, α-synuclein (αS), and phosphorylated transactive DNA binding protein 43 (pTDP43) seen in the brain and IAPP seen in the pancreas in subjects with and without DM applying immunohistochemical techniques. HP in the brain and IAPP in the pancreas were observed in most subjects. The prevalence and the extent of all misfolded proteins increased with age but this increase was not influenced by DM. Interestingly the extent of misfolded proteins in the brain was higher in non-diabetics when compared with diabetics in demented. A significant correlation was observed between HP, Aβ, αS, and pTDP43, whereas IAPP showed no association with HP, Aβ, and αS. In subjects with DM, the extent of pTDP43 in brain correlated with the extent of IAPP in pancreas. Thus, there is no evidence of a link between AD-related pathology and DM in humans, whereas an association was found between pTDP43 and IAPP in DM. TDP43 is ubiquitously expressed in all organs but whether TDP43 is phosphorylated in other organs in DM or whether the phosphorylation of TDP43 is influenced by glucose metabolism is yet unknown.

Sherry A. Ferguson, John J. Panos, Daniel Sloper, Vijayalakshmi Varma
Neurodegenerative Markers are Increased in Postmortem BA21 Tissue from African Americans with Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) presents with an earlier onset age and increased symptom severity in African Americans and Hispanics. Objective: Although the prevalence of plaques and tangles may not exhibit ethnicity-related differences, levels of neurodegenerative proteins have not been described. Methods: Here, levels of five proteins (i.e., S100B, sRAGE, GDNF, Aβ40, and Aβ42) and the Aβ42/Aβ40 ratio were measured in postmortem samples of the middle temporal gyrus (BA21) from age-matched African Americans and Caucasians with AD (n=6/gender/ethnicity). Results: S100B levels were increased 17% in African Americans (p<0.003) while sRAGE was mildly decreased (p<0.09). Aβ42 levels were increased 121% in African Americans (p<0.02), leading to a 493% increase in the Aβ42/Aβ40 ratio (p<0.002). Analysis of GDNF levels did not indicate any significant effects. There were no significant effects of gender and no significant ethnicity with gender interactions on any analyte. Effect size calculations indicated “medium” to “very large” effects. Conclusion: S100B is typically elevated in AD cases; however, the increased levels in African Americans here may be indicative of increased severity in specific populations. Increased Aβ42/Aβ40 ratios in the current study are compatible with increased disease severity and might indicate increased AD pathogenesis in African Americans. Overall, these results are compatible with a hypothesis of increased neuroinflammation in African Americans with AD.

Giovanna Viticchi, Lorenzo Falsetti, Laura Buratti, Giulia Sajeva, Simona Luzzi, Marco Bartolini, Leandro Provinciali, Mauro Silvestrini (Handling Associate Editor: Mario Tombini)
Framingham Risk Score and the Risk of Progression from Mild Cognitive Impairment to Dementia
Abstract: Background: Mild cognitive impairment (MCI) often represents the clinical manifestation of cognitive deterioration preceding Alzheimer’s disease (AD). Currently, there are no reliable approaches for an objective evaluation of the risk of developing AD in MCI patients. Objective: The aim of this study was to verify whether the Framingham cardiovascular risk profile (FCRP) could be useful to identify patients at the highest risk of conversion from MCI to AD. Methods: Patients with amnestic MCI (aMCI) were carefully investigated to assess their vascular risk profile. They were also submitted to a comprehensive neuropsychological evaluation. The FCRP was calculated for each patient and the apolipoprotein E (ApoE) genotype was determined from peripheral blood cells. The main outcome was defined as a conversion to AD within 24 months after inclusion. Results: 385 consecutive aMCI subjects were included. Age, FCRP, and vascular age showed a fairly predictive value on conversion to AD. Selecting the subpopulation of ApoE ε4 carriers, we observed that FCRP had an increased performance in predicting the conversion. The rate of conversion increased from 12.5% in the FCRP low-risk group to 43.2% in the high-risk group (p<0.0001). ApoE ε4 carriers had a 3.7-times increased probability of conversion with respect to the other subjects (p<0.0001). Conclusions: FCRP assessment could be considered a reliable approach to predict conversion to AD in aMCI subjects. The presence of ApoE ε4 increases significantly the risk of conversion. These data confirm the narrow relationship between genetic and vascular risk factors in influencing the evolution of cognitive impairment.

Takehiko Doi, Hiroyuki Shimada, Hyuma Makizako, Kota Tsutsumimoto, Joe Verghese, Takao Suzuki
Motoric Cognitive Risk Syndrome: Association with Incident Dementia and Disability
Abstract: Background: It is important to examine the etiology of motoric cognitive risk syndrome (MCR) and its association with dementia and disability to obtain biological insights and to develop preventive strategies. Objective: This study aimed to examine the association of MCR with incidence of dementia and disability in a Japanese community-dwelling sample of older adults. Methods: Participants were 4,235 older adults (50% women, mean age: 72 years). MCR was diagnosed at baseline using established criteria in non-demented seniors with self-reported cognitive complaints and slow gait. Incident cases of dementia were identified from insurance data monthly. Disability was regarded as certification by long-term care insurance. Results: At baseline, 265 participants (6.3%) met criteria for MCR. During follow-up (mean duration: 29 months), there were 138 incident cases of dementia (3.3%) and 207 incident cases of disability (4.9%). Cox-proportional hazards models, adjusted for demographical data, lifestyle, and medical conditions, showed that presence of MCR at baseline was a major risk factor for developing dementia (HR 2.49, 95%CI 1.52-4.10, p < 0.001). MCR also predicted risk for disability (HR 1.69, 95%CI 1.08-2.02, p < 0.001). Conclusions: MCR is helpful in the short-term prediction of risk for dementia and disability in the elderly Japanese population. Identification of seniors with MCR is recommended for early detection and instituting preventive measures for reducing the risk of dementia and disability.

Michelle K. Lupton, Beben Benyamin, Petroula Proitsi, Dale R. Nyholt, Manuel A. Ferreira, Grant W. Montgomery, Andrew C. Heath, Pamela A Madden, Sarah E. Medland, Scott D. Gordon, GERAD1 Consortium, the Alzheimer’s Disease Neuroimaging Initiative, Simon Lovestone, Magda Tsolaki, Iwona Kloszewska, Hilkka Soininen, Patrizia Mecocci, Bruno Vellas, John F. Powell, Ashley I. Bush, Margaret J. Wright, Nicholas G. Martin, John B. Whitfield
No Genetic Overlap Between Circulating Iron Levels and Alzheimer’s Disease
Abstract: Iron deposition in the brain is a prominent feature of Alzheimer’s disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n~10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n~9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

Feng Lin, Xixi Wang, Rachel Wu, George W. Rebok, Benjamin P. Chapman and the Alzheimer's Disease Neuroimaging Initiative
Identification of Successful Cognitive Aging in the Alzheimer's Disease Neuroimaging Initiative Study
Abstract: The present prospective observational study aimed to identify the existence of successful cognitive agers among a group of well-defined cognitively healthy older adults (n = 354, mean age = 75 years), and to examine baseline individual-level predictors and associated health outcomes over time. Episodic memory (EM) and executive function (EF) composite scores and multiple health outcomes were obtained annually over 5 years. Potential individual-level predictors that were related to Alzheimer’s disease pathology or genetic risk, neurodegeneration, and vascular risks were collected at baseline. Three latent classes with matched age and education were identified using growth mixture modeling: a group of participants who exhibited high, stable EM and EF (40.7% of the sample, “successful agers”); a group who had initial high cognitive performance that declined over time (21.2%, “declining agers”); and a group who had normal (EM) or poor (EF) but stable cognitive performance over time (38.1%, “low stable agers”). The group classification predicted significant differences in the incidence of global cognitive impairment, the development of at least one depressive symptom, and everyday functional impairment. Sex, apolipoprotein E allele 4, amyloid-β1-42, and t-tau significantly contributed to the difference in cognitive trajectories between the successful agers and the other two groups. Characterizing successful cognitive agers who are relatively resistant to both tau and amyloid pathology provides potential pathways for promoting successful cognitive aging and preventing cognitive decline.

Marnie E. Shaw, Walter P. Abhayaratna, Kaarin J. Anstey, Nicolas Cherbuin (Handling Associate Editor: Sven Haller)
Increasing Body Mass Index at Midlife is Associated with Increased Cortical Thinning in Alzheimer’s Disease-Vulnerable Regions
Abstract: Higher body mass index (BMI) at midlife is associated with greater decreases in cognitive function at older age as well as increased Alzheimer’s disease (AD) risk, compared to those with normal BMI. Here, we tested whether BMI at midlife was associated with cortical thinning in brain regions known to be affected in early AD. We examined a large sample (n=404) of midlife individuals (44-49 years) from the PATH population-based study. Individuals were scanned with magnetic resonance imaging (1.5T) on up to three occasions over eight years. Change in cortical thickness was modeled as a linear function of BMI and change in BMI longitudinally. Being obese was associated with thinner right frontal cortex at baseline (44-49 years). Across all individuals, increasing BMI over the 8-year study period was associated with increased cortical thinning in posterior cingulate bilaterally, as well as right lingual gyrus, anterior cingulate, and the peri-calcarine sulcus. Accelerated age-related cortical atrophy at midlife, particularly in posterior cingulate, is consistent with increased risk of AD in individuals with high BMI at this age. The findings suggest that management of body weight at midlife could reduce the risk of AD.

Rosanna Tortelli, Madia Lozupone, Vito Guerra, Maria Rosaria Barulli, Bruno P. Imbimbo, Rosa Capozzo, Alessandra Grasso, Marianna Tursi, Cristina Di Dio, Rodolfo Sardone, Gianluig Giannelli, Davide Seripa, Giovanni Misciagna, Francesco Panza, Giancarlo Logroscino
Midlife Metabolic Profile and the Risk of Late-life Cognitive Decline
Abstract: Among metabolic syndrome components, the effects of higher plasma glucose levels on cognitive decline (CD) have been considered in few studies. We evaluated the associations among midlife glycemia, total cholesterol, high-density lipoprotein cholesterol, triglycerides, midlife insulin resistance [homeostasis model assessment for insulin resistance (HOMA-index)], and CD in the older subjects of the population-based MICOL Study (Castellana Grotte, Italy) at baseline (M1) and at follow-ups seven (M2) and twenty years later (M3). At M1, a dementia risk score and a composite cardiovascular risk score for dementia were calculated. For 797 subjects out of 833, we obtained a Mini-Mental State Examination (MMSE) score at M3, subdividing these subjects in three cognitive functioning subgroups: normal cognition, mild CD, and moderate-severe CD. Mean fasting glycemia at baseline was significantly higher in moderate-severe CD subgroup (114.6±71.4 mg/dl) than in the normal cognition subgroup (101.2±20.6). Adjusting for gender, age, and other metabolic components, higher fasting glycemia values both at M1 [odds ratio (OR)=1.31; 95% confidence interval (CI): 1.08-1.59] and M2 (OR=1.26; 95% CI: 1.01-1.57) were associated with an increased risk of moderate-severe CD. Mean HOMA index value was significantly higher in the moderate-severe CD subgroup (5.7±9.4) compared to the normal cognition subgroup (2.9±1.4) at M1. The dementia risk probability (MMSE<24) increased moving through higher categories of the dementia risk score and decreased as long as the cardiovascular score increased. The present findings highlighted the indication to control blood glucose levels, regardless of a diagnosis of diabetes mellitus, as early as midlife for prevention of late-life dementia.

Moyra E. Mortby, Richard Burns, Ranmalee Eramudugolla, Zahinoor Ismail, Kaarin J. Anstey (Handling Associate Editor: Carlo Abbate)
Neuropsychiatric Symptoms and Cognitive Impairment: Understanding the Importance of Co-Morbid Symptoms
Abstract: Background: Neuropsychiatric symptoms (NPS) are common in older adults with cognitive impairment, yet little is known about population-based prevalence and clinical implications of co-morbid symptom presentation across the spectrum from normal cognition to dementia. Objective: To characterize the prevalence of NPS and explore the clinical implications of co-morbid symptom presentation. Methods: Cross-sectional study of 1,417 older adults (aged 73-79) with dementia (n=40); with mild cognitive impairment (MCI; n=133); who are ‘cognitively normal, but-at-risk’ (CN-AR; n=397); and who are cognitively normal (n=847). NPS were assessed by the Neuropsychiatric Inventory. Cluster analyses were conducted using a latent class analysis (LCA). Results: NPS are highly prevalent across the cognitive function spectrum (30.8%-80%). NPS were associated with a 3-fold increased risk of dementia, a 2-fold increased risk of MCI, and a 1.5-times increased risk of CN-AR. Each additional co-morbid symptom was associated with an additional 1.5-times increased risk of dementia, but not MCI or CN-AR. LCA revealed four distinctive sub-populations: 1) frontal/low comorbidity; 2) high prevalence/high comorbidity; 3) affective/low comorbidity; and 4) sleep/low comorbidity. Conclusion: Our findings confirm previous reports on the prevalence of NPS in community-based samples and are consistent with the profiles of NPS domain characteristics of MCI and dementia. Number of co-morbid NPS and not symptom clusters are associated with increased risk of dementia. Understanding such patterns will help inform our understanding of mild behavioral disorders and assist with clinical assessment.

Angélica González-Maciel, Rafael Reynoso-Robles, Ricardo Torres-Jardón, Partha S. Mukherjee, Lilian Calderón-Garcidueñas
Combustion-Derived Nanoparticles in Key Brain Target Cells and Organelles in Young Urbanites: Culprit Hidden in Plain Sight in Alzheimer’s Disease Development
Abstract: Millions of children and young adults are exposed to fine particulate matter (PM2.5) and ozone, associated with Alzheimer’s disease (AD) risk. Mexico City (MC) children exhibit systemic and brain inflammation, low cerebrospinal fluid (CSF) Aβ1-42, breakdown of nasal, olfactory, alveolar-capillary, duodenal, and blood-brain barriers, volumetric and metabolic brain changes, attention and short-term memory deficits, and hallmarks of AD and Parkinson's disease. Airborne iron-rich strongly magnetic combustion-derived nanoparticles (CDNPs) are present in young urbanites’ brains. Using transmission electron microscopy, we documented CDNPs in neurons, glia, choroid plexus, and neurovascular units of young MC residents versus matched clean air controls. CDNPs are associated with pathology in mitochondria, endoplasmic reticulum (ER), mitochondria-ER contacts (MERCs), axons, and dendrites. There is a significant difference in size and numbers between spherical CDNPs (>85%) and the angular, euhedral endogenous NPs (<15%). Spherical CDNPs (dogs 21.2±7.1 nm in diameter versus humans 29.1±11.2 nm, p=0.002) are present in neurons, glia, choroid plexus, endothelium, nasal and olfactory epithelium, and in CSF at significantly higher in numbers in MC residents (p<0.0001). Degenerated MERCs, abnormal mitochondria, and dilated ER are widespread, and CDNPs in close contact with neurofilaments, glial fibers, and chromatin are a potential source for altered microtubule dynamics, mitochondrial dysfunction, accumulation and aggregation of unfolded proteins, abnormal endosomal systems, altered insulin signaling, calcium homeostasis, apoptotic signaling, autophagy, and epigenetic changes. Highly oxidative, ubiquitous CDNPs constitute a novel path into AD pathogenesis. Exposed children and young adults need early neuroprotection and multidisciplinary prevention efforts to modify the course of AD at early stages.

Elena K. Festa, Andrew P. Katz, Brian R. Ott, Geoffrey Tremont, William C. Heindel (Handling Associate Editor: Jason Brandt)
Dissociable Effects of Aging and Mild Cognitive Impairment on Bottom-Up Audiovisual Integration
Abstract: Effective audiovisual sensory integration involves dynamic changes in functional connectivity between superior temporal sulcus and primary sensory areas. This study examined whether disrupted connectivity in early Alzheimer’s disease (AD) produces impaired audiovisual integration under conditions requiring greater corticocortical interactions. Audiovisual speech integration was examined in healthy young adult controls (YC), healthy elderly controls (EC), and patients with amnestic mild cognitive impairment (MCI) using McGurk-type stimuli (providing either congruent or incongruent audiovisual speech information) under conditions differing in the strength of bottom-up support and the degree of top-down lexical asymmetry. All groups accurately identified auditory speech under congruent audiovisual conditions, and displayed high levels of visual bias under strong bottom-up incongruent conditions. Under weak bottom-up incongruent conditions, however, EC and amnestic MCI groups displayed opposite patterns of performance, with enhanced visual bias in the EC group and reduced visual bias in the MCI group relative to the YC group. Moreover, there was no overlap between the EC and MCI groups in individual visual bias scores reflecting the change in audiovisual integration from the strong to the weak stimulus conditions. Top-down lexicality influences on visual biasing were observed only in the MCI patients under weaker bottom-up conditions. Results support a deficit in bottom-up audiovisual integration in early AD attributable to disruptions in corticocortical connectivity. Given that this deficit is not simply an exacerbation of changes associated with healthy aging, tests of audiovisual speech integration may serve as sensitive and specific markers of the earliest cognitive change associated with AD.

Kim N.H. Dillen, Heidi I.L. Jacobs, Juraj Kukolja, Nils Richter, Boris von Reutern, Özgür A. Onur, Karl-Josef Langen, Gereon R. Fink (Handling Associate Editor: Yong Liu)
Functional Disintegration of the Default Mode Network in Prodromal Alzheimer’s Disease
Abstract: Neurodegenerative brain changes can affect the functional connectivity strength between nodes of the default-mode network (DMN), which may underlie changes in cognitive performance. It remains unclear how the functional connectivity strength of DMN nodes differs from healthy to pathological aging and whether these changes are cognitively relevant. We used resting-state functional magnetic resonance imaging to investigate the functional connectivity strength across five DMN nodes in 25 healthy controls (HC), 28 subjective cognitive decline (SCD) participants, and 25 prodromal Alzheimer’s disease (AD) patients. After identifying the ventral medial prefrontal cortex (vmPFC), posterior cingulate cortex (PCC), retrosplenial cortex (RSC), inferior parietal lobule, and the hippocampus we investigated the functional strength between DMN nodes using temporal network modeling. Functional coupling of the vmPFC and PCC in prodromal AD patients was disrupted. This vmPFC-PCC coupling correlated positively with memory performance in prodromal AD. Furthermore, the hippocampus de-coupled from posterior DMN nodes in SCD and prodromal AD patients. There was no coupling between the hippocampus and the anterior DMN. Additional mediation analyses indicated that the RSC enables communication between the hippocampus and DMN regions in HC but none of the other two groups. These results suggest an anterior-posterior disconnection and a hippocampal de-coupling from posterior DMN nodes with disease progression. Hippocampal de-coupling already occurring in SCD may provide valuable information for the development of a functional biomarker.

Eleni Andreadou, Anastasia Pantazaki, Makrina Daniilidou, Magda Tsolaki
Rhamnolipids, Microbial Virulence Factors, in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) has been attributed to chronic bacterial infections. The recognition of human microbiota as a substantial contributor to health and disease is relatively recent and growing. During evolution, mammals live in a symbiotic state with myriads of microorganisms that survive at a diversity of tissue micro-surroundings. Microbes produce a plethora of secretory products [amyloids, lipopolysaccharides, virulence factors rhamnolipids (RLs), toxins, and a great number of neuroactive compounds]. The contribution of infectious microbial components to the pathophysiology of the human central nervous system including AD is considered potentially substantial, but the involvement of the RLs has never been reported. Here, RLs were isolated from serum and identified through various conventional methods including the colorimetric orcinol method, thin-layer chromatography, attenuated total reflection Fourier transform infrared (ATR-FTIR), and dot blot using antibodies against RLs. Dot blot demonstrated elevated RL levels in sera of AD patients compared to controls (p=0.014). Moreover, ELISA showed similarly elevated RL levels in cerebrospinal fluid of both AD (0.188 versus 0.080) (p=0.04) and mild cognitive impairment (0.188 versus 0.129) (p=0.088) patients compared to healthy, and are well-correlated with the AD stages severity assessed using the Mini-Mental State Examination. These results provide conclusive evidence for the newly-reported implication of RLs in AD, adding it to the list of bacterial components, opening new avenues for AD investigation. Moreover, they strengthen and vindicate the divergence of research toward the exploration of bacterial involvement in AD generation and progression.

Qing Yu*, Fang Du*, Justin T. Douglas, Shirley ShiDu Yan, Haiyang Yu, Shi Fang Yan (Handling Associate Editor: Hemachandra Reddy) *These authors contributed equally to this work.
Mitochondrial Dysfunction Triggers Synaptic Deficits via Activation of p38 MAP Kinase Signaling in Differentiated Alzheimer’s Disease Trans-Mitochondrial Cybrid Cells
Abstract: Loss of synapse and synaptic dysfunction contribute importantly to cognitive impairment in Alzheimer's disease (AD). Mitochondrial dysfunction and oxidative stress are early pathological features in AD-affected brain. However, the effect of AD mitochondria on synaptogenesis remains to be determined. Using human trans-mitochondrial “cybrid” (cytoplasmic hybrid) neuronal cells whose mitochondria were transferred from platelets of patients with sporadic AD or age-matched non-AD subjects with relatively normal cognition, we provide the first evidence of mitochondrial dysfunction compromises synaptic development and formation of synapse in AD cybrid cells in response to chemical-induced neuronal differentiation. Compared to non-AD control cybrids, AD cybrid cells showed synaptic loss which was evidenced by a significant reduction in expression of two synaptic marker proteins: synaptophysin (presynaptic marker) and postsynaptic density protein-95, and neuronal proteins (MAP-2 and NeuN) upon neuronal differentiation. In parallel, AD-mediated synaptic deficits correlate to mitochondrial dysfunction and oxidative stress as well as activation of p38 MAP kinase. Notably, inhibition of p38 MAP kinase by pharmacological specific p38 inhibitor significantly increased synaptic density, improved mitochondrial function, and reduced oxidative stress. These results suggest that activation of p38 MAP kinase signaling pathway contributes to AD-mediated impairment in neurogenesis, possibly by inhibiting the neuronal differentiation. Our results provide new insight into the crosstalk of dysfunctional AD mitochondria to synaptic formation and maturation via activation of p38 MAP kinase. Therefore, blockade of p38 MAP kinase signal transduction could be a potential therapeutic strategy for AD by alleviating loss of synapses.

Maria Stefania De Simone, Lucia Fadda, Roberta Perri, Massimo De Tollis, Marta Aloisi, Carlo Caltagirone, Giovanni Augusto Carlesimo
Retrograde Amnesia for Episodic and Semantic Memories in Amnestic Mild Cognitive Impairment
Abstract: Retrograde amnesia (RA), which includes loss of memory for past personal events (autobiographical RA) and for acquired knowledge (semantic RA), has been largely documented in patients with amnestic mild cognitive impairment (aMCI). However, previous studies have produced controversial results particularly concerning the temporal extent of memory impairment. Here we investigated whether, with the onset of hippocampal pathology, age of memory acquisition and retrieval frequency play different roles in modulating the progressive loss of semantic and episodic contents of retrograde memory respectively. For this purpose, aMCI patients and healthy controls were tested for the ability to recall semantic and autobiographical information related to famous public events as a function of both age of acquisition and retrieval frequency. In aMCI patients, we found that the impairment in recollecting past personal incidents was modulated by the combined action of memory age and retrieval frequency, because older and more frequently retrieved episodes are less susceptible to loss than more recent and less frequently retrieved ones. On the other side, we found that the loss of semantic information depended only on memory age, because the remoteness of the trace allows for better preservation of the memory. Our results provide evidence that the loss of the two components of retrograde memory is regulated by different mechanisms. This supports the view that diverse neural mechanisms are involved in episodic and semantic memory trace storage and retrieval, as postulated by the Multiple Trace Theory.

Yorghos Tripodis, Michael L. Alosco, Nikolaos Zirogiannis, Brandon E. Gavett, Christine Chaisson, Brett Martin, Michael D. McClean, Jesse Mez, Neil Kowall, Robert A. Stern (Handling Associate Editor: Maheen Adamson)
The Effect of Traumatic Brain Injury History with Loss of Consciousness on Rate of Cognitive Decline Among Older Adults with Normal Cognition and Alzheimer’s Disease Dementia
Abstract: Traumatic brain injury (TBI) is thought to be a risk factor for dementia, including dementia due to Alzheimer’s disease (AD). However, the influence of TBI history on the neuropsychological course of AD is unknown and, more broadly, the effect of TBI history on age-related cognitive change is poorly understood. We examined the relationship between history of TBI with loss of consciousness (LOC) history and cognitive change in participants with normal cognition and probable AD, stratified by APOE ε4 allele status. The sample included 706 participants (432 with normal cognition; 274 probable AD) from the National Alzheimer’s Coordinating Center (NACC) dataset that completed the Uniform Data Set evaluation between 2005 and 2014. Normal and probable AD participants with a history of TBI were matched to an equal number of demographically and clinically similar participants without a TBI history. In this dataset, TBI with LOC was defined as brain trauma with brief or extended unconsciousness. For the normal and probable AD cohorts, there was an average of 3.2±1.9 and 1.8±1.1 years of follow-up, respectively. 30.8% of the normal cohort were APOE ε4 carriers, whereas 70.8% of probable AD participants were carriers. Mixed effects regressions showed TBI with LOC history did not affect rates of cognitive change in APOE ε4 carriers and non-carriers. Findings from this study suggest that TBI with LOC may not alter the course of cognitive function in older adults with and without probable AD. Future studies that better characterize TBI (e.g., severity, number of TBIs, history of subconconcussive exposure) are needed to clarify the association between TBI and long-term neurocognitive outcomes.

Swati Anand, Justin M. Barnes, Sydney A. Young, Diana M. Garcia, H. Dennis Tolley, John S.K. Kauwe, Steven W. Graves (Handling Associate Editor: Catherine Roe)
Discovery and Confirmation of Diagnostic Serum Lipid Biomarkers for Alzheimer’s Disease Using Direct Infusion Mass Spectrometry
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder lacking early biochemical diagnosis and treatment. Lipids have been implicated in neurodegenerative disorders including AD. A shotgun lipidomic approach was undertaken to determine if lipid biomarkers exist that can discriminate AD cases from controls. The discovery study involved sera from 29 different stage AD cases and 32 controls. Lipid extraction was performed using organic solvent and the samples were directly infused into a time-of-flight mass spectrometer. Differences between AD cases and controls were detected with 87 statistically significant lipid candidate markers found. These potential lipid markers were reevaluated in a second confirmatory study involving 27 cases and 30 controls. Of the 87 candidates from the first study, 35 continued to be statistically significant in the second confirmatory set. Tandem MS studies were performed and almost all confirmed markers were characterized and classified. Using a Bayesian lasso probit regression model on the confirmed markers, a multi-marker set with AUC=0.886 was developed comparing all stages of AD with controls. Additionally, using confirmed biomarkers, multi-marker sets with AUCs >0.90 were developed for each specific AD Clinical Dementia Rating versus controls, including the earliest stage of AD. More conservative and likely more realistic statistical analyses still found multi-marker sets that appeared useful in diagnosing AD. Finally, using ordinal modeling a set of markers was developed that staged AD accurately 70% of the time, p=0.0079. These results suggest that these serum lipidomic biomarkers may help diagnose and perhaps even stage AD.

Heather M. Wilkins, Jonathan D. Mahnken, Paul Welch, Rebecca Bothwell, Scott Koppel, Richard L. Jackson, Jeffrey M. Burns, Russell H. Swerdlow
A Mitochondrial Biomarker-Based Study of S-Equol in Alzheimer’s Disease Subjects: Results of a Single-Arm, Pilot Trial
Abstract: Reductions in bioenergetic fluxes, mitochondrial enzyme activities, and mitochondrial number are observed in Alzheimer’s disease (AD). Preclinical work indicates estrogen pathway signaling by either estrogen or selective β estrogen receptor (ERβ) agonists benefits these parameters. To assess whether an ERβ agonist could improve mitochondrial function in actual AD subjects, we administered S-equol (10 mg twice daily) to 15 women with AD and determined the platelet mitochondria cytochrome oxidase (COX) activity before initiating S-equol (lead-in), after two weeks of S-equol (active treatment), and two weeks after stopping S-equol (wash-out). Because the intra-individual variation of this enzyme across samples taken at different times was unknown we used a nonparametric, single-arm, dichotomous endpoint that classified subjects whose active treatment COX activity exceeded the average of their lead-in and wash-out measures as positive responders. Eleven positive responses were observed (p<0.06). The implications of this finding on our null hypothesis (that S-equol does not influence platelet mitochondria COX activity) are discussed. To our knowledge, this is the first time a direct mitochondrial target engagement biomarker has been utilized in an AD clinical study.

Lucy Beishon, Victoria J. Haunton, Ronney B. Panerai, Thompson G. Robinson
Cerebral Hemodynamics in Mild Cognitive Impairment: A Systematic Review
Abstract: Background: The incidence of dementia is projected to rise over the coming decades, but with no sensitive diagnostic tests available. Vascular pathology precedes the deposition of amyloid and is an attractive early target. Objective: The aim of this review was to investigate the use of cerebral hemodynamics and oxygenation as a novel biomarker for mild cognitive impairment (MCI), focusing on transcranial Doppler ultrasonography (TCD) and near-infrared spectroscopy (NIRS). Methods: 2,698 articles were identified from Medline, Embase, PsychINFO, and Web of Science databases. 306 articles were screened and quality assessed independently by two reviewers; 26 met the inclusion criteria. Meta-analyses were performed for each marker with two or more studies and limited heterogeneity. Results: Eleven studies were TCD, 8 NIRS, 5 magnetic resonance imaging, and 2 positron/single photon emission tomography. Meta-analyses showed reduced tissue oxygenation index, cerebral blood flow and velocity, with higher pulsatility index, phase and cerebrovascular resistance in MCI compared to controls. The majority of studies found reduced CO2 reactivity in MCI, with mixed findings in neuroactivation studies. Conclusion: Despite small sample sizes and heterogeneity, meta-analyses demonstrate clear abnormalities in cerebral hemodynamic and oxygenation parameters, even at an early stage of cognitive decline. Further work is required to investigate the use of cerebral hemodynamic and oxygenation parameters as a sensitive biomarker for dementia.

Anna Krasnianski, Geeske T. Bohling, Uta Heinemann, Daniela Varges, Bettina Meissner, Walter J. Schulz-Schaeffer, Andreas Reif, Inga Zerr
Neuropsychological Symptoms in Sporadic Creutzfeldt-Jakob Disease Patients in Germany
Abstract: Background: The polymorphism at codon 129 of the prion protein gene (PRNP) and the PrPSc types 1 and 2 belong to a molecular classification of sporadic Creutzfeldt-Jakob disease (sCJD) that correlates well with the clinical and neuropathological phenotype of sCJD. Objective: The aim of the study was to perform the first detailed evaluation of neuropsychological deficits in a large group of definite sCJD patients with known molecular subtype. Methods: We analyzed neuropsychological symptoms in a cohort of 248 sCJD patients with known M129V polymorphism of PRNP and prion protein type. Results: Neuropsychological symptoms were very frequent in our patients (96%) and occurred as early as in the first third of the disease course. Besides amnesia and impaired attention (89% each), frontal lobe syndrome (75%), aphasia (63%), and apraxia (57%) were the most common neuropsychological deficits. There was no statistically significant difference with regard to frequency of neuropsychological symptoms between the subtypes. In MV2 and VV2 patients, the onset of neuropsychological symptoms was significantly later than in all other subtypes. Conclusion: We provide the first detailed analysis of neuropsychological symptoms in a large group of sCJD patients with known M129V genotype and prion protein type. We suggest that the rate of progression of neuropsychological symptoms is subtype-specific. These data may improve the diagnosis in atypical sCJD subtypes.

David A. Loewenstein, Rosie E. Curiel, Steven DeKosky, Monica Rosselli, Russell Bauer, Maria Grieg-Custo, Ailyn Penate, Chunfei Li, Gabriel Lizagarra, Todd Golde, Malek Adjouadi, Ranjan Duara
Recovery from Proactive Semantic Interference and MRI Volume: A Replication and Extension Study
Abstract: Background: The rise in incidence of Alzheimer’s disease (AD) has led to efforts to advance early detection of the disease during its preclinical stages. To achieve this, the field needs to develop more sensitive cognitive tests that relate to biological markers of disease pathology. Failure to recover from proactive interference (frPSI) is one such cognitive marker that is associated with volumetric reductions in the hippocampus, precuneus, and other AD-prone regions, and to amyloid load in the brain. Objective: The current study attempted to replicate and extend our previous findings that frPSI is a sensitive marker of early AD, and related to a unique pattern of volumetric loss in AD prone areas. Methods: Three different memory measures were examined relative to volumetric loss and cortical thickness among 45 participants with amnestic mild cognitive impairment. Results: frPSI was uniquely associated with reduced volumes in the hippocampus (r=0.50) precuneus (r=0.41), and other AD prone regions, replicating previous findings. Strong associations between frPSI and lower entorhinal cortex volumes and cortical thickness (r0.60) and precuneus (r=0.50) were also observed. Conclusion: Unique and strong associations between volumetric reductions and frPSI as observed by Loewenstein and colleagues were replicated. Together with cortical thickness findings, these results indicate that frPSI is worthy of further study as a sensitive and early cognitive marker of AD.

Mehmet Cansev, Mesut Turkyilmaz, John W.C. Sijben, Cansu Sevinc, Laus M. Broersen, Nick van Wijk (Handling Associate Editor: Deborah Gustafson)
Synaptic Membrane Synthesis in Rats Depends on Dietary Sufficiency of Vitamin C, Vitamin E, and Selenium: Relevance for Alzheimer’s Disease
Abstract: Chronic consumption of a diet enriched with nutritional precursors of phospholipids, including uridine and the polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), was shown previously to enhance levels of brain phospholipids and synaptic proteins in rodents. Vitamin C, vitamin E, and selenium may directly affect the breakdown or synthesis of membrane phospholipids. The present study investigated the necessity of antioxidants for the effectiveness of supplementation with uridine plus DHA and EPA (as fish oil) in rats. Rats were randomized to four treatment groups and received, for 6 weeks, one of four experimental diets, i.e., a diet low in antioxidants, a diet high in antioxidants, a diet low in antioxidants supplemented with DHA+EPA+uridine, or a diet high in antioxidants supplemented with DHA+EPA+uridine. On completion of dietary treatment, rats were sacrificed, and brain levels of phospholipids, synaptic proteins, and two enzymes involved in phospholipid synthesis (choline-phosphate cytidylyltransferase, PCYT1A, and choline/ethanolamine phosphotransferase, CEPT1) were analyzed. Levels of phospholipids, the pre- and post-synaptic proteins Synapsin-1 and PSD95, and the enzymes PCYT1A and CEPT1 were significantly enhanced by combined supplementation of DHA+EPA+uridine and antioxidants and not enhanced by supplementation of DHA+EPA+uridine with insufficient antioxidant levels. Our data suggest that dietary vitamin C, vitamin E, and selenium are essential for the phospholipid precursors’ effects on increasing levels of membrane phospholipids and synaptic proteins, the indirect indicators of synaptogenesis. Their concomitant supply may be relevant in Alzheimer’s disease patients, because the disease is characterized by synapse loss and lower plasma and brain levels of phospholipid precursors and antioxidants.

Michiaki Okuda, Yuki Fujita, Ichiro Hijikuro, Mei Wada, Takuya Uemura, Yukako Kobayashi, Tomonori Waku, Naoki Tanaka, Takaaki Nishimoto, Yasuhiko Izumi, Toshiaki Kume, Akinori Akaike, Takashi Takahashi, Hachiro Sugimoto
PE859, A Novel Curcumin Derivative, Inhibits Amyloid-β and Tau Aggregation, and Ameliorates Cognitive Dysfunction in Senescence-Accelerated Mouse Prone 8
Abstract: Aggregation of amyloid-β (Aβ) and tau plays a crucial role in the onset and progression of Alzheimer’s disease (AD). Therefore, the inhibition of Aβ and tau aggregation may represent a potential therapeutic target for AD. Herein, we designed and synthesized both Aβ and tau dual aggregation inhibitors based on the structure of curcumin and developed the novel curcumin derivative PE859. In this study, we investigated the inhibitory activity of PE859 on Aβ aggregation in vitro and the therapeutic effects of PE859 on cognitive dysfunction via dual inhibition of Aβ and tau aggregation in vivo. PE859 inhibited Aβ aggregation in vitro and protected cultured cells from Aβ-induced cytotoxicity. Furthermore, PE859 ameliorated cognitive dysfunction and reduced the amount of aggregated Aβ and tau in brains of senescence-accelerated mouse prone 8 (SAMP8). These results warrant consideration of PE859 as a candidate drug for AD.

Claudio Babiloni, Claudio Del Percio, Roberta Lizio, Giuseppe Noce, Susanna Cordone, Susanna Lopez, Andrea Soricelli, Raffaele Ferri, Maria Teresa Pascarelli, Flavio Nobili, Dario Arnaldi, Francesco Famà, Dag Aarsland, Francesco Orzi, Carla Buttinelli, Franco Giubilei, Marco Onofrj, Fabrizio Stocchi, Paola Stirpe, Peter Fuhr, Ute Gschwandtner, Gerhard Ransmayr, Georg Caravias, Heinrich Garn, Fabiola Sorpresi, Michela Pievani, Fabrizia D'Antonio, Carlo De Lena, Bahar Güntekin, Lutfu Hanoğlu, Erol Başar, Görsev Yener, Derya Durusu Emek-Savaş, Antonio Ivano Triggiani, Raffaella Franciotti, Giovanni B. Frisoni, Laura Bonanni, Maria Francesca De Pandis (Handling Associate Editor: Irena Rektorová)
Abnormalities of Cortical Neural Synchronization Mechanisms in Subjects with Mild Cognitive Impairment due to Alzheimer’s and Parkinson’s Diseases: An EEG Study
Abstract: The aim of this retrospective and exploratory study was that the cortical sources of resting state eyes-closed electroencephalographic (rsEEG) rhythms might reveal different abnormalities in cortical neural synchronization in groups of patients with mild cognitive impairment due to Alzheimer’s disease (ADMCI) and Parkinson’s disease (PDMCI) as compared to healthy subjects. Clinical and rsEEG data of 75 ADMCI, 75 PDMCI, and 75 cognitively normal elderly (Nold) subjects were available in an international archive. Age, gender, and education were carefully matched in the three groups. The Mini-Mental State Evaluation (MMSE) was matched between the ADMCI and PDMCI groups. Individual alpha frequency peak (IAF) was used to determine the delta, theta, alpha1, alpha2, and alpha3 frequency band ranges. Fixed beta1, beta2, and gamma bands were also considered. eLORETA estimated the rsEEG cortical sources. Receiver operating characteristic curve (ROC) classified these sources across individuals. Results showed that compared to the Nold group, the posterior alpha2 and alpha3 source activities were more abnormal in the ADMCI than the PDMCI group, while the parietal delta source activities were more abnormal in the PDMCI than the ADMCI group. The parietal delta and alpha sources correlated with MMSE score and correctly classified the Nold and diseased individuals (area under the ROC = 0.77-0.79). In conclusion, the PDMCI and ADMCI patients showed different features of cortical neural synchronization at delta and alpha frequencies underpinning brain arousal and vigilance in the quiet wakefulness. Future prospective cross-validation studies will have to test these rsEEG markers for clinical applications and drug discovery.

Megha M. Vasavada, Brittany Martinez, Jianli Wang, Paul J. Eslinger, David J. Gill, Xiaoyu Sun, Prasanna, Karunanayaka, Qing X. Yang (Handling Associate Editor: Caroline Huart)
Central Olfactory Dysfunction in Alzheimer’s Disease and Mild Cognitive Impairment: A Functional MRI Study
Abstract: Background: Olfactory deficits are present in early Alzheimer’s disease (AD) and mild cognitively impaired (MCI) patients. However, whether these deficits are due to dysfunction of the central or peripheral olfactory nervous system remains uncertain. This question is fundamentally important for developing imaging biomarkers for AD using olfactory testing. Objective: This study sought to use olfactory functional magnetic resonance imaging (fMRI) to further demonstrate the involvement of the central olfactory system in olfactory deficits in MCI and AD. Methods: We investigated the central olfactory system in 27 cognitively normal controls (CN), 21 MCI, and 15 AD subjects using olfactory fMRI with an odor-visual association paradigm during which a visual cue was paired with lavender odorant (odor condition) or odorless air (no-odor condition). Results: The CN subjects had significantly greater activated volume in the primary olfactory cortex during both the odor and no-odor conditions compared to either the MCI or AD groups (p < 0.05). No significant differences were observed between the odor and no-odor conditions within each group. No-odor condition activation in AD and MCI correlated with the cognitive and olfactory assessments. Conclusion: The no-odor condition, allowing investigation of activation patterns when the peripheral olfactory system was not directly involved, elicited the same functional response as the odor condition for each of the three groups. Thus, the olfactory activation deficits present in AD and MCI patients are most likely caused by degeneration of the central olfactory nervous system.