Volume 78, Number 3, IN PRESS

Review
Michael R. Duggan, Bahareh Torkzaban, Taha Mohseni Ahooyi, Kamel Khalili
Potential Role for Herpesviruses in Alzheimer’s Disease
Abstract: Across the fields of virology and neuroscience, the role of neurotropic viruses in Alzheimer’s disease (AD) has received renewed enthusiasm, with a particular focus on human herpesviruses (HHVs). Recent genomic analyses of brain tissue collections and investigations of the antimicrobial responses of amyloid-β do not exclude a role of HHVs in contributing to or accelerating AD pathogenesis. Due to continued expansion in our aging cohort and the lack of effective treatments for AD, this composition examines a potential neuroviral theory of AD in light of these recent data. Consideration reveals a possible viral “Hit-and-Run” scenario of AD, as well as neurobiological mechanisms (i.e., neuroinflammation, protein quality control, oxidative stress) that may increase risk for AD following neurotropic infection. Although limitations exist, this theoretical framework reveals several novel therapeutic targets that may prove efficacious in AD.

Review
Minos Kritikos, Samuel Gandy, Jaymie R. Meliker, Benjamin J. Luft, Sean A.P. Clouston
Acute versus Chronic Exposures to Inhaled Particulate Matter and Neurocognitive Dysfunction: Pathways to Alzheimer’s Disease or a Related Dementia
Abstract: An estimated 92% of the world’s population live in regions where people are regularly exposed to high levels of anthropogenic air pollution. Historically, research on the effects of air pollution have focused extensively on cardiovascular and pulmonary health. However, emerging evidence from animal and human studies has suggested that chronic exposures to air pollution detrimentally change the functioning of the central nervous system with the result being proteinopathy, neurocognitive impairment, and neurodegenerative disease. Case analyses of aging World Trade Center responders suggests that a single severe exposure may also induce a neuropathologic response. The goal of this report was to explore the neuroscientific support for the hypothesis that inhaled particulate matter might cause an Alzheimer’s-like neurodegenerative disease, in order to consider proposed mechanisms and latency periods linking inhaled particulate matter and neurodegeneration, and to propose new directions in this line of research.

Review
Tianying Zhang*, Xiaojuan Han*, Xiaohua Zhang, Zhi Chen, YajingMi, Xingchun Gou *These authors contributed equally to this work.
Dietary Fatty Acid Factors in Alzheimer’s Disease: A Mini-Review
Abstract: Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by brain function disorder and chronic cognitive function impairment. The onset of AD is complex and is mostly attributed to interactions between genetic factors and environmental factors. Lifestyle, dietary habits, and food consumption are likely to play indispensable functions in aged-related neurodegenerative diseases in elderly people. An increasing number of epidemiological studies have linked dietary fatty acid factors to AD, raising the point of view that fatty acid metabolism plays an important role in AD initiation and progression as well as in other central nervous system disorders. In this paper, we review the effects of the consumption of various dietary fatty acids on AD onset and progression and discuss the detrimental and beneficial effects of some typical fatty acids derived from dietary patterns on the pathology of AD. We outline these recent advances, and we recommend that healthy dietary lifestyles may contribute to preventing the occurrence and decreasing the pathology of AD.

Commentary
Ruth F. Itzhaki
Antivirals Against SARS-CoV2: Relevance to the Treatment of Alzheimer’s Disease
Abstract: A recent study in vitro has shown that a sulphated polysaccharide, a type of fucoidan, has potent antiviral activity against SARS-Cov2. If the antiviral action were successful also for COVID-19 patients, it would be enormously valuable against not only acute disease but also long-term mental effects, which might include Alzheimer’s disease (AD). In a trial of AD patients, the apparent success of treatment with a polysaccharide, GV971, was suggested to result from antiviral action against herpes simplex virus type 1 (HSV1) in brain, a pathogen strongly implicated in AD, and that sulphation of GV971, making it fucoidan-like, might increase its putative antiviral action. These data indicate that treatment of AD patients might be very effective using valacyclovir, a conventional antiviral, which inhibits viral replication, together with a fucoidan, which blocks virus entry into cells.

Short Communication
Eric Jouvent, Nassira Alilli, Dominique Hervé, Hugues Chabriat
Vanishing White Matter Hyperintensities in CADASIL: A Case Report with Insight into Disease Mechanisms
Abstract: In a woman with Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) followed for 15 years, we observed magnetic resonance imaging white matter hyperintensities that vanished in the anterior temporal poles while the brain volume decreased unexpectedly. These imaging changes were transient and detected when the patient was being treated by valproic acid for stabilizing mood disturbances. This intriguing case supports that mechanisms underlying white matter hyperintensities can vary from one brain area to another and that important modifications of water influx into the brain tissue might be involved in some imaging features of CADASIL.

Short Communication
Janina Krell-Roesch, Jeremy A. Syrjanen, Michelle M. Mielke, Teresa J. Christianson, Walter K. Kremers, Mary M. Machulda, David S. Knopman, Ronald C. Petersen, Maria Vassilaki, Yonas E. Geda
Association Between Neuropsychiatric Symptoms and Functional Change in Older Non-Demented Adults: Mayo Clinic Study of Aging
Abstract: We examined the associations between baseline neuropsychiatric symptoms (NPS) and longitudinal changes in functional performance among 5,394 non-demented individuals aged ≥ 50 years (2,729 males; median age 74.2 years; 4,716 cognitively unimpaired, 678 mild cognitive impairment). After adjusting for age, sex, education, and medical comorbidities, NPS assessed by the Neuropsychiatric Inventory Questionnaire, clinical depression (Beck Depression Inventory score ≥ 13) and anxiety (Beck Anxiety Inventory score ≥ 10) were significantly associated with an increase in the Functional Activities Questionnaire score, indicating functional decline over time. This association may vary depending on the degree of cognitive impairment at baseline.

Short Communication
Marjut Haapanen, Kasper Katisko, Tuomo Hänninen, Johanna Krüger, Päivi Hartikainen, Annakaisa Haapasalo, Anne M. Remes, Eino Solje
C9orf72 Repeat Expansion Does Not Affect the Phenotype in Primary Progressive Aphasia
Abstract: Primary progressive aphasia (PPA) forms the spectrum of language variants of frontotemporal lobar degeneration (FTLD), including three subtypes each consisting of distinctive speech and language features. Repeat expansion in C9orf72 gene is the most common genetic cause of FTLD. However, thus far only little is known about the effects of the C9orf72 repeat expansion on the phenotype of PPA. This retrospective study aimed at determining the differences between the PPA phenotypes of the C9orf72 expansion carriers and non-carriers. Our results demonstrated no significant differences between these groups, indicating that the C9orf72 repeat expansion does not substantially affect the phenotype of PPA.

Musa Gabere, Nha Trang Thu Pham, Jonathan Graff-Radford, Mary M. Machulda, Joseph R. Duffy, Keith A. Josephs, Jennifer L. Whitwell, for Alzheimer’s Disease Neuroimaging Initiative
Automated Hippocampal Subfield Volumetric Analyses in Atypical Alzheimer’s Disease
Abstract: Background: Posterior cortical atrophy (PCA) and logopenic progressive aphasia (LPA) are two of the most common variants of atypical Alzheimer’s disease (AD). Both PCA and LPA are associated with relative sparing of hippocampus compared to neocortex, although hippocampal atrophy is observed. It is unclear whether regional patterns of hippocampal subfield involvement differ between PCA and LPA, and whether they differ from typical AD. Objective: To assess volume of specific subfields of the hippocampus in PCA, LPA, and typical AD. Methods: Fifty-nine patients with PCA and 77 patients with LPA were recruited and underwent T1-weighted MRI and Pittsburgh Compound B (PiB) PET at Mayo Clinic. Thirty-six probable AD patients and 100 controls were identified from the Alzheimer’s Disease Neuroimaging Initiative. Hippocampal subfield volumes were calculated using Freesurfer, and volumes were compared between PCA, LPA, AD, and controls using Kruskal-Wallis and Dunn tests. Results: The LPA and PCA groups both showed the most striking abnormalities in CA4, presubiculum, molecular layer of the hippocampus, molecular and granule cell layers of the dentate gyrus, and the hippocampal-amygdala transition area, although atrophy was left-sided in LPA. PCA showed smaller volume of right presubiculum compared to LPA, with trends for smaller volumes of right parasubiculum and fimbria. LPA showed a trend for smaller volumes of left CA1 compared to PCA. The AD group showed smaller volumes of the right subiculum, CA1, and presubiculum compared to LPA. Conclusion: Patterns of hippocampal subfield atrophy differ across the different syndromic variants of AD.

Matthieu Ghilain*, Lise Hobeika*, Micheline Lesaffre, Loris Schiaratura, Ashmita Singh, Joren Six, Dominique Huvent-Grelle, François Puisieux, Séverine Samson (Handling Associate Editor: Isabelle Rouch) *These authors contribute equally to this work.
Does a Live Performance Impact Synchronization to Musical Rhythm in Cognitively Impaired Elderly?
Abstract: Background: Music-based interventions appear to be efficient approaches to improve emotional, social, and cognitive functioning of patients with neurodegenerative diseases. Objective: Because benefits seem to increase with patient’s motor involvement, we studied sensorimotor synchronization (SMS) abilities of patients with cognitive impairments (Alzheimer’s disease, vascular and mixed dementia) and of patients with no evidence of cognitive impairments. More specifically, we compared the impact of a live performance by a musician to a video recording on SMS. Methods: SMS to a metronomic or a musical stimulus was assessed while patients watched a live musician or his pre-recorded video. Results: SMS to a metronome was better than to music but this effect was modulated by the social context. While SMS to a metronome was better when facing a video than a live performance, there was no impact of social context on SMS to music. No group differences of SMS were found. Conclusion: The decrease in SMS to a metronome in a live performance may be due to social pressure. Such a pressure might be removed in pleasant social activities, like moving with music in a group, explaining the lack of effect on SMS to music. We found no performance differences in groups, suggesting relatively spared SMS in cognitively impaired patients. By showing that it is possible to encourage patients to synchronize with others, even when facing a video, our results indicate that SMS can be used as a relevant predictor in clinical trials and open up promising therapeutic options for isolated patients.

Marvin Ruiter, Lotte J. Herstel, Corette J. Wierenga (Handling Associate Editor: Tao Ma)
Reduction of Dendritic Inhibition in CA1 Pyramidal Neurons in Amyloidosis Models of Early Alzheimer’s Disease
Abstract: Background: In an early stage of Alzheimer’s disease (AD), before the formation of amyloid plaques, neuronal network hyperactivity has been reported in both patients and animal models. This suggests an underlying disturbance of the balance between excitation and inhibition. Several studies have highlighted the role of somatic inhibition in early AD, while less is known about dendritic inhibition. Objective: In this study we investigated how inhibitory synaptic currents are affected by elevated Aβ levels. Methods: We performed whole-cell patch clamp recordings of CA1 pyramidal neurons in organotypic hippocampal slice cultures after treatment with Aβ-oligomers and in hippocampal brain slices from AppNl-F-G mice (APP-KI). Results: We found a reduction of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons in organotypic slices after 24-h Aβ treatment. sIPSCs with slow rise times were reduced, suggesting a specific loss of dendritic inhibitory inputs. As miniature IPSCs and synaptic density were unaffected, these results suggest a decrease in activity-dependent release after Aβ treatment. We observed a similar, although weaker reduction in sIPSCs in CA1 pyramidal neurons from APP-KI mice compared to control. When separated by sex, the strongest reduction in sIPSC frequency was found in slices from male APP-KI mice. Consistent with hyperexcitability in pyramidal cells, dendritically targeting interneurons received slightly more excitatory input. GABAergic action potentials had faster kinetics in APP-KI slices. Conclusion: Our results show that Aβ affects dendritic inhibition via impaired action potential driven release, possibly due to altered kinetics of GABAergic action potentials. Reduced dendritic inhibition may contribute to neuronal hyperactivity in early AD.

Kelsey M. Loupy, Thomas Lee, Cristian A. Zambrano, Ahmed I. Elsayed, Heather M. D’Angelo, Laura K. Fonken, Matthew G. Frank, Steven F. Maier, Christopher A. Lowry
Alzheimer’s Disease: Protective Effects of Mycobacterium vaccae, a Soil-Derived Mycobacterium with Anti-Inflammatory and Anti-Tubercular Properties, on the Proteomic Profiles of Plasma and Cerebrospinal Fluid in Rats
Abstract: Background: Alzheimer’s disease (AD) is an inflammatory neurodegenerative disease that may be associated with prior bacterial infections. Microbial “old friends” can suppress exaggerated inflammation in response to disease-causing infections or increase clearance of pathogens such as Mycobacterium tuberculosis, which causes tuberculosis (TB). One such “old friend” is Mycobacterium vaccae NCTC 11659, a soil-derived bacterium that has been proposed either as a vaccine for prevention of TB, or as immunotherapy for the treatment of TB when used alongside first line anti-TB drug treatment. Objective: The goal of this study was to use a hypothesis generating approach to explore the effects of M. vaccae on physiological changes in the plasma and cerebrospinal fluid (CSF). Methods: Liquid chromatography-tandem mass spectrometry-based proteomics were performed in plasma and CSF of adult male rats after immunization with a heat-killed preparation of M. vaccae NCTC 11659 or borate-buffered saline vehicle. Gene enrichment analysis and protein-protein interactions were performed to integrate physiological network changes in plasma and CSF. We used RT-qPCR to assess immune and metabolic gene expression changes in the hippocampus. Results: In both plasma and CSF, immunization with M. vaccae increased proteins associated with immune activation and downregulated proteins corresponding to lipid (including phospholipid and cholesterol) metabolism. Immunization with M. vaccae also increased hippocampal expression of interleukin-4 (IL-4) mRNA, implicating anti-inflammatory effects in the central nervous system. Conclusion: M. vaccae alters host immune activity and lipid metabolism. These data are consistent with the hypothesis that microbe-host interactions may protect against possible infection-induced, inflammation-related cognitive impairments.

Gary E. Gibson, José A. Luchsinger, Rosanna Cirio, Huanlian Chen, Jessica Franchino-Elder, Joseph A. Hirsch, Lucien Bettendorff, Zhengming Chen, Sarah Flowers, Linda Gerber, Thomas Grandville, Nicole Schupf, Hui Xu, Yaakov Stern, Christian Habeck, Barry Jordan, Pasquale Fonzetti
Benfotiamine and Cognitive Decline in Alzheimer’s Disease: Results of a Randomized Placebo-Controlled Phase IIa Clinical Trial
Abstract: Background: In preclinical models, benfotiamine efficiently ameliorates the clinical and biological pathologies that define Alzheimer’s disease (AD) including impaired cognition, amyloid-β plaques, neurofibrillary tangles, diminished glucose metabolism, oxidative stress, increased advanced glycation end products (AGE), and inflammation. Objective: To collect preliminary data on feasibility, safety, and efficacy in individuals with amnestic mild cognitive impairment (aMCI) or mild dementia due to AD in a placebo-controlled trial of benfotiamine. Methods: A twelve-month treatment with benfotiamine tested whether clinical decline would be delayed in the benfotiamine group compared to the placebo group. The primary clinical outcome was the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). Secondary outcomes were the clinical dementia rating (CDR) score and fluorodeoxyglucose (FDG) uptake, measured with brain positron emission tomography (PET). Blood AGE were examined as an exploratory outcome. Results: Participants were treated with benfotiamine (34) or placebo (36). Benfotiamine treatment was safe. The increase in ADAS-Cog was 43% lower in the benfotiamine group than in the placebo group, indicating less cognitive decline, and this effect was nearly statistically significant (p=0.125). Worsening in CDR was 77% lower (p=0.034) in the benfotiamine group compared to the placebo group, and this effect was stronger in the APOE ε4 non-carriers. Benfotiamine significantly reduced increases in AGE (p=0.044), and this effect was stronger in the APOE ε4 non-carriers. Exploratory analysis derivation of an FDG PET pattern score showed a treatment effect at one year (p=0.002). Conclusion: Oral benfotiamine is safe and potentially efficacious in improving cognitive outcomes among persons with MCI and mild AD.

Perla Werner, Hanan AboJabel (Handling Associate Editor: Key Deckers)
Perceptions About and Engagement in Behaviors to Reduce the Risk of Dementia Among Adult Persons in Israel
Abstract: Background: Engagement in behaviors aimed at reducing the risk of developing dementia is a leading recommendation in most National Dementia Strategy programs. Objective: In an effort to advance knowledge regarding the implementation of this recommendation, the current study examined the perceptions and engagement of the adult population in Israel regarding behaviors aimed at reducing the risk of developing dementia, and its correlates. Methods: A cross-sectional survey was conducted among 502 Israeli adults aged 40 and over. Approximately half of the participants (51.2%) were female, and the majority (80.1%) were Jewish. Results: Overall, while the percentage of participants reporting that the examined activities were important for brain health was moderate, percentages reporting engaging in these behaviors were low. The most important correlate of engagement in health behaviors was participants' perceptions about the importance of these behaviors for their brain health. Increased age, being Jewish, and enhanced perceived susceptibility to develop dementia were also significantly associated with increased engagement in behaviors to reduce the risk of dementia. Conclusion: The results of this study emphasize the need to develop intervention programs aimed at promoting engagement in behaviors to reduce the risk of dementia development. These programs will benefit from assessing participants’ perceived importance of these behaviors, and from identifying the needs of unique groups, such as older persons and those pertaining to ethno-cultural groups.

Alaine E. Reschke-Hernández, Amy M. Belfi, Edmarie Guzmán-Vélez, Daniel Tranel (Handling Associate Editor: Amy Clements-Cortes)
Hooked on a Feeling: Influence of Brief Exposure to Familiar Music on Feelings of Emotion in Individuals with Alzheimer’s Disease
Abstract: Background: Research has indicated that individuals with Alzheimer’s-type dementia (AD) can experience prolonged emotions, even when they cannot recall the eliciting event. Less is known about whether music can modify the emotional state of individuals with AD and whether emotions evoked by music linger in the absence of a declarative memory for the eliciting event. Objective: We examined the effects of participant-selected recorded music on self-reported feelings of emotion in individuals with AD, and whether these feelings persisted irrespective of declarative memory for the emotion-inducing stimuli. Methods: Twenty participants with AD and 19 healthy comparisons (HCs) listened to two 4.5-minute blocks of self-selected music that aimed to induce either sadness or happiness. Participants reported their feelings at baseline and three times post-induction and completed recall and recognition tests for the music selections after each induction. Results: Participants with AD had impaired memory for music selections compared to HCs. Both groups reported elevated sadness and negative affect after listening to sad music and increased happiness and positive affect after listening to happy music, relative to baseline. Sad/negative and happy/positive emotions endured up to 20 minutes post-induction. Conclusion: Brief exposure to music can induce strong and lingering emotions in individuals with AD. These findings extend the intriguing phenomenon whereby lasting emotions can be prompted by stimuli that are not remembered declaratively. Our results underscore the utility of familiar music for inducing emotions in individuals with AD and may ultimately inform strategies for using music listening as a therapeutic tool with this population.

Teresa Juárez-Cedillo, Lidia Gutiérrez-Gutiérrez, Luis Alejandro Sánchez-Hurtado, Nancy Martínez-Rodríguez, Enrique Juarez-Cedillo
Randomized Controlled Trial of Multi-Component Cognitive Stimulation Therapy (SADEM) in Community-Dwelling Demented Adults
Abstract: Background: Dementia is a persistent, progressive state of cognitive decline against which pharmacological intervention has a modest efficacy, reducing behavioral but not cognitive symptoms. Therefore, different non-pharmacological therapies have been developed; the most scientifically recognized are cognitive therapies that have improved cognitive function and daily life activities. Objective: To evaluate the effectiveness of a multicomponent cognitive stimulation therapy (SADEM) on cognitive and behavioral function and daily life activities in patients with mild stage dementia. Methods: Controlled clinical trial with pre- and post-intervention (12 months) and follow-up (24 months after) evaluations. Participants (67) diagnosed with mild dementia were randomly assigned to intervention group (n = 39) or control group (n = 28). The intervention took place throughout one year and consisted of two weekly 90-minute sessions and one more a year after a monthly follow-up. Instruments were used to evaluate outcomes in cognitive, behavioral, and affective domains. Results: The results showed statistically significant differences, with improvement in the cognitive outcomes and the Dementia Index post-intervention (p = 0.01). No progression of the disease was observed at the end of the study. Conclusion: The multicomponent intervention tested had positive effects on cognitive and behavioral functions and daily life activities in people with mild stage dementia, delaying progression for at least two years.

Nena Lejko, Daouia I. Larabi, Christoph S. Herrmann, André Aleman, Branislava Ćurčić-Blake
Alpha Power and Functional Connectivity in Cognitive Decline: A Systematic Review and Meta-Analysis
Abstract: Background: Mild cognitive impairment (MCI) is a stage between expected age-related cognitive decline and dementia. Dementias have been associated with changes in neural oscillations across the frequency spectrum, including the alpha range. Alpha is the most prominent rhythm in human EEG and is best detected during awake resting state (RS). Though several studies measured alpha power and synchronization in MCI, findings have not yet been integrated. Objective: To consolidate findings on power and synchronization of alpha oscillations across stages of cognitive decline. Methods: We included studies published until January 2020 that compared power or functional connectivity between 1) people with MCI and cognitively healthy older adults (OA) or people with a neurodegenerative dementia, and 2) people with progressive and stable MCI. Random-effects meta-analyses were performed when enough data was available. Results: Sixty-eight studies were included in the review. Global RS alpha power was lower in AD than in MCI (ES=-0.30; 95% CI=-0.51, -0.10; k=6), and in MCI than in OA (ES=-1.49; 95% CI=-2.69, -0.29; k=5). However, the latter meta-analysis should be interpreted cautiously due to high heterogeneity. The review showed lower RS alpha power in progressive than in stable MCI, and lower task-related alpha reactivity in MCI than in OA. People with MCI had both lower and higher functional connectivity than OA. Publications lacked consistency in MCI diagnosis and EEG measures. Conclusion: Research indicates that RS alpha power decreases with increasing impairment, and could—combined with measures from other frequency bands—become a biomarker of early cognitive decline.

Mara Gkioka*, Julia Schneider*, Andreas Kruse, Magda Tsolaki, Despina Moraitou, Birgit Teichmann *These authors contributed equally to this work.
Evaluation and Effectiveness of Dementia Staff Training Programs in General Hospital Settings: A Narrative Synthesis with Holton’s Three-Level Model Applied
Abstract: Background: People with dementia (PwD) are frequently admitted to hospital settings. The lack of proper dementia knowledge, poor communication skills, negative attitudes toward dementia, and lack of confidence affects the quality of care, thus development of dementia trainings has increased. Nevertheless, literature regarding the effectiveness of training implementation is limited. Objective: The aim of this narrative synthesis is to 1) identify the characteristics of training programs and 2) explore the effectiveness of these training programs in everyday clinical practice. Methods: A systematic search in PubMed, PsycINFO, CINAHL, and Cochrane was conducted, including qualitative and quantitative peer-reviewed studies. Holton’s evaluation model with its three outcome levels (learning, individual performance, and organizational results) was adopted. 14 studies were included. Results: The synthesis of the results was divided into two parts: 1) to describe the characteristics and content of trainings 2) to evaluate the effectiveness of training programs according to the three outcome levels of Holton’s model, taking into consideration its construct domains: ability, motivation, and environment. Learning outcomes were assessed in all selected studies: 13 studies observed changes in individual performance, four studies reported changes within the organizational level, and only five showed sustainable changes over time. Conclusion: Person-centered care (PCC) approaches, interactive and varied teaching methods, supporting conditions like champions, action plans, and setting care policies, are all characteristics of effective trainings. Successful programs should be sustainable over time, demonstrating positive outcomes across the organization. Based on current findings, there is a lack of adequate evaluation with regard to training programs on the organizational level.

Taylor N. Fields, Kimberly D. Mueller, Rebecca L. Koscik, Sterling C. Johnson, Ozioma C. Okonkwo, Ruth Y. Litovsky
Self-Reported Hearing Loss and Longitudinal Cognitive Function in a Cohort Enriched with Risk for Alzheimer’s Disease
Abstract: Background: Growing evidence suggests hearing loss is a risk factor for mild cognitive impairment and dementia, but few studies have examined its relationship to sub-clinical cognitive outcomes. Objective: To investigate the effect of self-reported hearing loss on longitudinal cognitive function in a risk-enriched cohort of clinically-unimpaired, late middle-aged adults. Methods: 579 participants from the Wisconsin Registry for Alzheimer’s Prevention (WRAP) were included. Hearing status was determined via self-reported history of diagnosed hearing loss. Each participant with self-reported hearing loss was age- and sex-matched to two participants who never reported hearing loss using nearest-neighbor matching. Linear mixed-effects models were used to examine associations between self-reported hearing loss and age-related cognitive trajectories with covariates of sex, literacy, and ethnicity, person-level random intercepts and age-related slopes. Cognitive outcomes encompassed measures of speed and flexibility, visuospatial memory, and verbal fluency. Results: Participants with self-reported hearing loss exhibited significantly poorer performance on a speed and flexibility factor score and single test of psychomotor speed and executive function, relative to participants who never reported hearing loss. There was no association between self-reported hearing loss and visuospatial memory or verbal fluency. Longitudinally, self-reported hearing loss was associated with less rapid decline in speed and flexibility and no difference in rate of decline for any other cognitive measure. Conclusion: Self-reported hearing loss was associated with poorer speed and flexibility but not with accelerated decline in any domain studied, contrary to previous findings. Further studies involving behavioral auditory measures in this cohort would clarify the robustness of these findings.

Kathy Y. Liu, Harry Costello, Suzanne Reeves, Robert Howard, for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Joshua Stott)
The Relationship Between Anxiety and Incident Agitation in Alzheimer’s Disease
Abstract: Background: Agitation in Alzheimer’s disease (AD) has been hypothesized to be an expression of anxiety, but whether anxiety early in the course of dementia could be a risk factor for developing later agitation is unknown. Objective: We used the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database to examine the longitudinal relationship between anxiety and incident agitation in individuals with a diagnosis of AD at baseline or during follow-up. Methods: Longitudinal neuropsychiatric symptom data from AD individuals who were agitation-free at study baseline (N=272) were analyzed using mixed effects regression models to test the longitudinal relationship between baseline and incident anxiety with incident agitation. Results: Anxiety at baseline was not associated with subsequent agitation, but there was a positive linear relationship between incident anxiety and agitation over the study duration. Baseline apathy and delusions were consistently associated with subsequent agitation and greater disease severity and illness duration also appeared to be risk factors for agitation. Conclusion: Our findings support the concept that anxiety and agitation are likely to be distinct rather than equivalent constructs in mild-moderate AD. Future longitudinal cohort studies are needed to replicate these findings and further characterize potential risk factors for agitation, such as apathy and delusions.

Meng-Shan Tan, Yu-Xiang Yang, Hui-Fu Wang, Wei Xu, Chen-Chen Tan, Chuan-Tao Zuo, Qiang Dong, Lan Tan, Jin-Tai Yu, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Yong Liu)
PET Amyloid and Tau Status Are Differently Affected by Patient Features
Abstract: Background: Amyloid-β (Aβ) plaques and tau neurofibrillary tangles are two neuropathological hallmarks of Alzheimer’s disease (AD), which both can be visualized in vivo using PET radiotracers, opening new opportunities to study disease mechanisms. Objective: Our study investigated 11 non-PET factors in 5 categories (including demographic, clinical, genetic, MRI, and cerebrospinal fluid (CSF) features) possibly affecting PET amyloid and tau status to explore the relationships between amyloid and tau pathology, and whether these features had a different association with amyloid and tau status. Methods: We included 372 nondemented elderly from the Alzheimer’s Disease Neuroimaging Initiative cohort. All underwent PET amyloid and tau analysis simultaneously, and were grouped into amyloid/tau quadrants based on previously established abnormality cut points. We examined the associations of above selected features with PET amyloid and tau status using a multivariable logistic regression model, then explored whether there was an obvious correlation between the significant features and PET amyloid or tau levels. Results: Our results demonstrated that PET amyloid and tau status were differently affected by patient features, and CSF biomarker features provided most significant values associating PET findings. CSF Aβ42/40 was the most important factor affecting amyloid PET status, and negatively correlated with amyloid PET levels. CSF pTau could significantly influence both amyloid and tau PET status. Besides CSF pTau and Aβ42, APOE ε4 allele status and Mini-Mental State Examination scores also could influence tau PET status, and significantly correlated with tau PET levels. Conclusion: Our results support that tau pathology possibly affected by Aβ-independent factors, implicating the importance of tau pathology in AD pathogenesis.

Claudia Bartels, Anna Kögel, Mark Schweda, Jens Wiltfang, Michael Pentzek, Silke Schicktanz, Anja Schneider
Use of Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Risk in Mild Cognitive Impairment and Subjective Cognitive Decline in Routine Clinical Care in Germany
Abstract: Background: The National Institute of Aging and Alzheimer's Association’s diagnostic recommendations for preclinical Alzheimer’s disease (AD) and mild cognitive impairment (MCI) define AD by pathological processes which can be detected by biomarkers. These criteria were established as part of a research framework intended for research purposes but progressively enter the clinical practice. Objective: We investigated the availability, frequency of use, interpretation, and therapeutic implications of biomarkers for the etiologic diagnosis and prognosis in MCI and subjective cognitive decline (SCD) in routine clinical care. Methods: We conducted a cross-sectional questionnaire survey among 215 expert dementia centers (hospitals and memory clinics) in Germany. Results: From the 98 centers (45.6% of contacted centers) included, two-thirds reported use of the cerebrospinal fluid (CSF) biomarkers Aβ42, tau, and phospho-tau in the diagnostic workup of MCI and one third in SCD. CSF biomarker analysis was more often employed by neurological (MCI 84%; SCD 42%) compared to psychiatric institutions (MCI 61%; SCD 33%; p≤0.001). Although dementia experts disagreed on the risk of progression associated with different CSF biomarker constellations, CSF biomarker results guided therapeutic decisions: ~40% of responders reported to initiate cholinesterase inhibitor therapy in MCI and 18% in SCD (p=0.006), given that all CSF biomarkers were in the pathological range. Conclusion: Considering the vast heterogeneity among dementia expert centers in use of CSF biomarker analysis, interpretation of results, and therapeutic consequences, a standardization of biomarker-based diagnosis practice in pre-dementia stages is needed.

Asma Hallab, Catharina Lange, Ivayla Apostolova, Cansu Özden, Gabriel Gonzalez-Escamilla, Susanne Klutmann, Winfried Brenner, Michel J. Grothe, Ralph Buchert, for the Alzheimer’s Disease Neuroimaging Initiative
Impairment of Everyday Spatial Navigation Abilities in Mild Cognitive Impairment Is Weakly Associated with Reduced Grey Matter Volume in the Medial Part of the Entorhinal Cortex
Abstract: Background: Research in rodents identified specific neuron populations encoding information for spatial navigation with particularly high density in the medial part of the entorhinal cortex (ERC), which may be homologous with Brodmann area 34 (BA34) in the human brain. Objective: The aim of this study was to test whether impaired spatial navigation frequently occurring in mild cognitive impairment (MCI) is specifically associated with neurodegeneration in BA34. Methods: The study included baseline data of MCI patients enrolled in the Alzheimer’s Disease Neuroimaging Initiative with high-resolution structural MRI, brain FDG PET, and complete visuospatial ability scores of the Everyday Cognition test (VS-ECog) within 30 days of PET. A standard mask of BA34 predefined in MNI space was mapped to individual native space to determine grey matter volume and metabolic activity in BA34 on MRI and on (partial volume corrected) FDG PET, respectively. The association of the VS-ECog sum score with grey matter volume and metabolic activity in BA34, APOE4 carrier status, age, education, and global cognition (ADAS-cog-13 score) was tested by linear regression. BA28, which constitutes the lateral part of the ERC, was used as control region. Results: The eligibility criteria led to inclusion of 379 MCI subjects. The VS-ECog sum score was negatively correlated with grey matter volume in BA34 (β = -0.229, p = 0.022) and age (β = -0.124, p = 0.036), and was positively correlated with ADAS-cog-13 (β = 0.175, p = 0.003). None of the other predictor variables contributed significantly. Conclusion: Impairment of spatial navigation in MCI is weakly associated with BA34 atrophy.

Zhihua Zhang*, Hongxia Sheng*, Li Liao, Chen Xu, Ang Zhang, Yang Yang, Long Zhao, Lian Duan, Hu Chen, Bin Zhang ⁎These authors contributed equally to this work.
Mesenchymal Stem Cell-Conditioned Medium Improves Mitochondrial Dysfunction and Suppresses Apoptosis in Okadaic Acid-Treated SH-SY5Y Cells by Extracellular Vesicle Mitochondrial Transfer
Abstract: Background: Mesenchymal stem cells-conditioned medium (MSC-CM) provides a promising cell-free therapy for Alzheimer’s disease (AD) mainly due to the paracrine of MSCs, but the precise mechanisms remain unclear. Studies suggests that mitochondrial dysfunction precedes the accumulation of amyloid-β plaques and neurofibrillary tangles, and involves in the onset and development of AD. Objective: In the present study, we evaluated the protective effects and explored the related-mitochondrial mechanisms of human umbilical cord derived MSC-CM (hucMSC-CM) in an AD model in vitro. Methods: To this end, an AD cellular model was firstly established by okadaic acid (OA)-treated SH-SY5Y cells, and then treated by hucMSC-CM to assess the oxidative stress, mitochondrial function, apoptosis, AD-related genes, and signaling pathways. Results: hucMSC-CM significantly deceased tau phosphorylated at Thr181 (p181-tau) level, which was increased in AD. hucMSC-CM also alleviated intracellular and mitochondrial oxidative stress in OA-treated SH-SY5Y cells. In addition, hucMSC-CM suppressed apoptosis and improved mitochondrial function in OA-treated SH-SY5Y cells. Flow cytometric analysis indicated that hucMSC-CM exerted the protective effects relying on or partly extracellular vesicle (EV) mitochondrial transfer from hucMSCs to OA-treated SH-SY5Y cells. Moreover, RNA sequencing data further demonstrated that hucMSC-CM regulated many AD-related genes, signaling pathways and mitochondrial function. Conclusion: These results indicated that MSC-CM or MSC-EVs containing abundant mitochondria may provide a novel potential therapeutic approach for AD.

Kim E. Innes, Usha Sambamoorthi
The Potential Contribution of Chronic Pain and Common Chronic Pain Conditions to Subsequent Cognitive Decline, New Onset Cognitive Impairment, and Incident Dementia: A Systematic Review and Conceptual Model for Future Research
Abstract: Background: Growing evidence suggests that chronic pain and certain chronic pain conditions may increase risk for cognitive decline and dementia. Objective: In this systematic review, we critically evaluate available evidence regarding the association of chronic pain and specific common chronic pain conditions to subsequent decline in cognitive function, new onset cognitive impairment (CI), and incident Alzheimer’s disease and related dementias (ADRD); outline major gaps in the literature; and provide a preliminary conceptual model illustrating potential pathways linking pain to cognitive change. Methods: To identify qualifying studies, we searched seven scientific databases and scanned bibliographies of identified articles and relevant review papers. Sixteen studies met our inclusion criteria (2 matched case-control, 10 retrospective cohort, 2 prospective cohort), including 11 regarding the association of osteoarthritis (N=4), fibromyalgia (N=1), or headache/migraine (N=6) to incident ADRD (N=10) and/or its subtypes (N=6), and 5 investigating the relation of chronic pain symptoms to subsequent cognitive decline (N=2), CI (N=1), and/or ADRD (N=3). Results: Studies yielded consistent evidence for a positive association of osteoarthritis and migraines/headaches to incident ADRD; however, findings regarding dementia subtypes were mixed. Emerging evidence also suggests chronic pain symptoms may accelerate cognitive decline and increase risk for memory impairment and ADRD, although findings and measures varied considerably across studies. Conclusion: While existing studies support a link between chronic pain and ADRD risk, conclusions are limited by substantial study heterogeneity, limited investigation of certain pain conditions, and methodological and other concerns characterizing most investigations to date. Additional rigorous, long-term prospective studies are needed to elucidate the effects of chronic pain and specific chronic pain conditions on cognitive decline and conversion to ADRD, and to clarify the influence of potential confounding and mediating factors.

Guilherme J. Schmidt, Yolanda Eliza Moreira Boechat, Eelco van Duinkerken, Juliana J. Schmidt, Tayssa B. Moreira, Denise H. Nicaretta, Sergio L. Schmidt (Handling Associate Editor: Andrea Tales)
Detection of Cognitive Dysfunction in Elderly with a Low Educational Level Using a Reaction-Time Attention Task
Abstract: Background: Scales for cognitive deterioration usually depend on education level. Objective: We aimed to study the clinical utility of a culture-free Go/No-Go task in a multi-ethnic cohort with low education level. Methods: Sixty-four participants with less than 4 years of formal education were included and divided on the basis of their Clinical-Dementia-Rate scores (CDR) into cognitively unimpaired (CDR=0), mild cognitive impairment (MCI; CDR=0.5), and early Alzheimer’s disease (AD, CDR=1). All underwent a 90-s Continuous Visual Attention Test. This test consisted of a 90-s Go/No-go task with 72 (80%) targets and 18 (20%) non-targets. For each participant, reaction times and intraindividual variability of reaction times of all correct target responses, as well as the number of omission and commission errors were evaluated. Coefficient of variability was calculated for each participant by dividing the standard deviation of the reaction times by the mean reaction time. A MANCOVA was performed to examine between-group differences using age and sex as covariates. Discriminate analysis was performed to find the most reliable test-variable to discriminate the three groups. Results: Commission error, intraindividual variability of reaction time, and coefficient of variability progressively worsened with increasing CDR level. Discriminant analysis demonstrated that coefficient of variability was the best discriminant factor, followed by intraindividual variability of reaction time and commission error. Conclusion: The Go/No-Go task was able to discriminate people with MCI or early AD from controls in the setting of illiteracy.

Linda Clare, Anthony Martyr, Catherine Henderson, Laura Gamble, Fiona E. Matthews, Catherine Quinn, Sharon M. Nelis, Jennifer Rusted, Jeanette Thom, Martin Knapp, Nicola Hart, Christina Victor
Living Alone with Mild-To-Moderate Dementia: Findings from the IDEAL Cohort
Abstract: Background: A significant proportion of people with dementia live alone, but little is known about their specific needs. Objective: To understand the profile of people living alone with mild-to-moderate dementia in the UK and identify any systematic differences associated with living situation. Methods: We analyzed cross-sectional data from 1,541 people with mild-to-moderate dementia and 1,277 caregivers participating in the IDEAL cohort at the first wave of assessment. Results: There were 1,256 (81.5%) people with dementia living with others and 285 (18.5%) living alone, of whom 51 (3% of whole sample) reported little or no informal support. There were relatively few differences associated with living situation and odds ratios were generally small. People living alone were older on average, and more likely to be female, than those living with others. Those living alone were more likely to have higher cognitive ability and self-reported functional ability, and more social contact with those from other households. They were also lonelier, expressed less satisfaction with life, and used home care services and equipment more. There were no differences in symptoms, mood, quality of life, or well-being. Conclusion: The findings support the view that it is possible to ‘live well’ with mild-to-moderate dementia while living alone, given appropriate support, including home care and equipment. Nevertheless, it is important to consider how those living alone may be supported to have a more satisfactory experience, and how health and social care services can best respond to their needs.

Ying Zhang*, Yajing Hao*, Lang Li, Kai Xia, Guorong Wu, for the Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
A Novel Computational Proxy for Characterizing Cognitive Reserve in Alzheimer’s Disease
Abstract: Background: Although the abnormal depositions of amyloid plaques and neurofibrillary tangles are the hallmark of Alzheimer’s disease (AD), converging evidence shows that the individual’s neurodegeneration trajectory is regulated by the brain’s capability to maintain normal cognition. Objective: The concept of cognitive reserve has been introduced into the field of neuroscience, acting as a moderating factor for explaining the paradoxical relationship between the burden of AD pathology and the clinical outcome. It is of high demand to quantify the degree of conceptual cognitive reserve on an individual basis. Methods: We propose a novel statistical model to quantify an individual’s cognitive reserve against neuropathological burdens, where the predictors include demographic data (such as age and gender), socioeconomic factors (such as education and occupation), cerebrospinal fluid biomarkers, and AD-related polygenetic risk score. We conceptualize cognitive reserve as a joint product of AD pathology and socioeconomic factors where their interaction manifests a significant role in counteracting the progression of AD in our statistical model. Results: We apply our statistical models to re-investigate the moderated neurodegeneration trajectory by considering cognitive reserve, where we have discovered that 1) high education individuals have significantly higher reserve against the neuropathology than the low education group; however, 2) the cognitive decline in the high education group is significantly faster than low education individuals after the level of pathological burden increases beyond the tipping point. Conclusion: We propose a computational proxy of cognitive reserve that can be used in clinical routine to assess the progression of AD.

Mana Shams, Juha Martola, Andreas Charidimou, Tobias Granberg, Daniel Ferreira, Eric Westman, Max Wintermark, Michael Iv, Mykol Larvie, Maria Kristoffersen Wiberg, Magnus Kaijser, Niklas Forsgard, Henrik Zetterberg, Lars-Olof Wahlund*, Sara Shams* *These two authors contributed equally to the last author position.
Cerebrospinal Fluid Metals and the Association with Cerebral Small Vessel Disease
Abstract: Background: Brain metal homeostasis is essential for brain health, and deregulation can result in oxidative stress on the brain parenchyma. Objective: Our objective in this study was to focus on two hemorrhagic MRI manifestations of small vessel disease [cerebral microbleeds (CMBs) and cortical superficial siderosis (cSS)] and associations with cerebrospinal fluid (CSF) iron levels. In addition, we aimed to analyze CSF biomarkers for dementia and associations with CSF metal levels. Methods: This is a cross-sectional study of 196 patients who underwent memory clinic investigation, including brain MRI. CSF was collected and analyzed for metals, amyloid-β (Aβ) 42, total tau (T-tau), and phosphorylated tau (P-tau), and CSF/serum albumin ratios. Statistical analyses were performed using generalized linear models. Results: No significant difference was found between CSF metal levels across diagnostic groups. Higher iron and copper levels were associated with higher CSF levels of Aβ42, T-tau, P-tau, and CSF/serum albumin ratios (p<0.05). Zinc was associated with higher CSF/serum albumin ratios. There was no significant association between CMBs or cSS and CSF iron levels. An increase in CSF iron with the number of CMBs was seen in APOE ɛ4 carriers. Conclusion: CSF iron levels are elevated with cerebral microbleeds in APOE ɛ4 carriers, with no other association seen with hemorrhagic markers of small vessel disease. The association of elevated CSF iron and copper with tau could represent findings of increased neurodegeneration in these patients.

Pankaj D. Mehta, Bruce A. Patrick, David L. Miller, Patricia K. Coyle, Thomas Wisniewski
A Sensitive and Cost-Effective Chemiluminescence ELISA for Measurement of Amyloid-β 1-42 Peptide in Human Plasma
Abstract: Background: Amyloid-β42 (Aβ42) is associated with plaque formation in the brain of patients with Alzheimer’s disease (AD). Studies have suggested the potential utility of plasma Aβ42 levels in the diagnosis, and in longitudinal study of AD pathology. Conventional ELISAs are used to measure Aβ42 levels in plasma but are not sensitive enough to quantitate low levels. Although ultrasensitive assays like single molecule array or immunoprecipitation-mass spectrometry have been developed to quantitate plasma Aβ42 levels, the high cost of instruments and reagents limit their use. Objective: We hypothesized that a sensitive and cost-effective chemiluminescence (CL) immunoassay could be developed to detect low Aβ42 levels in human plasma. Methods: We developed a sandwich ELISA using high affinity rabbit monoclonal antibody specific to Aβ42. The sensitivity of the assay was increased using CL substrate to quantitate low levels of Aβ42 in plasma. We examined the levels in plasma from 13 AD, 25 Down syndrome (DS), and 50 elderly controls. Results: The measurement range of the assay was 0.25 to 500 pg/ml. The limit of detection was 1 pg/ml. All AD, DS, and 45 of 50 control plasma showed measurable Aβ42 levels. Conclusion: This assay detects low levels of Aβ42 in plasma and does not need any expensive equipment or reagents. It offers a preferred alternative to ultrasensitive assays. Since the antibodies, peptide, and substrate are commercially available, the assay is well suited for academic or diagnostic laboratories, and has a potential for the diagnosis of AD or in clinical trials.

Brandon S. Klinedinst*, Scott T. Le*, Brittany Larsen, Colleen Pappas, Nathan J. Hoth, Amy Pollpeter, Qian Wang, Yueying Wang, Shan Yu, Li Wang, Karin Allenspach, Jonathan P. Mochel, David A. Bennett, Auriel A. Willette *These authors contributed equally to this work.
Genetic Factors of Alzheimer’s Disease Modulate How Diet Is Associated with Long-Term Cognitive Trajectories: A UK Biobank Study
Abstract: Background: Fluid intelligence (FI) involves abstract problem-solving without prior knowledge. Greater age-related FI decline increases Alzheimer’s disease (AD) risk, and recent studies suggest that certain dietary regimens may influence rates of decline. However, it is uncertain how long-term food consumption affects FI among adults with or without familial history of AD (FH) or APOE4 (ε4). Objective: Observe how the total diet is associated with long-term cognition among mid- to late-life populations at-risk and not-at-risk for AD. Methods: Among 1,787 mid-to-late-aged adult UK Biobank participants, 10-year FI trajectories were modeled and regressed onto the total diet based on self-reported intake of 49 whole foods from a Food Frequency Questionnaire (FFQ). Results: Daily cheese intake strongly predicted better FIT scores over time (FH-: β=0.207, p<0.001; ε4-: β=0.073, p=0.008; ε4+: β=0.162, p=0.001). Alcohol of any type daily also appeared beneficial (ε4+: β=0.101, p=0.022) and red wine was sometimes additionally protective (FH+: β=0.100, p=0.014; ε4-: β=0.59, p=0.039). Consuming lamb weekly was associated with improved outcomes (FH-: β=0.066, p=0.008; ε4+: β=0.097, p=0.044). Among at risk groups, added salt correlated with decreased performance (FH+: β=-0.114, p=0.004; ε4+: β=-0.121, p=0.009). Conclusion: Modifying meal plans may help minimize cognitive decline. We observed that added salt may put at-risk individuals at greater risk, but did not observe similar interactions among FH- and AD- individuals. Observations further suggest in risk status-dependent manners that adding cheese and red wine to the diet daily, and lamb on a weekly basis, may also improve long-term cognitive outcomes.