Volume 83, Number 4, IN PRESS

Mini-Forum: Photobiomodulation of the Brain: Shining Light on Alzheimer's and Other Neuropathological Diseases (Guest Editors: Michael R. Hamblin, Farzad Salehpour)

Introduction
Michael R. Hamblin, Farzad Salehpour
Photobiomodulation of the Brain: Shining Light on Alzheimer's and Other Neuropathological Diseases

Review
Daniel M. Johnstone, Catherine Hamilton, Luke C. Gordon, Cecile Moro, Napoleon Torres, Frank Nicklason, Jonathan Stone, Alim-Louis Benabid, John Mitrofanis
Exploring the Use of Intracranial and Extracranial (Remote) Photobiomodulation Devices in Parkinson’s Disease: A Comparison of Direct and Indirect Systemic Stimulations
Abstract: In recent times, photobiomodulation has been shown to be beneficial in animal models of Parkinson’s disease, improving locomotive behavior and being neuroprotective. Early observations in people with Parkinson’s disease have been positive also, with improvements in the non-motor symptoms of the disease being evident most consistently. Although the precise mechanisms behind these improvements are not clear, two have been proposed: direct stimulation, where light reaches and acts directly on the distressed neurons, and remote stimulation, where light influences cells and/or molecules that provide systemic protection, thereby acting indirectly on distressed neurons. In relation to Parkinson’s disease, given that the major zone of pathology lies deep in the brain and that light from an extracranial or external photobiomodulation device would not reach these vulnerable regions, stimulating the distressed neurons directly would require intracranial delivery of light using a device implanted close to the vulnerable regions. For indirect systemic stimulation, photobiomodulation could be applied to either the head and scalp, using a transcranial helmet, or to a more remote body part (e.g., abdomen, leg). In this review, we discuss the evidence for both the direct and indirect neuroprotective effects of photobiomodulation in Parkinson’s disease and propose that both types of treatment modality, when working together using both intracranial and extracranial devices, provide the best therapeutic option.

Luodan Yang*, Chongyun Wu*, Lorelei Tucker, Yan Dong, Yong Li, Peisheng Xu, Quanguang Zhang *These authors contributed equally to this work.
Photobiomodulation Therapy Attenuates Anxious-Depressive-Like Behavior in the TgF344 Rat Model
Abstract: Background: Anxious-depressive-like behavior has been recognized as an early endophenotype in Alzheimer’s disease (AD). Recent studies support early treatment of anxious-depressive-like behavior as a potential target to alleviate memory loss and reduce the risk of developing dementia. We hypothesize that photobiomodulation (PBM) could be an effective method to alleviate depression and anxiety at the early stage of AD pathogenesis. Objective: To analyze the effect of PBM treatment on anxious-depressive-like behavior at the early stage of AD. Methods: Using a novel transgenic AD rat model, animals were divided into wild-type, AD+sham PBM, and AD + PBM groups. Two-minute daily PBM was applied transcranially to the brain of AD animals from 2 months of age to 10 months of age. After completing PBM treatment at 10 months of age, behavioral tests were performed to measure learning, memory, and anxious-depressive-like behavior. Neuronal apoptosis, neuronal degeneration, neuronal damage, mitochondrial function, neuroinflammation, and oxidative stress were measured to test the effects of PBM on AD animals. Results: Behavioral tests showed that: 1) no spatial memory deficits were detected in TgF344 rats at 10 months of age; 2) PBM alleviated anxious-depressive-like behavior in TgF344 rats; 3) PBM attenuated neuronal damage, degeneration, and apoptosis; and 4) PBM suppresses neuroinflammation and oxidative stress. Conclusion: Our findings support our hypothesis that PBM could be an effective method to alleviate depression and anxiety during the early stage of AD development. The mechanism underlying these beneficial effects may be due to the improvement of mitochondria function and integrity and the inhibition of neuroinflammation and oxidative stress.

Farzad Salehpour, Mahsa Khademi, Michael R. Hamblin
Photobiomodulation Therapy for Dementia: A Systematic Review of Pre-Clinical and Clinical Studies
Abstract: Background: Photobiomodulation (PBM) involves the use of red and/or near-infrared light from lasers or LEDs to improve a wide range of medical disorders. Transcranial PBM, sometimes accompanied by intranasal PBM, has been tested to improve many brain disorders, including dementia. Objective: To conduct a systematic review according to PRISMA guidelines of pre-clinical and clinical studies reporting the use of PBM, which were considered relevant to dementia. Methods: Literature was searched between 1967 and 2020 using a range of keywords relevant to PBM and dementia. The light source and wavelength(s), output power, irradiance, irradiation time, fluence or total energy (dose), operation mode (continuous or pulsed) irradiation, approach and site, number of treatment sessions, as well as study outcome(s) were extracted. Results: Out of 10,473 initial articles, 36 studies met the inclusion criteria. Nine articles reported in vitro studies, 17 articles reported studies in animal models of dementia, and 10 studies were conducted in dementia patients. All of the included studies reported positive results. The clinical studies were limited by the small number of patients, lack of placebo controls in some instances, and only a few used objective neuroimaging methods. Conclusion: The preliminary evidence of clinical benefit, the lack of any adverse effects, and the remarkable ease of use, suggest larger clinical trials should be conducted as soon as possible.

Marco Antonio Caldieraro, Tatiana Laufer-Silva, Paolo Cassano
Dosimetry and Clinical Efficacy of Transcranial Photobiomodulation for Major Depression Disorder: Could they Guide Dosimetry for Alzheimer’s Disease?
Abstract: Background: Major depressive disorder (MDD) is prevalent and has significant impact on individuals and society. Cognitive symptoms are frequent in MDD and insufficiently treated by antidepressant medications. Transcranial photobiomodulation (t-PBM) is a novel device therapy which shows promise as an antidepressant and pro-cognitive treatment. To date, despite the encouraging results, the optimal stimulation parameters of t-PBM to treat MDD are not established, and clinical studies are very heterogeneous in terms of these parameters. While the literature provides guidance on the appropriate fluence to achieve therapeutic results, little is known on the other parameters. Objective: To evaluate the relationship between different parameters and the antidepressant effect of t-PBM. Methods: We reviewed clinical studies on MDD and on depressive symptoms comorbid with other diseases. We calculated the standardized effect size of the change in symptoms severity before and after t-PBM and we performed a descriptive analysis of the reviewed papers. Results: The greatest effect sizes for the antidepressant effect were found in studies using pulse-wave t-PBM with high peak irradiance (but low average irradiance) over large skin surface. One well-designed and sufficiently powered, double-blind, sham-controlled trial indicated that t-PBM with low irradiance over a small skin surface is ineffective to treat depression. Conclusion: The use of t-PBM for Alzheimer’s disease and for dementia is still at its inception; these dosimetry lessons from the use of t-PBM for depression might serve as guidance.

Agnes S. Chan, Tsz-lok Lee, Michael R. Hamblin, Mei-chun Cheung
Photobiomodulation Enhances Memory Processing in Older Adults with Mild Cognitive Impairment: A Functional Near-Infrared Spectroscopy Study
Abstract: Background: Recent studies of photobiomodulation (PBM) in patients with cognitive or psychological disorders (including traumatic brain injury, stroke, and dementia) have yielded some encouraging results. Objective: In this study, we aimed to investigate the effect of a single stimulation on memory in older adults with mild cognitive impairment (MCI). Methods: After PBM, hemodynamic changes, as a measure of functional brain activity, were evaluated using functional near-infrared spectroscopy (fNIRS). Eighteen subjects who met the criteria of MCI were randomly assigned to control and experimental groups. A single real or sham PBM session was administered to the forehead of each patient in the experimental and control groups, respectively. All subjects performed a visual memory span test before and after the stimulation, and their hemodynamic responses during the tasks were measured using fNIRS. Results: The results showed that among the MCI subjects, only those who received PBM, but not those who received the sham stimulation, demonstrated significant improvement in the visual memory performance and a reduction in the hemodynamic response during the tasks. Conclusion: These findings suggest that PBM may reduce the cognitive efforts needed to complete tasks that require high memory loads, and thus improve the cognitive performance of individuals with MCI.

Vincenza Spera*, Tatiana Sitnikova*, Meredith J. Ward, Parya Farzam, Jeremy Hughes, Samuel Gazecki, Eric Bui, Marco Maiello, Luis De Taboada, Michael R. Hamblin, Maria Angela Franceschini, Paolo Cassano *These authors contributed equally to this work.
Pilot Study on Dose-Dependent Effects of Transcranial Photobiomodulation on Brain Electrical Oscillations: A Potential Therapeutic Target in Alzheimer’s Disease
Abstract: Background: Transcranial photobiomodulation (tPBM) has recently emerged as a potential cognitive enhancement technique and clinical treatment for various neuropsychiatric and neurodegenerative disorders by delivering invisible near-infrared light to the scalp and increasing energy metabolism in the brain. Objective: We assessed whether transcranial photobiomodulation with near-infrared light modulates cerebral electrical activity through electroencephalogram (EEG) and cerebral blood flow (CBF). Methods: We conducted a single-blind, sham-controlled pilot study to test the effect of continuous (c-tPBM), pulse (p-tPBM), and sham (s-tPBM) transcranial photobiomodulation on EEG oscillations and CBF using diffuse correlation spectroscopy (DCS) in a sample of ten healthy subjects [6F/4 M; mean age 28.6±12.9 years]. c-tPBM near-infrared radiation (NIR) (830 nm; 54.8 mW/cm²; 65.8 J/cm²; 2.3 kJ) and p-tPBM (830 nm; 10 Hz; 54.8 mW/cm²; 33%; 21.7 J/cm²; 0.8 kJ) were delivered concurrently to the frontal areas by four LED clusters. EEG and DCS recordings were performed weekly before, during, and after each tPBM session. Results: c-tPBM significantly boosted gamma (t=3.02, df=7, p<0.02) and beta (t=2.91, df=7, p<0.03) EEG spectral powers in eyes-open recordings and gamma power (t=3.61, df=6, p<0.015) in eyes-closed recordings, with a widespread increase over frontal-central scalp regions. There was no significant effect of tPBM on CBF compared to sham. Conclusion: Our data suggest a dose-dependent effect of tPBM with NIR on cerebral gamma and beta neuronal activity. Altogether, our findings support the neuromodulatory effect of transcranial NIR.

Joanne Bullock-Saxton, Alexander Lehn, E-Liisa Laakso
Exploring the Effect of Combined Transcranial and Intra-Oral Photobiomodulation Therapy Over a Four-Week Period on Physical and Cognitive Outcome Measures for People with Parkinson’s Disease: A Randomized Double-Blind Placebo-Controlled Pilot Study
Abstract: Background: Neuroprotection against Parkinson’s disease degeneration by photobiomodulation has been reported in animal models but no true placebo-controlled human studies have been published. Objective: To understand if photobiomodulation therapy can produce clinically significant differences in physical performance measures in people with Parkinson’s disease; and what frequency of treatment is necessary to initiate clinical change. Methods: In a participant and assessor-blinded, randomized, placebo-controlled pilot study, 22 participants received either sham and/or active laser photobiomodulation (904 nm, 60 mW/diode, 50 Hz) for 33 s to each of 21 points at the cranium and intra-orally, on one, two or three times/week for 4 weeks. Two treatment phases were separated by a 4-week wash-out (Phase 2). Upper and lower limb physical outcome measures were assessed before and after each treatment phase. The Montreal Cognitive Assessment was evaluated prior to treatment Phase 1, and at the end of treatment Phase 3. Results: Montreal Cognitive Assessment remained stable between start and end of study. No measures demonstrated statistically significant changes. With regular treatment, the spiral (writing) test and the dynamic step test were most sensitive to change in a positive direction; and the 9-hole peg test demonstrated a minimum clinically important difference worthy of further investigation in a larger, adequately powered clinical trial. A placebo effect was noted. Conclusion: The results support the notion that combined transcranial and intra-oral photobiomodulation therapy needs to be applied at least 2 to 3 times per week for at least four weeks before some improvement in outcome measures becomes evident. Longer courses of treatment may be required.

Ji Soo Baik*, Tae Young Lee *, Nam Gyun Kim, Kyoungjune Pak, Sung-Hwa Ko, Ji Hong Min, Yong-Il Shin *These authors contributed equally to this work.
Effects of Photobiomodulation on Changes in Cognitive Function and Regional Cerebral Blood Flow in Patients with Mild Cognitive Impairment: A Pilot Uncontrolled Trial
Abstract: Background: Photobiomodulation (PBM) affects local blood flow regulation through nitric oxide generation, and various studies have reported on its effect on improving cognitive function in neurodegenerative diseases. However, the effect of PBM in the areas of the vertebral arteries (VA) and internal carotid arteries (ICA), which are the major blood-supplying arteries to the brain, has not been previously investigated. Objective: We aimed to determine whether irradiating PBM in the areas of the VA and ICA, which are the major blood-supplying arteries to the brain, improved regional cerebral blood flow (rCBF) and cognitive function. Methods: Fourteen patients with mild cognitive impairments were treated with PBM. Cognitive assessment and single-photon emission computed tomography were implemented at the baseline and at the end of PBM. Results: Regarding rCBF, statistically significant trends were found in the medial prefrontal cortex, lateral prefrontal cortex, anterior cingulate cortex, and occipital lateral cortex. Based on the cognitive assessments, statistically significant trends were found in overall cognitive function, memory, and frontal/executive function. Conclusion: We confirmed the possibility that PBM treatment in the VA and ICA areas could positively affect cognitive function by increasing rCBF. A study with a larger sample size is needed to validate the potential of PBM.

Ziqi Wang*, Yige Zhang*, Li Dong, Zihao Zheng, Dayong Zhong, Xunqin Long, Qingyan Cai, Wei Jian, Songge Zhang, Wenbin Wu, Dezhong Yao *These authors contributed equally to this work.
Effects of Morning Blue-Green 500 nm Light Therapy on Cognition and Biomarkers in Middle-Aged and Older Adults with Subjective Cognitive Decline and Mild Cognitive Impairment: Study Protocol for a Randomized Controlled Trial
Abstract: Background: Given that there is no specific drug to treat Alzheimer's disease, non-pharmacologic interventions in people with subjective cognitive decline (SCD) and amnestic mild cognitive impairment (aMCI) are one of the most important treatment strategies. Objective: To clarify the efficacy of blue-green (500 nm) light therapy on sleep, mood, and physiological parameters in patients with SCD and aMCI is an interesting avenue to explore. Methods: This is a monocentric, randomized, and controlled trial that will last for 4 weeks. We will recruit 150 individuals aged 45 years or older from memory clinics and divide them into 5 groups: SCD treatment (n = 30), SCD control (n = 30), aMCI treatment (n = 30), aMCI control (n = 30), and a group of healthy adult subjects (n = 30) as a normal control (NC). Results: The primary outcome is the change in subjective and objective cognitive performance between baseline and postintervention visits (4 weeks after baseline). Secondary outcomes include changes in performance assessing from baseline, postintervention to follow-up (3 months after the intervention), as well as sleep, mood, and physiological parameters (including blood, urine, electrophysiology, and neuroimaging biomarkers). Conclusion: This study aims to provide evidence of the impact of light therapy on subjective and objective cognitive performance in middle-aged and older adults with SCD or aMCI. In addition, we will identify possible neurophysiological mechanisms of action underlying light therapy. Overall, this trial will contribute to the establishment of light therapy in the prevention of Alzheimer’s disease.

Regular Section

Review
Sanchari Mukhopadhyay, Debanjan Banerjee (Handling Associate Editor: Jagannatha Rao Kosagisharaf)
A Primer on the Evolution of Aducanumab: The First Antibody Approved for Treatment of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most common form of dementia with global burden projected to triple by 2050. It incurs significant biopsychosocial burden worldwide with limited treatment options. Aducanumab is the first monoclonal antibody recently approved by the US-FDA for mild AD through the accelerated approval pathway. It is the first molecule to be approved for AD since 2003 and carries with it a therapeutic promise for the future. As the definition of AD has evolved from a pathological entity to a clinic-biological construct over the years, the amyloid-β (Aβ) pathway has been increasingly implicated in its pathogenesis. The approval of Aducanumab is based on reduction of the Aβ load in the brain, which forms a surrogate marker for this pathway. The research populace has, however, been globally divided by skepticism and hope regarding this approval. Failure to meet clinical endpoints in the trials, alleged transparency issues, cost-effectiveness, potential adverse effects, need for regular monitoring, and critique of ‘amyloid cascade hypothesis’ itself are the main caveats concerning the antibody. With this controversy in background, this paper critically looks at antibody research in AD therapeutics, evidence, and evolution of Aducanumab as a drug and the potential clinical implications of its use in future. While the efficacy of this monoclonal antibody in AD stands as a test of time, based on the growing evidence it is vital to rethink and explore alternate pathways of pathogenesis (oxidate stress, neuroinflammation, cholesterol metabolism, vascular factors, etc.) as possible therapeutic targets that may help elucidate the enigma of this complex yet progressive and debilitating neurodegenerative disorder.

Review
Feifei Ge, Donglin Zhu, Minjie Tian, Jingping Shi
The Role of Thyroid Function in Alzheimer’s Disease
Abstract: The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer's disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.

Review
Kevin Morris*, Mohammad Nami*, Joe F. Bolanos*, Maria A. Lobo, Melody Sadri-Naini, John Fiallos, Gilberto E. Sanchez, Teshia Bustos, Nikita Chintam, Marco Amaya, Susanne E. Strand, Alero Mayuku-Dore, Indira Sakibova, Grace Maria Nicole Biso, Alejandro DeFilippis, Daniela Bravo, Nevzat Tarhan, Carsten Claussen, Alejandro Mercado, Serge Braun, Louis Yuge, Shigeo Okabe, Farhad Taghizadeh-Hesary, Konstantin Kotliar, Christina Sadowsky, P. Sarat Chandra, Manjari Tripathi, Vasileios Katsaros, Brian Mehling, Maryam Noroozian, Kazem Abbasioun, Abbas Amirjamshidi, Gholam-Ali Hossein-Zadeh, Faridedin Naraghi, Mojtaba Barzegar, Ali A. Asadi-Pooya, Sajad Sahab-Negah, Saeid Sadeghian, Margaret Fahnestock, Nesrin Dilbaz, Namath Hussain, Zoltan Mari, Robert W Thatcher, Daniel Sipple, Kuldip Sidhu, Deepak Chopra, Francesco Costa, Giannantonio Spena, Ted Berger, Deborah Zelinsky, Christopher J. Wheeler, J. Wesson Ashford, Reinhard Schulte, M. A. Nezami, Harry Kloor, Aaron Filler, Dawn S. Eliashiv, Dipen Sinha, Antonio A.F. DeSalles, Venkatraman Sadanand, Sergey Suchkov, Ken Green, Barish Metin, Robert Hariri, Jason Cormier, Vicky Yamamoto, Babak Kateb *These authors contributed equally to this work.
Neuroscience20 (BRAIN20, SPINE20, and MENTAL20) Health Initiative: A Global Consortium Addressing the Human and Economic Burden of Brain, Spine, and Mental Disorders Through Neurotech Innovations and Policies
Abstract: Neurological disorders significantly impact the world's economy due to their often chronic and life-threatening nature afflicting individuals which, in turn, creates a global disease burden. The Group of Twenty (G20) member nations, which represent the largest economies globally, should come together to formulate a plan on how to overcome this burden. The Neuroscience-20 (N20) initiative of the Society for Brain Mapping and Therapeutics (SBMT) is at the vanguard of this global collaboration to comprehensively raise awareness about brain, spine, and mental disorders worldwide. This paper aims to provide a comprehensive review of the various brain initiatives worldwide and highlight the need for cooperation and recommend ways to bring down costs associated with the discovery and treatment of neurological disorders. Our systematic search revealed that the cost of neurological and psychiatric disorders to the world economy by 2030 is roughly $16T. The cost to the economy of the United States is $1.5T annually and growing given the impact of COVID-19. We also discovered there is a shortfall of effective collaboration between nations and a lack of resources in developing countries. Current statistical analyses on the cost of neurological disorders to the world economy strongly suggest that there is a great need for investment in neurotechnology and innovation or fast-tracking therapeutics and diagnostics to curb these costs. During the current COVID-19 pandemic, SBMT, through this paper, intends to showcase the importance of worldwide collaborations to reduce the population's economic and health burden, specifically regarding neurological/brain, spine, and mental disorders.

Yen Ying Lim, Darshini Ayton, Stephanie Perin, Alexandra Lavale, Nawaf Yassi, Rachel Buckley, Christopher Barton, Loren Bruns Jr, Renata Morello, Stephanie Pirotta, Emily Rosenich, Shanthakumar W. Rajaratnam, Richard Sinnott, Amy Brodtmann, Ashley I. Bush, Paul Maruff, Leonid Churilov, Anna Barker, Matthew P. Pase, on behalf of the BetterBrains Research Group
An Online, Person-Centered, Risk Factor Management Program to Prevent Cognitive Decline: Protocol for A Prospective Behavior-Modification Blinded Endpoint Randomized Controlled Trial
Abstract: Background: Several modifiable risk factors for dementia have been identified, although the extent to which their modification leads to improved cognitive outcomes remains unclear. Objective: The primary aim is to test the hypothesis that a behavior modification intervention program targeting personalized risk factors prevents cognitive decline in community-dwelling, middle-aged adults with a family history of dementia. Methods: This is a prospective, risk factor management, blinded endpoint, randomized, controlled trial, where 1510 cognitively normal, community-dwelling adults aged 40-70 years old will be recruited. Participants will be screened for risk factors related to vascular health (including physical inactivity), mental health, sleep, and cognitive/social engagement. The intervention is an online person-centered risk factor management program: BetterBrains. Participants randomized to intervention will receive telehealth-based person-centered goal setting, motivational interviewing, and follow-up support, health care provider communication and community linkage for management of known modifiable risk factors of dementia. Psychoeducational health information will be provided to both control and intervention groups. Results: The primary outcome is favorable cognitive performance at 24-months post-baseline, defined as the absence of decline on one or more of the following cognitive tests: (a) Cogstate Detection, (b) Cogstate One Card Learning, (c) Cogstate One Back, and (d) Cognitive Function Instrument total score. Conclusion: We will test the hypothesis that the BetterBrains intervention program can prevent cognitive decline. By leveraging existing community services and using a risk factor management pathway that tailors the intervention to each participant, we maximize likelihood for engagement, long-term adherence, and for preserving cognitive function in at-risk individuals.

Nikki L. Hill, Sakshi Bhargava, Emily Bratlee-Whitaker, Jennifer R. Turner, Monique J. Brown, Jacqueline Mogle (Handling Associate Editor: Kerryn Pike)
Longitudinal Relationships Between Subjective Cognitive Decline and Objective Memory: Depressive Symptoms Mediate Between-Person Associations
Abstract: Background: Subjective cognitive decline (SCD) may be an early indicator of cognitive impairment, but depressive symptoms can confound this relationship. Associations may be influenced by differences between individuals (i.e., between-persons) or how each individual changes in their experiences over time (i.e., within-persons). Objective: We examined depressive symptoms as a mediator of the between- and within-person associations of SCD and objective memory in older adults. Methods: Coordinated analyses were conducted across four datasets drawn from large longitudinal studies. Samples (range: n=1,889 to n=15,841) included participants 65 years of age or older with no dementia at baseline. We used multilevel structural equation modeling to examine the mediation of SCD and objective memory through depressive symptoms, as well as direct relationships among SCD, objective memory, and depressive symptoms. Results: Older adults who were more likely to report SCD had lower objective memory on average (between-person associations), and depressive symptoms partially mediated this relationship in three of four datasets. However, changes in depressive symptoms did not mediate the relationship between reports of SCD and declines in objective memory in three of four datasets (within-person associations). Conclusion: Individual differences in depressive symptoms, and not changes in an individual’s depressive symptoms over time, partially explain the link between SCD and objective memory. Older adults with SCD and depressive symptoms may be at greater risk for poor cognitive outcomes. Future research should explore how perceived changes in memory affect other aspects of psychological well-being, and how these relationships influence cognitive decline and Alzheimer’s disease risk.

Kelly J. Atkins, David Scott, Brendan Silbert, Kerryn E. Pike, Lis Evered
Preventing Delirium and Promoting Long-Term Brain Health: A Clinical Trial Design for the Perioperative Cognitive Enhancement (PROTECT) Trial
Abstract: Background: Perioperative neurocognitive disorders (PND), including postoperative delirium (POD), are common in older adults and, for many, precipitate functional decline and/or dementia. Objective: In this protocol, we describe a novel multidisciplinary, multicomponent perioperative intervention that seeks to prevent or reduce POD and associated cognitive decline. Methods: We will conduct a prospective, single-blind, pragmatic, randomized-controlled trial to compare our tailored multi-disciplinary perioperative pathway against current standard of care practices. We will recruit a total of 692 elective surgical patients aged 65 years or more and randomize them in a 1:1 design. Our perioperative intervention targets delirium risk reduction strategies by emphasizing the importance of early mobilization, nutrition, hydration, cognitive orientation, sensory aids, and avoiding polypharmacy. To promote healthy behavior change, we will provide a tailored psychoeducation program both pre- and postoperatively, focusing on cardiovascular and psychosocial risks for cognitive and functional decline. Results: Our primary outcome is the incidence of any PND (encapsulating POD and mild or major postoperative neurocognitive disorder) at three months postoperative. Secondary outcomes include any incidence of POD or neurocognitive disorder at 12 months. A specialized delirium screening instrument, the Confusion Assessment Method (3D-CAM), and a neuropsychological test battery, will inform our primary and secondary outcomes. Conclusion: Delirium is a common and debilitating postoperative complication that contributes to the cognitive and functional decline of older adults. By adopting a multicomponent, multidisciplinary approach to perioperative delirium prevention, we seek to reduce the burden of delirium and subsequent dementia in older adults.

Gry H.E. Syverstad Skaaraas, Christoffer Melbye, Maja A. Puchades, Doreen Siu Yi Leung, Øyvind Jacobsen, Shreyas B. Rao, Ole Petter Ottersen, Trygve B. Leergaard, Reidun Torp
Cerebral Amyloid Angiopathy in a Mouse Model of Alzheimer’s Disease Associates with Upregulated Angiopoietin and Downregulated Hypoxia-Inducible Factor
Abstract: Background: Vascular pathology is a common feature in patients with advanced Alzheimer’s disease, with cerebral amyloid angiopathy (CAA) and microvascular changes commonly observed at autopsies and in genetic mouse models. However, despite a plethora of studies addressing the possible impact of CAA on brain vasculature, results have remained contradictory, showing reduced, unchanged, or even increased capillary densities in human and rodent brains overexpressing amyloid-β in Alzheimer’s disease and Down’s syndrome. Objective: We asked if CAA is associated with changes in angiogenetic factors or receptors and if so, whether this would translate into morphological alterations in pericyte coverage and vessel density. Methods: We utilized the transgenic mice carrying the Arctic (E693G) and Swedish (KM670/6701NL) amyloid precursor protein which develop severe CAA in addition to parenchymal plaques. Results: The main finding of the present study was that CAA in Tg-ArcSwe mice is associated with upregulated angiopoietin and downregulated hypoxia-inducible factor. In the same mice, we combined immunohistochemistry and electron microscopy to quantify the extent of CAA and investigate to which degree vessels associated with amyloid plaques were pathologically affected. We found that despite a severe amount of CAA and alterations in several angiogenetic factors in Tg-ArcSwe mice, this was not translated into significant morphological alterations like changes in pericyte coverage or vessel density. Conclusion: Our data suggest that CAA does not impact vascular density but might affect capillary turnover by causing changes in the expression levels of angiogenetic factors.

Cuiling Wang, Mindy J. Katz, Katherine H. Chang, Jiyue Qin, Richard B. Lipton , Jessica L. Zwerling, Martin J. Sliwinski, Carol A. Derby, Laura Rabin (Handling Associate Editor: Erin Abner)
UDSNB 3.0 Neuropsychological Test Norms in Older Adults from a Diverse Community: Results from the Einstein Aging Study (EAS)
Abstract: Background: The Uniform Data Set, Version 3 Neuropsychological Battery (UDSNB3.0), from the database of the University of Washington’s National Alzheimer’s Coordinating Center (NACC), is widely used to characterize cognitive performance in clinical and research settings; however, norms for underrepresented community-based samples are scarce. Objective: We compared UDSNB 3.0 test scores between the Einstein Aging Study (EAS), composed of racially/ethnically diverse, community-dwelling older adults aged ≥70 and the NACC, and report normative data from the EAS. Methods: Analyses included 225 cognitively normal EAS participants and comparable data from 5,031 NACC database participants. Linear regression models compared performance between the samples, adjusting for demographics (sex, age, education, race/ethnicity), depressive symptoms, and whether English was the first language. Linear regression models to examine demographic factors including age, sex, education and race/ethnicity as predictors for the neuropsychological tests were applied in EAS and NACC separately and were used to create a demographically adjusted z-score calculator. Results: Cognitive performance across all domains was worse in the EAS than in the NACC, adjusting for age, sex, education, race/ethnicity, and depression, and the differences remained in visuo-construction, visuospatial memory, confrontation naming, visual attention/processing speed, and executive functioning after further adjusting for whether English was the first language. In both samples, non-Hispanic Whites outperformed non-Hispanic Blacks and more education was associated with better cognitive performance. Conclusion: Differences observed in demographic, clinical, and cognitive characteristics between the community-based EAS sample and the nationwide NACC sample suggest that separate normative data that more accurately reflect non-clinic, community-based populations should be established.

Zaina P. Qureshi, Ellen Thiel, James Nelson, Rezaul Khandker
Incremental Healthcare Utilization and Cost Burden of Comorbid Insomnia in Alzheimer’s Disease Patients
Abstract: Background: Insomnia is associated with worsened clinical outcomes among Alzheimer’s disease dementia (AD) patients, increased caregiver burden, and healthcare utilization. Objective: This study aimed to characterize the incremental healthcare burden of insomnia in AD using real-world data. Methods: A retrospective observational study was conducted on AD patients selected from the IBM® MarketScan Commercial and Medicare Supplemental Databases. AD patients with claims-based evidence of insomnia were direct matched to a non-insomnia cohort based on demographic factors. Healthcare utilization and associated costs were assessed for a 12-month follow-up period. Results: A total of 3,500 insomnia AD patients and 9,884 non-insomnia AD patients were analyzed. The insomnia cohort had a higher comorbidity burden at baseline (mean score on Charlson Comorbidity Index 2.5 versus 2.2, p<0.001) and higher proportions of patients with baseline diagnoses for other conditions including depression: 40%, insomnia cohort versus 25%, non-insomnia (p<0.001). AD patients with insomnia were more likely to have a claim for inpatient hospitalizations (39.8% versus 32.3%), emergency room services (56.4% versus 48.0%), and skilled-nursing services (42.6% versus 31.9%) (all p<0.05). Mean total annual healthcare costs during the 12-month follow-up period were significantly higher among AD patients with insomnia as compared to those without. (Mean costs: $37,356 versus $27,990, p<0.001). Conclusion: AD patients with comorbid insomnia are more likely to use higher-cost healthcare services such as inpatient hospitalization, and skilled nursing, and have higher total healthcare costs. This real-world analysis provides evidence that AD disease management should consider proper treatment of comorbid insomnia due to the incremental burden and cost implications.

Jorge A. Sierra-Fonseca, Minerva Rodriguez, Anapaula Themann, Omar Lira, Francisco J. Flores-Ramirez, Javier Vargas-Medrano, Bharathi S. Gadad, Sergio D. Iñiguez
Autophagy Induction and Accumulation of Phosphorylated Tau in the Hippocampus and Prefrontal Cortex of Adult C57BL/6 Mice Subjected to Adolescent Fluoxetine Treatment
Abstract: Background: Fluoxetine (FLX) represents the antidepressant of choice for the management of pediatric mood-related illnesses. Accumulating preclinical evidence suggests that ontogenic FLX exposure leads to deregulated affect-related phenotypes in adulthood. Mood-related symptomatology constitutes a risk-factor for various neurological disorders, including Alzheimer’s disease (AD), making it possible for juvenile FLX history to exacerbate the development of neurodegenerative diseases. Objective: Because AD is characterized by the pathological accumulation of hyperphosphorylated tau, which can result from impaired function of protein degradation pathways, such as autophagy and the ubiquitin-proteasome system (UPS), we evaluated the long-term effects of adolescent FLX exposure on these pathways, using mice as a model system. Methods: We subjected C57BL/6 adolescent male mice to FLX (20 mg/kg/day) from postnatal day (PD) 35 to PD49. Twenty-one days after the last FLX injection (i.e., adulthood; PD70), mice were euthanized and, using immunoblotting analysis, we evaluated protein markers of autophagy (Beclin-1, LC3-II, p62) and the UPS (K48-pUb), as well as AD-associated forms of phosphorylated tau, within the hippocampus and prefrontal cortex. Results: Juvenile FLX pre-exposure mediated long-term changes in the expression of protein markers (increased LC3-II and decreased p62) that is consistent with autophagy activation, particularly in the prefrontal cortex. Furthermore, FLX history induced persistent accumulation of AD-associated variants of tau in both the hippocampus and prefrontal cortex. Conclusion: Adolescent FLX treatment may have enduring effects in the neuronal protein degradation machinery, which could adversely influence clearance of abnormal proteins, potentially predisposing individuals to developing AD in later life.

Jeffrey Cummings, Gregory G. Schwartz, Stephen J. Nicholls, Aziz Khan, Chris Halliday, Peter P. Toth, Michael Sweeney, Jan O. Johansson, Norman C.W. Wong, Ewelina Kulikowski, Kamyar Kalantar-Zadeh, Kenneth Lebioda, Henry N. Ginsberg, Bengt Winblad, Henrik Zetterbergj, Kausik K. Ray (Handling Associate Editor: Babak Tousi)
Cognitive Effects of the BET Protein Inhibitor Apabetalone: A Prespecified Montreal Cognitive Assessment Analysis Nested in the BETonMACE Randomized Controlled Trial
Abstract: Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. 464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score ≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score ≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of ≤21 (p = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders.

Giulia Bommarito, Dimitri Van De Ville, Giovanni B. Frisoni, Valentina Garibotto, Federica Ribaldi, Sara Stampacchia, Frédéric Assal, Gilles Allali, Alessandra Griffa
Alzheimer’s Disease Biomarkers in Idiopathic Normal Pressure Hydrocephalus: Linking Functional Connectivity and Clinical Outcome
Abstract: Background: Alzheimer’s disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC). Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC, in iNPH patients based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD. Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels. Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT in iNPH. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp. Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH.

Prashanthi Vemuri, Cynthia Davey, Kirsten L. Johansen, Samantha M. Zuk, Robert I. Reid, Kaely B. Thostenson, Ashritha L. Reddy, Clifford R. Jack Jr., David S. Knopman, Anne M. Murray
Chronic Kidney Disease Associated with Worsening White Matter Disease and Ventricular Enlargement
Abstract: Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase.

Jing–jing Zhang, Lin Li, Dan Liu, Fei-fei Hu, Gui–rong Cheng, Lang Xu, Ping–ting Yan, Yuan Tian, Heng Hu, Ya–fu Yu, Xu–guang Gan, Li–na An, Bo Zhang, Jin Qian, Li–yan Fu, Xi Cheng, Peng–fei Lian, Ming–jun Zou, Chong Chen, Qing–ming Wu, Yan Zeng
Urban–Rural Disparities in the Association Between Body Mass Index and Cognitive Impairment in Older Adults: A Cross–Sectional Study in Central China
Abstract: Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. Objective: This cross–sectional study investigated the associations between BMI and cognitive impairment among community–dwelling older adults from rural and urban areas. Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. Results: Being underweight in the rural–dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural–dwelling participants aged 65–69 years and 75–79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03–1.83; p < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas.

Maria Pisu, Roy C. Martin, Liang Shan, Giovanna Pilonieta, Richard E. Kennedy, Gabriela Oates, Young-Il Kim, David S. Geldmacher
Dementia Care in Diverse Older Adults in the U.S. Deep South and the Rest of the United States
Abstract: Background: Use of specialists and recommended drugs has beneficial effects for older adults living with Alzheimer’s disease and related dementia (ADRD). Gaps in care may exist for minorities, e.g., Blacks, and especially in the United States (U.S.) Deep South (DS), a poor U.S. region with rising ADRD cases and minority overrepresentation. Currently, we have little understanding of ADRD care utilization in diverse populations in this region and elsewhere in the U.S. (non-DS), and the factors that adversely impact it. Objective: To examine utilization of specialists and ADRD drugs (outcomes) in racial/ethnic groups of older adults with ADRD and the personal or context-level factors affecting these outcomes in DS and non-DS. Methods: We obtained outcomes and personal-level covariates from claims for 127,512 Medicare beneficiaries with ADRD in 2013-2015, and combined county-level data in exploratory factor analysis to define context-level covariates. Adjusted analyses tested significant association of outcomes with Black/White race and other factors in DS and non-DS. Results: Across racial/ethnic groups, 33%-43% in DS and 43%-50% in non-DS used specialists; 47%-55% in DS and 41%-48% in non-DS used ADRD drugs. In adjusted analyses, differences between Blacks and Whites were not significant. Vascular dementia, comorbidities, poverty, and context-level factor “Availability of Medical Resources” were associated with specialist use; Alzheimer’s disease and senile dementia, comorbidities, and specialist use were associated with drug use. In non-DS only, other individual, context-level covariates were associated with the outcomes. Conclusion: We did not observe significant gaps in ADRD care in DS and non-DS; however, research should further examine determinants of low specialist and drug use in these regions.

Heather Ma, Rachel E. Kiekhofer, Sarah M. Hooper, Sarah Dulaney, Katherine L. Possin, Winston Chiong
Goals of Care Conversations and Subsequent Advance Care Planning Outcomes for People with Dementia
Abstract: Background: Advance care planning has been shown to improve end of life decision-making for people with dementia. However, the impact of goals of care conversations between people with dementia and their caregivers has not been characterized. Objective: In this study, we evaluate the association between goals of care conversations and advance care planning outcomes. Methods: Retrospective advance care planning measures were collected via a questionnaire administered to 166 caregivers after the death of the person with dementia for whom they provided care. Results: At time of death, the majority of decedents with dementia had advance directives, health care agents, and previous goals of care conversations with their caregiver. Goals of care conversations were significantly associated with the perceived usefulness of advance directives, the perceived adherence to advance directives, and decedent dying at their desired place of death, but not with disagreements around end-of-life care. Conclusion: Our findings suggest that goals of care conversations are an important component of advance care planning. These findings support the development of interventions that facilitate such conversations between people with dementia and their caregivers.

Moritz Platen, Steffen Fleßa, Anika Rädke, Diana Wucherer, Jochen René Thyrian, Wiebke Mohr, Annelie Scharf, Franka Mühlichen, Wolfgang Hoffmann, Bernhard Michalowsky (Handling Associate Editor: Anders Wimo)
Prevalence of Low-Value Care and Its Associations with Patient-Centered Outcomes in Dementia
Abstract: Background: Low-value care (LvC) is defined as care unlikely to provide a benefit to the patient regarding the patient's preferences, potential harms, costs, or available alternatives. Avoiding LvC and promoting recommended evidence-based treatments, referred to as high-value care (HvC), could improve patient-reported outcomes for people living with dementia (PwD). Objective: This study aims to determine the prevalence of LvC and HvC in dementia and the associations of LvC and HvC with patients' quality of life and hospitalization. Methods: The analysis was based on data of the DelpHi trial and included 516 PwD. Dementia-specific guidelines, the "Choosing Wisely" campaign and the PRISCUS list were used to indicate LvC and HvC treatments, resulting in 347 LvC and HvC related recommendations. Of these, 77 recommendations (51 for LvC, 26 for HvC) were measured within the DelpHi-trial and finally used for this analysis. The association of LvC and HvC treatments with PwD health-related quality of life (HRQoL) and hospitalization was assessed using multiple regression models. Results: LvC was highly prevalent in PwD (31%). PwD receiving LvC had a significantly lower quality of life (b=-0.07; 95% CI 0.14– 0.01) and were significantly more likely to be hospitalized (OR=2.06; 95% CI 1.26–3.39). Different HvC treatments were associated with both positive and negative changes in HRQoL. Conclusion: LvC could cause adverse outcomes and should be identified as early as possible and tried to be replaced. Future research should examine innovative models of care or treatment pathways supporting the identification and replacement of LvC in dementia.

Sara Isernia*, Monia Cabinio*, Sonia Di Tella, Stefania Pazzi, Federica Vannetti, Filippo Gerli, Irene Eleonora Mosca, Gemma Lombardi, Claudio Macchi, Sandro Sorbi, Francesca Baglio (Handling Associate Editor: Marco Bozzali) *These authors contributed equally to this work.
Diagnostic Validity of the Smart Aging Serious Game: An Innovative Tool for Digital Phenotyping of Mild Neurocognitive Disorder
Abstract: Background: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. Objective: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. Methods: 161 subjects (74 HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. Results: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs>0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable-to-excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). Conclusion: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation.

Emily M. Briceño, Alden L. Gross, Bruno J. Giordani, Jennifer J. Manly, Rebecca F. Gottesman, Mitchell S.V. Elkind, Stephen Sidney, Stephanie Hingtgen, Ralph L. Sacco, Clinton B. Wright, Annette Fitzpatrick, Alison E. Fohner, Thomas H. Mosley, Kristine Yaffe, Deborah A. Levine
Pre-Statistical Considerations for Harmonization of Cognitive Instruments: Harmonization of ARIC, CARDIA, CHS, FHS, MESA, and NOMAS
Abstract: Background: Meta-analyses of individuals’ cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item’s administration and scoring procedures, and score distributions. Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42% were common across ≥2 cohorts. 86% of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies.

Zhizhong Zhang, Mengmeng Wang, Shuai Yuan, Huan Cai, Shuang-Gen Zhu, Xinfeng Liu
Genetically Predicted Coffee Consumption and Risk of Alzheimer’s Disease and Stroke
Abstract: Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n = 54,162), ischemic stroke (n = 440,328), and intracerebral hemorrhage (ICH, n = 3,026) was adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased risk of AD (OR = 1.26, 95% CI = 1.05-1.51). Moreover, genetically predicted 50% increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95% CI: 1.08-4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95% CI: 0.51-0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p < 0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study.

Alex Handy, Jodie Lord, Rebecca Green, Jin Xu, Dag Aarsland, Latha Velayudhan, Abdul Hye, Richard Dobson, Petroula Proitsi; on behalf of the Alzheimer’s Disease Neuroimaging initiative*, AddNeuroMed, and the GERAD1 Consortium (Handling Associate Editor: Madhav Thambisetty)
Assessing Genetic Overlap and Causality Between Blood Plasma Proteins and Alzheimer’s Disease
Abstract: Background: Blood plasma proteins have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/- PRS) and tested for association with AD status across three cohorts (n=6,244). An AD PRS was also tested for association with protein levels in one cohort (n=410). Proteins showing association with AD were taken forward for MR. Results: For APOE ε3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p<0.00017). No protein APOE- PRS or AD PRS (APOE+/-) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p=0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p=0.025, protein APOE- PRS p=0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p<0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power.

Mohamad El Haj, Philippe Allain, Cédric Annweiler, Claire Boutoleau-Bretonnière, Guillaume Chapelet, Karim Gallouj, Dimitrios Kapogiannis, Jean Roche, Abdel Halim Boudoukha
High Exhaustion in Geriatric Healthcare Professionals During the COVID-19 Second Lockdown
Abstract: Background: In a previous study, we assessed burnout in geriatric healthcare workers during the first lockdown that lasted from March to May 2020 in France, in response to the COVID-19 crisis. Objective: We carried out a follow-up study to assess burnout in the same population during the second lockdown that was implemented at the end of October 2020. Methods: We used an online survey to assess burnout in terms of exhaustion and disengagement in a sample of 58 geriatric healthcare workers. Results: We found higher levels of exhaustion, disengagement, and burnout among geriatric healthcare workers during the second than during the first lockdown. We also found high levels of exhaustion but moderate disengagement and burnout during the second lockdown. Conclusion: The increased exhaustion, disengagement, and burnout during the second lockdown can be attributed to the increased workload in geriatric facilities throughout this crisis and during the second lockdown due to shortage in staff and increased number of shifts and allocated duties. The high levels of exhaustion reported among geriatric healthcare workers during the second lockdown can reflect their physical fatigue, as well as their feelings of being emotionally overextended and exhausted by their workload.

Marco Canevelli, Alessandra Di Pucchio, Fabrizio Marzolini, Flavia Mayer, Marco Massari, Emanuela Salvi, Ilaria Palazzesi, Eleonora Lacorte, Ilaria Bacigalupo, Teresa Di Fiandra, Nicola Vanacore
A National Survey of Centers for Cognitive Disorders and Dementias in Italy
Abstract: Background: Italy has one of the oldest populations in the World and more than one million dementia cases can be estimated at the national level. Objective: The objectives of this national survey include: 1) to report the administrative features and the professional competencies of Centers for Cognitive Disorders and Dementias (CCDDs); 2) to document possible discrepancies by geographic macro-area; and 3) to identify the features of CCDDs that are associated with a better quality in the provision of care. Methods: A survey of Italian CCDDs was conducted between February 2014 and December 2015. A list of CCDDs was obtained through direct interactions with designed delegates from each Italian region. A questionnaire was defined on five sections concerning: 1) location of the CCDD; 2) access to the CCDD; 3) organization of the CCDD; 4) services and treatments provided; and 5) quantitative data on the activities of the CCDD. Results: Overall, 577 out of the 597 eligible CCDDs returned the completed survey questionnaire (response rate: 96.6%): 260 (45.1%) from Northern Italy, 103 (17.8%) from Central Italy, and 214 (37.1%) from Southern-Islands Italy. More than a third of CCDDs were open only once or twice weekly. A median of 450 (IQR: 200-800) patients regularly attended these services. Most patients (70%) were affected by dementia or mild cognitive impairment (19%). Conclusion: We have provided a snapshot of the organization and activities of CCDDs in Italy and documented existing inequalities in the provision of care.

Zihuan Liu, Tapabrata Maiti, Andrew R. Bender for the Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Ali Ezzati)
A Role for Prior Knowledge in Statistical Classification of the Transition from Mild Cognitive Impairment to Alzheimer’s Disease
Abstract: Background: The transition from mild cognitive impairment (MCI) to dementia is of great interest to clinical research on Alzheimer’s disease and related dementias. This phenomenon also serves as a valuable data source for quantitative methodological researchers developing new approaches for classification. However, the growth of machine learning (ML) approaches for classification may falsely lead many clinical researchers to underestimate the value of logistic regression (LR), which often demonstrates classification accuracy equivalent or superior to other ML methods. Further, when faced with many potential features that could be used for classifying the transition, clinical researchers are often unaware of the relative value of different approaches for variable selection. Objective: The present study sought to compare different methods for statistical classification and for automated and theoretically guided feature selection techniques in the context of predicting conversion from MCI to dementia. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate different influences of automated feature preselection on LR and support vector machine (SVM) classification methods, in classifying conversion from MCI to dementia. Results: The present findings demonstrate how similar performance can be achieved using user-guided, clinically informed pre-selection versus algorithmic feature selection techniques. Conclusion: These results show that although SVM and other ML techniques are capable of relatively accurate classification, similar or higher accuracy can often be achieved by LR, mitigating SVM’s necessity or value for many clinical researchers.

Michela Pievani, Anna Mega, Giulia Quattrini, Giacomo Guidali, Clarissa Ferrari, Annamaria Cattaneo, Ilari D’Aprile, Lorella Mascaro, Roberto Gasparotti, Daniele Corbo, Debora Brignani, Marta Bortoletto
Targeting Default Mode Network Dysfunction in Persons at Risk of Alzheimer's Disease with Transcranial Magnetic Stimulation (NEST4AD): Rationale and Study Design
Abstract: Background: Default mode network (DMN) dysfunction is well established in Alzheimer's disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. Objective: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE) ε4 allele. Methods: We will recruit 64 older participants without cognitive deficits, 32 APOE ε4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. Results: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ε4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. Conclusion: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD.

Dennis van de Veen, Christian Bakker, Kirsten Peetoom, Yolande Pijnenburg, Janne M. Papma, the PRECODE study group, Marjolein de Vugt, Raymond Koopmans (Handling Associate Editor: Nagaendran Kandiah)
An Integrative Literature Review on the Nomenclature and Definition of Dementia at a Young Age
Abstract: Background: There has been growing interest in young people living with dementia. Future research requires consensus on the terminology and operational definition of this group. Objective: The purpose of this integrative review was to explore and include all operational definitions used to define dementia at a young age. Methods: On August 14, 2020, the PubMed, Embase, Cinahl, and PsycInfo databases were searched for empirical and theoretical literature using Google. Various terms to describe and define ‘dementia’ and ‘at a young age’ were used to collect literature concerning terminology; age-related aspects, including cut-off ages and criteria; and etiologies of dementia at a young age. Results: The search yielded 6,891 empirical and 4,660 theoretical publications, resulting in the inclusion of 89 publications, including 36 publications containing an explicit discussion and 53 publications as confirmation. ’Young-onset dementia’ was the most commonly used term of seven identified terms, in the last two decades. The age of 65 years at symptom onset was used most frequently when considering a total of six upper age limits and four criteria to define a cut-off age. Eight lower age limits and an option for subdivision based on age were included. We identified 251 different etiologies and 27 categories of etiologies. Conclusion: Despite relative consensus on the term young-onset dementia and an age at symptom onset being used as a cut-off criterion, much is still unclear concerning possible etiologies of dementia at a young age. In the current study, controversies were detected for discussion in an international consensus study.

Kumiko Utsumi, Ryo Fukatsu, Yuko Hara, Yuji Takamaru, Shuichi Yasumura (Handling Associate Editor: Akihiko Nunomura)
Psychotic Features Among Patients in the Prodromal Stage of Dementia with Lewy Bodies During Longitudinal Observation
Abstract: Background: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described. Objective: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment. Methods: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through indicative and supportive biomarkers of scintigraphy. Results: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1 ± 4.6 (mean ± SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean ± SD) years. Conclusion: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis.