Volume 76, Number 1, 2020

Page 1

George Perry
Alzheimer’s Disease Patients in the Crosshairs of COVID-19

Pages 3-19

Majid Fotuhi, Ali Mian, Somayeh Meysami, Cyrus A. Raji
Neurobiology of COVID-19
Abstract: Anosmia, stroke, paralysis, cranial nerve deficits, encephalopathy, delirium, meningitis, and seizures are some of the neurological complications in patients with coronavirus disease-19 (COVID-19) which is caused by acute respiratory syndrome coronavirus 2 (SARS-Cov2). There remains a challenge to determine the extent to which neurological abnormalities in COVID-19 are caused by SARS-Cov2 itself, the exaggerated cytokine response it triggers, and/or the resulting hypercoagulapathy and formation of blood clots in blood vessels throughout the body and the brain. In this article, we review the reports that address neurological manifestations in patients with COVID-19, who may present with acute neurological symptoms (e.g., stroke), even without typical respiratory symptoms such as fever, cough, or shortness of breath. Next, we discuss the different neurobiological processes and mechanisms that may underlie the link between SARS-Cov2 and COVID-19 in the brain, cranial nerves, peripheral nerves, and muscles. Finally, we propose a basic “NeuroCovid” classification scheme that integrates these concepts and highlights some of the short-term challenges for the practice of neurology today and the long-term sequalae of COVID-19 such as depression, OCD, insomnia, cognitive decline, accelerated aging, Parkinson’s disease, or Alzheimer’s disease in the future. In doing so, we intend to provide a basis from which to build on future hypotheses and investigations regarding SARS-Cov2 and the nervous system.

Pages 21-25

Sean X. Naughton, Urdhva Raval, Giulio M. Pasinetti
Potential Novel Role of COVID-19 in Alzheimer’s Disease and Preventative Mitigation Strategies
Abstract: There are a number of potential implications for the field of Alzheimer’s disease (AD) stemming from the global spread of SARS-CoV-2. Neuroinflammation is known to be a prominent feature of neurodegeneration and plays a major role in AD pathology. Immune response and excessive inflammation in COVID-19 may also accelerate the progression of brain inflammatory neurodegeneration, and elderly individuals are more susceptible to severe outcomes after SARS-CoV-2 infection. Individuals with type 2 diabetes (T2D) are at an increased risk for AD as well as severe outcomes after SARS-CoV-2 infection. Genetic and socioeconomic factors influencing the rates of T2D, AD, and COVID-19 severity may create an exceptionally high-risk profile for certain demographics such as African Americans and Hispanic Americans. Type I interferon response plays an important role in both host response to viral infection, as well as AD pathology and may be a sensible therapeutic target in both AD and COVID-19.

Pages 27-31
Short Communication

Suzanne E. Schindler, Gregory A. Jicha, Peter T. Nelson, C. Dirk Keene, Kaj Blennow, José Luis Molinuevo, Colin L. Masters, Oskar Hansson, Charlotte E. Teunissen, Douglas Galasko, Leslie M. Shaw, Allan I. Levey, Nina Silverberg
Maximizing Safety in the Conduct of Alzheimer’s Disease Fluid Biomarker Research in the Era of COVID-19
Abstract: The coronavirus disease 2019 (COVID-19) pandemic led to an abrupt halt of many Alzheimer’s disease (AD) research studies at sites spanning the world. This is especially true for studies requiring in-person contact, such as studies collecting biofluids. Since COVID-19 is likely to remain a threat for an extended period, the resumption of fluid biomarker studies requires the development and implementation of procedures that minimize the risk of in-person visits to participants, staff, and individuals handling the biofluid samples. Some issues to consider include structuring the visit workflow to minimize contacts and promote social distancing; screening and/or testing participants and staff for COVID-19; wearing masks and performing hand hygiene; and precautions for handling, storing, and analyzing biofluids. AD fluid biomarker research remains a vitally important public health priority and resuming studies requires appropriate safety procedures to protect research participants and staff.

Pages 33-40
Alba Benaque, Miren Jone Gurruchaga, Carla Abdelnour, Isabel Hernández, Pilar Cañabate, Montserrat Alegret, Isabel Rodríguez, Maitee Rosende-Roca, Juan Pablo Tartari, Ester Esteban, Rogelio López, Silvia Gil, Liliana Vargas, Ana Mauleón, Ana Espinosa, Gemma Ortega, Angela Sanabria, Alba Pérez, Emilio Alarcón, Antonio González-Pérez, Marta Marquié, Sergi Valero, Lluís Tárraga, Agustín Ruiz, Mercè Boada for the Research Center and Memory Clinic, Fundació ACE
Dementia Care in Times of COVID-19: Experience at Fundació ACE in Barcelona, Spain
Abstract: Background: Fundació ACE is a non-profit organization providing care based on a holistic model to persons with cognitive disorders and their families for 25 years in Barcelona, Spain. Delivering care to this vulnerable population amidst the COVID-19 pandemic has represented a major challenge to our institution. Objective: To share our experience in adapting our model of care to the new situation to ensure continuity of care. Methods: We detail the sequence of events and the actions taken within Fundació ACE to swiftly adapt our face-to-face model of care to one based on telemedicine consultations. We characterize individuals under follow-up by the Memory Unit from 2017 to 2019 and compare the number of weekly visits in 2020 performed before and after the lockdown was imposed. Results: The total number of individuals being actively followed by Fundació ACE Memory Unit grew from 6,928 in 2017 to 8,147 in 2019. Among those newly diagnosed in 2019, most patients had mild cognitive impairment or mild dementia (42% and 25%, respectively). Weekly visits dropped by 60% following the suspension of face-to-face activity. However, by April 24 we were able to perform 78% of the visits we averaged in the weeks before confinement began. Discussion: We have shown that Fundació ACE model of care has been able to successfully adapt to a health and social critical situation as COVID-19 pandemic. Overall, we were able to guarantee the continuity of care while preserving the safety of patients, families, and professionals. We also seized the opportunity to improve our model of care.

Pages 41-47
Claire Boutoleau-Bretonnière, Hélene Pouclet-Courtemanche, Aurelie Gillet, Amelie Bernard, Anne Laure Deruet, Ines Gouraud, Aurelien Mazoue, Estelle Lamy, Laetitia Rocher, Dimitrios Kapogiannis, Mohamad El Haj
The Effects of Confinement on Neuropsychiatric Symptoms in Alzheimer’s Disease During the COVID-19 Crisis
Abstract: Background: Neuropsychiatric symptoms, such as depression, anxiety, apathy, agitation, and hallucinations, are frequent in Alzheimer’s disease (AD) and their prevalence tends to increase with external stressors. Objective: We offer the first investigation of the effects of confinement during the COVID-19 crisis on neuropsychiatric symptoms in patients with AD. Methods: We contacted caregivers of 38 patients with AD who were confined to their homes for nearly two months and asked them to report whether patients experienced any change in neuropsychiatric symptoms during, compared to before, the confinement and rate its severity and impact on themselves using the Neuropsychiatric Inventory-Questionnaire. Results: Among the 38 patients, only 10 demonstrated neuropsychiatric changes during the confinement. Cognitive function of these 10 patients, assessed with the Mini-Mental State Examination, was worse than that of patients who did not demonstrate neuropsychiatric changes. Interestingly, among the 10 patients with neuropsychiatric changes, the duration of confinement significantly correlated with the severity of symptoms as well as with their caregivers’ distress. Discussion: The confinement seems to impact neuropsychiatric symptomatology in AD patients with low baseline cognitive function.

Pages 49-62

Yixuan (Amy) Pei, Julie Davies, Melanie Zhang, Han-Ting Zhang
The Role of Synaptic Dysfunction in Alzheimer’s Disease
Abstract: Deemed as incurable, Alzheimer’s disease (AD) research is becoming less convoluted as our understanding of its pathology increases. With current treatments focusing on merely mitigating the symptoms of AD, there have been many attempts to find a molecular culprit to serve as the single underlying cause and therapeutic target for clinical applications to approach the disease from its roots. Indeed, over the course of decades, the endless search for a singular target culprit in AD has uncovered a cascade of pathological defects, adding on to each other throughout the progression of the disease. The developmental patterns of amyloid-β (Aβ) oligomers have been studied as a means to discover the complex molecular interplay between various immune responses, genetic mutations, pathway disturbances, and regulating factors that disturb synapse homeostasis before disease manifestation. This new understanding has shifted the underlying goal of the research community from merely removing Aβ oligomers to finding methods that can predict high risk individuals and resorting to cocktail-drug treatments in an attempt to regulate multiple pathways that cumulatively result in the debilitating symptoms of the disease. By utilizing various assays from immuno-targeting to molecular biomarkers, we then interfere in the molecular cascades in an endeavor to avoid synapse dysfunction before disease maturity. Here, we review the current literature supporting the importance of synapses in AD, our current understanding of the molecular interactions leading up to clinical diagnoses, and the techniques used in targeted therapies.

Pages 63-84

Jack C. de la Torre
Hemodynamic Instability in Heart Failure Intensifies Age-Dependent Cognitive Decline
Abstract: This review attempts to examine two key elements in the evolution of cognitive impairment in the elderly who develop heart failure. First, major left side heart parts can structurally and functionally deteriorate from aging wear and tear to provoke hemodynamic instability where heart failure worsens or is initiated; second, heart failure is a major inducer of cognitive impairment and Alzheimer’s disease in the elderly. In heart failure, when the left ventricular myocardium of an elderly person does not properly contract, it cannot pump out adequate blood to the brain, raising the risk of cognitive impairment due to the intensification of chronic brain hypoperfusion. Chronic brain hypoperfusion originates from chronically reduced cardiac output which progresses as heart failure worsens. Other left ventricular heart parts, including atrium, valves, myocardium, and aorta can contribute to the physiological shortfall of cardiac output. It follows that hemodynamic instability and perfusion changes occurring from the aging heart’s blood pumping deficiency will, in time, damage vulnerable brain cells linked to specific cognitive regulatory sites, diminishing neuronal energy metabolism to a level where progressive cognitive impairment is the outcome. Could cognitive impairment progress be reversed with a heart transplant? Evidence is presented detailing the errant hemodynamic pathways leading to cognitive impairment during aging as an offshoot of inefficient structural and functional heart parts and their contribution to heart failure.

Pages 85-87

Ruth F. Itzhaki
Hypothesis: Does the Apparent Protective Action of Green Valley’s Drug GV971 Against Cognitive Decline Result from Antiviral Action Against Herpes Simplex Virus Type 1 in Brain?
Abstract: There has been much interest in the clinical trial of GV972 for treatment of Alzheimer's disease in that the data have indicated that the compound is protective against cognitive decline. This effect has been attributed to a remodelling of the gut microbiota. I suggest that the effect might be caused by an antiviral action of GV971 against herpes simplex virus type 1 in brain, which many studies have strongly implicated as having a major role in Alzheimer’s disease. The antiviral action of GV971 is proposed on the basis that it is an acidic polysaccharide consisting of linear sodium oligomannurarate molecules of a range of sizes, derived from brown algae. Marine-derived polysaccharides are well known for possessing various bioactivities, including antiviral and antibacterial properties.

Pages 89-95
Short Communication

Jean-Pierre Jacus, Amandine Mayelle, Virginie Voltzenlogel, Christine-Vanessa Cuervo-Lombard, Pascal Antoine
Modeling Awareness in Alzheimer’s Disease
Abstract: This study aimed to provide a model of awareness in Alzheimer’s disease using the stage of the disease as a risk factor. Awareness was assessed using three methods (patient-caregiver discrepancy, prediction-performance discrepancy, clinical rating). Twenty-five healthy control subjects and sixty-one patients participated, with measures of cognition, apathy, depression, and awareness. These measures were introduced into a manual backward regression. Confounding factors impacting at least 15% of the exposure factor estimate were maintained in the model. Except for the prediction performance discrepancy, also presenting cognitive associations, the other awareness assessments suggested a major role of depression and apathy as impacting factors.

Pages 97-119
Sheida Rabipour, Sricharana Rajagopal, Elsa Yu, Stamatoula Pasvanis, Marie-Elyse Lafaille-Magnan, John Breitner, PREVENT-AD Research Group, M. Natasha Rajah (Handling Associate Editor: Mohammed El Haj)
APOE4 Status Is Related to Differences in Memory-Related Brain Function in Asymptomatic Older Adults with Family History of Alzheimer’s Disease: Baseline Analysis of the PREVENT-AD Task Functional MRI Dataset
Abstract: Background: Episodic memory decline is one of the earliest symptoms of late-onset Alzheimer’s disease (AD). Older adults with the apolipoprotein E ε4 (+APOE4) genetic risk factor for AD may exhibit altered patterns of memory-related brain activity years prior to initial symptom onset. Objective: Here we report the baseline episodic memory task functional MRI results from the PRe-symptomatic EValuation of Experimental or Novel Treatments for Alzheimer’s Disease cohort in Montreal, Canada, in which 327 healthy older adults were scanned within 15 years of their parent’s conversion to AD. Methods: Volunteers were scanned as they encoded and retrieved object-location spatial source associations. The task was designed to discriminate between brain activity related to spatial source recollection and object-only (recognition) memory. We used multivariate partial least squares to test the hypothesis that +APOE4 adults with family history of AD would exhibit altered patterns of brain activity in the recollection-related memory network, comprised of medial frontal, parietal, and medial temporal cortices, compared to APOE4 non-carriers (-APOE4). We also examined group differences in the correlation between event-related brain activity and memory performance. Results: We found group similarities in memory performance and in task-related brain activity in the recollection network, but differences in brain activity-behavior correlations in ventral occipito-temporal, medial temporal, and medial prefrontal cortices during episodic encoding. Conclusion: These findings are consistent with previous literature on the influence of APOE4 on brain activity and provide new perspective on potential gene-based differences in brain-behavior relationships in people with first-degree family history of AD.

Pages 121-138
Martina Parizkova, Ondrej Lerch, Ross Andel, Jana Kalinova, Hana Markova, Martin Vyhnalek, Jakub Hort, Jan Laczó (Handling Associate Editor: Sharon Naismith)
Spatial Pattern Separation in Early Alzheimer’s Disease
Abstract: Background: The hippocampus, entorhinal cortex, and basal forebrain are among the first brain structures affected by Alzheimer’s disease (AD). They play an essential role in spatial pattern separation, a process critical for accurate encoding of similar spatial information. Objective: Our aim was to examine spatial pattern separation and its association with volumetric changes of the hippocampus, entorhinal cortex, and basal forebrain nuclei projecting to the hippocampus (the medial septal nuclei and vertical limb of the diagonal band of Broca – Ch1-2 nuclei) in the biomarker-defined early clinical stages of AD. Methods: A total of 98 older adults were recruited from the Czech Brain Aging Study cohort. The participants with amnestic mild cognitive impairment (aMCI) due to AD (n=44), mild AD dementia (n=31), and cognitively normal older adults (CN; n=23) underwent spatial pattern separation testing, comprehensive cognitive assessment, and MRI brain volumetry. Results: Spatial pattern separation accuracy was lower in the early clinical stages of AD compared to the CN group (p < 0.001) and decreased with disease severity (CN > aMCI due to AD > AD dementia). Controlling for general memory and cognitive performance, demographic characteristics and psychological factors did not change the results. Hippocampal and Ch1-2 volumes were directly associated with spatial pattern separation performance while the entorhinal cortex operated on pattern separation indirectly through the hippocampus. Conclusion: Smaller volumes of the hippocampus, entorhinal cortex, and basal forebrain Ch1-2 nuclei are linked to spatial pattern separation impairment in biomarker-defined early clinical AD and may contribute to AD-related spatial memory deficits.

Pages 139-147
Priya Palta, Gerardo Heiss, A. Richey Sharrett, Kelley Pettee Gabriel, Keenan Walker, Kelly R. Evenson, David Knopman, Thomas H. Mosley, Dean Wong, Rebecca F. Gottesman
Mid- and Late-Life Leisure-Time Physical Activity and Global Brain Amyloid Burden: The Atherosclerosis Risk in Communities (ARIC)-PET Study
Abstract: Background: Physical activity (PA) may slow the development of dementia by reducing the accumulation of amyloid. Objective: We tested the hypothesis that higher levels of leisure-time PA in mid- or late-life were associated with lower brain amyloid burden in late-life among 326 non-demented participants from the Atherosclerosis Risk in Communities Study of brain florbetapir positron emission tomography (ARIC-PET) ancillary. Methods: Self-reported PA was quantified using a past-year recall, interviewer-administered questionnaire in mid-life (1987-1989, aged 45-64 years) and late-life (2011-2013, aged 67-89 years). Continuous PA estimates were classified as 1) any leisure-time PA participation (yes/no); 2) meeting the 2018 United States’ PA guidelines (yes/no); and 3) per 1 standard deviation (SD) higher metabolic equivalent of task (MET) minutes per week (MET·min·wk-1). A brain magnetic resonance imaging scan with Florbetapir PET was performed in late-life. Adjusted odds ratios (OR) of elevated amyloid burden, defined as a global cortical standardized uptake value ratio (>1.2), compared to no elevated amyloid burden were estimated according to PA measures. Results: Among the 326 participants (mean age: 76 years, 42% male, 41% Black), 52% had elevated brain amyloid burden. Mid-life leisure-time PA did not show a statistically significant lower odds of elevated late-life amyloid burden (OR=0.71, 95% CI: 0.43-1.18). A 1 SD (970 MET·min·wk-1) higher PA level in mid-life was also not significantly associated with elevated amyloid burden (OR= 0.89, 95% CI: 0.69-1.15). Similar estimates were observed for meeting versus not meeting PA guidelines in both mid- and late-life. Conclusion: Self-reported higher mid- and late-life leisure-time PA were not significantly associated with lower amyloid burden. Data show a trend of an association, which is, however, imprecise, suggesting replication in larger studies.

Pages 149-157
Ya Su*, Jiayu Fu*, Jintai Yu, Qianhua Zhao, Yihui Guan, Chuantao Zuo, Ming Li, Haibo Tan, Xin Cheng *These authors contributed equally to this work.
Tau PET Imaging with [18F]PM-PBB3 in Frontotemporal Dementia with MAPT Mutation
Abstract: Background: Flortaucipir (AV-1451) and pyridinyl-butadienyl-benzothiazole 3 (PBB3) are newly developed and commonly used positron emission tomography (PET) tracers to detect tau deposition in tauopathies, including frontotemporal dementia (FTD). [18F]PM-PBB3, as a second-generation compound, has not been described in FTD so far. Objective: We aim to explore the in vivo performance of [18F]PM-PBB3 tau PET in an FTD case caused by microtubule-associated protein tau (MAPT) mutation and compare the binding to different tau strains between AV-1451 and PBB3. Methods: We reported the clinical and FDG, [18F]AV45 amyloid and [18F]PM-PBB3 tau PET findings in a patient with FTD of P301L MAPT mutation. Based on our results and published data, we summarized and compared the different utilities of tau PET tracers of AV-1451 and PBB3 in FTD with MAPT mutation. Results: The patient demonstrated slightly diffuse [18F]PM-PBB3 tau deposition in cerebral lobes especially in the left frontal lobe overlapping with the hypometabolic region detected by FDG PET. From our analysis of 35 FTD patients with MAPT mutation who underwent tau PET, AV-1451 was positive in all (n=11) patients with mutations known to cause three and four repeat (3R/4R) tau deposition and in 14.3% (n=2/14) of 4R tauopathies, while positive PBB3 retention was found in all patients with both 3R/4R (n=2) and 4R (n=8) tau. Conclusions: [18F]PM-PBB3 tau PET assisted the diagnosis of FTD with P301L MAPT mutation, and might be useful in the in vivo detection of both 3R/4R and 4R tau domains in the brain of FTD with MAPT mutation.

Pages 159-163
Atik Kridawati, Hardinsyah Hardinsyah, Ahmad Sulaeman, Tri Budi W. Rahardjo, Eef Hogervorst
Tempe, Tofu, and Amyloid-β 1-40 Serum Levels in Ovariectomized Rats
Abstract: Background: Estrogens have been found to reduce amyloid-β (Aβ) levels, a risk factor associated with dementia. We hypothesized that phytoestrogenic soybean products such as tempe and tofu might show similar effects. Objective: The aims of this study were to analyze the effect of tempe and tofu flour on Aβ1-40 serum levels in elderly rats. Methods: This research was conducted on female Sprague Dawley rats, aged 12 months. Before the intervention rats underwent ovariectomy (OVx) and were grouped into 5 intervention groups which were given tempe flour, tofu flour, estradiol, or casein as an active control. There was also a non-OVx control group which was fed a normal diet. Results: The intake of tempe and tofu flour decreased Aβ serum levels in all estrogen and phytoestrogenic treatment groups, offsetting effects of OVx (but not in the casein group, where Aβ levels rise). Conclusion: The tempe flour group showed the strongest decrease in serum Aβ levels compared to the other groups. Future studies should investigate whether tempe can reduce Aβ levels in patients with dementia.

Pages 165-178
Firoz Akhter, Doris Chen, Asma Akhter, Alexander A. Sosunov, Allen Chen, Guy M. McKhann, Shi Fang Yan, Shirley ShiDu Yan (Handling Associate Editor: P. Hemachandra Reddy)
High Dietary Advanced Glycation End Products Impair Mitochondrial and Cognitive Function
Abstract: Background: Advanced glycation end products (AGEs) are an important risk factor for the development of cognitive decline in aging and late-onset neurodegenerative diseases including Alzheimer’s disease. However, whether and how dietary AGEs exacerbate cognitive impairment and brain mitochondrial dysfunction in the aging process remains largely unknown. Objective: We investigated the direct effects of dietary AGEs on AGE adducts accumulation, mitochondrial function, and cognitive performance in mice. Methods: Mice were fed the AGE+ diet or AGE- diet. We examined levels of AGE adducts in serum and cerebral cortexes by immunodetection and immunohistochemistry, determined levels of reactive oxygen species by biochemical analysis, detected enzyme activity associated with mitochondrial respiratory chain complexes I & IV and ATP levels, and assessed learning and memory ability with Morris Water Maze and Nesting Behavior study. Results: Levels of AGE adducts (MG-H1 and CEL) were robustly increased in the serum and brain of AGE+ diet fed mice compared to AGE- group. Furthermore, greatly elevated levels of reactive oxygen species, decreased activities of mitochondrial respiratory chain complexes I & IV, reduced ATP levels, and impaired learning and memory were evident in AGE+ diet fed mice compared to AGE- group. Conclusion: These results indicate that dietary AGEs are important sources of AGE accumulation in vivo, resulting in mitochondrial dysfunction, impairment of energy metabolism, and subsequent cognitive impairment. Thus, reducing AGEs intake to lower accumulation of AGEs could hold therapeutic potential for the prevention and treatment of AGEs-induced mitochondrial dysfunction linked to cognitive decline.

Pages 179-193
Ryan S. Falck, Jennifer C. Davis, John R. Best, Patrick C.Y. Chan, Linda C. Li, Anne B. Wyrough, Kimberly J. Bennet, Daniel Backhouse, Teresa Liu-Ambrose
Effect of a Multimodal Lifestyle Intervention on Sleep and Cognitive Function in Older Adults with Probable Mild Cognitive Impairment and Poor Sleep: A Randomized Clinical Trial
Abstract: Background: Poor sleep is common among older adults with mild cognitive impairment (MCI) and may contribute to further cognitive decline. Whether multimodal lifestyle intervention that combines bright light therapy (BLT), physical activity (PA), and good sleep hygiene can improve sleep in older adults with MCI and poor sleep is unknown. Objective: To assess the effect of a multimodal lifestyle intervention on sleep in older adults with probable MCI and poor sleep. Methods: This was a 24-week proof-of-concept randomized trial of 96 community-dwelling older adults aged 65-85 years with probable MCI (<26/30 on the Montreal Cognitive Assessment) and poor sleep (>5 on the Pittsburgh Sleep Quality Index [PSQI]). Participants were allocated to either a multimodal lifestyle intervention (INT); or 2) education + attentional control (CON). INT participants received four once-weekly general sleep hygiene education classes, followed by 20-weeks of: 1) individually-timed BLT; and 2) individually-tailored PA promotion. Our primary outcome was sleep efficiency measured using the MotionWatch8© (MW8). Secondary outcomes were MW8-measured sleep duration, fragmentation index, wake-after-sleep-onset, latency, and PSQI-measured subjective sleep quality. Results: There were no significant between-group differences in MW8 measured sleep efficiency at 24-weeks (estimated mean difference [INT – CON]: 1.18%; 95% CI [-0.99, 3.34]), or any other objective-estimate of sleep. However, INT participants reported significantly better subjective sleep quality at 24-weeks (estimated mean difference: -1.39; 95% CI [-2.72, -0.06]) compared to CON. Conclusion: Among individuals with probable MCI and poor sleep, a multimodal lifestyle intervention improves subjective sleep quality, but not objectively estimated sleep.

Pages 195-205
Shuoqi Chen, Jianping Jia
Tenuifolin Attenuates Amyloid-β42-Induced Neuroinflammation in Microglia Through the NF-κB Signaling Pathway
Abstract: Background: Inflammation and oxidative stress are believed to play an important role in the pathogenesis of Alzheimer's disease (AD). Tenuifolin (TEN) is a natural neuroprotective compound extracted from Polygala tenuifolia Willd, which may improve cognitive symptoms. Objective: This study was designed to evaluate the protective effect of TEN on inflammatory and oxidative stress induced by amyloid-β (Aβ)42 oligomers in BV2 cells, and to explore the underlying mechanisms. Methods: We conducted cell viability assays to estimate drug toxicity and drug effects on cells. Quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assays were performed to detect the release of inflammatory factors. Nitric oxide (NO) assays were used to measure the degree of oxidative stress. Western blot and immunofluorescence analysis were used to explore the influence of TEN on the nuclear factor-κB (NF-κB) pathway. Results: Pretreatment of BV2 microglial cells with TEN inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β, alleviated NO-induced oxidative stress by inhibiting the expression of inducible nitric oxide synthase and cyclo-oxygenase-2, and protected SH-SY5Y cells from the toxicity induced by the medium conditioned by BV2 cells previously exposed to Aβ42 oligomers. Moreover, TEN suppressed upstream activators of NF-κB, as well as NF-κB translocation to the nucleus in BV2 microglial cells. Conclusion: This study demonstrates that TEN can protect SH-SY5Y cells from Aβ42 oligomer-induced microglia-mediated inflammation, and oxidative stress by downregulating the NF-κB signaling pathway.

Pages 207-215
Eric J. Schwaber*, Atalie C. Thompson*, Gordon Smilnak, Sandra S. Stinnett, Heather E. Whitson, Eleonora M. Lad (Handling Associate Editor: Carol Yim-lui Cheung) *These authors contributed equally to this work.
Co-Prevalence of Alzheimer’s Disease and Age-Related Macular Degeneration Established by Histopathologic Diagnosis
Abstract: Background: Previous epidemiologic studies have suggested an association between AMD and AD, and several therapeutic agents are being developed based on this principle. However, prior studies have provided conflicting results due in part to their reliance on clinical diagnoses that are not based on gold-standard histopathology. Objective: To use histopathologic standards for diagnosis in order to determine the co-prevalence of AD among patients with and without AMD. Methods: This is a cross-sectional study of 157 autopsy ocular specimens from patients with and without AMD that were greater than 75 years of age at death. Sarks staging was used to document the severity of AMD, and Braak and Braak staging was used to assess the severity of AD in corresponding brain specimens. The prevalence of AD within different severities of AMD was determined using univariable and multivariable logistic regression. Results: 58% of autopsy eyes had AMD. The prevalence of AD was lower in AMD subjects (63%) compared to non-AMD subjects (73%), even when grouped by severity (all p > 0.15). The likelihood of AD was significantly less in AMD subjects, even after adjusting for age and sex in multivariable analysis (OR 0.47, p=0.049). Conclusion: Histopathologic diagnoses fail to support an increase in prevalence of AD among subjects with AMD, even when disease severity is considered.

Pages 217-224
Xin Wang, Helena R. Zimmermann, Samuel N. Lockhart, Suzanne Craft, Tao Ma (Handling Associate Editor: Weiming Xia)
Decreased Levels of Blood AMPKα1 but not AMPKα2 Isoform in Patients with Mild Cognitive Impairment and Alzheimer’s Disease: A Pilot Study
Abstract: Background: There is an urgent need to develop feasible biomarkers for diagnosis and prognosis of Alzheimer’s disease (AD). Mounting evidence implicates that dysregulation of energy metabolism is a key and early event in AD pathogenesis. AMP-activated protein kinase (AMPK) is a central molecular sensor that plays a critical role in maintaining cellular energy homeostasis, and aberrant brain AMPK activities are linked to AD pathophysiology. Objective: We aimed to investigated protein levels of AMPKα isoforms, AMPKα1 and AMPKα2, in plasma samples from patients clinically diagnosed with mild cognitive impairment (MCI) or AD, along with age-matched healthy controls. Methods: 30 participants (10 MCI, 10 AD, and 10 controls) were included in our pilot study. Plasma levels of AMPKα1 and AMPKα2 were determined by ELISA. Receiver operating characteristic (ROC) analysis was used to assess sensitivity and specificity. Linear regression was used to assess the correlation between levels of AMPKα isoforms and other biomarkers. Results: Plasma levels of AMPKα1 were decreased in MCI and AD patients, while levels of AMPKα2 were unaltered as compared to controls. ROC analysis showed relatively high sensitivity and specificity for AMPKα1 to distinguish MCI and AD from controls. Linear regression analysis showed that plasma levels of AMPKα1 were correlated with a brain imaging biomarker (AD signature cortical thicknesses). Conclusion: Plasma levels of AMPKα1 were decreased in MCI and AD patients. Future endeavor to explore whether blood AMPKα1 protein expression has the value as a potential biomarker for AD and MCI diagnosis shall be encouraged.

Pages 225-236
Chih-Hao Chen*, Ya-Fang Chen*, Ping-Huan Tsai*, Jeng-Min Chiou, Liang-Chuan Lai, Ta-Fu Chen, Hung Hung, Jen-Hau Chen, Yen-Ching Chen (Handling Associate Editor: Sang Won Seo) *These authors contributed equally to this work.
Impacts of Kidney Dysfunction and Cerebral Cortical Thinning on Cognitive Change in Elderly Population
Abstract: Background: Cerebral cortical thickness is a neuroimaging biomarker to predict cognitive decline, and kidney dysfunction (KD) is associated with cortical thinning. Objective: This study aimed to investigate the effects of KD and cortical thinning on cognitive change in a prospective cohort study. Methods: A total of 244 non-demented participants were recruited from elderly health checkup program and received cognitive exams including Montreal Cognitive Assessment (MoCA) and different cognitive domains at baseline and three biannual follow-ups afterwards. KD was defined as having either glomerular filtration rate <60 ml/min/1.73 m2 or proteinuria. Cortical thickness of global, lobar, and Alzheimer’s disease (AD) signature area were derived from magnetic resonance imaging at baseline, and cortical thinning was defined as the lowest tertile of cortical thickness. Generalized linear mixed models were applied to evaluate the effects of KD and cortical thinning on cognitive changes. Results: KD was significantly associated with the decline in attention function (β=−0.29). Thinning of global (β=−0.06), AD signature area (β=−0.06), temporal (β=−0.06), and parietal lobes (β=−0.06) predicted poor verbal fluency over time, while temporal lobe thinning also predicted poor MoCA score (β=−0.19). KD modified the relationship between thinning of global, frontal, and limbic, and change of logical memory function (pinteraction<0.05). When considering jointly, participants with both KD and cortical thinning had greatest decline in attention function compared with those without KD or cortical thinning (β=−0.51, ptrend=0.008). Conclusions: KD and cortical thinning have joint effect on cognitive decline, especially the attention function. Reverse associations may exist between cortical thinning and memory function in participants with KD, though the results should be interpreted cautiously as an exploratory analysis.

Pages 237-248
Yan Shi*, Feng Gao*, Xiaoli Yang, Dongwei Liu, Qiuxia Han, Zhangsuo Liu, Hanyu Zhu, Yong Shen *These authors contributed equally to this work.
Increase of BACE1, Brain-Renal Risk Factor, Contributes to Kidney Damage in an Alzheimer’s Disease Mouse Model
Abstract: Background: It is believed that there is a certain correlation between the brain and kidneys, but it is poorly understood. Many findings suggested that there were previously unknown signaling pathways involving AβPP and BACE1 in the kidney. Objective: Exploring the changes of BACE1 activity in APP23 mouse kidneys, providing evidence for the function of AβPP and BACE1 activity in the kidney. Methods: The activity and expression of BACE1 were detected in the kidney of APP23 mice by enzymatic assay and western blotting. The protein expression levels of AβPP, claudin1, occludin, VE-cadherin, and Klotho (membrane-form klotho) were examined by using western blotting. The renal pathological changes of APP23 mice were examined by the routine renal pathological procedures. Results: In this study, we found that the AβPP protein level was increased in kidneys of APP23 mice compared with wild-type (WT) mice. Additionally, the activity and expression of BACE1 were increased in kidneys of APP23 mice compared to that of WT. BACE1 was predominantly distributed on the lumen side of renal tubular epithelial cells. The protein levels of Klotho and VE-cadherin were decreased, occludin expression was also decreased, and claudin-1 expression was increased. Renal pathological damage which observed in kidneys of APP23 mice was more serious than that in kidneys of WT mice. Conclusion: Our findings suggest that the increase of AβPP protein levels under Thy-1 neuron promoter in the APP23 mice promoted the increase of renal BACE1 expression and enzymatic activity in the kidneys. Moreover, certain pathological damage in the kidneys of APP23 mice were observed. APP23 mice are easily affected by external risk factors compared with WT mice.

Pages 249-260
Kun Yang*, Guanqun Chen*, Can Sheng, Yunyan Xie, Yuxia Li, Xiaochen Hu, Yu Sun, Ying Han (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Cognitive Reserve, Brain Reserve, APOE ε4, and Cognition in Individuals with Subjective Cognitive Decline in the SILCODE Study
Abstract: Background: Cognitive reserve (CR) and brain reserve (BR) could offer protective effects on cognition in the early stage of Alzheimer’s disease (AD). However, the effects of CR or BR on cognition in individuals with subjective cognitive decline (SCD) are not clear. Objective: To explore the effects of CR and BR on cognition in subjects with SCD. Methods: We included 149 subjects from the Sino Longitudinal Study on Cognitive Decline (SILCODE) study. Education was used as a proxy for CR, and head circumference was used as a proxy for BR. Multiple linear regression models were conducted to examine the effects of CR and BR on cognitive scores. Furthermore, we assessed differences in effects between APOE ε4 carriers with SCD (n=35) and APOE ε4 non-carriers with SCD (n=114) and linear trends among 4 reserve levels (low BR/CR, high BR/low CR, low BR/high CR, and high BR/high CR). Results: Both CR and BR had independent positive effects on multiple cognitive measures in SCD participants, and the effects of CR were greater than those of BR. CR has positive effects on cognitive measures in both APOE ε4 carriers and non-carriers with SCD. However, the positive effects of BR on cognitive measures were observed in APOE ε4 non-carriers with SCD but not in APOE ε4 carriers with SCD. Furthermore, there was a linear trend toward better cognitive performance on all cognitive measures in the BR+/CR+ group, followed by the BR−/CR+, BR+/CR−, and BR−/CR− groups. Conclusion: This study suggests that both CR and BR have the potential to delay or slow cognitive decline in individuals with SCD.

Pages 261-274
Nikki H. Stricker, Emily S. Lundt, Sabrina M. Albertson, Mary M. Machulda, Shehroo B. Pudumjee, Walter K. Kremers, Clifford R. Jack, Jr., David S. Knopman, Ronald C. Petersen, Michelle M. Mielke (Handling Associate Editor: Yen Ying Lim)
Diagnostic and Prognostic Accuracy of the Cogstate Brief Battery and Auditory Verbal Learning Test in Preclinical Alzheimer’s Disease and Incident Mild Cognitive Impairment: Implications for Defining Subtle Objective Cognitive Impairment
Abstract: Background: There are detectable cognitive differences in cognitively unimpaired (CU) individuals with preclinical Alzheimer’s disease (AD). Objective: To determine whether cross-sectional performance on the Cogstate Brief Battery (CBB) and Auditory Verbal Learning Test (AVLT) could identify 1) CU participants with preclinical AD defined by neuroimaging biomarkers of amyloid and tau, and 2) incident mild cognitive impairment (MCI)/dementia. Method: CU participants age 50+ were eligible if they had 1) amyloid (A) and tau (T) imaging within two years of their baseline CBB or 2) at least one follow-up visit. AUROC analyses assessed the ability of measures to differentiate groups. We explored the frequency of cross-sectional subtle objective cognitive impairment (sOBJ) defined as performance ≤ -1 SD on CBB Learning/Working Memory Composite (Lrn/WM) or AVLT delayed recall using age-corrected normative data. Results: A+T+ (n=33, mean age 79.5) and A+T- (n=61, mean age 77.8) participants were older than A-T- participants (n=146, mean age 66.3), and comparable on sex and education. Lrn/WM did not differentiate A+T+ or A+T- from A-T- participants. AVLT differentiated both A+T+ and A+T- from A-T- participants; 45% of A+T+ and 25% of A+T- participants met sOBJ criteria. The follow-up cohort included 150 CU individuals who converted to MCI/dementia and 450 age, sex, and education matched controls. Lrn/WM and AVLT differentiated between stable and converter CU participants. Conclusions: Among CU participants, AVLT helped differentiate A+T+ and A+T- from A-T- participants. The CBB did not differentiate biomarker subgroups, but showed potential for predicting incident MCI/dementia. Results inform future definitions of sOBJ.

Pages 275-280
Cyrus A. Raji*, Somayeh Meysami*, David A. Merrill, Verna R. Porter, Mario F. Mendez *These authors contributed equally to this work.
Brain Structure in Bilingual Compared to Monolingual Individuals with Alzheimer’s Disease: Proof of Concept
Abstract: Background: Bilingualism is increasingly recognized as protective in persons at risk for Alzheimer’s disease (AD). Objective: Compare MRI measured brain volumes in matched bilinguals versus monolinguals with AD. Methods: This IRB approved study analyzed T1 volumetric brain MRIs of patients with criteria-supported Probable AD. We identified 17 sequential bilinguals (any native language) with Probable AD, matched to 28 (62%) monolinguals on age and MMSE. Brain volumes were quantified with Neuroreader. Regional volumes as fraction of total intracranial volume (TIV) were compared between both groups, and Cohen’s D effect sizes were calculated for statistically significant structures. Partial correlations between bilingualism and brain volumes adjusted for age, gender, and TIV. Results: Bilinguals had higher brain volumes in 37 structures. Statistical significance (p<0.05) was observed in brainstem (t=2.33, p=0.02, Cohen’s D=0.71) and ventral diencephalon (t=3.01, p=0.004, Cohen’s D=0.91). Partial correlations showed statistical significance between bilingualism and larger volumes in brainstem (rp=0.37, p=0.01), thalamus (rp=0.31, p=0.04), ventral diencephalon (rp=0.50, p=0.001), and pallidum (rp=0.38, p=0.01). Bilingualism positively correlated with hippocampal volume, though not statistically significant (rp=0.17, p=0.26). No brain volumes were larger in monolinguals. Conclusion: Bilinguals demonstrated larger thalamic, ventral diencephalon, and brainstem volumes compared to matched monolinguals with AD. This may represent a neural substrate for increased cognitive reserve in bilingualism. Future studies should extrapolate this finding into cognitively normal persons at risk for AD.

Pages 281-290
Soo Hyun Cho*, Yeong Sim Choe*, Young Ju Kim, Hee Jin Kim, Hyemin Jang, Yeshin Kim, Si Eun Kim, Seung Joo Kim, Jun Pyo Kim, Young Hee Jung, Byeong C. Kim, Samuel N. Lockhart, Gill Farrar, Duk L. Na, Seung Hwan Moon, Sang Won Seo *These authors contributed equally to this work.
Head-to-Head Comparison of 18F-Florbetaben and 18F-Flutemetamol in the Cortical and Striatal Regions
Abstract: Background: 18F-florbetaben (FBB) and 18F-flutemetamol (FMM) amyloid PET have been developed and approved for clinical use. It is important to understand the distinct features of these ligands to compare and correctly interpret the results of different amyloid PET studies. Objective: We performed a head-to-head comparison of FBB and FMM to compare with regard to imaging characteristics, including dynamic range of retention, and differences in quantitative measurements between the two ligands in cortical, striatal, and white matter (WM) regions. Methods: Paired FBB and FMM PET images were acquired in 107 participants. Correlations of FBB and FMM amyloid deposition in the cortex, striatum, and WM were investigated and compared in different reference regions (cerebellar gray matter (CG), whole cerebellum (WC), WC with brainstem (WC + B), and pons). Results: The cortical SUVR (R2= 0.97) and striatal SUVR (R2= 0.95) demonstrated an excellent linear correlation between FBB and FMM using a WC as reference region. There was no difference in the cortical SUVR ratio between the two ligands (p = 0.90), but the striatal SUVR ratio was higher in FMM than in FBB (p < 0.001). Also, the effect size of differences in striatal SUVR seemed to be higher with FMM (2.61) than with FBB (2.34). These trends were similarly observed according to four different reference regions (CG, WC, WC + B, and pons). Conclusion: Our findings suggest that FMM might be better than FBB to detect amyloid burden in the striatum, although both ligands are comparable for imaging AD pathology in vivo.

Pages 291-301
Pratishtha Chatterjee*, Maryam Mohammadi*, Kathryn Goozee, Tejal M. Shah, Hamid R. Sohrabi, Cintia B. Dias, Kaikai Shen, Prita R. Asih , Preeti Dave, Steve Pedrini, Nicholas J. Ashton, Abdul Hye, Kevin Taddei, David B. Lovejoy, Henrik Zetterberg, Kaj Blennow, Ralph N. Martins *These authors contributed equally to this work.
Serum Hepcidin Levels in Cognitively Normal Older Adults with High Neocortical Amyloid-β Load
Abstract: Background/Objective: Hepcidin, an iron-regulating hormone, suppresses the release of iron by binding to the iron exporter protein, ferroportin, resulting in intracellular iron accumulation. Given that iron dyshomeostasis has been observed in Alzheimer’s disease (AD) together with elevated serum hepcidin levels, the current study examined whether elevated serum hepcidin levels are an early event in AD pathogenesis by measuring the hormone in cognitively normal older adults at risk of AD, based on high neocortical amyloid-β load (NAL). Methods: Serum hepcidin levels in cognitively normal participants (n=100) aged between 65-90 years were measured using ELISA. To evaluate NAL, all participants underwent 18F-florbetaben positron emission tomography. A standard uptake value ratio (SUVR) < 1.35 was classified as low NAL (n=65) and ≥1.35 (n=35) was classified as high NAL. Results: Serum hepcidin was significantly higher in participants with high NAL compared to those with low NAL before and after adjusting for covariates: age, gender, and APOE ε4 carriage (p < 0.05). A receiver operating characteristic curve based on a logistic regression of the same covariates, the base model, distinguished high from low NAL (area under the curve, AUC=0.766), but was outperformed when serum hepcidin was added to the base model (AUC=0.794) and further improved with plasma Aβ42/40 ratio (AUC=0.829). Conclusion: The present findings indicate that serum hepcidin is increased in individuals at risk for AD and contribute to the body of evidence supporting iron dyshomeostasis as an early event of AD. Further, hepcidin may add value to a panel of markers that contribute toward identifying individuals at risk of AD; however, further validation studies are required.

Pages 303-315
Wei Ling Florence Lim^, Kevin Huynh^, Pratishtha Chatterjee, Ian Martins, Kaushala S. Jayawardana, Corey Giles, Natalie A. Mellett, Simon M. Laws, Ashley I. Bush, Christopher C. Rowe, Victor L. Villemagne, David Ames, Brian G. Drew, Colin L. Masters, Peter J. Meikle*, Ralph N. Martins*, AIBL research group (Handling Associate Editor: Jürgen Götz) ^These authors contributed equally to this work. *Joint senior and corresponding authors
Relationships Between Plasma Lipids Species, Gender, Risk Factors, and Alzheimer’s Disease
Abstract: Background: Lipid metabolism is altered in Alzheimer’s disease (AD); however, the relationship between AD risk factors (age, APOE ε4, and gender) and lipid metabolism is not well defined. Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals. Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species. Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOE ε4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOE ε4 may, in part, be mediated by changes in lipid metabolism. Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.

Pages 317-329
Enea Traini, Anna Carotenuto, Angiola Maria Fasanaro, Francesco Amenta
Volume Analysis of Brain Cognitive Areas in Alzheimer’s Disease: Interim 3-Year Results from the ASCOMALVA Trial
Abstract: Background: Cerebral atrophy is a common feature of several neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, brain atrophy is associated with loss of gyri and sulci in the temporal and parietal lobes, and in parts of the frontal cortex and cingulate gyrus. Objective: The ASCOMALVA trial has assessed, in addition to neuropsychological analysis, whether the addition of the cholinergic precursor choline alphoscerate to treatment with donepezil has an effect on brain volume loss in patients affected by AD associated with cerebrovascular injury. Methods: 56 participants to the randomized, placebo-controlled, double-blind ASCOMALVA trial were assigned to donepezil+placebo (D+P) or donepezil+choline alphoscerate (D+CA) treatments and underwent brain magnetic resonance imaging and neuropsychological tests every year for 4 years. An interim analysis of 3-year MRI data was performed by voxel morphometry techniques. Results: The D+P group (n=27) developed atrophy of the gray and white matter with concomitant increase in ventricular space volume. In the D+CA group (n=29) the gray matter atrophy was less pronounced compared to the D+P group in frontal and temporal lobes, hippocampus, and amygdala. These morphological data are consistent with the results of the neuropsychological tests. Conclusion: Our findings indicate that the addition of choline alphoscerate to standard treatment with the cholinesterase inhibitor donepezil counters to some extent the loss in volume occurring in some brain areas of AD patients. The observation of parallel less pronounced decrease in cognitive and functional tests in patients with the same treatment suggests that the morphological changes observed may have functional relevance.

Pages 331-340
Nicolas Nicastro, Maura Malpetti, Thomas E. Cope, William Richard Bevan-Jones, Elijah Mak1, Luca Passamonti, James B. Rowe*, John T. O’Brien* *co-senior authors
Cortical Complexity Analyses and Their Cognitive Correlate in Alzheimer’s Disease and Frontotemporal Dementia
Abstract: Background: The changes of cortical structure in Alzheimer’s disease (AD) and frontotemporal dementia (FTD) are usually described in terms of atrophy. However, neurodegenerative diseases may also affect the complexity of cortical shape, such as the fractal dimension of the brain surface. Objective: In this study, we aimed at assessing the regional patterns of cortical thickness and fractal dimension changes in a cross-sectional cohort of patients with AD and FTD. Methods: Thirty-two people with symptomatic AD-pathology (clinically probable AD, n=18, and amyloid-positive mild cognitive impairment, n=14), 24 with FTD and 28 healthy controls underwent high-resolution 3T structural brain MRI. Using surface-based morphometry, we created vertex-wise cortical thickness and fractal dimension maps for group comparisons and correlations with cognitive measures in AD and FTD. Results: In addition to the well-established pattern of cortical thinning encompassing temporoparietal regions in AD and frontotemporal areas in FTD, we observed reductions of fractal dimension encompassing cingulate areas and insula for both conditions, but specifically involving orbitofrontal cortex and paracentral gyrus for FTD (FDR p<0.05). Correlational analyses between fractal dimension and cognition showed that these regions were particularly vulnerable with regards to memory and language impairment, especially in FTD. Conclusion: While the present study demonstrates globally similar patterns of fractal dimension changes in AD and FTD, we observed distinct cortical complexity correlates of cognitive domains impairment. Further studies are required to assess cortical complexity measures at earlier disease stages (e.g., in prodromal/asymptomatic carriers of FTD-related gene mutations) to assess whether fractal dimension represents a sensitive imaging marker for prevention and diagnostic strategies.

Pages 341-347
Marina Picillo, Emilia Vitale, Antonella Rendina, Aldo Donizetti, Vincenza Aliperti, Maria Francesca Tepedino, Giovanna Dati, Monia Ginevrino, Enza Maria Valente, Paolo Barone
Clinical and Molecular Characterization of a Novel Progranulin Deletion Associated with Different Phenotypes
Abstract: Background: Mutations in the GRN gene are causative for an autosomal dominant form of frontotemporal dementia. Objective/Methods: The objective of the present study is to describe clinical and molecular features of three siblings harboring the GRN deletion NM_002087.3:c.295_308delTGCCCACGGGGCTT, p.(Cys99Profs*15) identified with next generation sequencing. Results: Our patients demonstrated heterogeneous clinical phenotypes, such as progressive supranuclear palsy-like in the proband and the behavioral variant of frontotemporal dementia in the two affected siblings. Progranulin haploinsufficiency was revealed by both gene expression and protein analyses. Conclusion: The pathogenicity of the novel GRN deletion c.295_308del TGCCCACGGGGCTT is confirmed by both functional analysis and segregation in three affected siblings.

Pages 349-368
Mei Chen, Weiming Xia
Proteomic Profiling of Plasma and Brain Tissue from Alzheimer’s Disease Patients Reveals Candidate Network of Plasma Biomarkers
Abstract: Background: Alzheimer’s disease (AD) is the most prevalent form of dementia with two pathological hallmarks of tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. Although Aβ and tau have been explored as potential biomarkers, levels of these pathological proteins in blood fail to distinguish AD from healthy control subjects. Objective: We aim to discover potential plasma proteins associated with AD pathology by performing tandem mass tag (TMT)-based quantitative proteomic analysis of proteins from peripheral and central nervous system compartments. Methods: We performed comparative proteomic analyses of plasma collected from AD patients and cognitively normal subjects. In addition, proteomic profiles from the inferior frontal cortex, superior frontal cortex, and cerebellum of postmortem brain tissue from five AD patients and five non-AD controls were compared with plasma proteomic profiles to search for common biomarkers. Liquid chromatography-mass spectrometry was used to analyze plasma and brain tissue labeled with isobaric TMT for relative protein quantification. Results: Our results showed that the proteins in complement coagulation cascade and interleukin-6 signaling were significantly altered in both plasma and brains of AD patients. Conclusion: Our results demonstrate the relevance in immune responses between the peripheral and central nervous systems. Those differentially regulated plasma proteins are explored as candidate biomarker profiles that illustrate chronic neuroinflammation in brains of AD patients.

Pages 369-385
Sandrine Benhamron*, Keren Nitzan*, Michael Valitsky*, Neta Lax, Dimitrios Karussis, Ibrahim Kassis, Hanna Rosenmann *These authors contributed equally to this work.
Cerebrospinal Fluid (CSF) Exchange Therapy with Artificial CSF Enriched with Mesenchymal Stem Cell Secretions Ameliorates Cognitive Deficits and Brain Pathology in Alzheimer’s Disease Mice
Abstract: Background: The high complexity of neurodegenerative diseases, including Alzheimer's disease (AD), and the lack of effective treatments point to the need for a broader therapeutic approach to target multiple components involved in the disease pathogenesis. Objective: To test the efficacy of ‘cerebrospinal fluid (CSF) exchange therapy’ in AD-mice. This novel therapeutic approach we recently proposed is based on the exchange of the endogenous pathogenic CSF with a new and healthy one by drainage of the endogenous CSF and its continuous replacement with artificial CSF (aCSF) enriched with secretions from human mesenchymal stem cells (MSCs). Methods: We treated AD-mice (amyloid-beta injected) with MSC secretions-enriched-aCSF using an intracerebroventricular CSF exchange procedure. Cognitive and histological analysis were performed. Results: We show that the MSC secretions enriched CSF exchange therapy improved cognitive performance, paralleled with increased neuronal counts (NeuN positive cells), reduced astrocytic burden (GFAP positive cells), and increased cell proliferation and neurogenesis (Ki67 positive cells and DCX positive cells) in the hippocampus. This beneficial effect was noted on days 5-10 following 3-consecutive daily exchange treatments (3 hours a day). A stronger effect was noted using a more prolonged CSF exchange protocol (3-consecutive daily exchange treatments with 3 additional treatments twice weekly), with cognitive follow-up performed as early as 2-3 days after treatment. Some increase in hippocampal cell proliferation, but no change in the other histological parameters, was noticed when performing CSF exchange therapy using unenriched aCSF relative to untreated AD-mice, yet smaller than with the enriched aCSF treatment. Conclusion: These findings point to the therapeutic potential of the CSF exchange therapy using MSC secretions-enriched aCSF in AD, and might be applied to other neurodegenerative and dementia diseases.

Pages 387-398
Takafumi Fukuda, Tohru Ohnuma, Kuniaki Obara, Sumio Kondo, Heii Arai, Yasuhisa Ano
Supplementation with Matured Hop Bitter Acids Improves Cognitive Performance and Mood State in Healthy Older Adults with Subjective Cognitive Decline
Abstract: Background: Prevention of age-related cognitive decline and depression is becoming urgent because of rapid growing aging populations. Effects of vagal nerve activation on brain function by food ingredients are inadequately investigated; matured hop bitter acid (MHBA) administration reportedly improves cognitive function and depression via vagal nerve activation in model mice. Objective: We investigated the effects of MHBA supplementation on cognitive function and mood state in healthy older adults with perceived subjective cognitive decline. Methods: Using a randomized double-blind placebo-controlled trial design, 100 subjects (aged 45–69 years) were randomly assigned into placebo (n = 50) and MHBA (n = 50) groups, and received placebo or MHBA capsules daily for 12 weeks. Results: Symbol Digit Modalities Test (SDMT) score assessing divided attention at week 12 was significantly higher (p = 0.045) and β-endorphin at week 12 was significantly lower (p = 0.043) in the subjects receiving MHBA. Transthyretin in serum, a putative mild cognitive impairment marker, was significantly higher at week 12 in the MHBA group than in the placebo group (p = 0.048). Subgroup analysis classified by the subjective cognitive decline questionnaire revealed that in addition to improved SDMT scores, memory retrieval assessed using the standard verbal paired-associate learning tests and the Ray Verbal Learning Test at week 12 had significantly improved in the subgroup with perceived subjective cognitive decline and without requirement for medical assistance in the MHBA group compared with that in the placebo group. Conclusion: This study suggested that MHBA intake improves cognitive function, attention, and mood state in older adults.

Pages 399-421
Dale S. Sherman, Kelly A. Durbin, David M. Ross
Meta-Analysis of Memory-Focused Training and Multidomain Interventions in Mild Cognitive Impairment
Abstract: Background: Meta-analysis examining the efficacy of cognitive interventions on neuropsychological outcomes have suggested interventions that focus on memory may actually provide greater benefit against the cognitive declines associated with mild cognitive impairment (MCI). However, it remains unclear if memory-based training would be more effective at addressing the cognitive deficits associated with MCI than multidomain forms of intervention. Objective: A meta-analytic review and subgroup analysis was conducted to examine the effects of cognitive training in individuals diagnosed with MCI and to compare the efficacy of memory-based training with multidomain interventions. Methods: A total of 32 randomized controlled trials met inclusion criteria for the meta-analysis, which included 9 studies on memory-focused training and 17 studies on multidomain interventions. Results: We found significant, large effects for memory-focused training (Hedges’ g observed = 0.947; 95% CI [-1.668, 3.562]; Z = 2.517; p = 0.012) and significant, moderate effects for multidomain interventions (Hedges’ g observed = 0.420; 95% CI [-0.4491, 1.2891]; Z = 3.525; p < 0.001). A subgroup analysis found significant point estimates for memory-based forms of training and multidomain interventions, with memory-based forms of content yielding significantly greater summary effects than multidomain interventions (SMD Z = 2.162; p = 0.031, two-tailed; all outcomes). There was no difference between effect sizes when comparing outcomes limited to its respective domain. Conclusion: Overall, these findings suggest that, while both interventions were beneficial, treatment interventions that were strictly memory-based were more effective at improving cognition in individuals diagnosed with MCI than interventions that targeted multiple cognitive domains.

Pages 423-433
Mona Dehhaghi, Hamed Kazemi Shariat Panahi, Nady Braidy, Gilles J. Guillemin
Herpetosiphon Secondary Metabolites Inhibit Amyloid-β Toxicity in Human Primary Astrocytes
Abstract: Background: The accumulation of extracellular plaques containing amyloid-β protein (Aβ) in the brain is one of the main pathological hallmarks of Alzheimer's disease (AD). Aβ peptide can promote the production of highly volatile free radicals and reactive oxygen species (ROS) that can induce oxidative damage to neurons and astrocytes. At present, numerous studies have investigated the neuroprotective and glioprotective effects of natural products derived from plants, animals, and microorganisms. Objective: We investigated the glioprotective effect of secondary metabolites obtained from Herpetosiphon sp. HM 1988 against Aβ40-induced toxicity in human primary astrocytes. Methods: The protective effect of bacterial secondary metabolites against Aβ40-induced inducible nitric oxide synthase (iNOS) activity was evaluated using the citrulline assay. To confirm the iNOS activity, nitrite production was assessed using the fluorometric Griess diazotization assay. Intracellular NAD+ depletion and lactate dehydrogenase (LDH) release in human primary astrocytes were also examined using well‐established spectrophotometric assays. Results: Our results indicate that Aβ40 can induce elevation in iNOS and LDH activities, nitrite production, and cellular energy depletion. Importantly, extract of Herpetosiphon sp. HM 1988 decreased iNOS activity, nitrite production, and LDH release. In addition, metabolites of the strain were able to restore cellular energy deficits through inhibition of NAD+ depletion mediated by Aβ40. Conclusion: These findings suggest that Herpetosiphon metabolites may represent a promising, novel source for the prevention of Aβ toxicity in AD.

Pages 435-442
Hiroyuki Umegaki, Viviana Bonfiglio, Hitoshi Komiya, Kazuhisa Watanabe, Masafumi Kuzuya
Association Between Sarcopenia and Quality of Life in Patients with Early Dementia and Mild Cognitive Impairment
Abstract: Background: Cognitive impairment is linked to decreased quality of life (QOL), but few studies have investigated the impact of comorbid sarcopenia. Objective: The aim of this study was to elucidate the association of sarcopenia with QOL in patients with early dementia and mild cognitive impairment. Methods: Individuals with a Clinical Dementia Rating of 0.5 or 1 and a Mini-Mental State Examination score of 20–30 underwent a battery of neuropsychological assessments administered by a group of well-trained clinical psychologists. The EQ-5D was completed by both the patients and their main caregivers. EQ-5D utility and visual analog scale scores were measured. Sarcopenia was defined according to the criteria published in the 2019 consensus update by the Asian Working Group for Sarcopenia. Results: Patients with sarcopenia had significantly lower scores on the Digit Symbol Substitution Test and Trail Making Test Part A. There was a significant negative association between sarcopenia and both self- and proxy-rated EQ-5D utility scores independent of potential confounding factors. However, there was no association between QOL visual analog scale scores and sarcopenia. Conclusion: Given that sarcopenia is often found in individuals with cognitive impairment, early detection by timely screening and effective intervention may help to maintain or improve QOL in this population. However, this study could not determine whether reduced QOL is a direct consequence of sarcopenia.