Volume 83, Number 3, IN PRESS

Review
Mariana Van Zeller, Diogo M. Dias, Ana M. Sebastião, Cláudia A. Valente (Handling Associate Editor: Zhou Wu)
NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

Review
Yanli Li, Rui Wang, Qian Li, Yan-Jiang Wang, Junhong Guo
Gut Microbiota and Alzheimer’s Disease: Pathophysiology and Therapeutic Perspectives
Abstract: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive decline in cognitive function. Amyloid-β protein accumulation is believed to be the key pathological hallmark of AD. Increasing evidence has shown that the gut microbiota has a role in brain function and host behaviors. The gut microbiota regulates the bidirectional interactions between the gut and brain through neural, endocrine, and immune pathways. With increasing age, the gut microbiota diversity decreases, and the dominant bacteria change, which is closely related to systemic inflammation and health status. Dysbiosis of the gut microbiota is related to cognitive impairment and neurodegenerative diseases. The purpose of this review is to discuss the impacts of the gut microbiota on brain function and the development of AD. It is a feasible target for therapeutic invention. Modulating the composition of the gut microbiota through diet, physical activity or probiotic/prebiotic supplements can provide new prevention and treatment options for AD.

Review
Federica Cioffi, Rayan Hassan Ibrahim Adam, Ruchi Bansal, Kerensa Broersen
A Review of Oxidative Stress Products and Related Genes in Early Alzheimer’s Disease
Abstract: Oxidative stress is associated with the progression of Alzheimer’s disease (AD). Reactive oxygen species can modify lipids, DNA, RNA, and proteins in the brain. The products of their peroxidation and oxidation are readily detectable at incipient stages of disease. Based on these oxidation products, various biomarker-based strategies have been developed to identify oxidative stress levels in AD. Known oxidative stress-related biomarkers include lipid peroxidation products F2-isoprostanes, as well as malondialdehyde and 4-hydroxynonenal which both conjugate to specific amino acids to modify proteins, and DNA or RNA oxidation products 8-hydroxy-2'-deoxyguanosine (8-OHdG) and 8-hydroxyguanosine (8-OHG), respectively. The inducible enzyme heme oxygenase type 1 (HO-1) is found to be upregulated in response to oxidative stress-related events in the AD brain. While these global biomarkers for oxidative stress are associated with early-stage AD, they generally poorly differentiate from other neurodegenerative disorders that also coincide with oxidative stress. Redox proteomics approaches provided specificity of oxidative stress-associated biomarkers to AD pathology by the identification of oxidatively damaged pathology-specific proteins. In this review, we discuss the potential combined diagnostic value of these reported biomarkers in the context of AD and discuss eight oxidative stress-related mRNA biomarkers in AD that we newly identified using a transcriptomics approach. We review these genes in the context of their reported involvement in oxidative stress regulation and specificity for AD. Further research is warranted to establish the protein levels and their functionalities as well as the molecular mechanisms by which these potential biomarkers are involved in regulation of oxidative stress levels and their potential for determination of oxidative stress and disease status of AD patients.

Review
Liane Kaufmann, Korbinian Moeller, Josef Marksteiner
Pain and Associated Neuropsychiatric Symptoms in Patients Suffering from Dementia: Challenges at Different Levels and Proposal of a Conceptual Framework
Abstract: Old age is critically associated with multi-morbidity, chronic pain, and high risk for dementia. Recognizing and treating pain is very much dependent on language comprehension and production. Both may be impaired in dementia. Moreover, neuropsychiatric symptoms may interact with pain perception. The main aims of the present article were 1) to identify key areas for future research to elucidate the relation between pain and associated neuropsychiatric symptoms in dementia, and 2) to provide a conceptual framework for ameliorating the clinical process of recognizing, assessing, and managing pain in non-communicating patients with advanced dementia.

Short Communication
Pablo Agüero, María José Sainz, Raquel Téllez, Isabel Lorda, Almudena Ávila, Guillermo García-Ribas, Patricia Paredes Rodríguez, Estrella Gómez-Tortosa
De Novo PS1 Mutation (Pro436Gln) in a Very Early-Onset Posterior Variant of Alzheimer’s Disease Associated with Spasticity: A Case Report
Abstract: We report a patient with sporadic Alzheimer’s disease with onset in his twenties found to carry the de novo Pro436Gln mutation in the presenilin 1 gene (PS1). Clinical phenotype featured a posterior cortical syndrome with severe visual agnosia and mild limb spasticity with brisk reflexes. Brain MRI and FDG-PET scans revealed severe parieto-occipital atrophy/hypometabolism. Cerebrospinal fluid biomarkers showed a decrease in Aβ42 level and Aβ42/40 ratio, increased phospho-tau, and normal total tau. Amyloid PET identified a very high burden of amyloid-β neuritic plaques in the posterior cortex. Similarities between this and two previously reported cases with this variant support that this mutation has a very strong impact on the clinical phenotype and is consistently associated with spasticity.

Short Communication
Peter Bentham, Roger T. Staff, Bjoern O. Schelter, Helen Shiells, Charles R. Harrington, Claude M. Wischik
Long-Term Hydromethylthionine Treatment Is Associated with Delayed Clinical Onset and Slowing of Cerebral Atrophy in a Pre-Symptomatic P301S MAPT Mutation Carrier
Abstract: One of the genetic mutations in the microtubule-associated protein tau, P301S, is causative for dominantly inherited frontotemporal dementia characterized by extensive tau pathology for which no licensed treatment is available. Hydromethylthionine is a potent tau aggregation inhibitor. We report treatment of an asymptomatic carrier of the P301S mutation using hydromethylthionine over a 5-year period beginning at the mean age of onset of clinical decline in the family. During the period of treatment, the rates of progression of cerebral atrophy were reduced by 61%-66% in frontal and temporal lobes, and the patient remained clinically asymptomatic.

Short Communication
Hang-Rai Kim, Ja Hyun Jang, Honggi Ham, Seung Ho Choo, Jeongho Park, Sung Hoon Kang, Song Hwangbo, Hyemin Jang, Duk L. Na, Sang Won Seo, Ji Hyun Baek, Hee Jin Kim
A Case of Early-Onset Alzheimer’s Disease Mimicking Schizophrenia in a Patient with Presenilin 1 Mutation (S170P)
Abstract: Atypical psychological symptoms frequently occur in early-onset Alzheimer’s disease (EOAD), which makes it difficult to differentiate it from other psychiatric disorders. We report the case of a 28-year-old woman with EOAD, carrying a presenilin-1 mutation (S170P), who was initially misdiagnosed with schizophrenia because of prominent psychiatric symptoms in the first 1–2 years of the disease. Amyloid-β positron emission tomography (PET) showed remarkably high tracer uptake in the striatum and thalamus. Tau PET showed widespread cortical uptake and relatively low uptake in the subcortical and medial temporal regions. Our case advocates for considering EOAD diagnosis for young patients with psychiatric and atypical cognitive symptoms.

Short Communication
Dominique Gouilly, Camille Tisserand, Leonor Nogueira, Laura Saint-Lary, Vanessa Rousseau, Marie Benaiteau, Marie Rafiq, Jasmine Carlier, Emilie Milongo-Rigal, Jean-Christophe Pagès, Jérémie Pariente (Handling Associate Editor: Eloi Magnin)
Taking the A Train? Limited Consistency of Aβ42 and the Aβ42/40 Ratio in the AT(N) Classification
Abstract: The consistency of cerebrospinal fluid amyloid-β (Aβ)42/40 ratio and Aβ42 has not been assessed in the AT(N) classification system. We analyzed the classification changes of the dichotomized amyloid status (A+/A-) in 363 patients tested for Alzheimer’s disease biomarkers after Aβ42 was superseded by the Aβ42/40 ratio. The consistency of Aβ42 and the Aβ42/40 ratio was very low. Notably, the proportions of “false” A+T- patients were considerable (74-91%) and corresponded mostly to patients not clinically diagnosed with Alzheimer’s disease. Our results suggest that the interchangeability of Aβ42/40 ratio and Aβ42 is limited for classifying patients in clinical setting using the AT(N) scheme.

Chad A. Pope, Heather M. Wilkins, Russell H. Swerdlow, Michael S. Wolfe
Mutations in the Amyloid-β Protein Precursor Reduce Mitochondrial Function and Alter Gene Expression Independent of 42-Residue Amyloid-β Peptide
Abstract: Background: Dominant missense mutations in the amyloid-β protein precursor (AβPP) cause early-onset familial Alzheimer’s disease (FAD) and are associated with changes in the production or properties of the amyloid-β peptide (Aβ), particularly of the 42-residue variant (Aβ42) that deposits in the Alzheimer’s disease (AD) brain. Recent findings, however, show that FAD mutations in AβPP also lead to increased production of longer Aβ variants of 45-49 residues in length. Objective: We aimed to test neurotoxicity of Aβ42 vis-à-vis longer variants, focusing specifically on mitochondrial function, as dysfunctional mitochondria are implicated in the pathogenesis of AD. Methods: We generated SH-SY5Y human neuroblastoma cells stably expressing AβPP mutations that lead to increased production of long Aβ peptides with or without Aβ42. These AβPP-expressing cells were tested for oxygen consumption rates (OCR) under different conditions designed to interrogate mitochondrial function. These cell lines were also examined for expression of genes important for mitochondrial or neuronal structure and function. Results: The mutant AβPP-expressing cells showed decreased basal OCRs as well as decreased OCRs associated with mitochondrial ATP production, even more so in the absence of Aβ42 production. Moreover, mutant AβPP-expressing cells producing longer forms of Aβ displayed altered expression of certain mitochondrial- and neuronal-associated genes, whether or not Aβ42 was produced. Conclusion: These findings suggest that mutant AβPP can cause mitochondrial dysfunction that is associated with long Aβ but not with Aβ42.

Adrián Jorda, Martin Aldasoro, Constanza Aldasoro, Soraya L. Valles (Handling Associate Editor: Jack de la Torre)
Inflammatory Chemokines Expression Variations and Their Receptors in APP/PS1 Mice
Abstract: Background: In Alzheimer’s disease (AD), an increase in inflammation is distinctive. Amyloid precursor protein plus presenilin-1 (APP/PS1 mice) is a model for this illness. Chemokines secreted by central nervous system (CNS) cells could play multiple important roles in AD. Data looking for the chemokines involved in inflammatory mechanisms are lacking. To understand the changes that occur in the inflammation process in AD, it is necessary to improve strategies to act on specific inflammatory targets. Objective: Chemokines and their receptors involved in phagocytosis, demyelination, chemotaxis, and coagulation were the objective of our study. Methods: Female APPswe/PS1 double-transgenic mice (B6C3-Tg) were used and cortex brain from 20-22-month-old mice obtained and used to quantify chemokines and chemokine receptors expression using RT-PCR technique. Results: Significant inflammatory changes were detected in APP/PS1 compared to wild type mice. CCR1, CCR3, CCR4, and CCR9 were elevated, and CCR2 were decreased compared with wild type mice. Their ligands CCL7, CCL11, CCL17, CCL22, CCL25, and CXCL4 showed an increase expression; however, changes were not observed in CCL2 in APP/PS1 compared to wild type mice. Conclusion: This change in expression could explain the differences between AD patients and elderly people without this illness. This would provide a new strategy for the treatment of AD, with the possibility to act in specific inflammatory targets.

Robert Morris*, Gibret Umeukeje*, Kun Bu*, Feng Cheng *These authors contributed equally to this work.
The Association Between Use of Rivastigmine and Pneumonia: Systematic Analysis of FDA Adverse Event Reporting System
Abstract: Background: Pneumonia is an inflammatory condition induced by infection of the lungs and is frequently a cause of morbidity and mortality among patients with Alzheimer’s disease (AD). Some studies have shown a correlation between acetylcholinesterase inhibitor use and elevated pneumonia risk. Objective: The purpose of this study was to perform a comparative analysis of the number of reported pneumonia cases in individuals prescribed rivastigmine relative to the association between pneumonia risk for other therapeutics including over-the-counter drugs and other AD therapeutics, as reported to the FDA Adverse Event Reporting System (FAERS) database. Methods: A disproportionality analysis was conducted to investigate the association between using rivastigmine and risk of pneumonia. Age, gender, dosage, route of administration, temporality, and geographic distribution of reported cases were also assessed. Results: Patients prescribed rivastigmine were more likely to report pneumonia as an adverse event than many drugs except galantamine. Males were found to be 46% more likely than females to report pneumonia as an adverse event while likelihood of pneumonia diagnosis increases 3-5-fold in patients older than 65 years of age. Conclusion: The observed elevated frequency of aspiration pneumonia in patients prescribed rivastigmine may be due to an induced cholinergic crisis that is selective for the medulla oblongata, resulting in gastrointestinal distress, impaired swallowing, heightened salivation, and labored breathing. The observed elevated frequency of infectious pneumonia in patients prescribed rivastigmine may also be linked to overstimulation of neurons in the medulla oblongata and downstream suppression of localized inflammatory responses.

Elżbieta Kuźma*, Thomas J. Littlejohns*, Anthony P. Khawaja, David J. Llewellyn, Obioha C. Ukoumunne, Ulrich Thiem (Handling Associate Editor: Ruth Peters) *These authors contributed equally to this work.
Visual Impairment, Eye Diseases, and Dementia Risk: A Systematic Review and Meta-Analysis
Abstract: Background: Visual impairment and eye diseases have been associated with dementia, though with mixed findings and often in cross-sectional studies. Objective: To identify prospective studies investigating associations between visual impairment or common eye diseases and risk of all-cause dementia or key dementia subtypes. Methods: We searched Medline, PsycINFO, and Embase from inception to January 2020. We also conducted backward and forward citation searches of included studies and set up alerts to identify studies published after the search date. Random-effects meta-analysis was used to combine adjusted estimates across studies. Results: Thirty studies met our eligibility criteria. For visual impairment, pooled estimates indicated an increased risk of all-cause dementia (37,705 participants, 3,415 cases, risk ratio [RR]=1.38, 95% confidence interval [CI]: 1.19-1.59, I2=28.6%). Pooled estimates also suggested an increased dementia risk associated with cataract (6,659 participants, 1,312 cases, hazard ratio [HR]=1.17, 95% CI 1.00-1.38, I2=0.0%) and diabetic retinopathy (43,658 participants, 7,060 cases, HR=1.34, 95% CI 1.11-1.61, I2=63.9%), respectively. There was no evidence of an association between glaucoma (175,357 participants, 44,144 cases, HR= 0.97, 95% CI 0.90-1.04, I2=51.5%) or age-related macular degeneration (7,800,692 participants, >2,559 cases, HR=1.15, 95% CI 0.88-1.50, I2=91.0%) and risk of dementia, respectively. Conclusion: As visual impairment, cataract, and diabetic retinopathy are associated with an increased likelihood of developing dementia, early diagnosis may help identify those at risk of dementia. Given most causes of visual impairment are treatable or preventable, the potential for dementia prevention warrants further investigation.

Morgan Scarth, Ina Rissanen, Rob J.P.M. Scholten, Mirjam I. Geerlings (Handling Associate Editor: Jiu Chen)
Biomarkers of Alzheimer’s Disease and Cerebrovascular Lesions and Clinical Progression in Patients with Subjective Cognitive Decline: A Systematic Review
Abstract: Background: Early identification of Alzheimer’s disease (AD) may be extremely beneficial for delaying disease progression. Subjective cognitive decline (SCD) may be an early indicator of AD pathology. Not all individuals with SCD will eventually develop AD, making it critical to identify biomarkers during the SCD stage which indicate likely clinical progression. Objective: The present review aims to summarize available data on structural MRI and cerebrospinal fluid (CSF) biomarkers and their association with clinical progression to mild cognitive impairment (MCI) or AD in people with SCD. Methods: Database searches were conducted using Embase and PubMed until June 2020. Longitudinal studies assessing biomarkers in individuals with SCD and assessing clinical progression to MCI/AD were included. Two assessors performed data extraction and assessed the risk of bias in the included studies. Data were synthesized narratively. Results: An initial search identified 1,065 papers; after screening and review 14 studies were included. Sample size of the included studies ranged from 28-674, mean age was 60.0-68.6 years, and 10.2%-52% of participants converted to MCI/AD. Lower levels of CSF Aβ42 were consistently associated with clinical progression. Combination measures identifying an AD-like profile of Aβ42 and tau levels were strongly associated with clinical progression. Biomarkers identified with structural MRI were less conclusive, as some studies found significant associations while others did not. Conclusion: Biomarkers may be able to predict clinical progression in those with cognitive complaints. Aβ42, or combinations of Aβ42 and tau may be useful biomarkers in identifying individuals with SCD who will progress to MCI/AD.

Luciana Domett Siqueira, Ana Paula M. Celes, Hellin Dos Santos, Sergio T. Ferreira (Handling Associate Editor: Ricardo Maccioni)
A Specialized Nutritional Formulation Prevents Hippocampal Glial Activation and Memory Impairment Induced by Amyloid-β Oligomers in Mice
Abstract: Background: Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-β oligomers (AβOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment. Objective: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AβOs in mice. Methods: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AβOs (n = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n = 6-10 mice per experimental condition). Results: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AβOs. The AZ formulation further protected mice from AbO-induced memory impairment. Conclusion: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD.

Sana Rehan, Nathalie Giroud, Faisal Al-Yawer, Walter Wittich, Natalie Phillips
Visual Performance and Cortical Atrophy in Vision-Related Brain Regions Differ Between Older Adults with (or at Risk for) Alzheimer’s Disease
Abstract: Background: Visual impairment is associated with deficits in cognitive function and risk for cognitive decline and Alzheimer’s disease (AD). Objective: The purpose of this study was to characterize the degree of visual impairment and explore the association thereof with cortical atrophy in brain regions associated with visual processing in individuals with (or at risk for) AD. Methods: Using the Comprehensive Assessment of Neurodegeneration and Dementia (COMPASS-ND) dataset, we analyzed vision and brain imaging data from three diagnostic groups: individuals with subjective cognitive decline (SCD; N = 35), mild cognitive impairment (MCI; N = 74), and mild AD (N = 30). We used ANCOVAs to determine whether performance on reading acuity and contrast sensitivity tests differed across diagnostic groups. Hierarchical regression analyses were applied to determine whether visual performance predicted gray matter volume for vision-related regions of interest above and beyond group membership. Results: The AD group performed significantly worse on reading acuity (F(2,138) = 4.12, p < 0.01, ω2 = 0.04) compared to the SCD group and on contrast sensitivity (F(2,138) = 7.6, p < 0.01, ω2 = 0.09) compared to the SCD and MCI groups, which did not differ from each other. Visual performance was associated with volume in some vision-related structures beyond clinical diagnosis. Conclusion: Our findings demonstrate poor visual performance in AD and that both group membership and visual performance are predictors of cortical pathology, consistent with the idea that atrophy in visual areas and pathways contributes to the functional vision deficits observed in AD.

Anders Wimo, Mark Belger, Jaka Bon, Frank Jessen, Annette Dumas, Milica G. Kramberger, Laura Jamilis, Gunilla Johansson, Adrián Rodrigo Salas, Octavio Rodríguez Gómez, Lena Sannemann, Malou Stoekenbroek, Miren Gurruchaga Telleria, Sergi Valero, Lisa Vermunt, Lisa Waterink, Bengt Winblad, Peter Jelle Visser, Marissa Zwan, Mercè Boada; on behalf of the other members of the MOPEAD consortium
A Cost-Consequence Analysis of Different Screening Procedures in Alzheimer’s Disease: Results from the MOPEAD Project
Abstract: Background: For care planning and support, under-detection and late diagnosis of Alzheimer’s disease (AD) is a great challenge. Models of Patient-Engagement for Alzheimer's Disease (MOPEAD) is an EU-funded project aiming at testing different strategies to improve this situation. Objective: To make a cost-consequence analysis of MOPEAD. Methods: Four screening strategies were tested in five countries (Germany, the Netherlands, Slovenia, Spain, and Sweden): 1) a web-approach; 2) Open-House initiative; 3) in primary care; and 4) by diabetes specialists. Persons-at-risk of AD in all strategies were offered referral to a hospital-based specialist. The primary health-economic outcome was the cost per true-positive case (TP) of AD from the screened population. Results: Of 2,847 screened persons, 1,121 screened positive (39%), 402 were evaluated at memory clinics (14%), and 236 got an AD diagnosis (8%). The cost per TP of those screened was 3,115€ with the web-approach, 2,722€ with the Open-House, 1,530€ in primary care, and 1,190€ by diabetes specialists. Sensitivity analyses that more likely reflect the real-world situation confirmed the results. The number-needed-to-screen was 30 with the web-approach, 8 with the Open-House and primary care, and 6 with the diabetes specialists. There were country differences in terms of screening rates, referrals to memory clinics, staff-types involved, and costs per TP. Conclusion: In primary care and by the diabetes specialist, the costs per TP/screened population were lowest, but the capacity of such settings to identify cases with AD-risk must be discussed. Hence new diagnostic strategies such as web-solutions and Open-House initiatives may be valuable after modifications.

Gianna Fote, Jie Wu, Mark Mapstone, Fabio Macciardi, Massimo S. Fiandaca, Howard J. Federoff (Handling Associate Editor: Michelle Mielke)
Plasma Sphingomyelins in Late-Onset Alzheimer’s Disease
Abstract: Background: Altered plasma levels of sphingolipids, including sphingomyelins (SM), have been found in mouse models of Alzheimer’s disease (AD) and in AD patient plasma samples. Objective: This study assesses fourteen plasma SM species in a late-onset AD (LOAD) patient cohort (n=138). Methods: Specimens from control, preclinical, and symptomatic subjects were analyzed using targeted mass-spectrometry-based metabolomic methods. Results: Total plasma SM levels were not significantly affected by age or cognitive status. However, one metabolite that has been elevated in manifest AD in several recent studies, SM OHC14:1, was reduced significantly in pre-clinical AD and MCI relative to normal controls. Conclusion: We recommend additional comprehensive plasma lipidomics in experimental and clinical biospecimens related to LOAD that might advance the utility of plasma sphingomyelin levels in molecular phenotyping and interpretations of pathobiological mechanisms.

Ann-Katrin Schild, Jenny Volk, Daniel Scharfenberg, Katrin Schuermann, Dix Meibertha,c, Oezguer A. Onur, Frank Jessen, Franziska Maier (Handling Associate Editor: Sebastiaan Engelborghs)
Social Cognition in Patients with Amnestic Mild Cognitive Impairment and Mild Dementia of the Alzheimer Type
Abstract: Background: Social cognition (SC) is a core criterion for neurocognitive disorders. However, findings in patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (DAT) are inconsistent. Objective: We report assessments of emotion recognition (ER), affective and cognitive theory of mind (ToM) in young (YC) and older controls (OC) compared to aMCI and DAT. Methods: 28 aMCI, 30 DAT, 30 YC, and 29 OC received tests of SC and a comprehensive neuropsychological assessment. Analysis of covariance was used to determine group differences. Multiple regression models were applied to identify predictors for each SC task. Results: In controls, OC performed worse in ER and both ToM tasks compared to YC except for one subtest. No significant differences were found between OC and patients concerning ER and affective ToM. In cognitive ToM, differences between OC and patients depended on content and cognitive load with significant impairment in DAT compared to OC. A cognitive composite score predicted SC in OC, but not in patients. Associations of SC with single cognitive domains were found in all groups with language and complex attention as best predictors. Not all variance of SC performance was explained by variance in cognitive domains. Conclusion: Lower performance on SC tasks in OC versus YC was confirmed, although not all tasks were equally affected. With progressive cognitive impairment, cognitive ToM is more impaired than ER or affective ToM. SC seems to be at least partly independent of other cognitive domains, justifying its inclusion in batteries for dementia diagnostic.

Ziying Jiang, Xiaolei Han, Yongxiang Wang, Tingting Hou, Lin Cong, Shi Tang, Xiaodong Han, Tiia Ngandu, Miia Kivipelto, Bengt Winblad, Lenore J. Launer, Yifeng Du*, Chengxuan Qiu* *These authors shared senior authorship.
Red Cell Distribution Width and Dementia Among Rural-Dwelling Older Adults: The MIND-China Study
Abstract: Background: Evidence has emerged that anemia is associated with dementia, but data on the relationships of red blood cell distribution width (RDW) with dementia and cognitive function in older adults are sparse. Objective: We sought to investigate the associations of RDW with dementia and global cognitive performance among rural-dwelling Chinese older adults and further to examine their associations by anemia status. Methods: This population-based cross-sectional study included 5,115 participants (age≥65 years, 57.0% women) in the baseline examination (March-September 2018) of the Multimodal Interventions to Delay Dementia and Disability in rural China (MIND-CHINA). We collected data through face-to-face interviews, clinical examinations, and laboratory tests. Global cognitive function was evaluated using the Mini-Mental State Examination (MMSE). We defined dementia, Alzheimer’s disease (AD), and vascular dementia (VaD) following the respective international criteria. Data were analyzed using multinomial logistic and general linear regression models. Results: Of all participants, 300 were diagnosed with dementia, including 195 with AD and 95 VaD. The multiple-adjusted odds ratio of dementia associated with quartiles of RDW were 1.45 (95%CI: 0.87-2.44), 1.00 (reference), 1.77 (1.07-2.93), and 2.28 (1.40-3.72). Similar J-shaped patterns existed for the association of RDW with odds ratio of AD and VaD. Anemia was not significantly associated with dementia. The J-shaped associations of RDW with dementia and subtypes were statistically evident only among participants without anemia. There was an inverted J-shaped relationship between RDW quartiles and β-coefficients of MMSE score. Conclusion: There is a J-shaped association between RDW level and likelihood of dementias among rural-dwelling Chinese older adults, especially among people without anemia.

Keita Sakurai, Daita Kaneda, Yuto Uchida, Shohei Inui, Masahiko Bundo, Akio Akagi, Takashi Nihashi, Yasuyuki Kimura, Takashi Kato, Kengo Ito, Wataru Ohashi, Yoshio Hashizume (Handling Associate Editor: Ece Bayram)
Can Medial Temporal Impairment Be an Imaging Red Flag for Neurodegeneration in Disproportionately Enlarged Subarachnoid Space Hydrocephalus?
Abstract: Background: The differentiation of idiopathic normal pressure hydrocephalus (iNPH) from neurodegenerative diseases such as Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) is often challenging because of their non-specific symptoms. Therefore, various neuroradiological markers other than ventriculomegaly have been proposed. Despite the utility of disproportionately enlarged subarachnoid-space hydrocephalus (DESH) for the appropriate selection of shunt surgery candidates, the specificity and neuropathology of this finding have not been sufficiently evaluated. Objective: Investigation of the clinicopathological features and comparison of the neuroradiological findings between DESH with postmortem neuropathological diagnoses (pDESH) and clinically-diagnosed iNPH (ciNPH) patients are the main purposes of this study. Method: In addition to the retrospective evaluation of clinicopathological information, quantitative, semiquantitative, and qualitative magnetic resonance imaging (MRI) indices were compared between pathologically-investigated 10 patients with pDESH and 10 patients with ciNPH Results: Excluding one patient with multiple cerebral infarctions, the postmortem neuropathological diagnoses of the pathologically-investigated patients were mainly neurodegenerative diseases (five AD, one DLB with AD pathologies, one DLB, one argyrophilic grain disease, and one Huntington's disease). In addition to the common neuroradiological features including DESH and midbrain atrophy, more severe long-standing dementia and MRI findings reflecting hippocampal atrophy and deformation with temporal horn enlargement (i.e., lower hippocampal angle, and higher inferior horn area, IHPA-index, and medial temporal atrophy score) were observed in the pDESH patients. Conclusion: Hippocampal atrophy and deformation with temporal horn enlargement seem to be characteristic neuroradiological findings of long-standing severely demented patients with DESH and neurodegenerative diseases, mainly advanced-stage AD.

Maria I. Lazarova, Daniela S. Tsekova, Lyubka P. Tancheva, Kiril T. Kirilov, Diamara N. Uzunova, Lyubomir T. Vezenkov, Elina R. Tsvetanova, Albena V. Alexandrova, Almira P. Georgieva, Petja T. Gavrilova, Stela T. Dragomanova, Maria G. Papazova, Yordan S. Handzhiyski, Reni E. Kalfin
New Galantamine Derivatives with Inhibitory Effect on Acetylcholinesterase Activity
Abstract: Background: Inhibitors of acetylcholinesterase (AChE) are used to treat many disorders, among which are neurodegenerative upsets, like Alzheimer’s disease (AD). One of the limited licensed AChE inhibitors (AChEIs) used as drugs is the natural compound galantamine (Gal). Objective: As Gal is a toxic compound, here we expose data about its four derivatives in hybrid peptide-norgalantamine molecules, which have shown 100 times lower toxicity. Methods: Four newly synthesized galantamine derivatives have been involved in docking analysis made by Molegro Virtual Docker. Biological assessments were performed on ICR male mice. The change in short and long-term memory performance was evaluated by passive avoidance test. AChE activity and levels of main oxidative stress parameters: lipid peroxidation, total glutathione (GSH), enzyme activities of catalase (CAT), superoxide dismutase, and glutathione peroxidase were measured in brain homogenates. Results: Our experimental data revealed that the new hybrid molecules did not impair memory performance in healthy mice. Two of the compounds demonstrated better than Gal AChE inhibitory activity in the brain. None of them changed the level of lipid peroxidation products, one of the compounds increased GSH levels, and all of them increased CAT enzyme activity. Conclusion: The new galantamine-peptide hybrids demonstrated a potential for inhibition of AChE and antioxidant activity and deserve further attention.

Teruyuki Matsuoka, Daisuke Ueno, Zahinoor Ismail, Ellen Rubinstein, Hiroyuki Uchida, Masaru Mimura, Jin Narumoto (Handling Associate Editor: Laura Serra)
Neural Correlates of Mild Behavioral Impairment: A Functional Brain Connectivity Study Using Resting-State Functional Magnetic Resonance Imaging
Abstract: Background: Mild behavioral impairment (MBI) is associated with accelerated cognitive decline and greater risk of dementia. However, the neural correlates of MBI have not been completely elucidated. Objective: The study aimed to investigate the correlation between cognitively normal participants and participants with amnestic mild cognitive impairment (aMCI) using resting-state functional magnetic resonance imaging. Methods: The study included 30 cognitively normal participants and 13 participants with aMCI (20 men and 23 women; mean age, 76.9 years). The MBI was assessed using the MBI checklist (MBI-C). Region of interest (ROI)-to-ROI analysis was performed to examine the correlation between MBI-C scores and functional connectivity (FC) of the default mode network, salience network, and frontoparietal control network (FPCN). Age, Mini-Mental State Examination score, sex, and education were used as covariates. A p-value of 0.05, with false discovery rate correction, was considered significant. Results: A negative correlation was observed between the MBI-C total score and FC of the left posterior parietal cortex with the right middle frontal gyrus. A similar result was obtained for the MBI-C affective dysregulation domain score. Conclusion: FPCN dysfunction was detected as a neural correlate of MBI, especially in the affective dysregulation domain. This dysfunction may be associated with cognitive impairment in MBI and conversion of MBI to dementia; however, further longitudinal data are needed to examine this relationship.

Ester Esteban de Antonio*, Alba Pérez-Cordón*, Silvia Gil, Adelina Orellana, Amanda Cano, Montserrat Alegret, Ana Espinosa, Emilio Alarcón-Martín, Sergi Valero, Joan Martínez, Itziar de Rojas, Óscar Sotolongo-Grau, Elvira Martín, Assumpta Vivas, Marta Gomez-Chiari, Miguel Ángel Tejero, Mireia Bernuz, Lluis Tárraga, Agustín Ruiz, Marta Marquié, Mercè Boada on behalf of the BIOFACE study group (Handling Associate Editor: Ana Gabriela Henriques) *These authors contributed equally to this work.
BIOFACE: A Prospective Study of Risk Factors, Cognition, and Biomarkers in a Cohort of Individuals with Early-Onset Mild Cognitive Impairment. Study Rationale and Research Protocols
Abstract: Background: Mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) diagnosis is based on cerebrospinal fluid (CSF) or neuroimaging biomarkers. Currently, non-invasive and inexpensive blood-based biomarkers are being investigated, such as neuronal-derived plasma exosomes (NPEs). Neuroinflammation and early vascular changes have been described in AD pathogenesis and can be traced in plasma and NPEs. However, they have not been studied in early onset MCI (EOMCI). Objective: To describe the rationale, design, and baseline characteristics of the participants from the BIOFACE cohort, a two-year observational study on EOMCI conducted at Fundació ACE. The study goal is to characterize the different phenotypes from a clinical, neuropsychological, and biomarker point of view and to investigate the CSF and plasma proteomics as well as the role of NPEs as early biomarkers of AD. Methods: Participants underwent extended neurological and neuropsychological batteries, multimodal biomarkers including brain MRI, blood, saliva, CSF, anthropometric, and neuro-ophthalmological examinations. Results: Ninety-seven patients with EOMCI were recruited. 59.8% were women. Mean age at symptom onset was 57 years; mean MMSE was 28. First degree and presenile family history of dementia was present in 60.8% and 15.5%, respectively. Depressive and anxiety disorders along with vascular risk factors were the most frequent comorbidities. 29% of participants were APOE ɛ4 carriers, and 67% showed a CSF normal ATN profile. Conclusion: BIOFACE is a two-year study of clinical, cognition, and biomarkers that will shed light on the physiopathology and the potential utility of plasma and NPEs as non-invasive early diagnostic and prognostic biomarkers in people younger than 65 years.

Katie J Schenning, Sarah Holden, Brett A. Davis, Amelia Mulford, Kimberly A. Nevonen, Joseph F. Quinn, Jacob Raber, Lucia Carbone, Nabil J. Alkayed
Gene-Specific DNA Methylation Linked to Postoperative Cognitive Dysfunction in Apolipoprotein E3 and E4 Mice
Abstract: Background: Geriatric surgical patients are at higher risk of developing postoperative neurocognitive disorders (NCD) than younger patients. The specific mechanisms underlying postoperative NCD remain unknown, but they have been linked to genetic risk factors, such as the presence of APOE4, compared to APOE3, and epigenetic modifications caused by exposure to anesthesia and surgery. Objective: To test the hypothesis that compared to E3 mice, E4 mice exhibit a more pronounced postoperative cognitive impairment associated with differential DNA methylation in brain regions linked to learning and memory. Methods: 16-month-old humanized apolipoprotein-E targeted replacement mice bearing E3 or E4 were subjected to surgery (laparotomy) under general isoflurane anesthesia or sham. Postoperative behavioral testing and genome-wide DNA methylation were performed. Results: Exposure to surgery and anesthesia impaired cognition in aged E3, but not E4 mice, likely due to the already lower cognitive performance of E4 prior to surgery. Cognitive impairment in E3 mice was associated with hypermethylation of specific genes, including genes in the Ephrin pathway implicated in synaptic plasticity and learning in adults and has been linked to Alzheimer’s disease. Other genes, such as the Scratch Family Transcriptional Repressor 2, were altered after surgery and anesthesia in both the E3 and E4 mice. Conclusion: Our findings suggest that the neurocognitive and behavioral effects of surgery and anesthesia depend on baseline neurocognitive status and are associated with APOE isoform-dependent epigenetic modifications of specific genes and pathways involved in memory and learning.

Jenna Najar, Jeremiah A. Aakre, Maria Vassilaki, Hanna Wetterberg, Lina Rydén, Anna Zettergren, Ingmar Skoog, Clifford R. Jack Jr, David S. Knopman, Ronald C. Petersen, Silke Kern, Michelle M. Mielke (Handling Associate Editor: Anders Wimo)
Sex Difference in the Relation Between Marital Status and Dementia Risk in Two Population-Based Cohorts
Abstract: Background: The modifying effect of sex on the relation between marital status and dementia has yet to be determined. Objective: To examine if sex modifies the association between marital status and incident dementia. Methods: Population-based samples from the Mayo Clinic Study of Aging (MCSA, N=3,471) and the Gothenburg H70 Birth Cohort Study (H70-study, N=913) were used. A multiplicative interaction term was used to analyze the modifying effect of sex on the relation between marital status (married versus not married) and incident dementia using Cox regression models. Further, risk of dementia by marital status was also evaluated in models separated by sex. Results: In the MCSA, there was an interaction between marital status and sex in relation to dementia (p=0.015). In contrast, in the H70-study, no significant interaction was observed (p=0.28). Nevertheless, in both studies, not married men had increased risk of dementia compared to married men in models adjusted for age, education, and number of children (H70-study: 1.99; 1.06-3.76, MCSA: 1.43; 1.08-1.89). Associations remained similar after additional adjustment for depression, BMI, hypertension, dyslipidemia, and diabetes mellitus (H70-study: 2.00; 1.05-3.82, MCSA: 1.32; 0.99-1.76). Further, no significant association was observed between marital status and dementia in women (H70-study: 1.24; 0.82-1.89, MCSA: 0.82; 0.64-1.04). Conclusion: Sex had a modifying effect on the association between marital status and incident dementia. In analyses separated by sex, not married men had an increased risk of dementia compared to married men, while no significant association was observed between marital status and risk of dementia in women.

Hyun Ju Yang, Subin Lee, Myeong Ju Koh Ho Kyu Lee, Bong Soo Kim, Ki Woong Kim, Joon Hyuk Park (Handling Associate Editor: Miles Welstead)
The Association of White Matter Hyperintensities with Frailty in Patients with Very Mild to Moderate Alzheimer’s Disease
Abstract: Background: Frailty, one of serious global health problems in the elderly, is a growing concern in patients with Alzheimer’s disease (AD) because of its high prevalence in AD and its impact on the prognosis. Objective: To investigate the quantitative association between white matter hyperintensities (WMH) and frailty in AD. Methods: A total of 144 outpatients were included. All subjects were evaluated by using Korean version of the CERAD assessment battery and diagnosed very mild to moderate AD. WMH volume was calculated using automated segmentation analysis from the 3D MRI image and further partitioned according to the distance from the ventricular surface. Using the Korean Frailty Index, prefrailty was defined by the scores of 3 and 4 and frailty by the score of 5 and higher. Results: In total, 23.6% were frailty, 32.6% were pre-frailty, and 43.8% were classified as a robust group. The frailty group had higher WMH volume compared to the robust group (p=0.02), and these trends remained significant after linear regression analyses. According to the subclassification of WMH, using the robust group as a reference, total WMH (OR=6.297, p=0.013, 95% CI=1.463-27.114), juxtaventricular WMH (OR=12.955, p=0.014, 95% CI=1.687-99.509), and periventricular WMH (OR=3.382, p=0.025, 95% CI=1.163-9.8531) volumes were associated with frailty, but deep WMH volume was not. Conclusions A quarter of patients with very mild to moderate AD is suffering from frailty. Our study provides the evidence of a cross-sectional relationship between WMH and frailty, and there is a difference in the association between the subclassification of WMH volume and frailty.

Avin Tofiq, Henrik Zetterberg, Kaj Blennow, Hans Basun, Tommy Cederholm, Maria Eriksdotter, Gerd Faxén-Irving, Erik Hjorth, Fredrik Jernerén, Marianne Schultzberg, Lars-Olof Wahlund, Jan Palmblad, Yvonne Freund-Levi
Effects of Peroral Omega-3 Fatty Acid Supplementation on Cerebrospinal Fluid Biomarkers in Patients with Alzheimer’s Disease: A Randomized Controlled Trial—The OmegAD Study
Abstract: Background: Studies have suggested a connection between a decrease in the levels of polyunsaturated fatty acids (PUFAs) and Alzheimer’s disease (AD). We aimed to assess the effect of supplementation with omega-3 fatty acids (n-3 FAs) on biomarkers analyzed in the cerebrospinal fluid (CSF) of patients diagnosed with AD. Objective: To investigate the effects of daily supplementation with 2.3 g of PUFAs in AD patients on the biomarkers in CSF described below. We also explored the possible correlation between these biomarkers and the performance in the cognitive test Mini-Mental State Examination (MMSE). Methods: Thirty-three patients diagnosed with AD were randomized to either treatment with a daily intake of 2.3 g of n-3 FAs (n = 18) or placebo (n = 15). CSF samples were collected at baseline and after six months of treatment, and the following biomarkers were analyzed: Aβ38, Aβ40, Aβ42, t-tau, p-tau, neurofilament light (NfL), chitinase-3-like protein 1 (YKL-40), acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), soluble IL-1 receptor type II (sIL-1RII), and IL-6. Results: There were no significant differences between the groups concerning the level of the different biomarkers in the CSF at baseline. Within the treatment group, there was a small but significant increase in both YKL-40 (p=0.04) and NfL (p=0.03), while the other CSF biomarkers remained stable. Conclusion: Supplementation with n-3 FAs had a statistically significant effect on NfL and YKL-40, resulting in an increase of both biomarkers, indicating a possible increase of inflammatory response and axonal damage. This increase in biomarkers did not correlate with MMSE score.

Douglas Barthold, Laura E. Gibbons, Zachary A. Marcum, Shelly L. Gray, C. Dirk Keene, Thomas J. Grabowski, Nadia Postupna, Eric B. Larson, Paul K. Crane ( Handling Associate Editor: Sevil Yasar)
Alzheimer’s Disease-Related Neuropathology Among Patients with Medication Treated Type 2 Diabetes in a Community-Based Autopsy Cohort
Abstract: Background: Diabetes is a risk factor for Alzheimer’s disease and related dementias (ADRD). Epidemiologic evidence shows an association between diabetes medications and ADRD risk; cell and mouse models show diabetes medication association with AD-related neuropathologic change (ADNC). Objective: This hypothesis-generating analysis aimed to describe autopsy-measured ADNC for individuals who used diabetes medications. Methods: Descriptive analysis of ADNC for Adult Changes in Thought (ACT) Study autopsy cohort who used diabetes medications, including sulfonylureas, insulin, and biguanides; total N=118. ADNC included amyloid plaque distribution (Thal phasing), neurofibrillary tangle (NFT) distribution (Braak stage), and cortical neuritic plaque density (CERAD score). We also examined quantitative measures of ADNC using the means of standardized Histelide measures of cortical PHF-tau and Aβ1-42. Adjusted analyses control for age at death, sex, education, APOE genotype, and diabetes complication severity index. Results: Adjusted analyses showed no significant association between any drug class and traditional neuropathologic measures compared to nonusers of that class. In adjusted Histelide analyses, any insulin use was associated with lower mean levels of Aβ1-42 (-0.57 (CI: -1.12, -0.02)) compared to nonusers. Five years of sulfonylureas and of biguanides use was associated with lower levels of Aβ1-42 compared to nonusers (-0.15 (CI: -0.28, -0.02), -0.31 (CI: -0.54, -0.07), respectively). Conclusion: Some evidence exists that diabetes medications are associated with lower levels of Aβ1-42, but not traditional measures of neuropathology. Future studies are needed in larger samples to build understanding of the mechanisms between diabetes, its medications, and ADRD, and to potentially repurpose existing medications for prevention or delay of ADRD.

Federica Sorrentino*, Andrea Arighi*, Maria Serpente, Beatrice Arosio, Marina Arcaro, Caterina Visconte, Emanuela Rotondo, Roberto Vimercati, Evelyn Ferri, Giorgio G. Fumagalli, Anna M. Pietroboni, Tiziana Carandini, Elio Scarpini, Chiara Fenoglio*, Daniela Galimberti* (Handling Associate Editor: Laura Serra) °These authors contributed equally to this work.
Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition
Abstract: Background: Variants in Niemann-Pick Type C genes (NPC1 and NPC2) have been suggested to play a role as risk or disease modifying factors for Alzheimer’s disease (AD). Objective: The aim of this study was to analyze NPC1 and NPC2 variability in demented patients with evidence of brain amyloid-β 1-42 (Aβ) deposition and to correlate genetic data with clinical phenotypes. Methods: A targeted Next Generation Sequencing panel was customized to screen NPC1, NPC2, and main genes related to neurodegenerative dementias in a cohort of 136 demented patients with cerebrospinal fluid (CSF) low Aβ levels or positive PET with Aβ tracer and 200 non-demented geriatric subjects. Results: Seven patients were carriers of NPC variants in heterozygosis. Four of them displayed pathogenic variants previously found in NPC patients and one AD patient had a novel variant. The latter was absent in 200 non-demented elderly subjects. Five of seven patients (70%) exhibited psychiatric symptoms at onset or later as compared with 43% in non-carriers (p>0.05). Conclusion: The frequency of NPC1 and NPC2 heterozygous variants in patients with CSF evidence of Aβ deposition is higher than in the general population.

Hannah Rostalski, Ville Korhonen, Teemu Kuulasmaa, Eino Solje, Johanna Krüger, FinnGen, Karri Kaivola, Per Kristian Eide, Jean-Charles Lambert, Valtteri Julkunen, Pentti J. Tienari, Anne M. Remes, Ville Leinonen, Mikko Hiltunen*, Annakaisa Haapasalo* *These authors contributed equally to this work.
A Novel Genetic Marker for the C9orf72 Repeat Expansion in the Finnish Population
Abstract: Background: C9orf72 repeat expansion (C9exp) is the most common genetic cause underlying frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). However, detection of the C9exp requires elaborative methods. Objective: Identification of C9exp carriers from genotyped cohorts could be facilitated by using single nucleotide polymorphisms (SNPs) as markers for the C9exp. Methods: We elucidated the potential of the previously described Finnish risk haplotype, defined by the SNP rs3849942, to identify potential C9exp carriers among 218,792 Finns using the FinnGen database. The haplotype approach was first tested in an idiopathic normal pressure hydrocephalus (iNPH) patient cohort (European Alzheimer’s Disease DNA BioBank) containing C9exp carriers by comparing intermediate (15-30) and full-length (>60 repeats) C9exp carriers (n = 41) to C9exp negative patients (< 15 repeats, n = 801). Results: In this analysis, rs3849942 was associated with carriership of C9exp (OR 8.44, p < 2×10-15), while the strongest association was found with rs139185008 (OR 39.4, p < 5×10-18). Unbiased analysis of rs139185008 in FinnGen showed the strongest association with FTLD (OR 4.38, 3×10-15) and motor neuron disease ALS (OR 5.19, 3×10-21). rs139185008 was the top SNP in all diseases (iNPH, FTLD, ALS), and further showed a strong association with ALS in the UK Biobank (p = 9.0×10-8). Conclusion: Our findings suggest that rs139185008 is a useful marker to identify potential C9exp carriers in the genotyped cohorts and biobanks originating from Finland.

Hualong Wang*, Ying Xu*, Rujing Ren*, Feng Yao, Mei Chen, Zhihua Sheng, Xin Guo, Yan Li Shengdi Chen, Gang Wang (Handling Associate Editor: Jin-Tai Yu) *These authors contributed equally to this work.
Ambulatory Blood Pressure Characteristics of Patients with Alzheimer’s Disease: A Multicenter Study from China
Abstract: Background: Previous studies revealed that abnormal blood pressure (BP) plays an important role in the pathogenesis of Alzheimer's disease (AD). However, little is known about the ambulatory BP characteristics of AD in the mild or severe stage. Objective: We explored the ambulatory BP characteristics of AD in the mild or severe stage. Methods: In the present study, 106 AD patients (42.5% male, average age 81.6 years) were enrolled from three centers in China. Clinal BP measurements at the supine and standing positions, neurological evaluations, and the 24-h ambulatory BP monitoring were performed. Results: In the 106 AD patients, 49.2%, 36.8%, and 70% of patients had 24-h, daytime, and nighttime systolic hypertension, respectively, while 19.8%, 29.2%, and 5.7% had 24-h, daytime, and nighttime diastolic hypotension. The prevalence of the reduced and reverse dipping pattern was 34.0% and 48.1% for systolic BP and 32.1% and 45.3% for diastolic BP, respectively. The daytime diastolic BP was significantly correlated with cognitive performance. After adjustment for age, sex, and body mass index, only daytime diastolic BP was associated with remarkable cognitive deterioration (p≤0.008). Further, AD patients in the severe stage had significantly lower levels of the 24-h, daytime, and nighttime diastolic BP, compared with those in the mild stage. Conclusion: In general, AD patients were featured with high nighttime systolic BP, low daytime diastolic BP, and abnormal circadian BP rhythm of reduced and reverse dipping. The diastolic BP, especially daytime diastolic BP, was adversely correlated with the cognitive deterioration in AD.

Andrea Zangrossi, Sonia Montemurro, Gianmarco Altoè, Sara Mondini
Heterogeneity and Factorial Structure in Alzheimer’s Disease: A Cognitive Perspective
Abstract: Background: Alzheimer’s disease (AD) patients show heterogeneous cognitive profiles which suggest the existence of cognitive subgroups. A deeper comprehension of this heterogeneity could contribute to move toward a precision medicine perspective. Objective: In this study, we aimed 1) to investigate AD cognitive heterogeneity as a product of the combination of within- (factors) and between-patients (sub-phenotypes) components, and 2) to promote its assessment in clinical practice by defining a small set of critical tests for this purpose. Methods: We performed factor mixture analysis (FMA) on neurocognitive assessment results of N=230 patients with a clinical diagnosis of AD. This technique allowed to investigate the structure of cognitive heterogeneity in this sample and to characterize the core features of cognitive sub-phenotypes. Subsequently, we performed a tests selection based on logistic regression to highlight the best tests to detect AD patients in our sample. Finally, the accuracy of the same tests in the discrimination of sub-phenotypes was evaluated. Results: FMA revealed a structure characterized by five latent factors and four groups, which were identifiable by means of a few cognitive tests and were mainly characterized by memory deficits with visuospatial difficulties (“Visuospatial AD”), typical AD cognitive pattern (“Typical AD”), less impaired memory (“Mild AD”), and language/praxis deficits with relatively spared memory (“Nonamnestic AD”). Conclusion: The structure of cognitive heterogeneity in our sample of AD patients, as studied by FMA, could be summarized by four sub-phenotypes with distinct cognitive characteristics easily identifiable in clinical practice. Clinical implications under the precision medicine framework are discussed.

Fatima M. Felisberti (Handling Associate Editor: Jianping Jia)
Hedonic Preferences to Audio and Visual Stimulation in Seniors with Cognitive Impairments
Abstract: Background: Hedonic (or aesthetic) preferences to repeated sensory stimulation can remain stable over time (Island of Stability Effect, ISE) or vary with prior exposures (Mere Exposure Effect, MEE). Objective: Here we compared the liking ratings of seniors with cognitive impairments (mostly mild-to-moderate dementia, DPs) and neurotypical senior controls (CNs) to audio and visual stimuli and examined whether those ratings conformed to the ISE or the MEE predictions. Method: Participants (n = 212) rated sets of stimuli repeated three times at weekly intervals: images of Picasso’s paintings, PANTONE color cards, and avant-garde music clips. Results: The aggregated liking ratings of DPs and CNs were stable over time, in line with the ISE model. However, latent growth modeling indicated that those stable responses might have masked differences at the individual level, since seniors in both cohorts exhibited clusters of different responses over the time evaluated, supporting the predictions of the MEE. Notably, there was a dampening of hedonic experiences in DPs comparatively to CNs. Conclusion: The presence of hedonic responses (and individual variations) in DPs is relevant not only to their wellbeing and therapy interventions involving audio and visual stimulation, but also to the design of spaces that offset the downturn in hedonic experiences affecting seniors with cognitive impairments.

Kathleen Mommaerts, Eline A.J. Willemse, Monica Marchese, Catherine Larue, Wiesje M. van der Flier, Fay Betsou, Charlotte E. Teunissen
A Cystatin C Cleavage ELISA Assay as a Quality Control Tool for Determining Sub-Optimal Storage Conditions of Cerebrospinal Fluid Samples in Alzheimer’s Disease Research
Abstract: Background: An N-terminal octapeptide cleavage of the cystatin C protein was discovered by mass spectrometry when cerebrospinal fluid (CSF) was stored at -20°C for 3 months, which did not occur when CSF was stored at -80°C. Objective: The aim was to develop an immunoassay as quality assessment tool to detect this -20°C cleavage of cystatin C in CSF and support Alzheimer’s disease research. Methods: A specific monoclonal antibody and a double indirect sandwich ELISA were developed: one assay quantifies the octapeptide uncleaved protein specifically and the other quantifies the total cystatin C present in the biological fluid (both cleaved and uncleaved forms). The ratio of these concentrations was calculated to assess the extent of cleavage of cystatin C. The novel ELISA was validated and applied in a short-term (up to 4 weeks) and mid-term (up to one year) stability study of CSF stored at 4°C, -20°C, -80°C, and liquid nitrogen. Impact of freeze-thaw cycles, adsorption, and protease inhibitors were tested. Results: The ratio of truncated protein was modified following -20°C storage and seemed to reach a plateau after 6 months. The ratio was impacted neither by freeze-thaw cycles nor adsorption. The -20°C specific cleavage was found to be protease related. Conclusion: Using this novel double indirect sandwich ELISA, absolute levels of the total and uncleaved cystatin C and the ratio of truncated cystatin C can be measured. This assay is an easily applicable tool which can be used to confirm that CSF biospecimen are fit-for-purpose for Alzheimer’s disease research.

Willa D. Brenowitz, Adina Zeki Al Hazzouri, Eric Vittinghoff, Sherita H. Golden, Annette L. Fitzpatrick, Kristine Yaffe
Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline
Abstract: Background: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited. Objective: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline. Methods: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score. Results: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment=1.59 (95% CI: 1.35,1.87); mid-life OR=1.94 (95%CI:1.16, 3.26); and late-life OR=1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR=1.73; 95%CI: 1.42,2.11) and late-life (OR=1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05). Conclusion: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

Book Review
Of Synuclein and Other Demons. Synuclein and the Coelacanth: The Molecular and Evolutionary Origins of Parkinson’s Disease by James M. Gruschus, Academic Press, 2021, 312 pp. Reviewed by Alberto J. Espay