Pages 387-388
Announcement
Janina Krell-Roesch, PhD, and Yonas E. Geda, MD recipients of the 2022 Alzheimer Award
Pages 389-398
Review
Jing Hao, Yanping Guo*, Keke Guo, Qingcheng Yang
Peripheral Inflammatory Biomarkers of Alzheimer’s Disease
Abstract: Alzheimer's disease (AD) is a neurodegenerative disease of unknown pathological origin. The clinical diagnosis of AD is time-consuming and needs to a combination of clinical evaluation, psychological testing, and imaging assessments. Biomarkers may be good indicators for the clinical diagnosis of AD; hence, it is important to identify suitable biomarkers for the diagnosis and treatment of AD. Peripheral inflammatory biomarkers have been the focus of research in recent years. This review summarizes the role of inflammatory biomarkers in the disease course of AD.
Pages 399-416
Review
Narjes Baazaoui, Khalid Iqbal
COVID-19 and Neurodegenerative Diseases: Prion-Like Spread and Long-Term Consequences
Abstract: COVID-19 emerged as a global pandemic starting from Wuhan in China and spread at a lightning speed to the rest of the world. One of the potential long-term outcomes that we speculate is the development of neurodegenerative diseases as a long-term consequence of SARS-CoV-2 especially in people that have developed severe neurological symptoms. Severe inflammatory reactions and aging are two very strong common links between neurodegenerative diseases and COVID-19. Thus, patients that have very high viral load may be at high risk of developing long-term adverse neurological consequences such as dementia. We hypothesize that people with neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and aged people are at higher risk of getting the COVID-19 than normal adults. The basis of this hypothesis is the fact that SARS-CoV-2 uses as a receptor angiotensin-converting enzyme 2 to enter the host cell and that this interaction is calcium-dependent. This could then suggest a direct relationship between neurodegenerative diseases, ACE-2 expression, and the susceptibility to COVID-19. The analysis of the available literature showed that COVID-19 virus is neurotropic and was found in the brains of patients infected with this virus. Furthermore, that the risk of having the infection increases with dementia and that infected people with severe symptoms could develop dementia as a long-term consequence. Dementia could be developed following the acceleration of the spread of prion-like proteins. In the present review we discuss current reports concerning the prevalence of COVID-19 in dementia patients, the individuals that are at high risk of suffering from dementia and the potential acceleration of prion-like proteins spread following SARS-CoV-2 infection.
Pages 417-428
Systematic Review
Blossom C.M. Stephan, Eugene Y.H. Tang, Eduwin Pakpahan, Bijetri Biswas, Alisha Gupta, Andrea McGrattan, Alessandro Bosco, Connor D. Richardson, Louise Robinson, Mario Siervo
Secular Trends in Dementia Free Cognitive Function in Older Adults: A Systematic Review
Abstract: Background: Although numerous studies have reported a decrease in dementia risk in the last two decades, it is unclear whether dementia-free cognitive function is also changing across generations. Objective: The objective was to systematically evaluate the published data on generational differences in cognitive function in the older population. Methods: Searches were performed on PubMed, Embase, and PsychInfo for articles published in English before 20 June 2021. Included studies were from population-based samples that reported generational differences in cognition in individuals without dementia, aged ≥60 years. Results: 28,101 studies were identified and 15 selected covering the period from 1971 to 2015: including studies from China, Europe, and the USA. The results show generally consistent findings of improvements or stability in dementia free cognitive function in later versus earlier born generations, but not for all cognitive domains. Prevalence of mild cognitive impairment and cognitive impairment no dementia has remained stable in the USA, UK, and China over the last two decades. Prevalence of vascular related mild cognitive impairment has increased in China. Improvements in cognition may only partially be explained by increased educational attainment across generations. Conclusion: This review provides evidence for generational effects in dementia-free cognitive function, predominately stability or improvements in performance, in later compared to earlier born individuals across different world regions. There is an urgent need to determine the factors driving such changes and whether they are being experienced in all world regions, particularly low- and middle-income countries where the burden of cognitive impairment is greatest and rising.
Pages 429-438
Hypothesis
Philip Serwer, Elena T. Wright, Barbara Hunter
Additions to Alpha-Sheet Based Hypotheses for the Cause of Alzheimer’s Disease
Abstract: Protein amyloid-β (Aβ) oligomers with β-sheet-like backbone (β-structured) form extracellular amyloid plaques associated with Alzheimer’s disease (AD). However, the relationship to AD is not known. Some investigations suggest that the toxic Aβ component has α-sheet-like backbone (α-structured) subsequently detoxified by intracellular α-to-β conversion before plaque formation. Our objective is to compare this latter hypothesis with observations made by electron microscopy of thin sections of AD-cerebral cortex. We observe irregular, 200-2,000 nm, intracellular, lipofuscin-like inclusions. Some are light-staining and smooth. Others are dark-staining and made granular by fibers that are usually overlapping and are sometimes individually seen. Aspects unusual for lipofuscin include 1) dark and light inclusions interlocking as though previously one inclusion, 2) dark inclusion-contained 2.6 nm thick sub-fibers that are bent as though α-structured, and 3) presence of inclusions in lysosomes and apparent transfer of dark inclusion material to damaged, nearby lysosomal membranes. These data suggest the following additions to α-structure-based hypotheses: 1) Lipofuscin-associated, α-structured protein toxicity to lysosomal membranes is in the chain of AD causation; 2) α-to-β detoxification of α-structured protein occurs in lipofuscin and causes dark-to-light transition that, when incomplete, is the origin of cell-to-cell transmission essential for development of AD.
Pages 439-445
Hypothesis
Yi-Liang Tsai, Chieh-Tsung Yen, Yuh-Feng Wang
Astrocyte Dysregulation and Calcium Ion Imbalance May Link the Development of Osteoporosis and Alzheimer’s Disease
Abstract: The typical symptoms of patients with Alzheimer's disease (AD) are amyloid-β (Aβ) plaques and tau hyperphosphorylation. However, recent studies show that these symptoms are not the cause of the disease but are generated after the pathogenesis. Compared with other types of dementia, AD has the obvious features of pineal gland calcification and decreased melatonin production. The pineal gland is mainly composed of pinealocytes that release melatonin and astrocytes. Astrocytes function to maintain a balanced concentration of calcium ions, provide nerve cell nutrients, and migrate nutrients in vivo. Calcium ions are among the most important neurotransmitters. Once triggered, a calcium wave can be formed between astrocytes to activate other astrocytes to transmit information. Most calcium is stored in the skeleton. Bone tissue is composed mainly of osteocytes, osteoblasts, and osteoclasts. Of these, osteocyte is a kind of astrocyte which regulates the activity of osteoclasts and osteoblasts. The pineal gland is composed mainly of astrocytes; osteocytes are also a kind of astrocyte. Therefore, we conclude that when astrocytes are gradually disabled, calcium may be lost from the bones, prompting osteoporosis. The calcium ions then released into the blood may accumulate and cause ectopic calcification in the pineal gland, which promotes the occurrence of AD. Finally, this study used aspects of drugs and hormones (bone and calcium metabolism hormones and melatonin) to infer the hypothesis, which proposes that astrocyte dysregulation promotes the long-term imbalance of calcium ions in vivo and leads to osteoporosis and AD.
Pages 447-453
Short Communication
Joost M. Riphagen, Roy W.E. van Hooren, Gunter Kenis, Frans R.J. Verhey, Heidi I.L. Jacobs
Distinct Patterns Link the BDNF Val66Met Polymorphism to Alzheimer’s Disease Pathology
Abstract: The brain-derived neurotropic growth factor (BDNF) gene has been linked to dementia, inflammation, and Apolipoprotein E (APOE) ε4 status. We used cerebrospinal fluid (CSF) amyloid-β (Aβ)42 and phosphorylated tau (p-tau) to investigate associations with BDNF polymorphisms and modifications by APOE ε4 or inflammation in a memory clinic population (n=114; subjective cognitive decline, mild cognitive impairment, Alzheimer’s disease). We found distinct pathways to Alzheimer’s disease pathology: Val-Met displayed lower CSF-Aβ42 in APOE ε4+ carriers, independent of p-tau, while Val-Val displayed greater p-tau at higher IL-6 and sub-threshold Aβ42. This may contribute to resolving some inconsistencies in the BDNF literature and provide possible inroads to specific Aβ and tau interventions depending on BDNF polymorphism.
Pages 455-458
Commentary
Poul F. Høilund-Carlsen, Mona-Elisabeth Revheim, Abass Alavi
Alzheimer’s Disease at a Crossroad: Time to Part from Amyloid to More Promising Aspects—Atherosclerosis for a Start
Abstract: Three decades with the amyloid hypothesis, nearly two with amyloid-PET imaging, and one with testing of anti-amyloid therapy have not yielded benefits to patients with Alzheimer’s disease (AD). It is time to focus on more promising options, e.g., infection, low dose radiation, and atherosclerosis. The relevance of the latter in managing AD has fluctuated from being significant to insignificant. Current methodologies for detecting cerebral atherosclerosis reflect advanced changes in only major arteries. In contrast, 18F-sodium fluoride PET imaging assessing early-stage cerebral atherosclerosis regionally or in the entire vascular bed may provide new insight in this age-related process in dementia.
Pages 459-469
Amal A. Wanigatunga, Fangyu Liu, Hang Wang, Jacek K. Urbanek, Yang An, Adam P. Spira, Ryan J. Dougherty, Qu Tian, Abhay Moghekar, Luigi Ferrucci, Eleanor M. Simonsick, Susan M. Resnick, Jennifer A. Schrack (Handling Associate Editor: M. Arfan Ikram)
Daily Physical Activity Patterns as a Window on Cognitive Diagnosis in the Baltimore Longitudinal Study of Aging (BLSA)
Abstract: Background: Gradual disengagement from daily physical activity (PA) could signal present or emerging mild cognitive impairment (MCI) or Alzheimer’s disease (AD). Objective: This study examined whether accelerometry-derived patterns of everyday movement differ by cognitive diagnosis in participants of the Baltimore Longitudinal Study of Aging (BLSA). Methods: Activity patterns, overall and by time-of-day, were cross-sectionally compared between participants with adjudicated normal cognition (n=549) and MCI/AD diagnoses (n=36; 5 participants [14%] living with AD) using covariate-adjusted regression models. Results: Compared to those with normal cognition, those with MCI/AD had 2.1% higher activity fragmentation (SE=1.0%, p=0.036) but similar mean total activity counts/day (p=0.075) and minutes/day spent active (p=0.174). Time-of-day analyses show MCI/AD participants had lower activity counts and minutes spent active during waking hours (6:00 am-5:59 pm; p<0.01 for all). Also, they had lower activity fragmentation from 12:00-5:59 am (p<0.001), but higher fragmentation from 12:00-5:59 pm (p=0.026). Conclusion: Differences in the timing and patterns of physical activity throughout the day linked to MCI/AD diagnoses warrant further investigation into potential clinical utility.
Pages 471-492
Gabrielle Frame, Adam Schuller, Matthew A. Smith, Samuel D. Crish, Christine M. Dengler-Crish
Alterations in Retinal Signaling Across Age and Sex in 3xTg Alzheimer’s Disease Mice
Abstract: Background: Visual disturbances often precede cognitive dysfunction in patients with Alzheimer’s disease (AD) and may coincide with early accumulation of amyloid-β (Aβ) protein in the retina. These findings have inspired critical research on in vivo ophthalmic Aβ imaging for disease biomarker detection but have not fully answered mechanistic questions on how retinal pathology affects visual signaling between the eye and brain. Objective: The goal of this study was to provide a functional and structural assessment of eye-brain communication between retinal ganglion cell (RGCs) and their primary projection target, the superior colliculus, in female and male 3xTg-AD mice across disease stages. Methods: Retinal electrophysiology, axonal transport, and immunofluorescence were used to determine RGC projection integrity, and retinal and collicular Aβ levels were assessed with advanced protein quantitation techniques. Results: 3xTg mice exhibited nuanced deficits in RGC electrical signaling, axonal transport, and synaptic integrity that exceeded normal age-related decrements in RGC function in age- and sex- matched healthy control mice. These deficits presented in sex-specific patterns among 3xTg mice, differing in the timing and severity of changes. Conclusion: These data support the premise that retinal Aβ is not just a benign biomarker in the eye, but may contribute to subtle, nuanced visual processing deficits. Such disruptions might enhance the biomarker potential of ocular amyloid and differentiate patients with incipient AD from patients experiencing normal age-related decrements in visual function.
Pages 493-502
Miharu Nakanishi, Syudo Yamasaki, Shuntaro Ando, Kaori Endo, Marcus Richards, Mariko Hiraiwa-Hasegawa, Kiyoto Kasai, Atsushi Nishida
Neighborhood Social Cohesion and Dementia-Related Stigma Among Mothers of Adolescents in the Pre- and Current COVID-19 Period: An Observational Study Using Population-Based Cohort Data
Abstract: Background: Middle-aged adults may be the ideal target group for dementia-related stigma reduction interventions to encourage the utilization of services among those who may become family caregivers. Neighborhood social cohesion may diminish dementia-related stigma, particularly in terms of perceived public attitudes. The COVID-19 pandemic can further negatively impact perceived public stigma. Objective: To investigate the association between neighborhood social cohesion and dementia-related stigma during the pre- and current COVID-19 period. Methods: We employed a cross-sectional design using data from a large population-based cohort, the Tokyo Teen Cohort, in Japan. Overall, 2,469 mothers of 16-year-old adolescents self-completed a questionnaire comprising nine dementia-related stigma questions evaluating perceived public and personal attitudes. Neighborhood social cohesion was assessed using a five-item instrument. The participants were divided into two groups according to the time of assessment: prior to the pandemic’s onset (February 2019–March 2020) and during the pandemic (April 2020–July 2021). A multiple regression analysis of stigma was performed using neighborhood social cohesion as an independent variable, and caring experience, age, educational level, and working status as covariates. Results: Personal and perceived public stigma were significantly lower in participants who perceived greater neighborhood social cohesion. However, level of personal and perceived public stigma did not differ between pre- and during the pandemic period. Conclusion: Neighborhood social cohesion may be a modifiable factor for dementia-related stigma. A localized intervention to enhance social cohesion in the neighborhood community would promote the utilization of services among those who may become family caregivers.
Pages 503-512
Ernesto García-Roldán, José Enrique Arriola-Infante, Carlota Méndez-Barrio, Fátima Montiel-Herrera, Gonzalo Mendoza-Vázquez, Alba Marta Marín-Cabañas, Silvia Rodrigo-Herrero, Andrea Luque-Tirado, María Bernal Sánchez-Arjona, Didier Maillet, Emilio Franco-Macías
Testing Visual Binding by the TMA-93 in People Aged 75 and Over
Abstract: Background: TMA-93 examines relational binding using images. The test has been proven to be discriminative for diagnosing early Alzheimer’s disease by biomarkers. Norms for this test are available, but the elderly, at high risk for Alzheimer’s disease, have not yet been widely represented. Objective: To extend normative data on the TMA-93 for people aged 75 and over. Methods: An extension of the Spanish TMA-93 normative study was undertaken. Only cognitively unimpaired people aged 75 and over were included. Age, gender, and educational attainment were registered as socio-demographic variables. Using histograms analysis, median comparisons, and linear regression analysis, we selected variables that demonstrated influence on TMA-93 total scores and provided percentile-base reference data according to combinations of those variables. Results: We included 431 new participants, resulting in a total sample of 657 individuals (median age=78, interquartile range=76-81, range=75-93). Percentile-base reference data stratified by a combination of age ranges (75-79, n=428; and ≥80 years, n=229), and educational attainment (first grade, n=195) revealed that participants achieved a minimum TMA-93 total score of 26/30 at the 50th-percentile regardless of stratum. At the 10th-percentile, a maximum of 24/30 was achieved in the more educated stratum contrasting with a minimum of 19/30 in the less educated stratum. Conclusion: Although mitigated by lower levels of education, performance on the TMA-93 is widely preserved in cognitively unimpaired people aged 75 and over. The test could facilitate the screening of elderly patients with memory complaints.
Pages 513-519
Jesús Gonzalez-Moreno, Encarnacion Satorres, Gema Soria-Urios, Juan C. Meléndez
Cognitive Stimulation Program Presented Through New Technologies in a Group of People with Moderate Cognitive Impairment
Abstract: Background: Cognitive stimulation is one of the non-pharmacological therapies recommended for intervention in dementia, consisting of activities involving different cognitive domains and involving brain activation. New technologies can be very useful in this field, favoring intervention tasks. Objective: The objective of this work is to test the effectiveness of a cognitive stimulation intervention mediated with new technologies on a group of people with moderate dementia. Methods: This is a quantitative, quasi-experimental study with a control and treatment group, with three measurement times (pre, post, and follow-up months after the end of the intervention). Ninety-eight subjects with moderate dementia were randomly assigned to the treatment group (N = 50) and the control group (N = 48). The treatment group received 16 intervention sessions including attention, executive function, and memory tasks, which were presented using new technologies and the activity was conducted in a group setting. Control group remained on a waiting list. The evaluators did not know which group each subject belonged to. All participants were assessed with a battery of neuropsychological tests. Results: The results show an improvement in post-intervention outcomes in the treatment group compared to the control group on cognitive variables. No differences were found in mood depression. These results fade overtime after a few months without intervention. Conclusion: This type of intervention is useful to maintain cognitive functioning using new technologies and in a group setting, which favors the intervention. The improvements of the intervention disappear at follow-up, which would indicate the need to maintain the intervention over time.
Pages 521-535
Mackenzie E. Fowler, Nicole C. Wright, Kristen Triebel, Gabrielle B. Rocque, Marguerite R. Irvin, Richard E. Kennedy (Handling Associate Editor: Erin Abner)
The Relationship Between Prior Cancer Diagnosis and All-Cause Dementia Progression Among US Adults
Abstract: Background: Cancer-related cognitive impairment (CRCI), a frequent effect of cancer and its treatments, shares common cognitive symptoms with dementia syndromes. Cross-sectional studies demonstrate an inverse relationship between cancer and dementia. However, the longitudinal relationship between dementia decline and cancer has not been investigated. Objective: To evaluate the association between cancer and longitudinal progression of dementia. Methods: We extracted electronic health record data from July 2003 to February 2020 from a single academic medical center. We identified dementia and cancer history prior to dementia using ICD-9/10 codes. We measured cognitive decline with the Alabama Brief Cognitive Screener (ABCs). We used adjusted linear mixed models to estimate baseline cognition and rate of progression by cancer history, including differences by race. Results: The study included 3,809 participants with dementia, of which 672 (17.6%) had cancer history. Those with cancer history had higher baseline cognition (β: 1.07, 95% CI: 0.45, 1.69), but similar rate of decline. Non-Hispanic Blacks had lower cognitive scores at baseline and throughout follow-up regardless of cancer status compared to non-Hispanic Whites and other races/ethnicities with and without cancer history. Conclusion: In this longitudinal retrospective study, participants with cancer history demonstrate better cognition at dementia diagnosis and no difference in cognitive decline than those without cancer history. Smoking and comorbidities attenuate this association and results indicate non-Hispanic Blacks have worse cognitive outcomes in dementia regardless of cancer history than other race/ethnicity groups. Further exploration of the role of smoking, comorbidities, and race/ethnicity on cancer and dementia-related cognitive decline is needed.
Pages 537-547
Anna Tsiakiri, Pinelopi Vlotinou, Aikaterini Terzoudi, Ioannis Heliopoulos, Konstantinos Vadikolias
Cognitive, Functional, and Emotional Changes During the COVID-19 Pandemic in Greek Patients with Neurocognitive Disorders
Abstract: Background: Prolonged periods of social deprivation, such as COVID-19-related lockdowns, are associated with deleterious effects on cognitive functions. Objective: The aim of this study was to gauge the effect of prolonged social isolation on the cognitive function of older adults with neurocognitive disorders. Methods: We recruited 125 older adults with minor or major neurocognitive disorders divided into two groups. The control group was tested at the first period of the study (October 2018–May 2019), whereas the experimental group was evaluated at the second chronological period of the study (October 2020¬–May 2021) during the second wave of COVID-19. Neuropsychological tests were performed at baseline and six months after baseline. Results: In the control group, significant changes in the scores from the Montreal Cognitive Assessment (MoCA; p=0.049) and the Functional Rating Scale for Symptoms of Dementia (FRSSD; p=0.005) were found between baseline and follow-up assessments, whereas no changes were identified in Mini-Mental State Examination (MMSE; p=0.229) and Geriatric Depression Scale (GDS; p=0.619) scores. In the experimental group, the scores from all neuropsychological tests (MoCA, MMSE, GDS, and FRSSD; p < 0.001 for all) were significantly different at follow-up when compared with those at baseline measurements. Moreover, significant deterioration of specific functions assessed in MMSE and FRSSD was detected, especially in the experimental group. Conclusion: This study highlights cognitive functions directly affected by social deprivation of individuals with neurocognitive disorders. The findings can be used in the rehabilitation from confinement and its negative consequences.
Pages 549-561
Daniella Castro Araújo, Adriano Alonso Veloso, Karina Braga Gomes, Leonardo Cruz de Souza, Nivio Ziviani, Paulo Caramelli, Alzheimer’s Disease Neuroimaging Initiative (Handling Associate Editor: Barbara Borroni)
A Novel Panel of Plasma Proteins Predicts Progression in Prodromal Alzheimer’s Disease
Abstract: Background: A cheap and minimum-invasive method for early identification of Alzheimer's disease (AD) pathogenesis is key to disease management and the success of emerging treatments targeting the prodromal phases of the disease. Objective: To develop a machine learning-based blood panel to predict the progression from mild cognitive impairment (MCI) to dementia due to AD within a four-year time-to-conversion horizon. Methods: We created over one billion models to predict the probability of conversion from MCI to dementia due to AD and chose the best-performing one. We used Alzheimer’s Disease Neuroimaging Initiative (ADNI) data of 379 MCI individuals in the baseline visit, from which 176 converted to AD dementia. Results: We developed a machine learning-based panel composed of 12 plasma proteins (ApoB, Calcitonin, C-peptide, CRP, IGFBP-2, Interleukin-3, Interleukin-8, PARC, Serotransferrin, THP, TLSP 1-309, and TN-C), and which yielded an AUC of 0.91, accuracy of 0.91, sensitivity of 0.84, and specificity of 0.98 for predicting the risk of MCI patients converting to dementia due to AD in a horizon of up to four years. Conclusion: The proposed machine learning model was able to accurately predict the risk of MCI patients converting to dementia due to AD in a horizon of up to four years, suggesting that this model could be used as a minimum-invasive tool for clinical decision support. Further studies are needed to better clarify the possible pathophysiological links with the reported proteins.
Pages 563-575
Yilin Wang*, Lei Li*, Xiaodong Zhao, Shaomei Sui, Qi Wang, Guizhi Shi, Huilian Xu, Xiujun Zhang Yan He, Jinsong Gu (Handling Associate Editor: Jianping Jia) *These authors contributed equally to this work.
Intestinal Microflora Changes in Patients with Mild Alzheimer’s Disease in a Chinese Cohort
Abstract: Background: Understanding the relationship between Alzheimer's disease (AD) and intestinal flora is still a major scientific topic that continues to advance. Objective: To determine characterized changes in the intestinal microbe community of patients with mild AD. Methods: Comparison of the 16S ribosomal RNA (rRNA) high-throughput sequencing data was obtained from the Illumina MiSeq platform of fecal microorganisms of the patients and healthy controls (HC) which were selected from cohabiting caregivers of AD patients to exclude environmental and dietary factors. Results: We found that the abundance of several bacteria taxa in AD patients was different from that in HC at the genus level, such as Anaerostipes, Mitsuokella, Prevotella, Bosea, Fusobacterium, Anaerotruncus, Clostridium, and Coprobacillus. Interestingly, the abundance of Akkermansia, an emerging probiotic, increased significantly in the AD group compared with that in the HC group. Meanwhile, the quantity of traditional probiotic Bifidobacteria of the AD group also rose. Conclusion: These alterations in fecal microbiome of the AD group indicate that patients with mild AD have unique gut microbial characteristics. These specific AD-associated intestinal microbes could serve as novel potential targets for early intervention of AD.
Pages 577-588
Alette M. Wessels, Mark Belger, Joseph A. Johnston, Youying Yu, Dorene M. Rentz, Sherie A. Dowsett, Julie Chandler
Demonstration of Clinical Meaningfulness of the Integrated Alzheimer’s Disease Rating Scale (iADRS): Association Between Change in iADRS Scores and Patient and Caregiver Health Outcomes
Abstract: Background: The integrated Alzheimer’s Disease Rating Scale (iADRS) is a validated cognitive/functional composite that effectively captures cognitive and functional decline over a broad spectrum of disease. The clinical meaningfulness of change on iADRS can be supported by establishing an association with changes on important health outcome measures. Objective: To evaluate the relationship between change on the iADRS and changes in health outcomes in individuals with mild cognitive impairment (MCI) due to Alzheimer’s disease (AD), or mild or moderate AD dementia using placebo data from four AD clinical trials and data from one AD observational study. Methods: Analysis of covariate (ANCOVA) models were used to estimate the relationship between 18-month change on the iADRS and changes on health outcome measures (related to cost, quality of life, and caregiver burden). The regression coefficients for the iADRS were used to compute impact of natural disease progression and disease-modifying treatment on health outcomes. Additional ANCOVAs were conducted to understand whether cognition and/or function was the underlying explanation of any association between iADRS and health outcome change. Results: Across datasets and disease stages, a worsening on the iADRS was significantly associated with increased societal costs, caregiver burden (time and distress) and worsening in measures of patient quality of life. Conclusion: Decline on the iADRS was associated with worsening in health outcome measures. These findings suggest that the iADRS can be used in clinical trials as a proxy measure of clinically meaningful outcomes of AD progression.
Pages 589-599
Qing Wang*, Yachen Shi*, Xinyang Qi*, Lingyu Qi, Xiang Chen, Jingping Shi, Chunming Xie, Zhijun Zhang *These authors contributed equally to this work.
Platelet-Derived Amyloid-β Protein Precursor as a Biomarker of Alzheimer’s Disease
Abstract: Background: Platelet proteins may be associated with Alzheimer's disease (AD) pathology. Objective: To investigate the relationship between platelet proteins and cerebrospinal fluid (CSF) biomarkers of AD and cognition in individuals with memory decline to identify effective screening methods for detecting the early stages of the disease. Methods: We classified 68 participants with subjective memory decline according to the ATN framework determined by CSF amyloid-β (A), CSF p-tau (T), and t-tau (N). All participants underwent Mini-Mental State Examination (MMSE) and platelet-related protein content testing. Results: Eighteen participants had normal AD biomarkers (NCs), 24 subjects had non-AD pathologic changes (non-AD), and 26 subjects fell within the Alzheimer’s continuum (AD). The platelet amyloid-β protein precursor (AβPP) ratio in the AD group was significantly lower than in the non-AD and NCs groups, and positively correlated with MMSE scores and CSF amyloid-β42 level, which could affect MMSE scores through CSF amyloid-β42. Levels of platelet phosphorylated-tau 231 and ser396/404 phosphorylated tau were elevated in both AD and non-AD compared to NCs. Additionally, the receiver operating characteristic analysis demonstrated that the platelet AβPP ratio was a sensitive identifier for differentiating the AD from NCs (AUC = 0.846) and non-AD (AUC = 0.768). And ser396/404 phosphorylated tau could distinguish AD from NCs. Conclusion: Our study was the first to find an association between platelet AβPP ratio and CSF biomarkers of AD, which contribute to the understanding of the peripheral changes in AD. These findings may help to discover potential feasible and effective screening tools for AD.
Pages 601-608
Shunichiro Shinagawa, Ito Kawakami, Emi Takasaki, Masahiro Shigeta, Tetsuaki Arai, Manabu Ikeda
The Diagnostic Patterns of Referring Physicians and Hospital Expert Psychiatrists Regarding Particular Frontotemporal Lobar Degeneration Clinical and Neuropathological Subtypes
Abstract:Background: It is important to make accurate clinical diagnosis of frontotemporal lobar degeneration (FTLD), which in turn, leads to future therapic approaches. The FTLD cases are frequently inaccurately identified, but the frequency of this misidentification according to the underlying pathological subtypes is still unclear. Objective: We aimed to quantify the accuracy of behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA) diagnoses by both the patients' referring physicians and hospital expert psychiatrists, and we investigated whether the physicians' and psychiatrists' diagnostic patterns are associated with a specific neuropathology. Methods: We retrospectively analyzed the cases of a series of Japanese patients with pathologically diagnosed FTLD (n=55): the bvFTD group (n=47) consisted of patients with FTLD-tau (n=20), FTLD-TDP (TAR DNA-binding protein of 43-kDA) (n=19), and FTLD-FUS (fused in sarcoma) (n=8). The svPPA patients (n=8) all had FTLD-TDP. Results: Only 31% of the patients' referring physicians mentioned FTD syndrome. The referring psychiatrists and neurologists showed similar diagnostic accuracy. High diagnostic accuracy was observed for the TDP pathology group (mainly svPPA patients). The FTLD-FUS patients were more likely to be diagnosed as having a psychiatric disorder by referring physicians. The hospital expert psychiatrists' accuracy for identifying FTLD-tau pathology was low. Conclusion: The results of our analyses revealed a specific diagnostic pattern associated with particular FTLD pathological subtypes, which will help to improve non-specialists' diagnostic ability.
Pages 609-618
Sanna Hannonen*, Sami Andberg*, Virve Kärkkäinen*, Minna Rusanen, Juha-Matti Lehtola, Toni Saari, Ville Korhonen, Laura Hokkanen, Merja Hallikainen, Tuomo Hänninen, Ville Leinonen, Kai Kaarniranta, Roman Bednarik, Anne M. Koivisto *These authors contributed equally to this work.
Shortening of Saccades as a Possible Easy-to-Use Biomarker to Detect Risk of Alzheimer’s Disease
Abstract: Background: Wide-ranging functional defects in eye movements have been reported in Alzheimer’s disease (AD) dementia. The detection of abnormal eye movements and reading problems may identify persons at risk of AD when clear clinical symptoms are lacking. Objective: To examine whether computer-based eye-tracking (ET) analysis of King-Devick (KD) test results differentiates cognitively healthy persons from persons with minor problems in cognitive testing or diagnosed mild AD. Methods: We recruited 78 participants (57 non-demented, 21 with mild AD) who underwent neurological examination, the Consortium to Establish a Registry for Alzheimer’s Disease neuropsychological test battery (CERAD-NB), and a Clinical Dementia Rating (CDR) interview. The non-demented participants were further divided into control (normal CERAD subtests, mean MMSE=28) and objective mild cognitive impairment (MCI; decline in at least one CERAD memory score, mean MMSE=27) groups. The KD reading test was performed using computer-based ET. The total time used for the reading test, errors made, fixation and saccade durations, and saccade amplitudes were analyzed. Results: We found significant differences between the control, objective MCI, and AD groups in regard to the mean saccade amplitude (3.58, 3.33, and 3.21 ms, respectively, p<0.03) and duration (27.1, 25.3, and 24.8 ms, respectively, p<0.05). The KD error scores in the AD group differed significantly (p<0.01) from the other groups. Conclusion: Computed ET analysis of the KD test may help detect persons with objective MCI early when clear clinical symptoms are lacking. The portable device for ET is easy to use in primary health care memory clinics.
Pages 619-629
Taha I. Huda, Michael J. Diaz, Etienne C. Gozlan, Andrea Chobrutskiy, Boris I. Chobrutskiy, George Blanck
Immunogenomics Parameters for Patient Stratification in Alzheimer’s Disease
Abstract: Background: Despite the fact that only modest adaptive immune system related approaches to treating Alzheimer’s disease (AD) are available, an immunogenomics approach to the study of AD has not yet substantially advanced. Objective: Thus, we sought to better understand adaptive immune receptor chemical features in the AD setting. Methods: We characterized T-cell receptor alpha (TRA) complementarity determining region-3 (CDR3) physicochemical features and identified TRA CDR3 homology groups, represented by TRA recombination reads extracted from 2,665 AD-related, blood- and brain-derived exome files. Results: We found that a higher isoelectric value for the brain TRA CDR3s was associated with a higher (clinically worse) Braak stage and that a number of TRA CDR3 chemical homology groups, in particular representing bloodborne TRA CDR3s, were associated with higher or lower Braak stages. Lastly, greater chemical complementarity of both blood- and brain-derived TRA CDR3s and tau, based on a recently described CDR3-candidate antigen chemical complementarity scoring process (http://adaptivematch.com), was associated with higher Braak stages. Conclusion: Overall, the data reported here raise the questions of (a) whether progression of AD is facilitated by the adaptive immune response to tau; and (b) whether assessment of such an anti-tau immune response could potentially serve as a basis for adaptive immune receptor related, AD risk stratification?
Pages 631-639
Louis Jacob, Lee Smith, Ai Koyanagi, Marcel Konrad, Josep Maria Haro, Jae Il Shin, Karel Kostev
Sex-Differential Associations Between Body Mass Index and the Incidence of Dementia
Abstract: Background: Little is known about the sex differences in the association between body mass index (BMI) and dementia in late life. Objective: Therefore, this retrospective cohort study aimed to analyze associations between BMI and dementia in older women and men separately in general practices in Germany. Methods: This study included patients followed in one of 832 general practices in Germany between 2006 and 2019 (index date: first visit date). Study variables included dementia (dependent variable), BMI (independent variable), age, sex, and comorbidities (control variables). Kaplan-Meier curves and adjusted Cox regression analyses were conducted to analyze associations between BMI and the 10-year incidence of dementia in women and men, separately. Results: There were 296,767 patients included in this study (mean [standard deviation] age 70.2 [5.9] years; 54.3% women). The proportion of underweight, normal weight, overweight, and obesity was 0.9%, 25.5%, 41.5%, and 32.1%, respectively. The 10-year incidence of dementia significantly decreased with increasing BMI, from 11.5% in women with underweight to 9.1% in those with obesity (log-rank p<0.001). Respective figures in men were 12.0% and 8.2% (log-rank p<0.001). In women, only overweight (versus normal weight) was significantly associated with dementia (HR=0.93, 95%CI=0.88-0.97). In contrast, in men, the only BMI category significantly associated with the incidence of dementia was underweight (HR=1.58, 95% CI=1.11-2.25). Conclusion: In this study conducted in Germany, overweight was negatively associated with dementia in women, whereas there was a positive underweight-dementia relationship in men. More data are needed to confirm or refute these findings in other settings.
Pages 641-651
Lin Sun*, Chunni Guo*, Yan Song*, Jianhua Sheng, Shifu Xiao, Alzheimer’s Disease Neuroimaging Initiative *These authors contributed equally to this work.
Blood BMP6 Associated with Cognitive Performance and Alzheimer’s Disease Diagnosis: A Longitudinal Study of Elders
Abstract: Background: Bone morphogenetic protein (BMP) plays important roles in the pathology of Alzheimer’s disease (AD). Objective: We sought blood BMP6 involved in the processes underlying cognitive decline and detected them in association with AD. Methods: A total of 309 participants in Shanghai Mental Health Center (SMHC) and 547 participants in Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort were included. Blood BMP6 and cognitive functions were measured in all subjects of both cohorts at baseline, and in 482 subjects of ADNI cohort after one year. A total of 300 subjects in ADNI cohort were detected cerebrospinal fluid (CSF) tau biomarker, and 244 received 1-year follow-up. Results: AD patients had lower levels of blood BMP6 compared to normal controls, and BMP6 was positively associated with cognitive functions. Longitudinal BMP6 combing with APOE genotype could distinguish probable AD from normal controls. The influence of blood BMP6 on cognition was modulated by tau pathology. Conclusion: Blood BMP6 was associated with cognitive performance and identified as a potential predictor for probable AD.
Pages 653-661
Puja Agarwal, Thomas M. Holland, Bryan D. James, Laurel J. Cherian, Neelum T. Aggarwal, Sue E. Leurgans, David A. Bennett, Julie A. Schneider (Handling Associate Editor: Hannah Gardener)
Pelargonidin and Berry Intake Association with Alzheimer’s Disease Neuropathology: A Community-Based Study
Abstract: Background: An anthocyanidin, pelargonidin, primarily found in berries, has antioxidant and anti-inflammatory properties, and is associated with better cognition and reduced Alzheimer’s dementia risk. Objective: This study investigated if pelargonidin or berry intake is associated with Alzheimer’s disease (AD) neuropathology in human brains. Methods: The study was conducted among 575 deceased participants (age at death=91.3±6.1 years; 70% females) of the Rush Memory and Aging Project, with dietary data (assessed using a food frequency questionnaire) and neuropathological evaluations. Calorie-adjusted pelargonidin intake was modeled in quartiles and berry intake as continuous (servings/week). Mean amyloid-beta load and phosphorylated tau neuronal neurofibrillary tangle density across multiple cortical regions were assessed using immunohistochemistry. Global AD pathology burden, a quantitative summary score of neurofibrillary tangles, and diffuse and neuritic plaques using Bielschowsky silver stains in multiple brain regions, was also assessed. Results: In a linear regression model adjusted for age at death, sex, education, APOE ε4 status, vitamin E, and vitamin C, participants in the highest quartile of pelargonidin intake when compared to those in the lowest quartile, had less amyloid-β load (β (SE)=-0.293 (0.14), p=0.038), and fewer phosphorylated tau tangles (β (SE)= -0.310, p=0.051). Among APOE ε4 non-carriers, higher strawberry (β (SE)=-0.227 (0.11), p=0.037) and pelargonidin (Q4 versus Q1: β (SE)=-0.401 (0.16), p=0.011; p trend=0.010) intake was associated with less phosphorylated tau tangles, no association was observed in APOE ε4 carriers. Berry intake was not associated with AD pathology. However, excluding participants with dementia or mild cognitive impairment at baseline, strawberry (p=0.004) and pelargonidin (ptrend=0.007) intake were associated with fewer phosphorylated tau tangles. Conclusion: Higher intake of pelargonidin, a bioactive present in strawberries, is associated with less AD neuropathology, primarily phosphorylated tau tangles.
Pages 663-677
Jeff Schein, Christy R. Houle, Annette L. Urganus, Eddie Jones, James Pike, Joseph Husbands, Cynthia J. Willey
The Impact of Agitation in Dementia on Caregivers: A Real-World Survey
Abstract: Background: Dementia patients frequently depend on caregivers. Agitation is a common behavioral dementia symptom particularly burdensome to patients and caregivers. Objective: To assess the association of agitation severity with non-professional caregiver hours, burden, health status, and productivity. Secondarily, to assess the association of agitation severity with these outcomes for patients receiving remote (not living with the patient) and proximate (living with the patient) caregiving. Methods: A retrospective analysis of physician and non professional caregiver-reported data from a US point-in-time survey. Patients were aged ≥50 years, with early cognitive impairment or dementia. Regression analyses compared outcomes by agitation severity; covariates included age, sex, and clinical characteristics. Results: Data were included for 1,349 patients (non-agitated n=656, agitated n=693; no care n=305, remote care n=248, proximate care n=691; unknown care n=105). Greater agitation was significantly associated (p<0.05) in all caregivers with increasing: Zarit Burden Interview (ZBI) Total Caregiver Burden, Personal Strain, Role Strain, and Guilt; Work Productivity and Activity Index (WPAI) presenteeism, overall work impairment, and total activity impairment. Higher ZBI Total Caregiver Burden, Personal Strain, and Role Strain were associated with greater agitation in proximate caregivers and higher ZBI Guilt associated with greater agitation in remote caregivers (p<0.05). Higher WPAI presenteeism and total activity impairment were associated (p<0.05) with greater agitation in proximate caregivers. Caregiving hours increased with increasing agitation for proximate caregiving (p=0.001). Conclusion: Greater agitation severity was associated with higher caregiver burden and lower productivity, with higher indirect costs a likely outcome of agitation.
Pages 679-692
Laura D. Gamble, Sophie Parker, Catherine Quinn, Holly Q. Bennett, Anthony Martyr, Serena Sabatini, Claire Pentecost, Rachel Collins, Eleanor Dawson, Anna Hunt, Louise Allan, Alistair Burns, Rachael Litherland, Christina Victor, Fiona E. Matthews, Linda Clare
A Comparison of Well-Being of Carers of People with Dementia and Their Ability to Manage Before and During the COVID-19 Pandemic: Findings from the IDEAL Study
Abstract: Background: Social restriction measures imposed to curb the spread of COVID-19 in the United Kingdom impacted on carers of people with dementia, limiting access to support services and increasing perceived burden of caring. Few studies have compared data collected both during and before the pandemic to examine the effect of these changes. Objective: To explore whether the COVID-19 pandemic affected the well-being of carers of people with dementia living in the community, and their ability to cope with their caring responsibilities. Methods: Analysis was conducted on two groups of carers who were enrolled in the IDEAL programme; the ‘pre-pandemic group’ (n=312), assessed at two time points prior to the pandemic, and the ‘pandemic group’, assessed prior to and several months into the pandemic (n=156). For the pre-pandemic group, carers were matched 2:1 to carers in the pandemic group on certain characteristics. Differences in change over time between the two groups on self-reported well-being, quality of life, coping, perceived competence, and role captivity, was investigated using mixed effect modelling. Results: Compared to the pre-pandemic group, those in the pandemic group appeared to cope better and had more stable self-rated competency and role captivity. They did not differ in terms of well-being or quality of life. Conclusion: Despite reports of negative impacts on carers early in the pandemic, the findings suggest the pandemic had little negative longer-term impact on carers of people with dementia, and in fact they appeared to have a more positive attitude towards coping several months into the pandemic.
Pages 693-705
Wenna Duan, Parshant Sehrawat, Tony D. Zhou, James T. Becker, Oscar L. Lopez, H. Michael Gach, Weiying Dai
Pattern of Altered Magnetization Transfer Rate in Alzheimer’s Disease
Abstract: Background: Biomarkers for Alzheimer’s disease (AD) are crucial for early diagnosis and treatment monitoring once disease modifying therapies become available. Objective: This study aims to quantify the forward magnetization transfer rate (kfor) map from brain tissue water to macromolecular protons and use it to identify the brain regions with abnormal kfor in AD and AD progression. Methods: From the Cardiovascular Health Study (CHS) cognition study, magnetization transfer imaging (MTI) was acquired at baseline from 63 participants, including 20 normal controls (NC), 18 with mild cognitive impairment (MCI), and 25 AD subjects. Of those, 53 participants completed a follow-up MRI scan and were divided into four groups: 15 stable NC, 12 NC-to-MCI, 12 stable MCI, and 14 MCI/AD-to-AD subjects. kfor maps were compared across NC, MCI, and AD groups at baseline for the cross-sectional study and across four longitudinal groups for the longitudinal study. Results: We found a lower kfor in the frontal gray matter (GM), parietal GM, frontal corona radiata (CR) white matter (WM) tracts, frontal and parietal superior longitudinal fasciculus (SLF) WM tracts in AD relative to both NC and MCI. Further, we observed progressive decreases of kfor in the frontal GM, parietal GM, frontal and parietal CR WM tracts, and parietal SLF WM tracts in stable MCI. In the parietal GM, parietal CR WM tracts, and parietal SLF WM tracts, we found trend differences between MCI/AD-to-AD and stable NC. Conclusion: Forward magnetization transfer rate is a promising biomarker for AD diagnosis and progression.
Pages 707-720
José María García-Alberca, Esther Gris, Paz de la Guía, Silvia Mendoza
Effects of Tianeptine Treatment on Depression and Cognitive Function in Patients with Alzheimer's Disease: A 12-Month Retrospective Observational Study
Abstract: Background: Depression is a common manifestation in Alzheimer’s disease (AD). In clinical practice, antidepressant medication is often used for depression in AD. Objective: We explore the effectiveness of the atypical antidepressant tianeptine compared with other conventional antidepressants in AD patients with depression in a real-life setting. Methods: We retrospectively identified 126 AD patients who had received antidepressant treatment for 12 months with tianeptine or other antidepressants. Subjects were divided into two groups according to the treatment they had received: tianeptine group (n=38) or other antidepressant group (n=88). Drug effects on depression, cognition, behavior, and functional performance were evaluated at baseline, 6, and 12 months. A Mixed Effects Model Analysis was carried out to evaluate changes in performance scores. Results: Both tianeptine and other antidepressants showed an antidepressant effect after 12 months with significant improvement on the Cornell Scale for Depression in Dementia, the Hamilton Depression Rating Scale, and the Neuropsychiatric Inventory-Depression subscale. A statistically significant improvement at 12 months was shown in the tianeptine group versus the other antidepressants group on most of the cognitive measures such as the Mini-Mental State Examination, the Letter and Category Fluency Test, the Rey Auditory Verbal Learning Test, and the Boston Naming Test. Conclusion: Our results suggest that tianeptine reduces depressive symptoms and improve cognition in AD patients. This could be considered clinically relevant and should inspire the design of future long-term randomized controlled trials that contribute to supporting the use of tianeptine for improving cognitive function in AD patients.
Pages 721-729
Liliana Ramirez Gomez, Mark W. Albers, Ana Baena, Clara Vila-Castelar, Joshua T. Fox-Fuller, Justin Sanchez, Felipe Jain, Alefiya D. Albers, Francisco Lopera, Yakeel T. Quiroz
Olfactory Function and Markers of Brain Pathology in Non-Demented Individuals with Autosomal Dominant Alzheimer’s Disease
Abstract: Background: Olfactory dysfunction is one of the earliest signs of Alzheimer’s disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. Objective: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. Methods: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. Results: Worse olfactory identification performance was associated with greater age in mutation carriers (r=-0.52 p=0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r=0.55, p=0.024) and CERAD delayed recall (r= 0.63, p=0.007) and greater cortical amyloid-β (r= -0.53, p=0.042) and tau pathology burden (entorhinal: r= -0.59, p= 0.016; inferior temporal: r= -0.52, p= 0.038). Conclusion: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.
Pages 731-741
Nagato Kuriyama, Teruhide Koyama, Etsuko Ozaki, Satoshi Saito, Masafumi Ihara, Daisuke Matsui, Isao Watanabe, Masaki Kondo, Yoshinori Marunaka, Akihiro Takada, Kentaro Akazawa, Satomi Tomida, Reo Nagamitsu, Fumitaro Miyatani, Masahiro Miyake, Eri Nakano, Daiki Kobayashi, Yoshiyuki Watanabe, Shigeto Mizuno, Mizuho Maekawa, Tamami Yoshida, Yukiko Nukaya, Toshiki Mizuno, Kei Yamada, Ritei Uehara (Handling Associate Editor: Robert Friedland)
Association Between Cerebral Microbleeds and Circulating Levels of Mid-Regional Pro-Adrenomedullin
Abstract: Background: Mid-regional pro-adrenomedullin (MR-proADM) is a novel biomarker for cognitive decline based on its association with cerebral small vessel disease (SVD). Cerebral microbleeds (MBs) are characteristic of SVD; however, a direct association between MR-proADM and MBs has not been explored. Objective: We aimed to examine whether circulating levels of MR-proADM are associated with the identification of MBs by brain magnetic resonance imaging (MRI) and whether this association could be linked with cognitive impairment. Methods: In total, 214 participants (mean age: 75.9 years) without history of cerebral infarction or dementia were prospectively enrolled. All participants underwent brain MRI, higher cognitive function testing, blood biochemistry evaluation, lifestyle examination, and blood MR-proADM measurement using a time-resolved amplified cryptate emission technology assay. For between-group comparisons, the participants were divided into two groups according to whether their levels of MR-proADM were normal (< 0.65 nmol/L) or high (≥0.65 nmol/L). Results: The mean MR-proADM level was 0.515±0.127 nmol/L. There were significant between-group differences in age, hypertension, and HbA1c levels (p < 0.05). In the high MR-proADM group, the MR-proADM level was associated with the identification of MBs on brain MR images and indications of mild cognitive impairment (MCI). In participants with ≥3 MBs and MCI, high MR-proADM levels remained a risk factor after multivariate adjustment (OR: 2.94; p < 0.05). Conclusion: High levels of MR-proADM may be a surrogate marker for the early detection of cognitive decline associated with the formation of cerebral MBs. This marker would be valuable during routine clinical examinations of geriatric patients.
Pages 743-755
Antje Haehner*, Ben Chen*, Melanie Espin, Robert Haussmann, Claudia Matthes, Dmitriy Desser, Lorenz Loessner, Moritz D. Brandt, Markus Donix, Thomas Hummel *These authors contributed equally to this work.
Training with Odors Impacts Hippocampal Thickness in Patients with Mild Cognitive Impairment
Abstract:Background: The olfactory system is affected early in Alzheimer’s disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear. Objective: The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients. Methods: A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period. Results: After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function. Conclusion: Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.
Pages 757-762
Jung-Min Pyun, Young Ho Park, SangYun Kim
Subclinical Hypothyroidism and Cognitive Impairment
Abstract: Background: Although thyroid dysfunction has been considered as a cause of reversible cognitive impairment, association between subclinical hypothyroidism and cognitive impairment is controversial. Objective: We compared cognitive profiles of patients in an euthyroid or subclinical hypothyroid (sHypo) state, as well as their disease progression from mild cognitive impairment (MCI) to dementia within 3 years. Methods: We included 2,181 patients in a euthyroid and 284 in a sHypo state over 60 years of age who underwent an extensive cognitive assessment at Seoul National University Bundang Hospital but were not prescribed levothyroxine, methimazole, carbimazole, or propylthiouracil. After propensity score matching for age, sex, and education level, 1,118 patients in a euthyroid and 283 patients in a sHypo state were included. Attention, language, memory, visuocontructive, and executive functions were compared between the groups using Student’s t-test or the Mann-Whitney U test. To investigate the association between disease progression and subclinical hypothyroidism, a Cox regression analyses was performed in 1,265 patients with MCI. Patients with thyroid-stimulating hormone levels over 10 mlU/L was classified as the “sHypo10”, and hazard ratios for sHypo or sHypo10 were assessed. Results: There was no difference in attention, language, memory, visuoconstructive, and executive functions between the patient groups. Progression from MCI to dementia was not associated with sHypo or sHypo10. Conclusion: There was no difference in cognitive profile between euthyroid and sHypo patients, and no association between subclinical hypothyroidism and disease progression. This might suggest a clue of strategies regarding hormone therapy in subclinical hypothyroidism with cognitive impairment.
Pages 763-769
Liu-Ying Zhu*, Lin Shi*, Yishan Luo, Jason Leung, Timothy Kwok *These authors contributed equally to this work.
Brain MRI Biomarkers to Predict Cognitive Decline in Older People with Alzheimer’s Disease
Abstract: Background: Structural magnetic resonance imaging markers predicting symptomatic progression at the individual level can be highly beneficial for early intervention and treatment planning for Alzheimer's disease (AD). However, the correlation between baseline MRI findings and AD progression has not been fully established. Objective: To explore the correlation between baseline MRI findings and AD progression. Methods: Brain volumetric measures were applied to differentiate the patients at risk of fast deterioration in AD. We included 194 AD patients with a 24-month follow-up: 65 slow decliners, 63 normal decliners, and 66 fast decliners categorized by changes in Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog). ANOVA analyses were used to identify baseline brain atrophy between groups. Logistic regressions were further performed to explore the relative merits of AD resemblance structural atrophy index (AD-RAI) and individual regional volumetric measures in prediction of disease progression. Results: Atrophy in the temporal and insular lobes was associated with fast cognitive decline over 24 months. Smaller volumes of temporal and insular lobes in the left but not the right brain were associated with fast cognitive decline. Baseline AD-RAI predicted fast versus slow progression of cognitive decline (odds ratio 3.025 (95% CI: 1.064-8.600), high versus low, AUC 0.771). Moreover, AD-RAI was significantly lower among slow decliners when compared with normal decliners (p=0.039). Conclusion: AD-RAI on MRI showed potential in identifying clinical AD patients at risk of accelerated cognitive decline.
Pages 771-785
Xiaowei Ma*, Yizhou Zhang*, Dongyun Gou, Jingle Ma, Juan Du, Chang Wang, Sha Li, Huixian Cui (Handling Associate Editor: Ling-Qiang Zhu) *These authors contributed equally to this work.
Metabolic Reprogramming of Microglia Enhances Proinflammatory Cytokine Release through EphA2/p38 MAPK Pathway in Alzheimer’s Disease
Abstract: Background: The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimer's disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear. Objective: To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD. Methods: MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42. Results: Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42. The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2. Conclusion: This study demonstrated that EphA2/p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis.
Pages 787-798
Jordan D. Harper, Kang-Hsien Fan, M. Muaaz Aslam, Beth E. Snitz, Steven T. DeKosky, Oscar L. Lopez, Eleanor Feingold, M. Ilyas Kamboh
Genome-Wide Association Study of Incident Dementia in a Community-Based Sample of Older Subjects
Abstract: Background: Alzheimer’s disease (AD) is a complex disease influenced by the environment and genetics; however, much of the genetic component remains unaccounted for. Objective: The purpose of this work was to use genome-wide association analyses to detect genetic associations with incident AD in a sample of older adults aged 75 and above. Methods: We performed a genome-wide association study (GWAS) on genome-wide genotyped and imputed data (14,072,053 variants) on the Gingko Evaluation of Memory (GEM) study sample consisting of 424 incident dementia (mean age = 84.46±3.91) and 2,206 non-demented (mean age = 84.55±3.23) subjects. Results: The established association of APOE*4 carriers with AD was confirmed in this community-based sample of older subjects (odds ratio (OR)=2.22; p=9.36E-14) and was stronger in females (OR=2.72; p=1.74E-10) than in males (OR=1.88; p=2.43E-05). We observed a novel genome-wide significant (GWS) locus on chromosome 12 near ncRNA LOC105369711/rs148377161 (OR=3.31; p=1.66E-08). In addition, sex-stratified analyses identified two novel associations in males: one near ncRNA LOC729987/rs140076909 on chromosome 1 (OR=4.51; p=3.72E-08) and the other approaching GWS near ncRNA LOC105375138/rs117803234 on chromosome 7 (OR=3.76; p=6.93E-08). Conclusion: The use of community-based samples of older individuals and incident dementia as a phenotype may be a helpful approach for the identification of novel genes for AD, which may not be detected in standard case-control studies. Replication of these signals and further studies of these regions and genes will help to provide a clearer picture for their role in AD.
