Pages 1131-1142
Review
Ya Miao, Liang Cui, Junpeng Li, Yixin Chen, Xiangqing Xie, Qihao Guo
Cognitive Improvement After Multi-Domain Lifestyle Interventions in an APOE ε4 Homozygous Carrier with Mild Cognitive Impairment: A Case Report and Literature Review
Abstract: Alzheimer's disease (AD) is a degenerative disease of the central nervous system with insidious onset and chronic progression. The pathogenesis of AD is complex, which is currently considered to be the result of the interaction between genetic and environmental factors. The APOE ε4 is the strongest genetic risk factor for sporadic AD and a risk factor for progression from mild cognitive impairment (MCI) to AD. So far, no effective drugs have been found for the progression of MCI. However, the effects of nonpharmacological interventions such as nutrition, cognitive, and physical exercises on early AD have received increasing attention. We followed up cognitive assessment scales, Aβ-PET and MRI examination of a patient with MCI for 4 years, who carried APOE ε4 homozygous with a clear family history. After 4 years of multi-domain lifestyle interventions including nutrition, socialization, and physical exercises, the patient’s cognitive function, especially memory function, improved significantly. Intracerebral amyloid deposition was decreased, and hippocampal atrophy improved. Based on this case, this study reviewed and discussed the interaction of APOE ε4 with the environment in AD research in recent years, as well as the impact and mechanisms of non-pharmaceutical multi-domain lifestyle interventions on MCI or early AD. Both the literature review and this case showed that multi-domain lifestyle interventions may reduce the risk of disease progression by reducing Aβ deposition in the brain and other different pathologic mechanisms, which offers promise in brain amyloid-positivity or APOE ε4 carriers.
Pages 1143-1157
Systematic Review
Kazufumi Yoshida, Michael Seo, Yan Luo, Ethan Sahker, Andrea Cipriani, Stefan Leucht, Takeshi Iwatsubo, Orestis Efthimiou, Toshiaki A. Furukawa (Handling Associate Editor: Elżbieta Kuźma)
Personalized Prediction of Alzheimer’s Disease and Its Treatment Effects by Donepezil: An Individual Participant Data Meta-Analysis of Eight Randomized Controlled Trials
Abstract: Background: Patient characteristics may predict the progression of Alzheimer’s disease (AD) and may moderate the effects of donepezil. Objective: To build a personalized prediction model for patients with AD and to estimate patient-specific treatment effects of donepezil, using individual patient characteristics. Methods: We systematically searched for all double-masked randomized controlled trials comparing oral donepezil and pill placebo in the treatment of AD and requested individual participant data through its developer, Eisai. The primary outcome was cognitive function at 24 weeks, measured with the Alzheimer's Disease Assessment Scale-cognitive component (ADAS-cog). We built a Bayesian meta-analytical prediction model for patients receiving placebo and we performed an individual patient data meta-analysis to estimate patient-level treatment effects. Results: Eight studies with 3,156 participants were included. The Bayesian prediction model suggested that more severe cognitive and global function at baseline and younger age were associated with worse cognitive function at 24 weeks. The individual participant data meta-analysis showed that, on average, donepezil was superior to placebo in cognitive function (ADAS-cog scores, -3.2; 95% Credible Interval (CrI) -4.2 to -2.1). In addition, our results suggested that antipsychotic drug use at baseline might be associated with a lower effect of donepezil in ADAS-cog (2.0; 95%CrI, -0.02 to 4.3). Conclusion: Although our results suggested that donepezil is somewhat efficacious for cognitive function for most patients with AD, use of antipsychotic drugs may be associated with lower efficacy of the drug. Future research with larger sample sizes, more patient covariates, and longer treatment duration is needed.
Pages 1159-1172
Systematic Review
Rong Guo*, Ya-Nan Ou*, He-Ying Hu, Ya-Hui Ma, Lan Tan, Jin-Tai Yu *These authors contributed equally to this work.
The Association Between Osteoarthritis with Risk of Dementia and Cognitive Impairment: A Meta-Analysis and Systematic Review
Abstract: Background: The relationship between osteoarthritis (OA) and risk of dementia and cognitive impairment (CIM) has long been debated; however, uncertainties still persist. Objective: The aim of our present meta-analysis and systematic review was to roundly illuminate the association between OA and the risk of dementia and CIM. Methods: We identified relevant studies by searching PubMed, Embase, and Web of Science up to October 2021. The relative risk (RR) or odds ratio (OR) with 95% confidence interval (CI) were aggregated using random-effects methods. Credibility of each meta-analysis was assessed. Meta-regression and subgroup analyses were conducted. Publication bias was explored using funnel plot. Results: Of 21,925 identified literatures, 8 were eligible for inclusion in the systematic review and 19 observational studies involving 724,351 individuals were included in the meta-analysis. The risk of developing dementia and CIM among OA patients was demonstrated in 11 prospective studies (RR=1.42, 95% CI=1.07-1.86, I2=98.9%, p<0.001), 2 retrospective cohort studies (RR=1.35, 95% CI=1.19-1.52, I2=61.0%, p=0.109), 3 retrospective case-control studies (OR=1.21, 95% CI=0.96–1.53, I2=95.2%, p<0.001), and 4 cross-sectional studies (OR=1.51, 95% CI=1.09-2.09, I2=75.8%, p=0.006). Meta-regression analyses did not find any valid moderators. Heterogeneity in subgroup analyses for population age, OA location, year of publication, outcome type, adjusted for BMI, depression, and comorbidity decreased to zero. No significant evidence of publication bias was found. Conclusion: OA associated with an increased risk of dementia and CIM. Effective interventions in OA patients may decrease new incidence of dementia or CIM.
Pages 1173-1191
Systematic Review
Sofía Sánchez de Lara-Sánchez, Ana María Sánchez-Pérez
Probiotics Treatment Can Improve Cognition in Patients with Mild Cognitive Impairment: A Systematic Review
Abstract: Background: In recent years, the existence of the gut-brain axis and the impact of intestinal microbiota on brain function has received much attention. Accumulated evidence has prompted the postulation of the infectious hypothesis underlying or facilitating neurodegenerative diseases, such as Alzheimer's disease. Under this hypothesis, intervention with probiotics could be useful at a preventive and therapeutic level. Objective: The objective of this systematic review is to reveal a benefit of improved cognitive function following the use of probiotics in individuals with mild cognitive impairment. Methods: We searched bibliographic databases and analyzed in detail the evidence and methodological quality of five recent randomized, double-blind, placebo-controlled clinical trials using the Cochrane Tool and the SIGN checklist. Results: Overall, and with satisfactory methodological quality, the studies evaluated support the use of probiotics as a weapon to slow the progression of cognitive decline in subjects with mild cognitive impairment. The literature review also indicates that maximum benefit of probiotics is found in subjects with incipient cognitive dysfunction and has no effect in those with advanced disease or absence of disease. Conclusion: These results support the intervention with probiotics, especially as a preventive approach. However, caution is required in the interpretation of the results as microbiota has not been evaluated in all studies, and further large-scale research with a prolonged study period is necessary to ensure the translatability of the results into real practice.
Pages 1193-2022
Hypothesis
Mónica Alba Ahulló-Fuster, Tomás Ortiz, Enrique Varela-Donoso, Juan Nacher, M. Luz Sánchez-Sánchez
The Parietal Lobe in Alzheimer’s Disease and Blindness
Abstract: The progressive aging of the population will notably increase the burden of those diseases which leads to a disabling situation, such as Alzheimer’s disease (AD) and ophthalmological diseases that cause a visual impairment (VI). Eye diseases that cause a VI raise neuroplastic processes in the parietal lobe. Meanwhile, the aforementioned lobe suffers a severe decline throughout AD. From this perspective, diving deeper into the particularities of the parietal lobe is of paramount importance. In this article, we discuss the functions of the parietal lobe, review the parietal anatomical and pathophysiological peculiarities in AD, and also describe some of the changes in the parietal region that occur after VI. Although the alterations in the hippocampus and the temporal lobe have been well documented in AD, the alterations of the parietal lobe have been less thoroughly explored. Recent neuroimaging studies have revealed that some metabolic and perfusion impairments along with a reduction of the white and grey matter could take place in the parietal lobe during AD. Conversely, it has been speculated that blinding ocular diseases induce a remodeling of the parietal region which is observable through the improvement of the integration of multimodal stimuli and in the increase of the volume of this cortical region. Based on current findings concerning the parietal lobe in both pathologies, we hypothesize that the increased activity of the parietal lobe in people with VI may diminish the neurodegeneration of this brain region in those who are visually impaired by ocular diseases.
Pages 1203-1209
Short Communication
Christopher B. Morrow, Grace-Anna S. Chaney, Daniel Capuzzi, Arnold Bakker, Chiadi U. Onyike, Vidyulata Kamath
Hyperorality in Frontotemporal Dementia: Cognitive and Psychiatric Symptom Profiles in Early-Stage Disease
Abstract: Hyperorality is a distinctive feature of the behavioral variant of frontotemporal dementia (bvFTD), but little is known about its significance in early-stage disease. This study examined the cognitive and psychiatric symptom profiles associated with hyperorality, using data from subjects with early-stage bvFTD enrolled in Alzheimer’s Disease Research Centers. We found that hyperorality was not associated with cognitive performance, but was associated with psychosis, elation, and disinhibition. Hyperorality may share neurobiology with a subset of early psychiatric symptoms, a finding which could help identify targets for future treatment.
Pages 1211-1219
Mariusz Berdyński, Jan Ludwiczak, Anna Barczak, Maria Barcikowska-Kotowicz, Magdalena Kuźma-Kozakiewicz, Stanisław Dunin-Horkawicz, Cezary Żekanowski, Beata Borzemska
TREM2 Gene Compound Heterozygosity in Neurodegenerative Disorders
Abstract: Background: Homozygous variants of the TREM2 and TYROBP genes have been shown to be causative for multiple bone cysts and neurodegeneration leading to progressive dementia (NHD, Nasu-Hakola disease). Objective: To determine if biallelic variants of these genes and/or oligogenic inheritance could be responsible for a wider spectrum of neurodegenerative conditions. Methods: We analyzed 52 genes associated with neurodegenerative disorders using targeted next generation sequencing in a selected group of 29 patients (n=14 Alzheimer's disease, n=8 frontotemporal dementia, n=7 amyotrophic lateral sclerosis) carrying diverse already determined rare variants in exon 2 of TREM2. Molecular modeling was used to get an insight into the potential effects of the mutation. Results: We identified a novel mutation c.401_406delinsTCTAT; p.(Asp134Valfs*55) in exon 3 of TREM2 in an Alzheimer's disease patient also carrying the p.Arg62His TREM2 variant. Molecular modeling revealed that the identified mutation prevents anchoring of the TREM2 protein in the membrane, leaving the core of the Ig-like domain intact. Conclusion: Our results expand the spectrum of neurodegenerative diseases, where the carriers of biallelic mutations in TREM2 have been described for Alzheimer's disease, and highlight the impact of variant burden in other genes on phenotypic heterogeneity.
Pages 1221-1231
Suyi Ooi, Sheila K Patel, Dhamidhu Eratne, Christopher Kyndt, Natalie Reidy, Courtney Lewis, Sarah C.M. Lee, David Darby, Amy Brodtmann
Plasma Neurofilament Light Chain and Clinical Diagnosis in Frontotemporal Dementia Syndromes
Abstract: Background: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. Objective: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. Methods: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. Results: Fifty participants were studied: bvFTD=20, semantic variant FTD (svFTD)=11, non-fluent variant FTD (nfvFTD)=9, FTD with motor neuron disease (MND)=4, phFTD=2, slow progressors=3, FTD mimic=1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p=0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). Conclusion: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily lack of, neurodegeneration and therefore appears limited distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility.
Pages 1233-1240
Lolita S. Nidadavolu, Danielle Feger, Yuqiong Wu, Francine Grodstein, Alden L. Gross, David A. Bennett, Jeremy D. Walston, Esther S. Oh*, Peter M. Abadir* *These authors contributed equally to this work.
Circulating Cell-Free Genomic DNA Is Associated with an Increased Risk of Dementia and with Change in Cognitive and Physical Function
Abstract: Background: Altered cell homeostasis, seen in cognitive decline and frailty, leads to cell death and turnover, releasing circulating cell-free DNA (ccf-DNA). Objective: The goal of this study is to determine if serum genomic cell-free DNA (ccf-gDNA) is associated with physical and cognitive decline in older adults. Methods: We used serum from 631 community-dwelling individuals from the Religious Orders Study or Rush Memory and Aging Project who were without cognitive impairment at baseline. ccf-gDNA fragments in serum were quantified using digital PCR. An array of cognitive and physical traits, risk of dementia, global cognition, and frailty at or nearest the time of blood draw were regressed on ccf-DNA, with adjustment for age, sex, race, and education. Results: Cross-sectionally, higher ccf-gDNA levels were associated with lower global cognition score and slower gait speed at the evaluation nearest to blood draw. Higher ccf-gDNA levels were associated with increased odds of incident dementia (OR 1.27, 95% CI 1.05, 1.54). Longitudinally, higher levels of ccf-gDNA were associated with steeper general cognitive decline and worsening frailty over eight years of follow up. Conclusion: This study demonstrates that ccf-gDNA fragments have utility for identifying persons at higher risk of developing dementia and worsening cognition and frailty.
Pages 1241-1248
Sam Creavin, Mark Fish, Antony Bayer, John Gallacher, Yoav Ben-Shlomo
Decline in Cognition from Mid-Life Improves Specificity of Mini-Mental State Examination: Diagnostic Test Accuracy in Caerphilly Prospective Study (CaPs)
Abstract: Background: The merit of using baseline cognitive assessments in mid-life to help interpret cross-sectional cognitive tests scores in later life is uncertain. Objective: Evaluate how accuracy for diagnosing dementia is enhanced by comparing cross-sectional results to a midlife measure. Methods: Cohort study of 2,512 men with repeated measures of Mini-Mental State Examination (MMSE) over approximately 10 years. Index test MMSE at threshold of 24 indicating normal, as a cross-sectional measure and in combination with decline in MMSE score from mid-life. Reference standard consensus clinical diagnosis of dementia by two clinicians according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Results: 1,150 men participated at phase 4 of whom 75 had dementia. A cross-sectional MMSE alone produced a sensitivity of 60% (50% to 70%) and specificity 95% (94% to 97%) with a threshold of ≥24 points indicating normal. For lower-scoring men in late life, with cross sectional scores of <22, combining cross-sectional AND a three-point or more decline over time had a sensitivity of 52% (39% to 64%) and specificity 99% (99% to 100%). For higher-scoring men in later life, with cross sectional scores <26 combining cross-sectional OR decline of at least three points had a sensitivity of 98% (92% to 100%) and specificity 38% (32% to 44%). Conclusion: It may be helpful in practice to formally evaluate cognition in mid-life as a baseline to compare with if problems develop in future, as this may enhance diagnostic accuracy and classification of people in later life.
Pages 1249-1262
Jingjing Yang, Shahram Oveisgharan, Xizhu Liu, Robert S. Wilson, David A. Bennett, Aron S. Buchman
Risk Models Based on Non-Cognitive Measures May Identify Presymptomatic Alzheimer’s Disease
Abstract: Background: Alzheimer’s disease (AD) is a progressive disorder without a cure. Develop risk prediction models for detecting presymptomatic AD using non-cognitive measures is necessary to enable early interventions. Objective: Examine if non-cognitive metrics alone can be used to construct risk models to identify adults at risk for AD dementia and cognitive impairment. Methods: Clinical data from older adults without dementia from the Memory and Aging Project (MAP, n=1,179) and Religious Orders Study (ROS, n=1,103) were analyzed using Cox proportional hazard models to develop risk prediction models for AD dementia and cognitive impairment. Models using only non-cognitive covariates were compared to models that added cognitive covariates. All models were trained in MAP, tested in ROS, and evaluated by the AUC of ROC curve. Results: Models based on non-cognitive covariates alone achieved AUC (0.800,0.785) for predicting AD dementia (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.916,0.881). A model with a single covariate of composite cognition score achieved AUC (0.905,0.863). Models based on non-cognitive covariates alone achieved AUC (0.717,0.714) for predicting cognitive impairment (3.5) years from baseline. Including additional cognitive covariates improved AUC to (0.783,0.770). A model with a single covariate of composite cognition score achieved AUC (0.754,0.730). Conclusion: Risk models based on non-cognitive metrics predict both AD dementia and cognitive impairment. However, non-cognitive covariates do not provide incremental predictivity for models that include cognitive metrics in predicting AD dementia, but do in models predicting cognitive impairment. Further improved risk prediction models for cognitive impairment are needed.
Pages 1263-1278
Kristina Shkirkova, Krista Lamorie-Foote, Nathan Zhang, Andrew Li, Arnold Diaz, Qinghai Liu, Max A. Thorwald, Jose A. Godoy-Lugo, Brandon Ge, Carla D’Agostino, Zijiao Zhang, Wendy J. Mack, Constantinos Sioutas, Caleb E. Finch, William J. Mack, Hongqiao Zhang
Neurotoxicity of Diesel Exhaust Particles
Abstract: Background: Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer’s disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. Objective: Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. Methods: For dose-response, adult C57BL/6 male mice were exposed to 0, 25, 50, and 100 µg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100 µg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-β peptides, inflammation, oxidative damage, and microglial activity and morphology. Results: DEP exposure at 100 µg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aβ, white matter injury, and microglial soma enlargement that differed by cortical layer. Conclusion: Exposure to 100 µg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia.
Pages 1279-1291
Shalini Kanagasingam, Christopher von Ruhland, Richard Welbury, Sim K. Singhrao
Antimicrobial, Polarizing Light, and Paired Helical Filament Properties of Fragmented Tau Peptides of Selected Putative Gingipains
Abstract: Background: Tau is an established substrate for gingipains secreted by Porphyromonas gingivalis. Hyperphosphorylation of tau and neurofibrillary tangle (NFT) formation is a defining lesion of Alzheimer’s disease (AD) where NFT distribution is related to Braak stage and disease severity. Objective: To assess gingipains’-fragmented tau peptides for their antimicrobial properties and for the likelihood of paired helical/straight filament (PHF/SF) formation with implications for the NFT lesion. Methods: Seven non-phosphorylated (A-G) and three phosphorylated (A-C) tau peptides, were tested for antimicrobial properties against P. gingivalis. Polarizing light properties were determined using Congo Red staining. Secondary and tertiary structures of peptides B-F were determined using transmission electron microscopy (TEM) and circular dichroism (CD) was undertaken for the soluble peptides A in phosphorylated and non-phosphorylated states. Results: Phosphorylated tau peptide A displayed a significant effect against planktonic P. gingivalis. The CD results demonstrated that both peptides A, in phosphorylated and non-phosphorylated states, in aqueous solution, adopted mainly β-type structures. Non-phosphorylated peptides B-F and phosphorylated peptides B-C were insoluble and fibrillar under the TEM. The secondary and tertiary structures of the non-phosphorylated peptide B demonstrated fewer helical twists, whereas peptide C displayed significantly more helical twists along the whole fiber(s) length following its phosphorylation. Conclusion: Phosphorylated peptide A reduced P. gingivalis viability. CD spectroscopy demonstrated the phosphorylated and the non-phosphorylated peptide A predominantly formed from β-sheet structures in aqueous solution with potential antimicrobial activity. Phosphorylation of tau peptides physically changed their tertiary structure into PHFs with potential for self-aggregation and binding to the NFT lesion.
Pages 1293-1302
Mélissa Gentreau, Christelle Reynes, Robert Sabatier, Jerome J. Maller, Chantal Meslin, Jeremy Deverdun, Emmanuelle Le Bars, Michel Raymond, Claire Berticat*, Sylvaine Artero* *These authors contributed equally to this work
Glucometabolic Changes Are Associated with Structural Gray Matter Alterations in Prodromal Dementia
Abstract: Background: Glucometabolic changes, such as high glycemic load (GL) diet and insulin resistance (IR), are potential risk factor of Alzheimer’s disease (AD). Yet, the effect of these factors on brain alterations that contribute to AD pathology has not been clearly demonstrated. Objective: We aimed to assess the relationship of GL and IR with gray matter volumes involved in prodromal dementia. Methods: GL and Triglyceride-Glucose (TyG) index, an IR surrogate marker, were calculated in 497 participants who underwent magnetic resonance imaging (MRI). The gray matter volumes most related to prodromal dementia/mild cognitive impairment (diagnosed in 18/158 participants during the 7-year follow-up) were identified using a data-driven machine learning algorithm. Results: Higher GL diet was associated with reduced amygdala volume. The TyG index was negatively associated with the hippocampus, amygdala, and putamen volumes. Conclusion: These results suggest that GL and IR are associated with lower gray matter volumes in brain regions involved in AD pathology.
Pages 1303-1314
Sofia Michopoulou, Angus Prosser, Christopher Kipps, John Dickson, Matthew Guy, Jessica Teeling
Biomarkers of Inflammation Increase with Tau and Neurodegeneration but not with Amyloid-β in a Heterogenous Clinical Cohort
Abstract: Background: Neuroinflammation is an integral part of Alzheimer’s disease (AD) pathology. Inflammatory mediators can exacerbate the production of amyloid-β (Aβ), the propagation of tau pathology and neuronal loss. Objective: To evaluate the relationship between inflammation markers and established markers of AD in a mixed memory clinic cohort. Methods: 105 cerebrospinal fluid (CSF) samples from a clinical cohort under investigation for cognitive complaints were analyzed. Levels of Aβ42, total tau, and phosphorylated tau were measured as part of the clinical pathway. Analysis of inflammation markers in CSF samples was performed using multiplex immune assays. Participants were grouped according to their Aβ, tau, and neurodegeneration status and the Paris-Lille-Montpellier (PLM) scale was used to assess the likelihood of AD. Results: From 102 inflammatory markers analyzed, 19 and 23 markers were significantly associated with CSF total tau and phosphorylated tau levels respectively (p<0.001), while none were associated with Aβ42. The CSF concentrations of 4 inflammation markers were markedly elevated with increasing PLM class indicating increased likelihood of AD (p<0.001). Adenosine deaminase, an enzyme involved in sleep homeostasis, was the single best predictor of high likelihood of AD (AUROC 0.788). Functional pathway analysis demonstrated a widespread role for inflammation in neurodegeneration, with certain pathways explaining over 30% of the variability in tau values. Conclusion: CSF inflammation markers increase significantly with tau and neurodegeneration, but not with Aβ in this mixed memory clinic cohort. Thus, such markers could become useful for the clinical diagnosis of neurodegenerative disorders alongside the established Aβ and tau measures.
Pages 1315-1322
Sijie Li, Bian Liu, Qing-hao Li, Yan Zhang, Haihua Zhang, Shan Gao, Longcai Wang, Tao Wang, Zhifa Han, Guiyou Liu, Kun Wang (Handling Associate Editor: Jin-Tai Yu)
Evaluating the Bidirectional Causal Association Between Daytime Napping and Alzheimer’s Disease Using Mendelian Randomization
Abstract: Background: Until now, both cross-sectional and longitudinal studies have identified controversial findings about the association between daytime napping and Alzheimer’s disease (AD) or cognitive decline. Therefore, it remains unclear about the causal association between daytime napping and AD or cognitive decline. Objective: We aim to investigate the causal association between daytime napping and AD. Methods: Here, we conduct a bidirectional Mendelian randomization (MR) analysis to investigate the causal association between daytime napping and AD using large-scale GWAS datasets from daytime napping including 452,633 individuals of European ancestry and AD including 35,274 AD and 59,163 controls of European ancestry. A total of five MR methods are selected including inverse-variance weighted (IVW), weighted median, MR-Egger, MR-PRESSO, and contamination mixture method. Results: MR analysis highlights significant causal association of AD with daytime napping using IVW (beta=-0.006, 95% CI [-0.009, -0.002], p=2.00E-03), but no significant causal association of daytime napping with AD using IVW (OR=0.76, 95% CI 0.53-1.10, p=1.40E-01). Conclusion: Our bidirectional MR analysis demonstrates the causal effect of AD on daytime napping. However, there is no causal effect of daytime napping on AD. Our current findings are consistent with recent evidence from other MR studies that highlight little evidence supporting a causal effect of sleep traits on AD and support the causal effect of AD on sleep traits.
Pages 1323-1330
Ting Pang, Eddie Jun Yi Chong, Zi Xuen Wong, Kimberly Ann Chew, Narayanaswamy Venketasubramanian, Christopher Chen, Xin Xu
Validation of the Informant Quick Dementia Rating System (QDRS) among Older Adults in Singapore
Abstract: Background: The Quick Dementia Rating System (QDRS) is a brief and rapid tool that can be administered by an informant without the need for a trained assessor. Objective: Our objective was to examine the validity, reliability, and cost-effectiveness of the informant QDRS in a Singapore memory clinic sample. Methods: We assessed a total of 177 older adults, among whom, 32 had no cognitive impairment (NCI), 61 had mild cognitive impairment (MCI), and 84 had dementia. Elderly underwent 1) the informant QDRS, 2) the Clinical Dementia Rating (CDR) as the gold standard diagnosis, 3) the Mini-Mental State Examination (MMSE), and 4) the Ascertain Dementia 8 (AD8) as comparisons to the QDRS. The extent to which the QDRS may reduce the recruitment cost (time) of clinical trials was also calculated. Results: The QDRS had excellent internal consistency (Cronbach alpha=0.939). It correlated highly with the CDR-global (R=0.897), CDR Sum-of-Boxes (R=0.915), MMSE (R=-0.848), and the AD8 (R=0.747), showing good concurrent validity. With an optimal cut-off of 1.5 for MCI (sensitivity 85.2%, specificity 96.3%) and 6 for dementia (sensitivity 90.1%, specificity 89.2%), the QDRS achieved a higher overall accuracy of 85.0%, as compared to MMSE (71.2%) and AD8 (73.4%). A simulated clinical trial recruitment scenario demonstrated that pre-screening with the QDRS followed by a confirmatory CDR would reduce the time needed to identify NCI subjects by 23.3% and MCI subjects by 75.3%. Conclusion: The QDRS is a reliable cognitive impairment screening tool which is suitable for informant-administration, especially for identification of MCI.
Pages 1331-1338
Barbara Helen Bardenheier, Linda J. Resnik, Eric Jutkowitz, Stefan Gravenstein
Patterns of Limitation in Physical Function in Late Midlife Associated with Late-Onset Alzheimer’s Disease and Related Dementias: A Cluster Analysis
Abstract: Background: To reduce the increasing societal and financial burden of Alzheimer’s disease and related dementias (ADRD), prevention is critical. Even small improvements of the modifiable dementia risk factors on the individual level have the potential to lead to a substantial reduction of dementia cases at the population level. Objective: To determine if pattern(s) of functional decline in midlife associate with late-onset ADRD years later. Methods: Using a longitudinal study of adults aged 51-59 years in 1998 without symptoms of ADRD by 2002 and followed them from 2002 to 2016 (n=5404). The outcome was incident ADRD identified by the Lange-Weir algorithm, death, or alive with no ADRD. We used cluster analysis to identify patterns of functional impairment at baseline and multinomial regression to assess their association with future ADRD. Results: Three groups of adults with differing patterns of functional impairment were at greater risk of future ADRD. Difficulty with climbing one flight of stairs was observed in all adults in two of these groups. In the third group, 100% had difficulty with lifting 10 pounds and pushing or pulling a large object, but only one-fourth had difficulty in climbing stairs. Conclusion: Results imply that improved large muscle strength could decrease future risk of ADRD. If confirmed in other studies, screening for four self-reported measures of function among adults in midlife may be used for targeted interventions.
Pages 1339-1349
Andrea M. Kurasz, Liselotte De Wit, Glenn E. Smith, Melissa J. Armstrong (Handling Associate Editor: Brittany Dugger)
Neuropathological and Clinical Correlates of Lewy Body Disease Survival by Race and Ethnicity in the National Alzheimer’s Coordinating Center
Abstract: Background: Survival and associated clinical and pathological characteristics in Lewy body disease (LBD)-related dementias are understudied. Available studies focus primarily on white non-Hispanic samples. Objective: We investigated demographic, clinical, and pathological correlates of survival by race and ethnicity in an autopsy-confirmed cohort of LBD cases. Methods: Using National Alzheimer’s Coordinating Center data, we selected participants who self-identified as Black, Hispanic, or white who had neuropathological assessments showing transitional or diffuse LBD pathology. We used Kruskal-Wallis and Pearson χ2 analyses to investigate group differences in demographic and presenting clinical and pathological characteristics. We used linear regressions to identify predictors of survival with sex, age at symptom onset, education, ethnoracial status, LBD pathology type, and Braak tangle stage included in the model. Results: Data from 1,441 white, 60 Black, and 54 Hispanic participants were available for analysis. Hispanics were more likely to have transitional LBD pathology and had a longer survival than white and Black participants. After controlling for demographic and pathological variables, length of survival did not differ between Hispanics and Black or white participants. Additional key findings demonstrated discrepancies between clinical diagnoses received at last visit and pathological findings, particularly among Black participants. Conclusion: LBD survival differences by race and ethnicity can be accounted for by LBD pathology type and co-occurring Alzheimer’s disease pathology. The discrepancies between clinical diagnoses and pathological findings raise the concern that dementia with Lewy bodies is underdiagnosed in NACC, especially for Black older adults.
Pages 1351-1366
Emilie Wawrziczny, Sandrine Picard, Amandine Buquet, Elodie Traversac, François Puisieux, Florence Pasquier, Dominique Huvent-Grelle, Karyn Doba
Hypnosis Intervention for Couples Confronted with Alzheimer’s Disease: Promising Results of a First Exploratory Study
Abstract: Background: Dementia has a negative impact on the quality of life of the person with dementia and their spouse caregivers, as well as on the couple's relationship, which can lead to high levels of distress for both partners. Hypnosis has been shown to be effective in managing distress and increasing the quality of the relationship. Objective: The aim was to develop a standardized hypnosis intervention for couples confronted with Alzheimer’s disease and evaluate its feasibility, acceptability, and helpfulness in managing the distress of both partners and increasing the quality of the relationship. Methods: In a single-arm study, sixteen couples received the 8-week intervention. Qualitative and quantitative assessments were conducted pre- and post-intervention as well as three months after. Results: 88.9% of couples (n=16) of the final sample (n=18) completed the intervention. Despite the negative representations of hypnosis, several factors led couples to accept to participate in this study: positive expectations, professional endorsement, medical application, non-drug approach, home-based, free, flexible, and couple-based intervention. The results showed a significant decrease in distress for both partners. These effects were maintained three months after the intervention. Couples felt more relaxed, had fewer negative emotions, accepted difficulties more easily, were more patient, and reported better communication and more affection in the relationship. Conclusion: Overall, this pilot study shows the feasibility and acceptability of hypnosis with couples confronted with Alzheimer’s disease. Although measures of the preliminary pre- and post-intervention effects are encouraging, confirmatory testing with a randomized controlled trial is needed.
Pages 1367-1374
Ifrah Zawar, Meghan K. Mattos, Carol Manning, Mark Quigg
Sleep Disturbances, Cognitive Status, and Biomarkers of Dementia
Abstract: Background: While sleep disturbances appear to be risk factors in Alzheimer’s disease (AD) progression, information such as the prevalence across dementia severity and the influence on the trajectory of cognitive decline is unclear. Objective: We evaluate the hypotheses that the prevalence of insomnia differs by cognitive impairment, that sleep disturbances track with AD biomarkers, and that longitudinal changes in sleep disorders affect cognition. Methods: We used the National Alzheimer’s Coordinating Center Database to determine the prevalence of clinician-identified insomnia and nighttime behaviors in normal, mild cognitive impairment (MCI), and demented individuals. We evaluated mean Montreal Cognitive Assessment (MoCA) scores, hippocampal volumes (HV), and CSF phosphorylated tau:amyloid-β ratios at first visit using analysis of variance with age as a covariate. In longitudinal evaluations, we assessed changes in MoCA scores and HV in insomnia and nighttime behaviors between the first and last visits. Results: Prevalence of insomnia was 14%, 16%, and 11% for normal, MCI, and dementia groups. Prevalence of nighttime behaviors was 14%, 21%, and 29% respectively. Insomnia patients had higher MoCA scores, larger HV, and lower pTauBeta than individuals without insomnia, indicating less neurodegeneration. In contrast, nighttime behaviors were associated with worse cognition, smaller HV, and higher pTauBeta. Similar findings were seen between longitudinal associations of sleep disorders and cognition and HV. Conclusion: Our findings suggest that insomnia is unreliably recognized in patients with cognitive impairment. Nighttime behaviors may better indicate the presence of sleep disturbances and have diagnostic specificity in AD over insomnia.
Pages 1375-1384
Jaime Perales-Puchalt, Ryan Townley, Michelle Niedens, Eric D. Vidoni, K. Allen Greiner, Tahira Zufer, Tiffany Schwasinger-Schmidt, Jerrihlyn L. McGee, Hector Arreaza, Jeffrey M. Burns
Acceptability and Preliminary Effectiveness of a Remote Dementia Educational Training Among Primary Care Providers and Health Navigators
Abstract: Background: Optimal care can improve lives of families with dementia but remains under-implemented. Most healthcare professional training is in person, time-intensive, and does not focus on key aspects such as early detection, and cultural competency. Objective: We explored the acceptability and preliminary effectiveness of a training, The Dementia Update Course, which addressed these issues. We hypothesized that the training would lead to increased levels of perceived dementia care competency among key healthcare workers, namely primary care providers (PCPs) and health navigators (HNs). Methods: We conducted pre-post training assessments among 22 PCPs and 32 HNs. The 6.5-h training was remote, and included didactic lectures, case discussion techniques, and materials on dementia detection and care. Outcomes included two 5-point Likert scales on acceptability, eleven on perceived dementia care competency, and the three subscales of the General Practitioners Confidence and Attitude Scale for Dementia. We used paired samples t-tests to assess the mean differences in all preliminary effectiveness outcomes. Results: The training included 28.6% of PCPs and 15.6% of HNs that self-identified as non-White or Latino and 45.5% of PCPs and 21.9% of HNs who served in rural areas. PCPs (84.2%) and HNs (91.7%) reported a high likelihood to recommend the training and high satisfaction. Most preliminary effectiveness outcomes analyzed among PCPs (11/14) and all among HNs (8/8) experienced an improvement from pre- to post-training (p<0.05). Conclusion: A relatively brief, remote, and inclusive dementia training was associated with high levels of acceptability and improvements in perceived dementia care competency among PCPs and HNs.
Pages 1385-1402
Aldis P. Weible, Michael Wehr
Amyloid Pathology in the Central Auditory Pathway of 5XFAD Mice Appears First in Auditory Cortex
Abstract: Background: Effective treatment of Alzheimer’s disease (AD) will hinge on early detection. This has led to the search for early biomarkers that use non-invasive testing. One possible early biomarker is auditory temporal processing deficits, which reflect central auditory pathway dysfunction and precede cognitive and memory declines in AD. Gap detection is a measure of auditory temporal processing, is impaired in human AD, and is also impaired in the 5XFAD mouse model of AD. Gap detection deficits appear as early as postnatal day 60 in 5XFAD mice, months before cognitive deficits or cell death, supporting gap detection as an early biomarker. However, it remains unclear how gap detection deficits relate to the progression of amyloid pathology in the auditory system. Objective: To determine the progression of amyloid pathology throughout the central auditory system and across age in 5XFAD mice. Methods: We quantified intracellular and extracellular antibody labelling of Aβ42 in 6 regions of the central auditory system from p14 to p150. Results: Pathology appeared first in primary auditory cortex (A1) as intracellular accumulation of Aβ42 in layer 5 pyramidal neurons by age p21. Extracellular plaques appeared later, by age p90, in A1, medial geniculate body, and inferior colliculus. Auditory brainstem structures showed minimal amyloid pathology. We also observed pathology in the caudal pontine reticular nucleus, a brainstem structure that is outside of the central auditory pathway but which is involved in the acoustic startle reflex. Conclusion: These results suggest that Aβ42 accumulation, but not plaques, may impair gap detection.
Pages 1403-1412
Ebba Nyholm, Rozita Torkpoor, Kristin Frolich, Elisabet Londos, Claudia Cicognola
A Retrospective Study on Clinical Assessment of Cognitive Impairment in a Swedish Cohort: Is There Inequality Between Natives and Foreign-Born?
Abstract: Background: People with a migration background are underrepresented in dementia research and disfavored in assessment and treatment, and many foreign-born individuals with dementia remain undiagnosed. Objective: The aim of this study was to examine whether there is inequality in the clinical assessment of dementia between native and foreign-born individuals in Sweden. Methods: Information was gathered retrospectively from a cohort of 91 native and 36 foreign-born patients attending four memory clinics in Skåne, Sweden. Data included information on cognitive test results, cerebrospinal fluid biomarkers, scores at structural imaging scales of global cortical atrophy (GCA), medial temporal lobe atrophy (MTA) and the Fazekas scale, laboratory measures of thyroid-stimulating hormone, calcium, albumin, homocysteine, hemoglobin, cobalamine (vitamin B12), and folate (vitamin B9), contact with health care, and treatment. Results: Foreign-born patients had lower educational level and scored lower on Mini-Mental State Examination and Clock Drawing Test (p <0.001-0.011). Relatives initiated contact with health care to a higher extent in the foreign-born group (p=0.031). Foreign-born patients had less white matter lesions (p=0.018). Additionally, Alzheimer’s disease (AD) biomarkers were significantly less used in foreign-born patients to support an AD diagnosis (p=0.001). No significant differences were found for scores on GCA and MTA, laboratory measures, or initiated treatment. Conclusion: Although native and foreign-born patients were predominantly homogenous regarding examined variables, differences in the diagnostic process and underlying biological correlates of dementia exist and need to be further investigated in a larger sample.
Pages 1413-1425
Kazuya Ohno, Mona Abdelhamid, Chunyu Zhou, Cha-Gyun Jung, Makoto Michikawa
Bifidobacterium breve MCC1274 Supplementation Increased the Plasma Levels of Metabolites with Potential Anti-Oxidative Activity in APP Knock-In Mice
Abstract: Background: We previously reported the effects of a probiotic strain, Bifidobacterium breve MCC1274, in improving cognitive function in preclinical and clinical studies. Recently, we demonstrated that supplementation of this strain led to decreased amyloid-β production, attenuated microglial activation, and suppressed inflammation reaction in the brain of APP knock-in (AppNL-G-F) mice. Objective: In this study, we investigated the plasma metabolites to reveal the mechanism of action of this probiotic strain in this Alzheimer’s disease (AD)-like model. Methods: Three-month-old mice were orally supplemented with B. breve MCC1274 or saline for four months and their plasma metabolites were comprehensively analyzed using CE-FTMS and LC-TOFMS. Results: Principal component analysis showed a significant difference in the plasma metabolites between the probiotic and control groups (PERMANOVA, p=0.03). The levels of soy isoflavones (e.g., genistein) and indole derivatives of tryptophan (e.g., 5-methoxyindoleacetic acid), metabolites with potent anti-oxidative activities were significantly increased in the probiotic group. Moreover, there were increased levels of glutathione-related metabolites (e.g., glutathione (GSSG)_divalent, ophthalmic acid) and TCA cycle-related metabolites (e.g., 2-Oxoglutaric acid, succinic acid levels) in the probiotic group. Similar alternations were observed in the wild-type mice by the probiotic supplementation. Conclusion: These results suggest that the supplementation of B. breve MCC1274 enhanced the bioavailability of potential anti-oxidative metabolites from the gut and addressed critical gaps in our understanding of the gut-brain axis underlying the mechanisms of the probiotic action of this strain in the improvement of cognitive function.
Pages 1427-1437
Martin Comon*, Isabelle Rouch*, Arlette Edjolo, Catherine Padovan, Pierre Krolak-Salmon, Jean-Michel Dorey *These authors contributed equally to this work.
Impaired Facial Emotion Recognition and Gaze Direction Detection in Mild Alzheimer’s Disease: Results from the PACO Study
Abstract: Background: Facial emotion recognition (FER) and gaze direction (GD) identification are core components of social cognition, possibly impaired in many psychiatric or neurological conditions. Regarding Alzheimer’s disease (AD), current knowledge is controversial. Objective: The aim of this study was to explore FER and GD identification in mild AD compared to healthy controls. Methods: 180 participants with mild AD drawn from the PACO study and 74 healthy elderly controls were enrolled. Participants were asked to complete three socio-cognitive tasks: face sex identification, recognition of facial emotions (fear, happiness, anger, disgust) expressed at different intensities, and GD discrimination. Multivariate analyses were conducted to compare AD participants and healthy controls. Results: Sex recognition was preserved. GD determination for subtle deviations was impaired in AD. Recognition of prototypically expressed facial emotions was preserved while recognition of degraded facial emotions was impacted in AD participants compared to controls. Use of multivariate analysis suggested significant alteration of low-expressed fear and disgust recognition in the AD group. Conclusion: Our results showed emotion recognition and GD identification in patients with early-stage AD compared to elderly controls. These impairments could be the object of specific therapeutic interventions such as social cognition remediation or raising awareness of primary caregivers to improve the quality of life of patients with early AD.
Pages 1439-1452
Marcia C. de Oliveira Otto, Xinmin S. Li, Zeneng Wang, David Siscovick, Anne B. Newman, Heidi Tsz Mung Lai, Ina Nemet, Yujin Lee, Meng Wang, Amanda Fretts, Rozenn N. Lemaitre, W.H. Wilson Tang, Oscar Lopez, Stanley L. Hazen, Dariush Mozaffarian (Handling Associate Editor: Claudia Valente)
Longitudinal Associations of Plasma TMAO and Related Metabolites with Cognitive Impairment and Dementia in Older Adults: The Cardiovascular Health Study
Abstract: Background: Animal studies suggest that gut microbiome metabolites such as trimethylamine N-oxide (TMAO) may influence cognitive function and dementia risk. However potential health effects of TMAO and related metabolites remain unclear. Objective: We examined prospective associations of TMAO, γ-butyrobetaine, crotonobetaine, carnitine, choline, and betaine with risk of cognitive impairment and dementia among older adults aged 65 years and older in the Cardiovascular Health Study (CHS). Methods: TMAO and metabolites were measured in stored plasma specimens collected at baseline. Incident cognitive impairment was assessed using the 100-point Modified Mini-Mental State Examination administered serially up to 7 times. Clinical dementia was identified using neuropsychological tests adjudicated by CHS Cognition Study investigators, and by ICD-9 codes from linked Medicare data. Associations of each metabolite with cognitive outcomes were assessed using Cox proportional hazards models. Results: Over a median of 13 years of follow-up, 529 cases of cognitive impairment, and 522 of dementia were identified. After multivariable adjustment for relevant risk factors, no associations were seen with TMAO, carnitine, choline, or betaine. In contrast, higher crotonobetaine was associated with 20-32% higher risk of cognitive impairment and dementia per interquintile range (IQR), while γ-butyrobetaine was associated with ~25% lower risk of the same cognitive outcomes per IQR. Conclusion: These findings suggest that γ-butyrobetaine, crotonobetaine, two gut microbe and host metabolites, are associated with risk of cognitive impairment and dementia. Our results indicate a need for mechanistic studies evaluating potential effects of these metabolites, and their interconversion on brain health, especially later in life.
Pages 1453-1461
Xianmin Gong, Lin Shi, Yuanyuan Wu, Yishan Luo, Timothy Kwok
B Vitamin Supplementation Slows Cognitive Decline in Mild Cognitive Impairment Patients with Frontal Lobe Atrophy
Abstract: Background: The effects of B vitamins on mild cognitive impairment (MCI) patients' cognition have been mixed, suggesting the existence of moderating factors. Objective: A post hoc analysis of a negative B vitamin trial was performed to examine the potential modulating effect of regional brain atrophy on the cognitive response to B vitamins in MCI patients. Methods: In the 24-month randomized trial, 279 MCI outpatients took 500 μg methylcobalamin and 400 μg folic acid once per day or placebo tablets once per day. Sixty-four aspirin users were excluded from analysis as aspirin use has been found to have significant negative interaction effects. Subjects were followed up at months 12 and 24. The primary cognitive outcome was clinical dementia rating scale sum of boxes (CDR_SOB). In a subgroup of 83 subjects, MRI brain scans were performed at baseline to estimate regional brain atrophy ratios. Results: Among the trial subjects who had MRI data, B vitamin supplementation had no significant effect on CDR_SOB, despite having significant homocysteine lowering effects. The atrophy ratio of the left frontal lobe significantly moderated the effect of B vitamin supplementation on CDR_SOB, after adjusting for confounders, in that B vitamin supplementation was associated with lower CDR_SOB scores (i.e., better cognitive function) at the 24th month among those patients with above median atrophy ratios, but not among those with lower atrophy ratios, in the left frontal lobe. Conclusion: B vitamins may be more effective in slowing down cognitive decline in MCI patients with atrophy in the left frontal lobe.
Pages 1463-1472
Liisa Jaakkimainen, Raquel Duchen, Lisa Lix, Saeed Al-Azazi, Bing Yu, Debra Butt, Su-Bin Park, Jessica Widdifield
Identification of Early Onset Dementia in Population-Based Health Administrative Data: A Validation Study Using Primary Care Electronic Medical Records
Abstract: Background: Early onset dementia (EOD) occurs when symptoms of dementia begin between 45 to 64 years of age. Objective: We developed and validated health administrative data algorithms for EOD and compared demographic characteristics and presence of comorbid conditions amongst adults with EOD, late onset dementia (LOD) and adults with no dementia in Ontario, Canada. Methods: Patients aged 45 to 64 years identified as having EOD in their primary care electronic medical records had their records linked to provincial health administrative data. We compared several combinations of physician’s claims, hospitalizations, emergency department visits and prescriptions. Age-standardized incidence and prevalence rates of EOD were estimated from 1996 to 2016. Results: The prevalence of EOD for adults aged 45 to 64 years in our primary care reference cohort was 0.12%. An algorithm of ≥1 hospitalization or ≥3 physician claims at least 30 days apart in a two-year period or ≥1 dementia medication had a sensitivity of 72.9% (64.5-81.3), specificity of 99.7% (99.7-99.8), positive predictive value (PPV) of 23.7% (19.1-28.3), and negative predictive value of 100.0%. Multivariate logistic regression found adults with EOD had increased odds ratios for several health conditions compared to LOD and no dementia populations. From 1996 to 2016, the age-adjusted incidence rate increased slightly (0.055 to 0.061 per 100 population) and the age-adjusted prevalence rate increased three-fold (0.11 to 0.32 per 100 population). Conclusion: While we developed a health administrative data algorithm for EOD with a reasonable sensitivity, its low PPV limits its ability to be used for population surveillance.
Pages 1473-1482
Chun Liang Hsu, Ryan S. Falck, Daniel Backhouse, Patrick Chan, Elizabeth Dao, Lisanne F. ten Brinke, Brad Manor, Teresa Liu-Ambrose
Objective Sleep Quality and the Underlying Functional Neural Correlates Among Older Adults with Possible Mild Cognitive Impairment
Abstract: Background: Poor sleep quality is common among older individuals with mild cognitive impairment (MCI) and may be a consequence of functional alterations in the brain; yet few studies have investigated the underlying neural correlates of actigraphy-measured sleep quality in this cohort. Objective: The objective of this study was to examine the relationship between brain networks and sleep quality measured by actigraphy. Methods: In this cross-sectional analysis, sleep efficiency and sleep fragmentation were estimated using Motionwatch8 (MW8) over a period of 14 days in 36 community-dwelling older adults with possible MCI aged 65-85 years. All 36 participants underwent resting-state functional magnetic resonance imaging (fMRI) scanning. Independent associations between network connectivity and MW8 measures of sleep quality were determined using general linear modeling via FSL. Networks examined included the somatosensory network (SMN), frontoparietal network (FPN), and default mode network (DMN). Results: Across the 36 participants (mean age 71.8 years; SD=5.2 years), mean Montreal Cognitive Assessment score was 22.5 (SD=2.7) and Mini-Mental State Examination score was 28.3 (SD=1.5). Mean sleep efficiency and fragmentation index was 80.1% (SD=10.0) and 31.8 (SD=10.4) respectively. Higher sleep fragmentation was significantly correlated with increased connectivity between the SMN and insula, the SMN and posterior cingulate, as well as FPN and primary motor area (FDR-corrected, p<0.004). Conclusion: Functional connectivity between brain regions involved in attentional and somatosensory processes may be associated with disrupted sleep in older adults with MCI.
Pages 1483-1492
Joy R. Wright*, Quazi Fahm E. Deen*, Anna Stevenson, Leolie Telford-Cooke, Craig Parker, Carmen Martin-Ruiz, Joern R. Steinert, Raj N. Kalaria, Elizabeta B. Mukaetova-Ladinska *These authors contributed equally to this work.
Plasma Myeloperoxidase as a Potential Biomarker of Patient Response to Anti-Dementia Treatment in Alzheimer’s Disease
Abstract: Background: Myeloperoxidase (MPO), a neutrophil-derived pro-inflammatory protein, co-localizes with amyloid-β (Aβ) plaques in Alzheimer’s disease (AD). Anti-dementia treatment may facilitate efflux of Aβ and associated plaque proteins from the brain to the peripheral circulation, therefore providing potential biomarkers for the monitoring of donor response to drug treatment. Objective: We investigated the diagnostic utility of MPO as a biomarker of AD, and how anti-dementia treatment alters plasma MPO concentration. Methods: Thirty-two AD patients were recruited, and plasma collected pre-drug administration (baseline), and 1- and 6-months post-treatment. All patients received cholinesterase inhibitors (ChEIs). At baseline and 6 months, patients underwent neuropsychological assessment. Forty-nine elderly healthy individuals with normal cognitive status served as controls. Plasma MPO concentration was measured by ELISA. Results: AD drug naïve patients had similar plasma MPO concentration to their control counterparts (p>0.05). Baseline MPO levels positively correlated with Neuropsychiatric Inventory score (r=0.5080; p=0.011) and carer distress (r=0.5022; p=0.012). Following 1-month ChEI treatment, 84.4% of AD patients exhibited increased plasma MPO levels (p<0.001), which decreased at 6 months (p<0.001). MPO concentration at 1 month was greatest in AD patients whose memory deteriorated during the study period (p=0.028), and for AD patients with deterioration in Cornell assessment score (p=0.044). Conclusion: Whereas baseline MPO levels did not differentiate between healthy and AD populations, baseline MPO positively correlated with initial Neuropsychiatric Inventory evaluation. Post-treatment, transient MPO upregulation in ChEI-treated patients may reflect worse therapeutic outcome. Further studies are required to assess the potential of plasma MPO as an AD therapeutic biomarker.
Pages 1493-1502
Iman Beheshti, Natasha Geddert, Jarrad Perron, Vinay Gupta, Benedict C. Albensi, Ji Hyun Ko, for the Alzheimer’s Disease Neuroimaging Initiative
Monitoring Alzheimer’s Disease Progression in Mild Cognitive Impairment Stage Using Machine Learning-Based FDG-PET Classification Methods
Abstract: Background: We previously introduced a machine learning-based Alzheimer’s Disease Designation (MAD) framework for identifying AD-related metabolic patterns among neurodegenerative subjects. Objective: We sought to assess the efficiency of our MAD framework for tracing the longitudinal brain metabolic changes in the prodromal stage of AD. Methods: MAD produces subject scores using five different machine-learning algorithms, which include a general linear model (GLM), two different approaches of scaled subprofile modeling, and two different approaches of a support vector machine. We used our pre-trained MAD framework, which was trained based on metabolic brain features of 94 patients with AD and 111 age-matched cognitively healthy (CH) individuals. The MAD framework was applied on longitudinal independent test sets including 54 CHs, 51 stable mild cognitive impairment (sMCI), and 39 prodromal AD (pAD) patients at the time of the clinical diagnosis of AD, and two years prior. Results: The GLM showed excellent performance with area under curve (AUC) of 0.96 in distinguishing sMCI from pAD patients at two years prior to the time of the clinical diagnosis of AD while other methods showed moderate performance (AUC: 0.7-0.8). Significant annual increment of MAD scores were identified using all five algorithms in pAD especially when it got closer to the time of diagnosis (p<0.001), but not in sMCI. The increased MAD scores were also significantly associated with cognitive decline measured by Mini-Mental State Examination in pAD (q<0.01). Conclusion: These results suggest that MAD may be a relevant tool for monitoring disease progression in the prodromal stage of AD.
Pages 1503-1505
Book Review
Navigating Life with Dementia by James M. Noble, American Academy of Neurology, 2022, pp. 272. Reviewed by Daniel R. George, PhD, MSc
