Journal of Alzheimer's Disease - Volume 83, issue 2

Authors: Hlávka, Jakub P. | Kinoshita, Andrew T. | Fang, Samantha | Hunt, Adriana

Article Type: Research Article

Abstract: Background: A key challenge in studies that model outcomes, disease progression, and cost-effectiveness of existing and emerging dementia treatments is the lack of conversion criteria to translate, or ‘crosswalk’, scores on multiple measurement scales. Clinical status in dementia is commonly characterized in the cognitive, functional, and behavioral domains. Objective: We conducted a systematic review of peer-reviewed dementia measure crosswalks in the three domains. Methods: We systematically reviewed published literature for crosswalks between scales used to measure cognitive, functional, or behavioral outcomes in Alzheimer’s and related dementias. The search was conducted in PubMed, and additional crosswalks were …identified through snowballing and expert input from dementia modelers. Results: Of the reviewed articles, 2,334 were identified through a PubMed search, 842 articles were sourced from backward and forward citation snowballing, and 8 additional articles were recommended through expert input. 31 papers were eligible for inclusion, listing 74 unique crosswalks. Of those, 62 (83.8%) were between endpoints of the cognitive domain and 12 (16.2%) were either between endpoints of the functional domain or were hybrid in nature. Among crosswalks exclusively in the cognitive domain, a majority involved the Mini-Mental State Examination (MMSE) (37 crosswalks) or the Montreal Cognitive Assessment (MoCA) and its variants (25 crosswalks). MMSE was directly compared to MoCA or MoCA variants in 16 crosswalks. Conclusion: Existing crosswalks between measures of dementia focus largely on a limited selection of outcome measures, particularly MMSE and MoCA. Few crosswalks exist in the functional domain, and no crosswalks were identified for solely behavioral measures. Show more

Keywords: Alzheimer’s disease, cognition, cognitive dysfunction, health care, outcome assessment

DOI: 10.3233/JAD-210060

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 591-608, 2021

Authors: Liu, Pan | Yang, Qian | Yu, Ning | Cao, Yan | Wang, Xue | Wang, Zhao | Qiu, Wen-Ying | Ma, Chao

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is one of the most challenging diseases causing an increasing burden worldwide. Although the neuropathologic diagnosis of AD has been established for many years, the metabolic changes in neuropathologic diagnosed AD samples have not been fully investigated. Objective: To elucidate the potential metabolism dysregulation in the postmortem human brain samples assessed by AD related pathological examination. Methods: We performed untargeted and targeted metabolomics in 44 postmortem human brain tissues. The metabolic differences in the hippocampus between AD group and control (NC) group were compared. Results: The results show that a …pervasive metabolic dysregulation including phenylalanine metabolism, valine, leucine, and isoleucine biosynthesis, biotin metabolism, and purine metabolism are associated with AD pathology. Targeted metabolomics reveal that phenylalanine, phenylpyruvic acid, and N-acetyl-L-phenylalanine are upregulated in AD samples. In addition, the enzyme IL-4I1 catalyzing transformation from phenylalanine to phenylpyruvic acid is also upregulated in AD samples. Conclusion: There is a pervasive metabolic dysregulation in hippocampus with AD-related pathological changes. Our study suggests that the dysregulation of phenylalanine metabolism in hippocampus may be an important pathogenesis for AD pathology formation. Show more

Keywords: Alzheimer’s disease, hippocampus, neuropathology, phenylalanine metabolism

DOI: 10.3233/JAD-210461

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 609-622, 2021

Authors: Wittens, Mandy Melissa Jane | Sima, Diana Maria | Houbrechts, Ruben | Ribbens, Annemie | Niemantsverdriet, Ellis | Fransen, Erik | Bastin, Christine | Benoit, Florence | Bergmans, Bruno | Bier, Jean-Christophe | De Deyn, Peter Paul | Deryck, Olivier | Hanseeuw, Bernard | Ivanoiu, Adrian | Lemper, Jean-Claude | Mormont, Eric | Picard, Gaëtane | de la Rosa, Ezequiel | Salmon, Eric | Segers, Kurt | Sieben, Anne | Smeets, Dirk | Struyfs, Hanne | Thiery, Evert | Tournoy, Jos | Triau, Eric | Vanbinst, Anne-Marie | Versijpt, Jan | Bjerke, Maria | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer’s disease (AD) dementia (ADD) patients in selected research cohorts. Objective: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. Methods: The study population included HC (n  = 90), subjective cognitive decline (SCD, n  = 93), …mild cognitive impairment (MCI, n  = 357), and ADD (n  = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n  = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm’s (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. Results: icobrain dm outperformed FreeSurfer in processing time (15–30 min versus 9–32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). Conclusion: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting. Show more

Keywords: Alzheimer’s disease, automated volumetry, biomarkers, magnetic resonance imaging, mild cognitive impairment

DOI: 10.3233/JAD-210450

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 623-639, 2021

Authors: Zammit, Andrea R. | Yang, Jingyun | Buchman, Aron S. | Leurgans, Sue E. | Muniz-Terrera, Graciela | Lipton, Richard B. | Hall, Charles B. | Boyle, Patricia | Bennett, David A.

Article Type: Research Article

Abstract: Background: Methods that can identify subgroups with different trajectories of cognitive decline are crucial for isolating the biologic mechanisms which underlie these groupings. Objective: This study grouped older adults based on their baseline cognitive profiles using a latent variable approach and tested the hypothesis that these groups would differ in their subsequent trajectories of cognitive change. Methods: In this study we applied time-varying effects models (TVEMs) to examine the longitudinal trajectories of cognitive decline across different subgroups of older adults in the Rush Memory and Aging Project. Results: A total of 1,662 individuals (mean …age = 79.6 years, SD = 7.4, 75.4%female) participated in the study; these were categorized into five previously identified classes of older adults differing in their baseline cognitive profiles: Superior Cognition (n  = 328, 19.7%), Average Cognition (n  = 767, 46.1%), Mixed-Domains Impairment (n  = 71, 4.3%), Memory-Specific Impairment (n  = 274, 16.5%), and Frontal Impairment (n  = 222, 13.4%). Differences in the trajectories of cognition for these five classes persisted during 8 years of follow-up. Compared with the Average Cognition class, The Mixed-Domains and Memory-Specific Impairment classes showed steeper rates of decline, while other classes showed moderate declines. Conclusion: Baseline cognitive classes of older adults derived through the use of latent variable methods were associated with distinct longitudinal trajectories of cognitive decline that did not converge during an average of 8 years of follow-up. Show more

Keywords: Cognitive decline, cognitive function, cognitive impairment, cognitive trajectories, latent classes

DOI: 10.3233/JAD-210484

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 641-652, 2021

Authors: Du, Wenying | Ding, Changchang | Jiang, Jiehui | Han, Ying

Article Type: Research Article

Abstract: Background: Mounting evidence suggests that sex differences exist in cognitive reserve (CR) for cognitively unimpaired (CU) elderly individuals. Global left frontal connectivity (gLFC connectivity) is a reliable neural substrate of CR. Objective: The purpose of this study was to explore sex differences in gLFC connectivity among CU elderly individuals. Methods: One hundred thirteen normal controls (NCs) (women = 66) and 132 individuals with subjective cognitive decline (SCD) (women = 92) were recruited from the Sino Longitudinal Study on Cognitive Decline (SILCODE) (data 1). Among them, 88 subjects underwent amyloid-β (Aβ) imaging, including 32 Aβ+ and 56 Aβ–subjects. Forty-six subjects underwent …another rs-fMRI examination (data 2) to validate the repeatability of the calculation of gLFC connectivity, which was determined through seed-based functional connectivity between the LFC and voxels throughout the whole brain. Independent-sample t -tests were used to evaluate the sex differences in gLFC connectivity across different subgroups (NC versus SCD, Aβ+ versus Aβ–). Partial correlation analysis was used to calculate the correlations between gLFC connectivity and cognitive assessments. Results: Women exhibited lower gLFC connectivity in both the NC (p  = 0.001) and SCD (p  = 0.020) subgroups than men. Women also exhibited lower gLFC connectivity in both the Aβ–(p  = 0.006) and Aβ+ (p  = 0.025) groups. However, the significant difference disappeared in the Aβ+ group when considering the covariates of age, education, total intracranial volume, and APOE4 -carrying status. In addition, gLFC connectivity values were negatively correlated with Geriatric Depression Scale scores in the SCD group (r = –0.176, p  = 0.047). Conclusion: Women showed lower gLFC connectivity among CU elderly individuals. Show more

Keywords: Amyloid deposition, cognitive reserve, global left frontal cortex connectivity, sex differences, subjective cognitive decline

DOI: 10.3233/JAD-210376

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 653-663, 2021

Authors: Huang, Wanyi | Zeng, Fan | Gu, Yebo | Jiang, Muzhou | Zhang, Xinwen | Yan, Xu | Kadowaki, Tomoko | Mizutani, Shinsuke | Kashiwazaki, Haruhiko | Ni, Junjun | Wu, Zhou

Article Type: Research Article

Abstract: Background: Studies have reported that synaptic failure occurs before the Alzheimer’s disease (AD) onset. The systemic Porphyromonas gingivalis (P. gingivalis ) infection is involved in memory decline. We previously showed that leptomeningeal cells, covering the brain, activate glial cells by releasing IL-1β in response to systemic inflammation. Objective: In the present study, we focused on the impact of leptomeningeal cells on neurons during systemic P. gingivalis infection. Methods: The responses of leptomeningeal cells and cortical neurons to systemic P. gingivalis infection were examined in 15-month-old mice. The mechanism of IL-1β production by P. …gingivalis infected leptomeningeal cells was examined, and primary cortical neurons were treated with P. gingivalis infected leptomeningeal cells condition medium (Pg LCM). Results: Systemic P. gingivalis infection increased the expression of IL-1β in leptomeninges and reduced the synaptophysin (SYP) expression in leptomeninges proximity cortex in mice. Leptomeningeal cells phagocytosed P. gingivalis resulting in lysosomal rupture and cathepsin B (CatB) leakage. Leaked CatB mediated NLRP3 inflammasome activation inducing IL-1β secretion in leptomeningeal cells. Pg LCM decreased the expression of synaptic molecules, including SYP, which was inhibited by an IL-1 receptor antagonist pre-treatment. Conclusion: These observations demonstrate that P. gingivalis infection is involved in synaptic failure by inducing CatB/NLRP3 inflammasome-mediated IL-1β production in leptomeningeal cells. The periodontal bacteria-induced synaptic damage may accelerate the onset and cognitive decline of AD. Show more

Keywords: Alzheimer’s disease, cathepsin B, inflammasome, interleukin-1 beta, leptomeningeal cells, Porphyromonas gingivalis, synapses

DOI: 10.3233/JAD-210031

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 665-681, 2021

Authors: Dhana, Klodian | James, Bryan D. | Agarwal, Puja | Aggarwal, Neelum T. | Cherian, Laurel J. | Leurgans, Sue E. | Barnes, Lisa L. | Bennett, David A. | Schneider, Julie A.

Article Type: Research Article

Abstract: Background: MIND diet, a hybrid of the Mediterranean diet and the Dietary Approaches to Stop Hypertension diet, is associated with a slower cognitive decline and lower risk of Alzheimer’s disease (AD) dementia in older adults. Objective: We aim to examine whether the association of the MIND diet with cognition is independent of common brain pathologies. Methods: Utilizing data from the Rush Memory and Aging Project (MAP), a longitudinal clinical-pathologic study, we studied 569 decedents with valid dietary data, cognitive testing proximate to death, and complete autopsy data at the time of these analyses. A series of …regression analyses were used to examine associations of the MIND diet, dementia-related brain pathologies, and global cognition proximate to death adjusting for age, sex, education, APOE ɛ 4, late-life cognitive activities, and total energy intake. Results: A higher MIND diet score was associated with better global cognitive functioning proximate to death (β= 0.119, SE = 0.040, p  = 0.003), and neither the strength nor the significance of association changed substantially when AD pathology and other brain pathologies were included in the model. The β-estimate after controlling for global AD pathology was 0.111 (SE = 0.037, p  = 0.003). The MIND diet-cognition relationship remained significant when we restricted our analysis to individuals without mild cognitive impairment at the baseline (β= 0.121, SE = 0.042, p  = 0.005) or in people diagnosed with postmortem diagnosis of AD based on NIA-Reagan consensus recommendations (β= 0.114, SE = 0.050, p  = 0.023). Conclusion: MIND diet is associated with better cognitive functioning independently of common brain pathology, suggesting that the MIND diet may contribute to cognitive resilience in the elderly. Show more

Keywords: Amyloid-β, brain pathology, cognition, MIND diet

DOI: 10.3233/JAD-210107

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 683-692, 2021

Authors: Nous, Amber | Wittens, Mandy Melissa Jane | Vermeiren, Yannick | De Deyn, Peter Paul | Van Broeckhoven, Christine | Nagels, Guy | Smolders, Ilse | Engelborghs, Sebastiaan

Article Type: Research Article

Abstract: Background: Nocturnal cerebrospinal fluid (CSF) and blood melatonin levels are altered in Alzheimer’s disease (AD). However, literature remains inconclusive on daytime blood melatonin levels. A positive correlation between melatonin levels and Mini-Mental State Examination (MMSE) scores in AD subjects has been evidenced following cross-sectional analyses. Whereas a correlation between serum and spinal CSF melatonin has been shown in healthy volunteers, an equal investigation in AD patients still has to be undertaken. Objective: 1) To evaluate whether serum melatonin levels correlate with spinal CSF melatonin levels in AD. 2) To compare daytime CSF and serum melatonin levels between patients …with AD dementia, mild cognitive impairment due to AD, and healthy controls, and to evaluate whether melatonin can affect cognitive decline in AD. Methods: Subjects with AD and healthy controls included in two existing cohorts, of whom a CSF and serum sample was available at the neurobiobank and had at least 6 months of neuropsychological follow-up, were included in the present study. Melatonin concentrations were measured with liquid chromatography-mass spectrometry. Results: Daytime serum melatonin levels correlated with spinal CSF melatonin levels in AD (r  = 0.751, p  < 0.001). No significant differences regarding daytime melatonin levels were found between patients and controls. No correlations were observed between daytime melatonin levels and MMSE score changes. Conclusion: Daytime serum melatonin accurately reflects CSF melatonin levels in AD, raising the possibility to assess melatonin alterations by solely performing blood sampling if also confirmed for night-time values. However, daytime melatonin levels are not associated with changes of cognitive impairment. Show more

Keywords: Alzheimer’s disease, cerebrospinal fluid, dementia, melatonin

DOI: 10.3233/JAD-210562

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 693-704, 2021

Authors: van de Mortel, Laurens Ansem | Thomas, Rajat Mani | van Wingen, Guido Alexander | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by cognitive impairment and large loss of grey matter volume and is the most prevalent form of dementia worldwide. Mild cognitive impairment (MCI) is the stage that precedes the AD dementia stage, but individuals with MCI do not always convert to the AD dementia stage, and it remains unclear why. Objective: We aimed to assess grey matter loss across the brain at different stages of the clinical continuum of AD to gain a better understanding of disease progression. Methods: In this large-cohort study (N = 1,386) using neuroimaging data from the Alzheimer’s …Disease Neuroimaging Initiative, voxel-based morphometry analyses were performed between healthy controls, individuals with early and late and AD dementia stage. Results: Clear patterns of grey matter loss in mostly hippocampal and temporal regions were found across clinical stages, though not yet in early MCI. In contrast, thalamic volume loss seems one of the first signs of cognitive decline already during early MCI, whereas this volume loss does not further progress from late MCI to AD dementia stage. AD dementia stage converters already show grey matter loss in hippocampal and mid-temporal areas as well as the posterior thalamus (pulvinar) and angular gyrus at baseline. Conclusion: This study confirms the role of temporal brain regions in AD development and suggests additional involvement of the thalamus/pulvinar and angular gyrus that may be linked to visuospatial, attentional, and memory related problems in both early MCI and AD dementia stage conversion. Show more

Keywords: Alzheimer’s disease, angular gyrus, grey matter, hippocampus, neuroimaging, thalamus

DOI: 10.3233/JAD-210173

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 705-720, 2021

Authors: Galvin, James E. | Cohen, Iris | Greenfield, Keri K. | Walker, Marcia

Article Type: Research Article

Abstract: Background: Approximately 90%of persons living with dementia experience behavioral symptoms, including frontal lobe features involving motivation, planning, social behavior, language, personality, mood, swallowing, and gait. Objective: We conducted a two-stage study with a development sample (n  = 586) and validation sample (n  = 274) to evaluate a brief informant-rated measure of non-cognitive features of frontal lobe dysfunction: the Frontal Behavioral Battery (FBB). Methods: In the development sample, internal consistency, principal factor analysis, and correlations between the FBB and outcomes were evaluated. In the validation sample, we examined (a) FBB scores by diagnosis, (b) known-group validity by demographics, subjective …complaints, and dementia staging, and (c) correlation between FBB and MRI volumes. Receiver operator characteristic curves assessed the ability of the FBB to discriminate individuals with frontal lobe features due to a neurodegenerative disease. Results: The FBB characterized 11 distinct frontal lobe features. Individuals with dementia with Lewy bodies and frontotemporal degeneration had the greatest number of frontal lobe features. Premorbid personality traits of extroversion, agreeableness, and openness were associated with fewer frontal lobe behavioral symptoms, while subjective cognitive complaints were associated with greater symptoms. The FBB provided very good discrimination between individuals with and without cognitive impairment (diagnostic odds ratio: 13.1) and between individuals with and without prominent frontal lobe symptoms (diagnostic odds ratio: 84.8). Conclusion: The FBB may serve as an effective and efficient method to assess the presence of non-cognitive symptoms associated with frontal lobe dysfunction, but in a brief fashion that could facilitate its use in clinical care and research. Show more

Keywords: Alzheimer’s disease, behavior, dementia, dementia with lewy bodies, frontal lobe, frontotemporal degeneration, mild cognitive impairment

DOI: 10.3233/JAD-210446

Citation: Journal of Alzheimer's Disease, vol. 83, no. 2, pp. 721-739, 2021