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Article ; Online: Reader Response: Impact of C-Reactive Protein on Cognition and Alzheimer Disease Biomarkers in Homozygous

Royall, Donald R

2022 Volume 99, Issue 20, Page(s) 918–919

MeSH term(s)	Humans ; Alzheimer Disease/genetics ; C-Reactive Protein ; Apolipoprotein E4/genetics ; Cognition ; Heterozygote ; Biomarkers ; Apolipoproteins E/genetics ; Genotype
Chemical Substances	C-Reactive Protein (9007-41-4) ; Apolipoprotein E4 ; Biomarkers ; Apolipoproteins E
Language	English
Publishing date	2022-11-29
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	207147-2
ISSN	1526-632X ; 0028-3878
ISSN (online)	1526-632X
ISSN	0028-3878
DOI	10.1212/WNL.0000000000201508
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Article ; Online: INFLAMMATION's cognitive impact revealed by a novel "Line of Identity" approach.

Royall, Donald R / Palmer, Raymond F

PloS one

2024 Volume 19, Issue 3, Page(s) e0295386

Abstract: Importance: Dementia is an "overdetermined" syndrome. Few individuals are demented by any single biomarker, while several may independently explain small fractions of dementia severity. It may be advantageous to identify individuals afflicted by a ... ...

Abstract	Importance: Dementia is an "overdetermined" syndrome. Few individuals are demented by any single biomarker, while several may independently explain small fractions of dementia severity. It may be advantageous to identify individuals afflicted by a specific biomarker to guide individualized treatment. Objective: We aim to validate a psychometric classifier to identify persons adversely impacted by inflammation and replicate it in a second cohort. Design: Secondary analyses of data collected by the Texas Alzheimer's Research and Care Consortium (TARCC) (N = 3497) and the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1737). Setting: Two large, well-characterized multi-center convenience samples. Participants: Volunteers with normal cognition (NC), Mild Cognitive Impairment (MCI) or clinical "Alzheimer's Disease (AD)". Exposure: Participants were assigned to "Afflicted" or "Resilient" classes on the basis of a psychometric classifier derived by confirmatory factor analysis. Main outcome(s) and measure(s): The groups were contrasted on multiple assessments and biomarkers. The groups were also contrasted regarding 4-year prospective conversions to "AD" from non-demented baseline diagnoses (controls and MCI). The Afflicted groups were predicted to have adverse levels of inflammation-related blood-based biomarkers, greater dementia severity and greater risk of prospective conversion. Results: In ADNI /plasma, 47.1% of subjects were assigned to the Afflicted class. 44.6% of TARCC's subjects were afflicted, 49.5% of non-Hispanic Whites (NHW) and 37.2% of Mexican Americans (MA). There was greater dementia severity in the Afflicted class [by ANOVA: ADNI /F(1) = 686.99, p <0.001; TARCC /F(1) = 1544.01, p <0.001]. "INFLAMMATION" factor composite scores were significantly higher (adverse) in Afflicted subjects [by ANOVA in ADNI /plasma F(1) = 1642.64, p <0.001 and in TARCC /serum F(1) = 3059.96, p <0.001]. Afflicted cases were more likely to convert to AD in the next four years [by Cox's F, ADNI /plasma: F (252, 268) = 3.74 p < 0.001; TARCC /serum: F (160, 134) = 3.03, p < 0.001 (in TARCC's entire sample), F (110, 90) = 4.92, p <0.001 in NHW, and F(50, 44) = 2.13, p = 0.006 in MA]. The proportions converting were similar among afflicted NHW in both cohorts /biofluids but MA exhibited a lower risk (7% in TARCC /serum at 48 months). Conclusions and relevance: Our inflammation-specific psychometric classifier selects individuals with pre-specified biomarker profiles and predicts conversion to "AD" across cohorts, biofluids, and ethnicities. This algorithm might be applied to any dementia-related biomarker making the psychometric estimation of individual biomarker effects feasible without biomarker assessment. Our approach also distinguishes individuals resilient to individual biomarker effects allowing for more accurate prediction and precision intervention.
MeSH term(s)	Humans ; Alzheimer Disease/diagnosis ; Prospective Studies ; Cognitive Dysfunction/diagnosis ; Cognition ; Biomarkers ; Inflammation/complications
Chemical Substances	Biomarkers
Language	English
Publishing date	2024-03-22
Publishing country	United States
Document type	Journal Article
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0295386
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Article ; Online: The effects of CNS atrophy and ICVD on tests of executive function and functional status are mediated by intelligence.

Royall, Donald R / Palmer, Raymond F

Cerebral circulation - cognition and behavior

2023 Volume 5, Page(s) 100184

Abstract: Background: Impairments in executive function (EF) are often attributed to ischemic cerebrovascular disease (ICVD) and frontal circuit pathology. However, EF can be distinguished from general intelligence and the latter is likely to manifest in " ... ...

Abstract	Background: Impairments in executive function (EF) are often attributed to ischemic cerebrovascular disease (ICVD) and frontal circuit pathology. However, EF can be distinguished from general intelligence and the latter is likely to manifest in "executive" measures. We aimed to distinguish the effects of imaging biomarkers on these constructs. Methods: We tested neuroimaging biomarkers as independent predictors of observed 12 month-prospective cognitive performance by a Multiple Indicators Multiple Causes (MIMIC) model in the Alzheimer's Disease Neuroimaging Initiative (ADNI) ( Results: ICVD was associated with ''Organization" (ORG) and "Planning" (PLAN) domain scores from the test of Every Day Cognition. Left anterior cingulate (LAC) atrophy was independently associated with Trail-Making part B and Animal Naming. The MIMIC model had excellent fit and tests additional latent variables i.e., EF and dEF (a latent δ homolog derived from Spearman's general intelligence factor, Conclusions: Observed EF is independently determined by multiple factors. The effects of EF-associated MRI biomarkers can be related to disability and dementia only via their effects on
Language	English
Publishing date	2023-09-15
Publishing country	Netherlands
Document type	Journal Article
ISSN	2666-2450
ISSN (online)	2666-2450
DOI	10.1016/j.cccb.2023.100184
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Article ; Online: Multiple Adipokines Predict Dementia Severity as Measured by δ: Replication Across Biofluids and Cohorts.

Royall, Donald R / Palmer, Raymond F

Journal of Alzheimer's disease : JAD

2023 Volume 92, Issue 2, Page(s) 639–652

Abstract: Background: We have explored dementia's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with ... ...

Abstract	Background: We have explored dementia's blood-based protein biomarkers in the Texas Alzheimer's Research and Care Consortium (TARCC) study. Among them are adipokines, i.e., proteins secreted by adipose tissue some of which have been associated with cognitive impairment. Objective: To associate adipokines with dementia severity and replicate their association across cohorts and biofluids (serum /plasma). Methods: We used eight rationally chosen blood-based protein biomarkers as indicators of a latent variable, i.e., "Adipokines". We then associated that construct with dementia severity as measured by the latent dementia-specific phenotype "δ" in structural equation models (SEM). Significant factor loadings and Adipokines' association with δ were replicated across biofluids in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Results: Eight adipokine proteins loaded significantly on the Adipokines construct. Adipokines measured in plasma (ADNI) or serum (TARCC) explained 24 and 70% of δ's variance, respectively. An Adipokine composite score, derived from the latent variables, rose significantly across clinical diagnoses and achieved high areas under the receiver operating characteristic curve (ROC/AUC) for discrimination of Alzheimer's disease from normal controls (NC) or cases of mild cognitive impairment (MCI) and between NC and MCI. Conclusion: These results again suggest that SEM can be used to create latent biomarker classifiers that replicate across samples and biofluids, and that a substantial fraction of dementia's variance is attributable to peripheral blood-based protein levels via the patterns codified in those latent constructs.
MeSH term(s)	Humans ; Alzheimer Disease/diagnostic imaging ; Adipokines ; Neuropsychological Tests ; Cognitive Dysfunction/diagnostic imaging ; Cognitive Dysfunction/psychology ; Blood Proteins ; Biomarkers
Chemical Substances	Adipokines ; Blood Proteins ; Biomarkers
Language	English
Publishing date	2023-02-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-221052
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Article ; Online: Statin use moderates APOE's and CRP's associations with dementia and is associated with lesser dementia severity in ε4 carriers.

Royall, Donald R / Palmer, Raymond F

Alzheimer's & dementia : the journal of the Alzheimer's Association

2023 Volume 20, Issue 3, Page(s) 1627–1636

Abstract: Introduction: We tested the effect of statins on C-reactive protein (CRP) and apolipoprotein E (APOE)'s associations with dementia severity.: Methods: A total of 1725 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) were ... ...

Abstract	Introduction: We tested the effect of statins on C-reactive protein (CRP) and apolipoprotein E (APOE)'s associations with dementia severity. Methods: A total of 1725 participants of the Alzheimer's Disease Neuroimaging Initiative (ADNI) were assigned from 12-month follow-up data into the following groups: (1) ε4 (-)/statin (-), (2) ε4 (-)/statin (+), (3) ε4 (+)/statin (-), and (4) ε4 (+)/statin (+). Dementia severity was assessed by a δ homolog: "dHABS." A mediation model was stratified on statin use and moderation effects tested by a chi-square difference. Results: Plasma CRP level decreased with ε4 allelic dose. Statins had no effect on the dHABS d-score in non-carriers but were associated with better scores in carriers. Treated carriers did not have more severe dementia than non-carriers. Statin use moderated the mutual adjusted effects of APOE and CRP. CRP was not a mediator of APOE's effect. Discussion: Statins may provide a protective effect on the dementia severity of ε4 carriers. Highlights: δ is a dementia-specific phenotype related to general intelligence "g" and is assessed via a "d-score." Apolipoprotein E (APOE) and plasma C-reactive protein (CRP) are independently associated with δ. Plasma CRP decreases with ε4 allelic dose. Statins were associated with better (less demented) d-scores in ε4 carriers but had no effect in non-ε4 carriers. Treated ε4 carriers did not have more severe dementia than non-carriers. Statin use moderated the effects of APOE and CRP on δ. CRP was not a mediator of APOE's effect on δ.
MeSH term(s)	Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use ; C-Reactive Protein ; Apolipoproteins E/genetics ; Dementia/drug therapy ; Dementia/genetics ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Apolipoprotein E4/genetics ; Genotype
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; C-Reactive Protein (9007-41-4) ; Apolipoproteins E ; Apolipoprotein E4
Language	English
Publishing date	2023-12-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2211627-8
ISSN	1552-5279 ; 1552-5260
ISSN (online)	1552-5279
ISSN	1552-5260
DOI	10.1002/alz.13543
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Article ; Online: Comment on Andrews et al.

Royall, Donald R

Alzheimer disease and associated disorders

2019

Language	English
Publishing date	2019-06-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1002700-2
ISSN	1546-4156 ; 0893-0341
ISSN (online)	1546-4156
ISSN	0893-0341
DOI	10.1097/WAD.0000000000000326
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Article ; Online: Comment on Association Between Functional Performance and Alzheimer's Disease Biomarkers in Individuals Without Dementia.

Royall, Donald R

Journal of the American Geriatrics Society

2019 Volume 67, Issue 5, Page(s) 1098–1099

MeSH term(s)	Aged ; Alzheimer Disease/physiopathology ; Dementia ; Disease Progression ; Female ; Humans ; Male ; Motor Activity/physiology ; Physical Functional Performance
Language	English
Publishing date	2019-01-11
Publishing country	United States
Document type	Letter
ZDB-ID	80363-7
ISSN	1532-5415 ; 0002-8614
ISSN (online)	1532-5415
ISSN	0002-8614
DOI	10.1111/jgs.15752
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Article ; Online: Toward a cross-cultural understanding of intraindividual variability metrics.

Scott, Bonnie M / Royall, Donald R / Benge, Jared F / Hilsabeck, Robin C

Journal of clinical and experimental neuropsychology

2024 , Page(s) 1–11

Abstract: Objective: Compare the construct validity and predictive utility of cognitive intraindividual variability (IIV) in a sample of community-dwelling Hispanic and non-Hispanic white (NHW) older adults.: Methods: The present study included annual data ... ...

Abstract	Objective: Compare the construct validity and predictive utility of cognitive intraindividual variability (IIV) in a sample of community-dwelling Hispanic and non-Hispanic white (NHW) older adults. Methods: The present study included annual data from 651 older adult control participants (Hispanic = 293; NHW = 358) enrolled in the Texas Alzheimer's Research and Care Consortium for at least 5 years. Mean composite z-scores were calculated for attention, language, memory, and executive domains. IIV was calculated as was the standard deviation both within (IIV-Within) and between (IIV-Between) these domains. Results: At baseline, NHW individuals obtained significantly higher mean scores in each domain than their Hispanic counterparts. They also showed significantly greater variability within and between domains, except for IIV-Within the language domain which was significantly larger in the Hispanic group. IIV-Between domains was driven primarily by IIV-Within the executive function domain in the NHW cohort and by IIV-Within the language domain in the Hispanic cohort. In both groups, the addition of IIV-Within and IIV-Between cognitive domains at baseline significantly improved prediction of global cognitive status after 5 years above and beyond demographic characteristics, genetic and cardiovascular risk. However, IIV-Between domains was the strongest predictor in the NHW group, while IIV-Within the attention domain was the strongest predictor in the Hispanic group. Conclusions: Findings suggest that, while IIV-Between domains is a promising adjunctive method for predicting future cognitive decline, its construct validity and predictive utility varies based on ethnic group.
Language	English
Publishing date	2024-03-14
Publishing country	England
Document type	Journal Article
ZDB-ID	605982-x
ISSN	1744-411X ; 0168-8634 ; 1380-3395
ISSN (online)	1744-411X
ISSN	0168-8634 ; 1380-3395
DOI	10.1080/13803395.2024.2328870
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Article ; Online: The effects of CNS atrophy and ICVD on tests of executive function and functional status are mediated by intelligence

Donald R. Royall / Raymond F. Palmer

Cerebral Circulation - Cognition and Behavior, Vol 5, Iss , Pp 100184- (2023)

2023

Abstract	Background: Impairments in executive function (EF) are often attributed to ischemic cerebrovascular disease (ICVD) and frontal circuit pathology. However, EF can be distinguished from general intelligence and the latter is likely to manifest in “executive” measures. We aimed to distinguish the effects of imaging biomarkers on these constructs. Methods: We tested neuroimaging biomarkers as independent predictors of observed 12 month-prospective cognitive performance by a Multiple Indicators Multiple Causes (MIMIC) model in the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N ≅ 1750). Results: ICVD was associated with ‘’Organization” (ORG) and “Planning” (PLAN) domain scores from the test of Every Day Cognition. Left anterior cingulate (LAC) atrophy was independently associated with Trail-Making part B and Animal Naming. The MIMIC model had excellent fit and tests additional latent variables i.e., EF and dEF (a latent δ homolog derived from Spearman's general intelligence factor, g). Only dEF was associated with instrumental activities of daily living (IADL). ICVD and LAC were both associated with observed executive measures through dEF. ICVD was independently associated with those same measures through EF. Conclusions: Observed EF is independently determined by multiple factors. The effects of EF-associated MRI biomarkers can be related to disability and dementia only via their effects on g. Because g /δ are unlikely to be located within the frontal lobes, the dementia-specific variance in executive measures may have little to do with either frontal structure or function. Conversely, domain-specific variance in EF may have little to do with either IADL-impairment or dementia.
Keywords	ADNI ; Dementia ; Executive function ; g ; IADL ; intelligence ; Specialties of internal medicine ; RC581-951 ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
Subject code	150
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
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Article ; Online: δ scores predict multiple neuropsychiatric symptoms.

Royall, Donald R / Palmer, Raymond F

International journal of geriatric psychiatry

2020 Volume 35, Issue 11, Page(s) 1341–1348

Abstract: Objectives: Dementia severity is strongly related to Spearman's general intelligence factor "g", via the latent dementia phenotype "δ" and is distinct from domain-specific cognitive impairments arising from disease-specific regional pathologies. It is ... ...

Abstract	Objectives: Dementia severity is strongly related to Spearman's general intelligence factor "g", via the latent dementia phenotype "δ" and is distinct from domain-specific cognitive impairments arising from disease-specific regional pathologies. It is an empiric question whether behavioral and psychological symptoms of dementia (BPSD) are associated with δ or with domain-specific constructs. Methods: A recently developed δ homolog ("dDx") was tested as a predictor of 1 year prospective BPSD in n = 723 Mexican-American and non-Hispanic White participants in the Texas Alzheimer's Research and Care Consortium (TARCC). The informant-rated frequencies of 12 BPSD were rated by the neuropsychiatric inventory (NPI-Q). Baseline BPSD, demographic features, selected biomarkers, and treatment exposure to acetylcholinesterase inhibitors were used as covariates. Composite scores derived from orthogonal latent measures of domain-specific memory (MEM) and executive function (EF) were also tested as predictors. Results: "Functionally salient cognitive impairment (FSCI)" that is, categorical "dementia" as diagnosed by dDx was associated with increased prospective frequency of 11/12 BPSD, independently of baseline behavior and covariates. Age, depressive symptoms, and EF were associated with individual BPSD. MEM was not associated with any. Dementia severity, as measured by dDx, was also associated with a prospective increase in total NPI-Q scores. Conclusion: δ is associated non-specifically with multiple BPSD. This suggests the existence of a dementia-specific behavioral profile, arising from insults to general intelligence, and unrelated to disease-specific regional pathology(ies).
MeSH term(s)	Alzheimer Disease ; Behavioral Symptoms ; Cognitive Dysfunction/diagnosis ; Humans ; Neuropsychological Tests ; Prospective Studies ; Texas
Language	English
Publishing date	2020-08-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	806736-3
ISSN	1099-1166 ; 0885-6230
ISSN (online)	1099-1166
ISSN	0885-6230
DOI	10.1002/gps.5371
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