Journal of Alzheimer's Disease - Volume 49, issue 2

Authors: Royall, Donald R.

Article Type: Editorial

Abstract: The latent variable “δ ” (for “dementia”) has been proposed as a phenotype for all cause dementia. δ is extracted from cognitive batteries by a specific confirmatory factor analysis in a structural equation modeling framework. δ appears to be uniquely responsible for cognition’s association with functional status. Because it is extracted from Spearman’s general intelligence factor “g ”, this has broad implications for dementia’s assessment and pathophysiology. This issue of the Journal of Alzheimer’s Disease brings together several demonstrations of δ ’s psychometric properties by investigative groups from three continents. In their aggregate, they suggest that δ …homologs may have far ranging applications in dementia’s clinical assessment and biomarker selection. Show more

Keywords: Alzheimer’s disease, dementia, intelligence, latent variable, longitudinal

DOI: 10.3233/JAD-150249

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 515-519, 2016

Authors: Palmer, Raymond F. | Royall, Donald R.

Article Type: Research Article

Abstract: Background: Structural equation models (SEM) can explicitly distinguish dementia-relevant variance in cognitive task performance. The resulting latent construct “δ ” (for dementia) provides a relatively “error free” continuously varying dementia-specific phenotype. Objective: To estimate δ ’s change over time (Δδ ) and determine Δδ ’s predictive validity using future dementia status as an outcome. Methods: Data from n  = 2,191 participants of the Texas Alzheimer’s Research and Care Consortium (TARCC) were used to construct a latent growth curve model of longitudinal change over four years using five cognitive measures and one measure of Instrumental Activities of Daily …Living. Four final latent factors, including baseline δ and Δδ , were simultaneously entered as predictors of wave 4 dementia severity, as estimated by the Clinical Dementia Rating Scale “sum of boxes” (CDR). Results: All observed measures exhibited significant change [χ 2  = 1,152 (df = 229); CFI = 0.968; RMSEA = 0.043]. The final model demonstrated excellent fit to the data [χ 2  = 543 (df = 245); CFI = 0.991; RMSEA = 0.023]. All latent indicator loadings were significant, yielding four distinct factors. After adjustment for demographic covariates and baseline CDR scores, d and Δd were significantly independently associated with CDR4, explaining 25% and 49% of its variance, respectively. The latent variable g’ significantly explained 3% of CDR4 variance independently of d and Δd. Δg’ was not significantly associated with CDR4. Baseline CDR explained 16% of CDR4 variance. Conclusions: Future dementia severity is almost entirely explained by the latent construct δ ’s intercept and slope. Show more

Keywords: Alzheimer’s disease, dementia, latent variable, longitudinal

DOI: 10.3233/JAD-150254

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 521-529, 2016

Authors: Gavett, Brandon E. | John, Samantha E. | Gurnani, Ashita S. | Bussell, Cara A. | Saurman, Jessica L.

Article Type: Research Article

Abstract: Background: Dementia severity can be modeled as the construct δ, representing the “cognitive correlates of functionalstatus.” Objective: We recently validated a model for estimating δ in the National Alzheimer’s Coordinating Center’s Uniform Data Set; however, the association of δ with neuropathology remains untested. Methods: We used data from 727 decedents evaluated at Alzheimer’s Disease (AD) Centers nationwide. Participants spoke English, had no genetic abnormalities, and were pathologically diagnosed with AD as a primary or contributing etiology. Clinical data from participants’ last visit prior to death were used to estimate dementia severity (δ). Results: A …structural equation model using age, education, race, and apolipoprotein E (APOE ) genotype (number of ɛ 2 and ɛ 4 alleles) as predictors and latent AD pathology and cerebrovascular disease (CVD) pathology as mediators fit the data well (RMSEA = 0.031; CFI = 0.957). AD pathology mediated the effects of age and APOE genotype on dementia severity. An older age at death and more ɛ 2 alleles were associated with less AD pathology and, in turn, with less severe dementia. In contrast, more ɛ 4 alleles were associated with more pathology and more severe dementia. Although age and race contributed to differences in CVD pathology, CVD pathology was not related to dementia severity in this sample of decedents with pathologically-confirmed AD. Conclusions: Using δ as an estimate of dementia severity fits well within a structural model in which AD pathology directly affects dementia severity and mediates the relationship between age and APOE genotype on dementia severity. Show more

Keywords: Aging, Alzheimer’s disease, apolipoprotein E2, apolipoprotein E4, dementia, vascular dementia

DOI: 10.3233/JAD-150252

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 531-545, 2016

Authors: Koppara, Alexander | Wolfsgruber, Steffen | Kleineidam, Luca | Schmidtke, Klaus | Frölich, Lutz | Kurz, Alexander | Schulz, Stefanie | Hampel, Harald | Heuser, Isabella | Peters, Oliver | Reischies, Friedel M. | Jahn, Holger | Luckhaus, Christian | Hüll, Michael | Gertz, Hermann-Josef | Schröder, Johannes | Pantel, Johannes | Rienhoff, Otto | Rüther, Eckart | Henn, Fritz | Wiltfang, Jens | Maier, Wolfgang | Jessen, Frank | Kornhuber, Johannes | Wagner, Michael

Article Type: Research Article

Abstract: Background: The recently proposed latent variable δ is a new tool for dementia case finding. It is built in a structural equation modeling framework of cognitive and functional data and constitutes a novel endophenotype for Alzheimer’s disease (AD) research and clinical trials. Objective: To investigate the association of δ with AD biomarkers and to compare the prediction of δ with established scales for conversion to dementia in patients with mild cognitive impairment (MCI). Methods: Using data from a multicenter memory clinic study, we examined the external associations of the latent variable δ …and compared δ with well-established cognitive and functional scales and cognitive-functional composite scores. For that purpose, logistic regressions with cerebrospinal fluid (CSF) biomarkers and conversion to dementia as dependent variables were performed with the investigated scores. The models were tested for significant differences. Results: In patients with MCI, δ based on a broad range of cognitive scales (including the ADAS-cog, the MMSE, and the CERAD neuropsychological battery) predicted an abnormal CSF Aβ42 /tau ratio indicative of AD (n  = 340, AUC = 0.78, p  <  0.001), and predicted incident dementia within 1–3 years of follow-up (n  = 525, AUC = 0.84, p  <  0.001). These associations were generally stronger than for any other scale or cognitive-functional composite examined. Homologs of δ based on reduced test batteries yielded somewhat lower effects. Conclusion: These findings support the interpretation of δ as a construct capturing the disease-related “essence” of cognitive and functional impairments in patients with MCI and dementia, and suggest that δ might become an analytical tool for dementia research. Show more

Keywords: CSF AD biomarker signature, delta model, incident dementia, mild cognitive impairment

DOI: 10.3233/JAD-150257

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 547-560, 2016

Authors: Royall, Donald R. | Palmer, Raymond F. | Matsuoka, Teruyuki | Kato, Yuka | Taniguchi, Shogo | Ogawa, Mayu | Fujimoto, Hiroshi | Okamura, Aiko | Shibata, Keisuke | Nakamura, Kaeko | Nakaaki, Shutaro | Koumi, Hiroyuki | Mimura, Masaru | Fukui, Kenji | Narumoto, Jin

Article Type: Research Article

Abstract: The latent variable “δ ”, can accurately diagnose dementia. Its generalizability across populations is unknown. We constructed a δ homolog (“dT2J”) in data collected by the Texas Alzheimer’s Research and Care Consortium (TARCC). From this, we calculated a composite d-score “d”. We then tested d’s generalizability across random subsets of TARCC participants and to a convenience sample of elderly Japanese persons with normal cognition (NC), mild cognitive impairment (MCI), and dementia (AD) (n  = 176). dT2J was indicated by Instrumental Activities of Daily Living and psychometric measures. Embedded in this battery were the Mini-Mental Status Examination (MMSE) and an executive …clock-drawing task (CLOX). Only MMSE and CLOX were available in both TARCC and the Japanese cohort. Therefore, a second composite variable, “T2J”, was constructed solely from the factor loadings of CLOX and MMSE on d. The diagnostic accuracy of T2J was estimated in the validation sample, the remainder of the TARCC cohort, and in the Japanese sample. The areas under the receiver operating curve (AUC; ROC) for T2J were compared in each sample, and against d in TARCC. The AUCs for T2J were statistically indiscriminable within TARCC, and in Japanese persons. In Japanese persons, AUCs for T2J were 0.97 for the discrimination between AD versus NC, 0.86 for AD versus MCI, and 0.79 for NC versus MCI. The AUCs for T2J in Japanese persons were higher than any individual psychometric measure in that sample. Valid d-score composites can be extracted from a subset of δ ’s indicators. Moreover, those composites are exportable across cultural and linguistic boundaries. Show more

Keywords: CLOX, dementia, δ, Instrumental Activities of Daily Living, Spearman’s g

DOI: 10.3233/JAD-150261

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 561-570, 2016

Authors: Royall, Donald R. | Palmer, Raymond F. | Matsuoka, Teruyuki | Kato, Yuka | Taniguchi, Shogo | Ogawa, Mayu | Fujimoto, Hiroshi | Okamura, Aiko | Shibata, Keisuke | Nakamura, Kaeko | Nakaaki, Shutaro | Koumi, Hiroyuki | Mimura, Masaru | Fukui, Kenji | Narumoto, Jin

Article Type: Research Article

Abstract: “δ ”, a latent variable constructed from cognitive performance and functional status measures, can accurately diagnose dementia. The minimal assessment needed is unknown. We have constructed a δ homolog, “dTEXAS”, from Telephone Executive Assessment Scale (TEXAS) items, and validated it in a convenience sample of Japanese persons (n  = 176). dTEXAS scores correlated strongly with both Instrumental Activities of Daily Living (IADL) (r  = –0.86, p  <  0.001) and Clinical Dementia Rating Scale (CDR) (r  = 0.71, p  <  0.001). Constructed independently of their diagnoses, dTEXAS scores accurately distinguished dementia versus controls [area under the receiver operating curve (AUC; ROC) = 0.92, dementia versus …mild cognitive impairment (MCI) (AUC = 0.80) and controls versus MCI (AUC = 0.74)]. These AUCs are higher than those of multiple observed executive measures, as reported recently by Matsuoka et al., 2014. A dTEXAS score of –0.58 best discriminated between dementia versus controls with 90.1% sensitivity and 80.0% specificity. Show more

Keywords: CLOX, dementia, executive function, EXIT25, Instrumental Activities of Daily Living

DOI: 10.3233/JAD-150250

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 571-579, 2016

Authors: Ashford, J. Wesson

Article Type: Book Review

DOI: 10.3233/JAD-150885

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 581-581, 2016

Article Type: Other

DOI: 10.3233/JAD-150854

Citation: Journal of Alzheimer's Disease, vol. 49, no. 2, pp. 583-587, 2016