The relationship between hippocampal amyloid beta burden and spatial distribution of neurofibrillary degeneration.

INTRODUCTION: Neurofibrillary degeneration in Alzheimer's disease (AD) typically involves the entorhinal cortex and CA1 subregion of the hippocampus early in the disease process, whereas in primary age-related tauopathy (PART), there is an early selective vulnerability of the CA2 subregion. METHODS: Image analysis-based quantitative pixel assessments were used to objectively evaluate amyloid beta (Aß) burden in the medial temporal lobe in relation to the distribution of hyperphosphorylated-tau (p-tau) in 142 cases of PART and AD. RESULTS: Entorhinal, CA1, CA3, and CA4 p-tau deposition levels are significantly correlated with Aß burden, while CA2 p-tau is not. Furthermore, the CA2/CA1 p-tau ratio is inversely correlated with Aß burden and distribution. In addition, cognitive impairment is correlated with overall p-tau burden. DISCUSSION: These data indicate that the presence and extent of medial temporal lobe Aß may determine the distribution and spread of neurofibrillary degeneration. The resulting p-tau distribution patterns may discriminate between PART and AD. HIGHLIGHTS: Subregional hyperphosphorylated-tau (p-tau) distribution is influenced by hippocampal amyloid beta burden. Higher CA2/CA1 p-tau ratio is predictive of primary age-related tauopathy-like neuropathology. Cognitive function is correlated with the overall hippocampal p-tau burden.

Cognitive and Neuropsychological Profiles in Alzheimer's Disease and Primary Age-Related Tauopathy and the Influence of Comorbid Neuropathologies.

BACKGROUND: Alzheimer's disease neuropathologic change (ADNC) is defined by the progression of both hyperphosphorylated-tau (p-tau) and amyloid-ß (Aß) and is the most common underlying cause of dementia worldwide. Primary age-related tauopathy (PART), an Aß-negative tauopathy largely confined to the medial temporal lobe, is increasingly being recognized as an entity separate from ADNC with diverging clinical, genetic, neuroanatomic, and radiologic profiles. OBJECTIVE: The specific clinical correlates of PART are largely unknown; we aimed to identify cognitive and neuropsychological differences between PART, ADNC, and subjects with no tauopathy (NT). METHODS: We compared 2,884 subjects with autopsy-confirmed intermediate-high stage ADNC to 208 subjects with definite PART (Braak stage I-IV, Thal phase 0, CERAD NP score "absent") and 178 NT subjects from the National Alzheimer's Coordinating Center dataset. RESULTS: PART subjects were older than either ADNC or NT patients. The ADNC cohort had more frequent neuropathological comorbidities as well as APOE ɛ4 alleles than the PART or NT cohort, and less frequent APOE ɛ2 alleles than either group. Clinically, ADNC patients performed significantly worse than NT or PART subjects across cognitive measures, but PART subjects had selective deficits in measures of processing speed, executive function, and visuospatial function, although additional cognitive measures were further impaired in the presence of neuropathologic comorbidities. In isolated cases of PART with Braak stage III-IV, there are additional deficits in measures of language. CONCLUSION: Overall, these findings demonstrate underlying cognitive features specifically associated with PART, and reinforce the concept that PART is a distinct entity from ADNC.

A Critical Review of Neuropsychological Actuarial Criteria for Mild Cognitive Impairment.

BACKGROUND: The concept of mild cognitive impairment (MCI) has evolved since its original conception. So, too, have MCI diagnostic methods, all of which have varying degrees of success in identifying individuals at risk of conversion to dementia. The neuropsychological actuarial method is a straightforward diagnostic approach that has shown promise in large datasets in identifying individuals with MCI who are likely to have progressive courses. This method has been increasingly applied in various iterations and samples, raising questions of how best to apply this method and when caution should be used. OBJECTIVE: Our objective was to review the literature investigating use of the neuropsychological actuarial method to diagnose MCI to identify strengths and weaknesses of this approach, as well as highlight areas for further research. METHODS: Databases PubMed and PsychInfo were systematically searched for studies that compared the neuropsychological actuarial method to some other diagnostic method. RESULTS: We identified 13 articles and extracted relevant study characteristics and findings. Existing literature was reviewed and integrated, with focus on the neuropsychological actuarial method's performance relative to existing diagnostic methods/criteria as well as associations with longitudinal outcomes and biomarkers. Tables with pertinent methodological information and general findings are also provided. CONCLUSION: The neuropsychological actuarial method to diagnose MCI has shown utility some in large-scale homogenous databases compared to research criteria. However, its standing relative to consensus diagnostic methods is unclear, and emerging evidence suggests the neuropsychological actuarial method may be more prone to diagnostic errors in more demographically diverse populations.

The Spectrum of Alzheimer-Type Pathology in Cognitively Normal Individuals.

BACKGROUND: The strongest risk factor for the development of Alzheimer's disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. OBJECTIVE: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. METHODS: Utilizing neuropathology data obtained from the National Alzheimer's Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual's Alzheimer-type pathology varies from the estimated normal range of pathology. RESULTS: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer's Disease neuritic plaque score and Alzheimer's disease neuropathologic change remain at low levels. CONCLUSION: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-ß (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be "resilient" against the pathology (significantly above the normative values for age, but still cognitively normal) or "resistant" to the development of pathology (significantly below the normative values for age).

Impact of word properties on list learning: An explanatory item analysis.

OBJECTIVE: A variety of factors affect list learning performance and relatively few studies have examined the impact of word selection on these tests. This study examines the effect of both language and memory processing of individual words on list learning. METHOD: Item-response data from 1,219 participants, Mage = 74.41 (SD = 7.13), Medu = 13.30 (SD = 2.72), in the Harmonized Cognitive Assessment Protocol were used. A Bayesian generalized (non)linear multilevel modeling framework was used to specify the measurement and explanatory item-response theory models. Explanatory effects on items due to learning over trials, serial position of words, and six word properties obtained through the English Lexicon Project were modeled. RESULTS: A two parameter logistic (2PL) model with trial-specific learning effects produced the best measurement fit. Evidence of the serial position effect on word learning was observed. Robust positive effects on word learning were observed for body-object integration while robust negative effects were observed for word frequency, concreteness, and semantic diversity. A weak negative effect of average age of acquisition and a weak positive effect for the number of phonemes in the word were also observed. CONCLUSIONS: Results demonstrate that list learning performance depends on factors beyond the repetition of words. Identification of item factors that predict learning could extend to a range of test development problems including translation, form equating, item revision, and item bias. In data harmonization efforts, these methods can also be used to help link tests via shared item features and testing of whether these features are equally explanatory across samples. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Validation of a Bayesian Diagnostic and Inferential Model for Evidence-Based Neuropsychological Practice.

OBJECTIVE: Evidence-based diagnostic methods have clinical and research applications in neuropsychology. A flexible Bayesian model was developed to yield diagnostic posttest probabilities from a single person's neuropsychological score profile by utilizing sample descriptive statistics of the test battery across diagnostic populations of interest. METHODS: Three studies examined the model's performance. One simulation examined estimation accuracy of true z-scores. A diagnostic accuracy simulation utilized descriptive statistics from two popular neuropsychological tests, the Wechsler Adult Intelligence Scale-IV (WAIS-IV) and Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). The final simulation examined posterior predictive accuracy of scores to those reported in the WAIS manual. RESULTS: The model produced minimally biased z-score estimates (root mean square errors: .02-.18) with appropriate credible intervals (95% credible interval empirical coverage rates: .94-1.00). The model correctly classified 80.87% of simulated normal, mild cognitive impairment, and Alzheimer's disease cases using a four subtest WAIS-IV and the RBANS compared to accuracies of 60.67-65.60% from alternative methods. The posterior predictions of raw scores closely aligned to percentile estimates published in the WAIS-IV manual. CONCLUSION: This model permits estimation of posttest probabilities for various combinations of neuropsychological tests across any number of clinical populations with the principal limitation being the accessibility of applicable reference samples. The model produced minimally biased estimates of true z-scores, high diagnostic classification rates, and accurate predictions of multiple reported percentiles while using only simple descriptive statistics from reference samples. Future nonsimulation research on clinical data is needed to fully explore the utility of such diagnostic prediction models.

The impact of conventional versus robust norming on cognitive characterization and clinical classification of MCI and dementia.

We examined the impact of conventional versus robust normative approaches on cognitive characterization and clinical classification of MCI versus dementia. The sample included participants from the National Alzheimer's Coordinating Center Uniform Data Set. Separate demographically adjusted z-scores for cognitive tests were derived from conventional (n = 4273) and robust (n = 602) normative groups. To assess the impact of deriving scores from a conventional versus robust normative group on cognitive characterization, we examined likelihood of having a low score on each neuropsychological test. Next, we created receiver operating characteristic (ROC) curves for the ability of normed scores derived from each normative group to differentiate between MCI (n = 3570) and dementia (n = 1564). We examined the impact of choice of normative group on classification accuracy by comparing sensitivity and specificity values and areas under the curves (AUC). Compared with using a conventional normative group, using a robust normative group resulted in a higher likelihood of low cognitive scores for individuals classified with MCI and dementia. Comparison of the classification accuracy for distinguishing MCI from dementia did not suggest a statistically significant advantage for either normative approach (Z = -0.29, p = .77; AUC = 0.86 for conventional and AUC = 0.86 for robust). In summary, these results indicate that using a robust normative group increases the likelihood of characterizing cognitive performance as low. However, there is not a clear advantage of using a robust over a conventional normative group when differentiating between MCI and dementia.

Borderline personality features influence treatment response to suicide prevention.

BACKGROUND: Suicide is a notable risk for individuals with features of borderline personality disorder. Given the centrality of interpersonal difficulties in this disorder, we proposed that the negative interpersonal cognitions (perceived burdensomeness and thwarted belongingness) identified by the Interpersonal Theory of Suicide (IPTS) may explain the associations between suicidal ideation and borderline personality features. METHOD: Participants were 322 suicidal youth (74% girls) aged 11-18 years (M, SD = 14.74, 1.6) in an intensive outpatient program in the southwest United States. Youth completed measures assessing borderline personality features at program entry, and suicidal ideation and IPTS variables at entry and exit. RESULTS: Borderline personality features did not moderate associations of IPTS variables and suicidal ideation. For the entire sample, changes in suicidal ideation from entry to discharge occurred in tandem with changes in perceived burdensomeness and depressive symptoms, but not thwarted belongingness. Youth with elevated borderline personality features entered with greater suicidal ideation, but improved more from treatment entry to exit. Regardless of level of borderline personality features, changes in negative interpersonal cognitions over treatment were associated with changes in suicidal ideation. LIMITATIONS: Self-report measures and lack of sample diversity are study limitations. CONCLUSIONS: This research highlights the clinical utility of the IPTS variables and the importance of promoting competence and interpersonal connectedness when treating this population. Findings indicate that the IPTS variables carry the same fundamental information for contributing to suicidal ideation, regardless of level of borderline personality features.

Montreal Cognitive Assessment (MoCA) scores in medically compromised patients: A scoping review.

OBJECTIVE: The purpose of this review is to critically examine studies that have examined investigated the Montreal Cognitive Assessment (MoCA) and functional or medical outcomes and other health variables in patients with non-neurologic medical conditions. METHOD: Databases OVID Medline and Embase were systematically searched through April 2020, yielding 281 articles that were separately screened for inclusion. Study characteristics extracted from retained articles are presented in Table S1 (online supplemental materials). RESULTS: Thirty-six articles were retained. Cognitive impairment as assessed by the MoCA was associated with adverse health variables including increased morbidity/mortality, poorer functional abilities, increased length of hospital stay, and increased hospital readmissions in 34 of 36 articles. CONCLUSIONS: Cognitive impairment as detected by the MoCA was shown in 34 of 36 studies to be associated with worse functional or medical status compared to those with better cognitive functioning across a variety of medical populations. Further research is needed to better understand how to best use the MoCA to potentially inform treatment planning in medical populations, including referral for more detailed neuropsychological evaluation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Psychometric Equivalence of the Computerized and Original Halstead Category Test Using a Matched Archival Sample.

Objective: Investigate the equivalence of several psychometric measures between the traditional Halstead Category Test (HCT-Original Version [OV]) and the computer-based Halstead Category Test (HCT-Computerized Version [CV]). Method: Data were from a diagnostically heterogeneous, archival sample of 211 adults administered either the HCT by computer (n = 105) or cabinet (n = 106) as part of a neuropsychological evaluation. Groups were matched on gender, race, education, Full Scale Intelligence Quotient, and Global Neuropsychological Deficit Score. Confirmatory factor analysis was used to examine structural equivalence. Score, variability, and reliability equivalency were also examined. Differential item and test functioning under a Rasch model were examined. Results: An identified factor structure from research of the HCT-OV fit the HCT-CV scores adequately: χ2(4) = 8.83, p = .07; root mean square error of approximation = 0.10 [0.00, 0.20]; standardized root mean residual = 0.03; comparative fit index = 0.99. Total scores and variability of subtest scores were not consistently equivalent between the two administration groups. Reliability estimates were, however, similar and adequate for clinical practice: 0.96 for HCT-OV and 0.97 for HCT-CV. About 17% of items showed possible differential item functioning, though just three of these items were statistically significant. Differential test functioning revealed expected total score differences of <1% between versions. Conclusion: The results of this study suggest that the HCT-CV functions similar to the HCT-OV with there being negligible differences in expected total scores between these versions. The HCT-CV demonstrated good psychometric properties, particularly reliability and construct validity consistent with previous literature. Further study is needed to generalize these findings and to further examine the equivalency of validity evidence between versions.

Reynolds Intellectual Screening Instrument 1st versus 2nd Edition in a Memory Disorder Sample.

OBJECTIVE: The Reynolds Intellectual Screening Instrument (RIST) and its second edition (RIST-2) are brief intelligence screening instruments that potentially have value in older populations as their norms extend over age 90. This study examined performance on these two instruments in a sample of individuals presenting for evaluation in a memory disorder clinic. METHOD: A sample of 1,145 subjects over the age of 50 was chosen from 1,761 consecutive referrals. Individuals who obtained a consensus diagnosis of Mild Cognitive Impairment (MCI; n = 536), possible dementia of the Alzheimer Type (DAT; n = 400), or those with subjective cognitive complaints (SCC; n = 209) and who completed a neuropsychological battery that included either the RIST (n = 747) or the RIST-2 (n = 398) were included in the sample. No clinically significant demographic or neuropsychological performance differences were found for those taking either version of the RIST. RESULTS: Unlike the original version, RIST-2 Total and subtest scores were well below the mean for the DAT group and over 1 SD mean difference was seen for the DAT group when comparing the RIST and RIST-2 Totals. Diagnostic accuracy calculations suggested that the RIST-2 showed greater discrimination between the three groups although both versions achieved greater sensitivity than specificity. CONCLUSIONS: Performance differences were evident when comparing the RIST and RIST-2, particularly for the DAT group. Although the RIST-2 evidenced greater diagnostic accuracy than its predecessor it should not be utilized in isolation for the clinical determination of DAT or MCI.

Reconsidering the RBANS Factor Structure: a Systematic Literature Review and Meta-Analytic Factor Analysis.

The primary aim was to perform a systematic literature review and extract data necessary for a meta-analytic factor analysis of the RBANS. Secondary aims were to examine the potential validity and utility of the resulting factor structure. Literature was identified through a review of PsycINFO, PubMed, MEDLINE, Academic Search Complete, Psychology & Behavioral Sciences Collection, CINAHL Complete, Health Source: Nursing/Academic Edition, and SocINDEX. A two-stage meta-analytic structural equation modeling method was implemented to pool correlation matrices from primary studies and perform confirmatory factor analyses. Following model selection, factor scores were computed for two datasets and subjected to correlation and diagnostic accuracy analyses. A pooled correlation matrix was computed from 24 sample correlation matrices (N = 5299). Confirmatory factor analysis revealed that the theoretical five-factor model produced the best fit but only when error terms between Story Memory and Story Recall as well as between Figure Copy and Figure Recall were included. Regression-based factor scores showed mixed relationships with the manual-defined indices, and the overall diagnostic accuracy of the factor scores was adequate in both samples examined (AUC = 0.71 and 0.87). The five-factor model was an unexpected result given the failure of multiple previous studies to find support for that model. The five-factor model demonstrates several areas of potential improvement, including better representation of the factors by the indicators. The factor scores implied by this model also require further validation.

Relationship between smell identification testing and the neuropsychological assessment of dementia in community-dwelling adults.

The objective of this research was to investigate the relationship of the University of Pennsylvania Smell Identification Test (UPSIT) with neuropsychological tests and identify the utility of the UPSIT in detecting cognitive impairment. This research was an archival study of neuropsychological test results obtained from 70 clients (30 male/40 female) of a community-based memory clinic. The sample had an average age of 69.7 (SD = 9.7) and education of 14.6 (SD = 2.8) years. Hypotheses were tested using correlations, receiver operating characteristic (ROC) curves, and logistic regression. The UPSIT showed significant, weak to moderate correlations with neuropsychological tests. The UPSIT raw score correlated significantly with all but one cognitive ability domain. The UPSIT T-score was significantly correlated with all cognitive domains. Obtained areas under the ROC curve (AUC) for the UPSIT ranged from .60 to .87. The AUCs of the UPSIT did not differ significantly from verbal semantic fluency tests, but the Repeatable Battery for the Assessment of Neuropsychological Status Total Scale and Delayed Memory index tended to produce larger AUCs than the UPSIT. Results from step-wise logistic regressions suggest that the UPSIT raw score provides unique information beyond its relationship to age. Olfaction relates broadly to cognitive ability and may be sensitive to early symptoms of cognitive decline. Further research is needed to explore the relationships between smell identification tests and neuropsychological assessment.

A meta-analysis of the accuracy of embedded performance validity indicators from the repeatable battery for the assessment of neuropsychological status.

Objective: Meta-analyze the embedded performance validity tests of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), emphasizing two topics: diagnostic accuracy and relationships with demographics. Method: Literature was identified through a review of PsycINFO, PubMed, and Google Scholar. Bivariate linear mixed models were used for diagnostic accuracy analyses. Random-effects analysis of correlations with demographic variables was also used for the Effort Index. Results: Diagnostic accuracy analyses utilized 12 studies of the Effort Index (EI; N = 1469) and 6 studies of the Effort Scale (ES; N = 854). The EI was found to have a sensitivity of .44 (95% CI: .28 - .62), specificity of .87 (95% CI: .78 - .93), and diagnostic odds ratio (DOR) of 5.41 (95% CI: 3.74 - 7.58). The ES produced a sensitivity of .67 (95% CI: .50 - .81), specificity of .72 (95% CI: .53 - .85), and DOR of 5.97 (95% CI: 1.70 - 15.30). Meta-analysis of correlations utilized 14 samples of the EI (N = 3781), but insufficient data were available for the ES. Correlations between the EI and age (r = .10, 95% CI: .05 - .16), education (r = -.11, 95% CI: -.18 to -.04), and the RBANS Total Scale (r = -.45, 95% CI: -.62 to -.24) were significant. These results appeared to be robust to publication bias. Conclusion: Results support use of the EI over the ES; however, the latter is comparatively less studied and did not have similar variability in reported cut-off scores. ES accuracy statistics were significantly predicted by sample variables, which may be related to its relatively fewer studies. Both measures should be used cautiously in the context of genuine cognitive impairment.

Examination of Regression-based Discrepancy Scores for the RBANS in Detecting Cognitive Impairment from an Archival Sample.

OBJECTIVE: The purpose of this study was to evaluate the clinical utility of regression-based formulas for the RBANS indexes in screening for cognitive impairment. METHOD: A database of neuropsychological test results was created from archival records in a memory assessment clinic. The sample consisted of 83 individuals (37 males/46 females) with an average age of 70.1 (SD = 9.8) and 14.6 years of education (SD = 2.8). Diagnostic accuracy of regression-based predictions provided by Duff and Ramezani (2015) (Duff, K., & Ramezani, A. (2015). Regression-based normative formulae for the Repeatable Battery for the Assessment of Neuropsychological Status for older adults. Archives of Clinical Neuropsychology, 30, 600-604.) and from regression of WTAR standard score were examined via receiver operator characteristic curves. Preliminary generalizability investigation was completed using two additional datasets. RESULTS: The WTAR was found to mediate the relationship between education and all RBANS index scores. The WTAR standard score was also found to contribute uniquely and significantly to the prediction of RBANS performance. Results of diagnostic accuracy analyses showed similar discriminating accuracy for all scores. There was limited support for using the WTAR over demographic variables alone in the estimation of RBANS performance; however, the WTAR was found to be more predictive than education, indicating potential clinical utility to using the word-reading score over just years of attained education. CONCLUSIONS: Use of these derived Total Scale score variants is recommended for the screening of cognitive impairment, particularly in individuals with superior or poor educational quality. Further research is required to evaluate the utility of these variations in more diverse samples.

The relationship between smell identification and neuropsychological domains: Results from a sample of community-dwelling adults suspected of dementia.

OBJECTIVE: This study aimed to test the theoretical relationships between smell identification and cognitive tasks based on existing neuroimaging and anatomical findings. METHOD: Utilizing data collected from a memory assessment clinic, theory-derived mediation and moderation models were tested. The sample used in this study consisted of 103 (39 male, 64 female) individuals referred for memory assessments. The sample's mean education was 12.4 years (SD = 3.2), and the mean age of the sample was 77.2 years (SD = 6.3). RESULTS: The University of Pennsylvania Smell Identification Test (UPSIT) was a significant, partial mediator of the relationship between the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) Immediate and Delayed Memory indexes. Olfactory identification did not mediate list learning and retrieval; however, olfactory identification was a significant partial mediator of the relationship between story encoding and later memory retrieval of the story. Olfactory identification also fully mediated the relationship between a visuospatial construction task and its reconstruction from memory after a short delay. The relationship between processing speed and the olfactory identification was significantly mediated by semantic memory. Finally, the UPSIT moderated the relationship between a measure of premorbid ability, the Wechsler Test of Adult Reading, and current global cognitive functioning. CONCLUSIONS: Our results support theoretical relationships between olfaction and neuropsychological domains. Additionally, our results suggest that the UPSIT may serve as a proxy for cerebral integrity and is likely related to the duration of neurodegeneration.

Relationship Between the Mini-Mental State Examination and the Repeatable Battery for the Assessment of Neuropsychological Status in Patients Referred for a Dementia Evaluation.

The current study examined the relationship between the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Mini-Mental State Examination (MMSE) in a large, heterogeneous sample of patients referred for dementia assessment (N = 495; 37% males, 63% females; M age = 76.8 years, SD = 7.0). The MMSE showed a significant moderate correlation with the RBANS Total Scale score (r = .65). Moderate significant correlations were found between the MMSE and the RBANS indexes (r = .41 to .49). The MMSE demonstrated moderate correlations with RBANS factor scores of .63 for Factor 1 (memory/learning) and .58 for Factor 2 (visuospatial/attention). These correlations suggest that the MMSE is best considered a measure of global cognitive functioning with the strongest correlations between broader measures.