Identification of amnestic mild cognitive impairment among Black and White community-dwelling older adults using NIH Toolbox Cognition tablet battery.

OBJECTIVES: Identify which NIH Toolbox Cognition Battery (NIHTB-CB) subtest(s) best differentiate healthy controls (HC) from those with amnestic mild cognitive impairment (aMCI) and compare the discriminant accuracy between a model using a priori "Norm Adjusted" scores versus "Unadjusted" standard scores with age, sex, race/ethnicity, and education controlled for within the model. Racial differences were also examined. METHODS: Participants were Black/African American (B/AA) and White consensus-confirmed (HC = 96; aMCI = 62) adults 60-85 years old that completed the NIHTB-CB for tablet. Discriminant function analysis (DFA) was used in the Total Sample and separately for B/AA (n = 80) and White participants (n = 78). RESULTS: Picture Sequence Memory (an episodic memory task) was the highest loading coefficient across all DFA models. When stratified by race, differences were noted in the pattern of the highest loading coefficients within the DFAs. However, the overall discriminant accuracy of the DFA models in identifying HCs and those with aMCI did not differ significantly by race (B/AA, White) or model/score type (Norm Adjusted versus Unadjusted). CONCLUSIONS: Racial differences were noted despite the use of normalized scores or demographic covariates-highlighting the importance of including underrepresented groups in research. While the models were fairly accurate at identifying consensus-confirmed HCs, the models proved less accurate at identifying White participants with an aMCI diagnosis. In clinical settings, further work is needed to optimize computerized batteries and the use of NIHTB-CB norm adjusted scores is recommended. In research settings, demographically corrected scores or within model correction is suggested.

Performance of Fully-Automated High-Throughput Plasma Biomarker Assays for Alzheimer's Disease in Amnestic Mild Cognitive Impairment Subjects.

INTRODUCTION: Novel plasma biomarkers are promising for identifying Alzheimer's disease (AD) pathological processes in vivo, but most currently employed assays have limitations precluding widespread use. METHODS: CSF and plasma samples were collected from seventy amnestic mild cognitive impairment (aMCI) subjects, stratified as A+ and A-. CSF Aß40, Aß42, p-tau181 and t-tau and plasma Aß40, Aß42 and p-tau181 quantification were conducted using the Lumipulse G assays (Fujirebio), to evaluate the diagnostic performance of plasma biomarkers and assess their associations with CSF biomarkers. RESULTS: All plasma biomarkers except Aß40 showed a very good accuracy in distinguishing A+ aMCI from A- aMCI, Aß42/p-tau181 ratio being the most accurate (AUC 0.895, sensitivity 95.1%, specificity 82.8%). Plasma biomarkers levels were significantly associated with CSF biomarkers concentration. DISCUSSION: High-throughput and fully-automated plasma assays could be helpful in discriminating with high accuracy between aMCI in the AD continuum and aMCI unlikely due to AD in clinical settings.

Clinical Significance of the Plasma Biomarker Panels in Amyloid-Negative and Tau PET-Positive Amnestic Patients: Comparisons with Alzheimer's Disease and Unimpaired Cognitive Controls.

The purpose of this study was to investigate whether plasma biomarkers can help to diagnose, differentiate from Alzheimer disease (AD), and stage cognitive performance in patients with positron emission tomography (PET)-confirmed primary age-related tauopathy, termed tau-first cognitive proteinopathy (TCP) in this study. In this multi-center study, we enrolled 285 subjects with young-onset AD (YOAD; n = 55), late-onset AD (LOAD; n = 96), TCP (n = 44), and cognitively unimpaired controls (CTL; n = 90) and analyzed plasma Aß42/Aß40, pTau181, neurofilament light (NFL), and total-tau using single-molecule assays. Amyloid and tau centiloids reflected pathological burden, and hippocampal volume reflected structural integrity. Receiver operating characteristic curves and areas under the curves (AUCs) were used to determine the diagnostic accuracy of plasma biomarkers compared to hippocampal volume and amyloid and tau centiloids. The Mini-Mental State Examination score (MMSE) served as the major cognitive outcome. Logistic stepwise regression was used to assess the overall diagnostic accuracy, combining fluid and structural biomarkers and a stepwise linear regression model for the significant variables for MMSE. For TCP, tau centiloid reached the highest AUC for diagnosis (0.79), while pTau181 could differentiate TCP from YOAD (accuracy 0.775) and LOAD (accuracy 0.806). NFL reflected the clinical dementia rating in TCP, while pTau181 (rho = 0.3487, p = 0.03) and Aß42/Aß40 (rho = -0.36, p = 0.02) were significantly correlated with tau centiloid. Hippocampal volume (unstandardized ß = 4.99, p = 0.01) outperformed all of the fluid biomarkers in predicting MMSE scores in the TCP group. Our results support the superiority of tau PET to diagnose TCP, pTau181 to differentiate TCP from YOAD or LOAD, and NFL for functional staging.

Associations Between Free and Cued Selective Reminding Test and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment.

Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-ß positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aß42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aß42/40 ratio value, subjects were classified as either A+ or A-. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-ß status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A- aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aß42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-ß deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI.

Depressive symptoms-Not a predictor for five-year mortality in patients with subjective cognitive decline, non-amnestic and amnestic mild cognitive impairment.

The main aim of the present study is to evaluate the influence of depressive symptoms on mortality in patients with SCD (subjective cognitive decline), naMCI (non-amnestic mild cognitive impairment), and aMCI (amnestic mild cognitive impairment). Additional factors (age, sex, years of school attendance, and neuropsychological performance) were considered to determine the impact on survival probability. A monocentric retrospective data analysis based on adjusted patient protocols (n = 1221) from the observation period 1998-2021, using the Cox Proportional Hazards model, assessed whether depressivity had an explanatory value for survival, considering SCD as the reference level in relation to naMCI and aMCI. Covariates were included blockwise. Cox regression revealed that depressiveness (Beck Depression Inventory, Geriatric Depression Scale) did not make a significant contribution as a risk factor for mortality in all five model blocks, BDI-II with HR 0.997 [0.978; 1.02] and GDS-15 with HR 1.03 [0.98; 1.08]. Increasing age with HR 1.09 [1.07; 1.11] and male sex with HR (inverted) 1.53 [1.17; 2.00] appeared as risk factors for increased mortality across all five model blocks. aMCI (vs. SCD) with HR 1.91 [1.33; 2.76] showed a significant explanatory value only up to the fourth model block. By adding the six dimensions of the Neuropsychological Test Battery Vienna in the fifth model block, the domains attention and perceptual speed with HR 1.34 [1.18; 1.53], and executive functions with HR 1.24 [1.11; 1.39], showed substantial explanatory values for survival. Accordingly, no tendency can be attributed to depressiveness as a risk factor on the probability of survival, whereas the influence of certain cognitive dimensions, especially attention and perceptual speed, and executive functions, can be seen as protective for survival.

Novel Panel of Long Noncoding RNAs as Diagnostic Biomarkers for Amnestic Mild Cognitive Impairment in Peripheral Blood.

Background: Long noncoding RNAs (lncRNAs) regulate the pathogenesis of Alzheimer's disease (AD). Objective: To identify lncRNAs in the peripheral blood as potential diagnostic biomarkers for amnestic mild cognitive impairment. Methods: In the discovery group, a microarray was used to screen for significant differences in lncRNA expression between patients with mild cognitive impairment (MCI) caused by AD and normal controls (NCs) (n = 10; MCI, 5; NC, 5). Furthermore, two analytic groups were assessed (analytic group 1: n = 10; amnestic MCI (aMCI), 5; NC, 5; analytic group 2: n = 30; AD, 10; aMCI, 10; NC, 10) and finalized in the validation group (n = 150; AD, 50; aMCI, 50; NC, 50). In the analytic and validation groups, real-time quantitative reverse-transcription polymerase chain reaction was used to identify differentially expressed lncRNAs between the aMCI and NC groups. Results: We identified 67 upregulated and 220 downregulated lncRNAs among the expression profiles. The panel with lncRNAs T324988, NR_024049, ENST00000567919, and ENST00000549762 displayed the highest discrimination ability between patients with aMCI and NCs. The area under the receiver operating characteristic curve of this combined model was 0.941, with a sensitivity of 92.00% and specificity of 84.00%. Conclusions: This study reports on a panel of four lncRNAs as promising biomarkers to diagnose aMCIs.

Post-traumatic amnesia: a scoping review & content analysis of behavioral disturbances.

OBJECTIVE: The aim of this scoping review was to identify behavioral disturbances exhibited by patients in post-traumatic amnesia (PTA). While behavioral disturbances are common in PTA, research into their presentation and standardized measures for their assessment are limited. DESIGN: The study protocol was registered with PROSPERO (CRD42021268275). A scoping review of databases was performed according to pre-determined criteria on 29 July 2021 and updated on 13 July 2022. A conventional content analysis was used to examine and categorize behavioral disturbances. RESULTS: Thirty papers met the inclusion criteria, of which 27 reported observations and/or scores obtained on behavioral scales, and 3 on clinician interviews and surveys. None focused exclusively on children. Agitation was the most frequently assessed behavior, and Agitated Behavior Scale was the most used instrument. Content analysis, however, bore eight broad behavioral categories: disinhibition, agitation, aggression, lability, lethargy/low mood, perceptual disturbances/psychotic symptoms, personality change and sleep disturbances. CONCLUSION: Our study revealed that while standardized assessments of behavior of patients in PTA are often limited to agitation, clinical descriptions include a range of behavioral disturbances. Our study highlights a significant gap in the systematic assessment of a wide range of behavioral disturbances observed in PTA.

Mild Cognitive Impairment Subtype Performance in Comparison to Healthy Older Controls on the NIH Toolbox and Cogstate.

BACKGROUND: Early detection is necessary for the treatment of dementia. Computerized testing has become more widely used in clinical trials; however, it is unclear how sensitive these measures are to early signs of neurodegeneration. We investigated the use of the NIH Toolbox-Cognition (NIHTB-CB) and Cogstate-Brief computerized neuropsychological batteries in the identification of mild cognitive impairment (MCI) versus healthy older adults [healthy control (HC)] and amnestic (aMCI) versus nonamnestic MCI (naMCI). Exploratory analyses include investigating potential racial differences. METHODS: Two hundred six older adults were diagnosed as aMCI (n = 58), naMCI (n = 15), or cognitively healthy (HC; n = 133). RESULTS: The NIH Toolbox-CB subtests of Flanker, Picture Sequence Memory, and Picture Vocabulary significantly differentiated MCI from HC. Further, subtests from both computerized batteries differentiated patients with aMCI from those with naMCI. Although the main effect of race differences was noted on tests and in diagnostic groups was significant, there were no significant race-by-test interactions. CONCLUSIONS: Computer-based subtests vary in their ability to help distinguish MCI subtypes, though these tests provide less expensive and easier-to-administer clinical screeners to help identify patients early who may qualify for more comprehensive evaluations. Further work is needed, however, to refine computerized tests to achieve better precision in distinguishing impairment subtypes.

Ruling out feigned crime-related amnesia? A response to Acklin (2022).

In a recent paper, Acklin discussed a case of possible amnesia for a murder in terms of neurobiology, psychoanalysis, and personality assessment. Acklin accepted the defendant's claim of amnesia for the crime as genuine. The considerable literature that takes a skeptical view of crime-related amnesia was not cited, and the possibility of feigning or malingering was "ruled out" with a single sentence that does not withstand scrutiny. A review of the literature on feigned amnesia suggests that it may not be possible to rule out malingering even if the best available tools are used: There has been minimal investigation of most validity tests and estimates of base rates of feigned amnesia for a crime vary widely and make estimates of Negative Predictor Power highly unreliable. Although one cannot know from the information presented if Acklin's defendant legitimately experienced amnesia, feigning could not be ruled out using an interview and the test data cited by Acklin. I call for a moratorium on publication of further articles on crime specific amnesia that do not conscientiously examine other potential explanations and do not use current best practices for assessing negative response bias.

Prolonged duration of post-traumatic amnesia: A sensitive classification for predicting cognitive outcomes in children recovering from traumatic brain injury.

OBJECTIVE: A paucity of data exists regarding the duration of post-traumatic amnesia (PTA) as a predictor of cognitive functioning among children after traumatic brain injury (TBI). The study aimed to assess the relationship between PTA duration and areas of neurocognitive function among the pediatric population in the sub-acute phase of recovery and rehabilitation. METHODS: Data were collected from medical files on 103 children aged 5.5-16.5 hospitalized at a pediatric rehabilitation department with a diagnosis of moderate-severe TBI (msTBI) between the years 2004-2019. The Children Orientation and Amnesia Test was used to evaluate PTA duration. Measures of high-order cognitive abilities of attention and executive function were collected using the Test of Everyday Attention-Child version (TEA-Ch). RESULTS: Three PTA duration groups were assembled out of a cluster analysis: "Long PTA" (M = 21 days), "Very Long PTA" (M = 47 days), and "Extremely Long PTA" (M = 94 days). Analyses revealed that the "Long PTA" group preformed significantly better than the "Very Long PTA" and "Extremely Long PTA" groups on all TEA-Ch measures, that is, Selective Attention, Attentional Control Switching, and Sustained Attention. CONCLUSIONS: This study is the first to demonstrate that PTA duration is a useful predictor of high-order cognitive functions among children with msTBI in the sub-acute phase of recovery and rehabilitation. The findings emphasize the importance of using a more sensitive classification of prolonged PTA durations to improve outcome prediction and allocation of resources to those who can benefit most after severe brain injuries.

Factor Structure of the Agitated Behavior Scale in Traumatic Brain Injury During Posttraumatic Amnesia.

OBJECTIVE: To investigate the factor structure of the Agitated Behavior Scale (ABS) in patients with traumatic brain injury (TBI) in posttraumatic amnesia (PTA). SETTING: Inpatient TBI rehabilitation ward in Victoria, Australia. PARTICIPANTS: A total of 364 patients aged 16 to 92 years meeting diagnostic criteria for TBI and PTA admitted between September 2013 and October 2020. DESIGN: Retrospective cohort study utilizing electronic medical record data. MAIN MEASURES: The ABS and the Westmead Post-Traumatic Amnesia Scale (WPTAS). RESULTS: Exploratory factor analysis uncovered 2 moderately correlated underlying factors (0.52), labeled Restlessness and Aggression/Lability. Two items failed to demonstrate sufficiently large loadings on either factor. Both factors demonstrated adequate reliability (Cronbach α = 0.87 and 0.81 for Restlessness and Aggression/Lability, respectively). Linear regression indicated that higher WPTAS scores were associated with lower levels of Restlessness (ß = -.14, P < .001), supporting construct validity. Conversely, WPTAS scores were not significantly associated with Aggression/Lability (ß = -.12, P = .08). Subgroup analysis indicated that a history of mood disorder was associated with greater severity of Aggression/Lability (P = .02). Confirmatory factor analysis indicated superior fit of the identified 2-factor solution when compared with previously explored 1-, 2-, 3-, and 4-factor structures. CONCLUSION: This study suggests that the latent structure of the ABS is best explained by a single construct of agitation with 2 discrete facets reflecting Restlessness and Aggression/Lability. These subscales may be used in clinical practice to evaluate the severity of different aspects of agitated behavior, inform treatment decisions, and judge the efficacy of interventions over time. Further research is required to explain low factor loadings demonstrated by 2 items.

The Dissociation-Related Beliefs About Memory Questionnaire (DBMQ): Development and psychometric properties.

OBJECTIVE: Discontinuities in memory are the hallmark symptoms of most dissociative disorders but are also reported by patients diagnosed with related disorders, including PTSD. Memory discontinuity is most evident in dissociative identity disorder (DID), where patients may report amnesia in 1 identity for information available in other identities (i.e., interidentity amnesia). Studies indicate that even though patients subjectively report interidentity amnesia for material learned in, or pertaining to, another identity, objective findings show evidence of transfer of that material between identities. Subjective reports of dissociative amnesia may be explained by specific dissociation-related metamemory beliefs, which hinder voluntary retrieval, personal acknowledgment, and processing of memories. This study aimed to develop a questionnaire indexing metamemory beliefs related to trait dissociation. METHOD: Two studies in nonclinical populations provided information about the factor structure (Studies 1 and 2) of the newly developed Dissociation-related Beliefs about Memory Questionnaire (DBMQ). Information was also provided about the construct validity (Studies 2 and 3), and reliability of the scale (all 3 studies) in nonclinical as well as a clinical population. RESULTS: Results indicated sound psychometric properties of a short 16-item DBMQ with subscales assessing Fragmentation, Positive beliefs about amnesia, Lack of self-reference, and Fear of losing control, and correlations specifically with trait dissociation and posttraumatic avoidance symptoms. A sample of DID patients (N = 19) showed increased scores on the DBMQ. CONCLUSION: The DBMQ provides a short, reliable, and valid tool for indexing dissociation-related metamemory beliefs. These beliefs were associated with trait dissociation and posttraumatic avoidance symptoms. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Predictive validity of the Westmead Post-Traumatic Amnesia Scale for functional outcomes in school-aged children who sustained traumatic brain injury.

The Westmead Post-Traumatic Amnesia Scale (WPTAS) is routinely used for the assessment of post-traumatic amnesia (PTA) in children who sustained traumatic brain injury (TBI). Yet, the WPTAS' predictive validity for functional outcomes is largely unknown. We aimed to determine whether PTA duration measured by the WPTAS (i) differentially predicts functional outcomes and (ii) contributes to predictions of outcomes beyond the Glasgow Coma Scale (GCS) in children who sustained TBI. Participants were children and adolescents with moderate-to-severe TBI (n = 55) aged 8-15 years. PTA duration was assessed with the WPTAS. Outcomes at the first outpatient follow-up were scored on the Kings Outcome Scale for Childhood Head Injury (KOSCHI) and the TBI Outcome Domain Scale-Extended (ODS-E). Longer PTA and lower GCS were both significantly correlated with worse (i) global outcomes: presence of disability on the KOSCHI and lower score on the ODS-E and (ii) select specific outcomes on the ODS-E: mobility, mood and cognition. PTA duration predicted cognitive outcome on the ODS-E independently, beyond GCS. Together, PTA duration and GCS, predicted the global KOSCHI outcome, as well as the ODS-E mobility and mood outcomes. Neither GCS nor PTA duration correlated with the ODS-E communication, impulsivity/disinhibition, headache, fatigue, sensory impairments or somatic complaints outcomes. PTA duration measured by the WPTAS is a significant unique predictor of functional cognitive outcomes in children who sustained moderate-to-severe TBI, and in combination with the GCS, a significant predictor of global, and several specific functional outcomes.

A comparison of agreement between actigraphy and polysomnography for assessing sleep during posttraumatic amnesia.

STUDY OBJECTIVES: Sleep disturbance often emerges in the early recovery phase following a moderate to severe traumatic brain injury, known as posttraumatic amnesia. Actigraphy is commonly employed to assess sleep, as it is assumed that patients in posttraumatic amnesia (who display confusion, restlessness, and agitation) would better tolerate this measure over gold-standard polysomnography (PSG). This study evaluated the agreement between PSG and actigraphy for determining (sleep/wake time, sleep efficiency, sleep latency, and awakenings) in patients experiencing posttraumatic amnesia. It also compared the epoch-by-epoch sensitivity, specificity, and accuracy between the Actigraph device's 4 wake threshold settings (low, medium, high, and automatic) to PSG. METHODS: The sample consisted of 24 inpatients recruited from a traumatic brain injury inpatient rehabilitation unit. Ambulatory PSG was recorded overnight at bedside and a Philips Actiwatch was secured to each patient's wrist for the same period. RESULTS: There were poor correlations between PSG and actigraphy for all parameters (Lin's concordance correlation coefficient = < 0.80). The low threshold displayed the highest correlation with PSG for wake and sleep time, albeit still low. Actigraphy displayed low specificity (ranging from 17.1% to 36.6%). There appears to be a greater disparity between actigraphy and PSG for patients with increased wake time. CONCLUSIONS: Actigraphy, while convenient, demonstrated poorer performance in determining sleep-wake parameters in patients with significantly disturbed sleep. Ambulatory PSG can provide a clearer understanding of the extent of sleep disturbances in these patients with reduced mobility during early rehabilitation. Study findings can help design future protocols of sleep assessment during posttraumatic amnesia and optimize treatment. CITATION: Fedele B, McKenzie D, Williams G, Giles R, Olver J. A comparison of agreement between actigraphy and polysomnography for assessing sleep during posttraumatic amnesia. J Clin Sleep Med. 2022;18(11):2605-2616.

Improving Amnesia Diagnostic Accuracy with RAVLT Single Scores and Composite Indices: Italian Normative Data.

OBJECTIVE: The Rey Auditory Verbal Learning Test (RAVLT) is a widely used verbal memory measure that provides scores for different aspects of memory. It involves repeated auditory presentation and recall of a 15-item word list (List A) followed by presentation and recall of a distractor list (List B) and then un-cued immediate and delayed recalls (at 15 min and 1 week) of List A as well as recognition testing. Aims of this study are to provide Italian normative data for certain RAVLT Scores and Composite Indices to improve the diagnostic accuracy of the test in clinical settings and to provide further evidence on how RAVLT can differentiate different amnesia profiles due to focal lesions. METHODS: We enrolled 440 healthy participants and RAVLT Single Scores and Composite Indices have been analyzed by means of multiple regression to verify the influence of age, education, and gender. RESULTS: We computed the best linear models with RAVLT Single Scores and Composite Indices, as dependent variables, and the most suitable transformation of independent variables. By reversing the signs of the regression coefficients, the adjustment factors for each level of age and, if needed, education and gender have been computed and the adjusted scores have been standardized into Equivalent Scores. CONCLUSION: Using these standardized measures, we differentiate three profiles of amnesia due to selective hippocampal sclerosis with severe encoding deficit, fornix lesions with source memory problems, and temporal lobe epilepsy with consolidation failure.