An examination of the clinical utility of phonemic fluency in healthy adults and adults with mild cognitive impairment.

The Controlled Oral Word Association Test (COWAT) is a widely utilized measure of phonemic fluency. However, two issues remain: (1) whether demographic, cognitive variables, or version of test administered predict performance; (2) if the test is predictive of Mild Cognitive Impairment (MCI). Recent studies report that item-level analyses such as lexical frequency may be more sensitive to early cognitive change. The purpose of this study was to examine the clinical utility of the COWAT, considering both total correct words and the lexical frequency. Sixty-seven healthy adults and thirty-seven adults with MCI completed neuropsychological testing. Mann-Whitney U tests were used to determine if there was a difference in COWAT performance between groups. Elastic net regression models were used to assess whether variance in total scores/lexical frequencies can be predicted by demographics, test version, or diagnosis; which cognitive tests explained the variance in performance; and how total scores and lexical frequencies compared with other cognitive tests in predicting diagnosis. Overall, individuals with MCI produced fewer and higher frequency words. The variance in total correct words or lexical frequency was not explained by demographics, test version, or diagnosis. Total correct words was a more important predictor of diagnosis than lexical frequency.

Influence of endogenous estrogen on a network model of female brain integrity.

Recent reports document sex differences in midlife brain integrity and metabolic health, such that more relationships are detectable between metabolic syndrome (MetS) components and markers of brain health in females than in males. Midlife is characterized by a rapid decrease in endogenous estrogen levels for women which is thought to increase risk for cardiometabolic disease and neurocognitive decline. Our study used network models, designed to explore the interconnectedness and organization of relationships among many variables at once, to compare the influence of endogenous estrogen and chronological age on a network of brain and metabolic health in order to investigate the utility of estrogen as a biomarker for brain vulnerability. Data were analyzed from 82 females (ages 40-62). Networks consisted of known biomarkers of risk for late-life cognitive decline: the five components of MetS; Brain-predicted age difference calculated on gray and white matter volume; white matter hyperintensities; Default Mode Network functional connectivity; cerebral concentrations of N-acetyl aspartate, glutamate and myo-inositol; and serum concentrations of estradiol. A second network replaced estradiol with chronological age. Expected influence (EI) of estradiol on the network was -1.190, relative to chronological age at -0.524, indicating that estradiol had a stronger expected influence over the network than age. A negative expected influence indicates that higher levels of estradiol would be expected to decrease the number of relationships in the model, which is thought to indicate lower risk. Overall, levels of estradiol appear more influential than chronological age at midlife for relationships between brain integrity and metabolic health.

Network Modeling Sex Differences in Brain Integrity and Metabolic Health.

Hypothesis-driven studies have demonstrated that sex moderates many of the relationships between brain health and cardiometabolic disease, which impacts risk for later-life cognitive decline. In the present study, we sought to further our understanding of the associations between multiple markers of brain integrity and cardiovascular risk in a midlife sample of 266 individuals by using network analysis, a technique specifically designed to examine complex associations among multiple systems at once. Separate network models were constructed for male and female participants to investigate sex differences in the biomarkers of interest, selected based on evidence linking them with risk for late-life cognitive decline: all components of metabolic syndrome (obesity, hypertension, dyslipidemia, and hyperglycemia); neuroimaging-derived brain-predicted age minus chronological age; ratio of white matter hyperintensities to whole brain volume; seed-based resting state functional connectivity in the Default Mode Network, and ratios of N-acetyl aspartate, glutamate and myo-inositol to creatine, measured through proton magnetic resonance spectroscopy. Males had a sparse network (87.2% edges = 0) relative to females (69.2% edges = 0), indicating fewer relationships between measures of cardiometabolic risk and brain integrity. The edges in the female network provide meaningful information about potential mechanisms between brain integrity and cardiometabolic health. Additionally, Apolipoprotein ϵ4 (ApoE ϵ4) status and waist circumference emerged as central nodes in the female model. Our study demonstrates that network analysis is a promising technique for examining relationships between risk factors for cognitive decline in a midlife population and that investigating sex differences may help optimize risk prediction and tailor individualized treatments in the future.

Predicting language treatment response in bilingual aphasia using neural network-based patient models.

Predicting language therapy outcomes in bilinguals with aphasia (BWA) remains challenging due to the multiple pre- and poststroke factors that determine the deficits and recovery of their two languages. Computational models that simulate language impairment and treatment outcomes in BWA can help predict therapy response and identify the optimal language for treatment. Here we used the BiLex computational model to simulate the behavioral profile of language deficits and treatment response of a retrospective sample of 13 Spanish-English BWA who received therapy in one of their languages. Specifically, we simulated their prestroke naming ability and poststroke naming impairment in each language, and their treatment response in the treated and the untreated language. BiLex predicted treatment effects accurately and robustly in the treated language and captured different degrees of cross-language generalization in the untreated language in BWA. Our cross-validation approach further demonstrated that BiLex generalizes to predict treatment response for patients whose data were not used in model training. These findings support the potential of BiLex to predict therapy outcomes for BWA and suggest that computational modeling may be helpful to guide individually tailored rehabilitation plans for this population.

Metabolic syndrome components moderate the association between executive function and functional connectivity in the default mode network.

Middle aged individuals with Metabolic Syndrome are at high risk for cognitive decline. Dyssynchrony in the resting state Default Mode Network is one early indicator of brain vulnerability. We set out to explore the relationship between default mode resting state functional connectivity and cognitive performance in both memory and executive domains at midlife in the presence of Metabolic Syndrome components. Seed-based Correlation Analyses were performed between the seed voxel in the posterior cingulate cortex and the medial prefrontal cortex on 200 participants (ages 40-61). Executive domain scores were significantly predicted by the interaction between number of Metabolic Syndrome components and resting state connectivity in the Default Mode Network (p = .004) such that connectivity was negatively related to executive function at higher numbers of Metabolic Syndrome components. Results were not significant for memory. Our findings indicate that clusters of cardiovascular disease risk factors alter functional relationships in the brain and highlights the need to continue exploring how compensatory techniques might operate to support cognitive performance at midlife.

Predicting treatment outcomes for bilinguals with aphasia using computational modeling: Study protocol for the PROCoM randomised controlled trial.

INTRODUCTION: Bilinguals with aphasia (BWA) present varying degrees of lexical access impairment and recovery across their two languages. Because both languages may benefit from therapy, identifying the optimal target language for treatment is a current challenge for research and clinical practice. Prior research has demonstrated that the BiLex computational model can accurately simulate lexical access in healthy bilinguals, and language impairment and treatment response in bilingual aphasia. Here, we aim to determine whether BiLex can predict treatment outcomes in BWA in the treated and the untreated language and compare these outcome predictions to determine the optimal language for rehabilitation. METHODS AND ANALYSIS: The study involves a prospective parallel-group, double-blind, randomised controlled trial. Forty-eight Spanish-English BWA will receive 20 sessions of semantic treatment for lexical retrieval deficits in one of their languages and will complete assessments in both languages prior and after treatment. Participants will be randomly assigned to an experimental group receiving treatment in the optimal language determined by the model or a control group receiving treatment in the language opposite to the model's recommendation. Primary treatment outcomes include naming probes while secondary treatment outcomes include tests tapping additional language domains. Treatment outcomes will be compared across the two groups using 2×2 mixed effect models for repeated measures Analysis of variance (ANOVA) on metrics of treatment effects commonly employed in rehabilitation studies (ie, effect size and percentage change). ETHICS AND DISSEMINATION: All procedures included in this protocol (protocol number 29, issue date: 19 March 2019) were approved by the Boston University Charles River Campus Institutional Review Board at Boston, Massachusetts (reference number: 4492E). The results of this study will be published in peer-reviewed scientific journals and will be presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02916524.

Cognition, Brain Structure, and Brain Function in Individuals with Obesity and Related Disorders.

PURPOSE OF REVIEW: Obesity is one of the most serious public health concerns. Excess adipose tissue, particularly with a centralized distribution, is associated with cognitive decline. Indeed, obesity has been associated with a number of adverse changes in brain function and structure that can be detected by neuroimaging techniques. These obesity-associated changes in the brain are associated with cognitive dysfunction. RECENT FINDINGS: While the pathways by which excess adipose tissue affects brain function are not fully understood, available evidence points towards insulin resistance, inflammation, and vascular dysfunction, as possible mechanisms responsible for the observed relations between obesity and cognitive impairment. It appears that weight loss is related to better brain and cognitive outcomes and that cognitive impairment due to obesity may be reversible.

Videoconference Administration of the Western Aphasia Battery-Revised: Feasibility and Validity.

Purpose There is a rapid growth of telepractice in both clinical and research settings; however, the literature validating translation of traditional methods of assessments and interventions to valid remote videoconference administrations is limited. This is especially true in the field of speech-language pathology where assessments of language and communication can be easily conducted via remote administration. The aim of this study was to validate videoconference administration of the Western Aphasia Battery-Revised (WAB-R). Method Twenty adults with chronic aphasia completed the assessment both in person and via videoconference with the order counterbalanced across administrations. Specific modifications to select WAB-R subtests were made to accommodate interaction by computer and Internet. Results Results revealed that the two methods of administration were highly correlated and showed no difference in domain scores. Additionally, most participants endorsed being mostly or very satisfied with the videoconference administration. Conclusion These findings suggest that administration of the WAB-R in person and via videoconference may be used interchangeably in this patient population. Modifications and guidelines are provided to ensure reproducibility and access to other clinicians and scientists interested in remote administration of the WAB-R. Supplemental Material https://doi.org/10.23641/asha.11977857.

Is bilingualism protective for adults with aphasia?

The bilingual advantage proposes that bilingual individuals have enhanced cognitive control compared to their monolingual counterparts. Bilingualism has also been shown to contribute to cognitive reserve by offsetting the behavioral presentation of brain injury or neural degeneration. However, this effect has not been closely examined in individuals with post-stroke or post-TBI aphasia. Because bilingualism has been suggested as a factor of cognitive reserve, it may provide protective mechanisms for adults with aphasia. In the current study, evidence for the bilingual advantage was examined in 13 Spanish-English bilingual healthy adults (BHA) compared to 13 English monolingual healthy adults (MHA). Additionally, evidence for cognitive reserve as defined by a bilingual advantage was examined in 18 Spanish-English bilingual adults with aphasia (BAA) compared to 18 English monolingual adults with aphasia (MAA) who were otherwise matched on their age, education, language impairment, and non-verbal executive functions. All participants completed a non-linguistic cognitive control task that included congruent and incongruent conditions. Results indicated no bilingual cognitive control advantage on reaction times in healthy adult groups; however, BAA were faster than MAA, suggesting that bilingualism may contribute to cognitive reserve in adults with aphasia. Thus, manipulating multiple languages throughout the lifetime may be protective after an acquired brain injury.

BiLex: A computational approach to the effects of age of acquisition and language exposure on bilingual lexical access.

Lexical access in bilinguals can be modulated by multiple factors in their individual language learning history. We developed the BiLex computational model to examine the effects of L2 age of acquisition, language use and exposure on lexical retrieval in bilingual speakers. Twenty-eight Spanish-English bilinguals and five monolinguals recruited to test and validate the model were evaluated in their picture naming skills in each language and filled out a language use questionnaire. We examined whether BiLex can (i) simulate their naming performance in each language while taking into account their L2 age of acquisition, use and exposure to each language, and (ii) predict naming performance in other participants not used in model training. Our findings showed that BiLex could accurately simulate naming performance in bilinguals, suggesting that differences in L2 age of acquisition, language use and exposure can account for individual differences in bilingual lexical access.

Measuring instrumental activities of daily living in non-demented elderly: a comparison of the new performance-based Harvard Automated Phone Task with other functional assessments.

BACKGROUND: Impairment in instrumental activities of daily living (IADL) may occur in the earliest stages of mild cognitive impairment (MCI). However, there are few reliable measures of IADL in MCI or that have a sufficient range of scores in clinically normal (CN) elderly. The objective of this pilot study was to examine the convergent validity of a phone performance-based IADL instrument, the Harvard Automated Phone Task (APT), designed to measure the earliest IADL changes in Alzheimer's disease (AD), with other sensitive performance-based and subjective measures of everyday functional capacity among CN and MCI participants. METHODS: Twenty-nine CN and 17 MCI participants were administered the Harvard APT, the computer performance-based Czaja Functional Assessment Battery (CFAB), and the AD Cooperative Study ADL prevention instrument (ADCS ADL-PI) participant and study partner versions; in addition, 52 different CN and 7 MCI participants were administered the Harvard APT and the Subjective Study Partner and Participant-reported (SSPP) IADL scale. The Harvard APT was compared with the three other IADL assessments. RESULTS: In both CN and MCI, better performance on the Harvard APT was associated with better performance on the CFAB. In CN, better performance on the Harvard APT was associated with better ADCS ADL-PI participant-reported IADL, while in MCI better performance on the Harvard APT was associated with better ADCS ADL-PI study partner-reported IADL. Furthermore, in CN better performance on the Harvard APT was associated with better SSPP-IADL participant and study partner-reported IADL. CONCLUSIONS: In this small pilot study, the Harvard APT, a brief, self-administered, objective measure of IADL performance, appears to correlate well with other sensitive measures of everyday functioning, providing good preliminary convergent validity for this new measure. Moreover, it appears to perform well across both CN and MCI participants, which suggests that it is a promising measure of early, clinically meaningful functional change. This may not be the case as suggested in our small sample for subjective IADL scales that may perform differentially depending on the reporter (self vs. study partner) across the clinical spectrum possibly due to diminishing awareness of IADL difficulties in individuals who become cognitively impaired. Secondary prevention trials in AD have a great need for such ecologically valid and reliable measures of early IADL changes.

Activities of daily living measured by the Harvard Automated Phone Task track with cognitive decline over time in non-demented elderly.

BACKGROUND: Impairment in activities of daily living is a major burden to both patients and caregivers. Mild impairment in instrumental activities of daily living is often seen at the stage of mild cognitive impairment. The field of Alzheimer's disease is moving toward earlier diagnosis and intervention and more sensitive and ecologically valid assessments of instrumental or complex activities of daily living are needed. The Harvard Automated Phone Task, a novel performance-based activities of daily living instrument, has the potential to fill this gap. OBJECTIVE: To further validate the Harvard Automated Phone Task by assessing its longitudinal relationship to global cognition and specific cognitive domains in clinically normal elderly and individuals with mild cognitive impairment. DESIGN: In a longitudinal study, the Harvard Automated Phone Task was associated with cognitive measures using mixed effects models. The Harvard Automated Phone Task's ability to discriminate across diagnostic groups at baseline was also assessed. SETTING: Academic clinical research center. PARTICIPANTS: Two hundred and seven participants (45 young normal, 141 clinically normal elderly, and 21 mild cognitive impairment) were recruited from the community and the memory disorders clinics at Brigham and Women's Hospital and Massachusetts General Hospital. MEASUREMENTS: Participants performed the three tasks of the Harvard Automated Phone Task, which consist of navigating an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, repetitions, and correct completion of the task. The primary outcome measure used for each of the tasks was total time adjusted for correct completion. RESULTS: The Harvard Automated Phone Task discriminated well between young normal, clinically normal elderly, and mild cognitive impairment participants (APT-Script: p<0.001; APT-PCP: p<0.001; APT-Bank: p=0.04). Worse baseline Harvard Automated Phone Task performance or worsening Harvard Automated Phone Task performance over time tracked with overall worse performance or worsening performance over time in global cognition, processing speed, executive function, and episodic memory. CONCLUSIONS: Prior cross-sectional and current longitudinal analyses have demonstrated the utility of the Harvard Automated Phone Task, a new performance-based activities of daily living instrument, in the assessment of early changes in complex activities of daily living in non-demented elderly at risk for Alzheimer's disease. Future studies will focus on cross-validation with other sensitive activities of daily living tests and Alzheimer's disease biomarkers.

Neuroimaging markers associated with maintenance of optimal memory performance in late-life.

BACKGROUND: Age-related memory decline has been well-documented; however, some individuals reach their 8th-10th decade while maintaining strong memory performance. OBJECTIVE: To determine which demographic and biomarker factors differentiated top memory performers (aged 75+, top 20% for memory) from their peers and whether top memory performance was maintained over 3 years. METHODS: Clinically normal adults (n=125, CDR=0; age: 79.5±3.57 years) from the Harvard Aging Brain Study underwent cognitive testing and neuroimaging (amyloid PET, MRI) at baseline and 3-year follow-up. Participants were grouped into Optimal (n=25) vs. Typical (n=100) performers using performance on 3 challenging memory measures. Non-parametric tests were used to compare groups. RESULTS: There were no differences in age, sex, or education between Optimal vs. Typical performers. The Optimal group performed better in Processing Speed (p=0.016) and Executive Functioning (p<0.001). Optimal performers had larger hippocampal volumes at baseline compared with Typical Performers (p=0.027) but no differences in amyloid burden (p=0.442). Twenty-three of the 25 Optimal performers had longitudinal data and16 maintained top memory performance while 7 declined. Non-Maintainers additionally declined in Executive Functioning but not Processing Speed. Longitudinally, there were no hippocampal volume differences between Maintainers and Non-Maintainers, however Non-Maintainers exhibited higher amyloid burden at baseline in contrast with Maintainers (p=0.008). CONCLUSIONS: Excellent memory performance in late life does not guarantee protection against cognitive decline. Those who maintain an optimal memory into the 8th and 9th decades may have lower levels of AD pathology.

The Feasibility of At-Home iPad Cognitive Testing For Use in Clinical Trials.

BACKGROUND: Technological advances now make it feasible to administer cognitive assessments at-home on mobile and touch-screen devices such as an iPad or tablet computer. Validation of these techniques is necessary to assess their utility in clinical trials. OBJECTIVES: We used a Computerized Cognitive Composite for Preclinical Alzheimer's Disease (C3-PAD) developed for iPad 1) to determine the feasibility of performing the C3-PAD at home by older individuals without the presence of a trained psychometrician; 2) to explore the reliability of in-clinic compared to at-home C3-PAD performance and 3) to examine the comparability of C3-PAD performance to standardized neuropsychological tests. DESIGN SETTING PARTICIPANTS: Forty-nine cognitively normal older individuals (mean age, 71.467.7 years; 20% non-Caucasian) were recruited from research centers at the Massachusetts General Hospital and Brigham and Women's Hospital. Participants made two in-clinic visits one-week apart and took five 30-minute alternate versions of the C3-PAD at-home measuring episodic memory, reaction time and working memory. MEASUREMENTS: A reliability analysis explored equivalence of the six alternate C3-PAD test versions. A feasibility assessment calculated the percentage of individuals who completed all at-home tests correctly, in contrast to incomplete assessments. Correlational analyses examined the association between C3-PAD-clinic compared to C3-PAD-home assessments and between C3-PAD performance and standardized paper and pencil tests. RESULTS: Excellent reliability was observed among the 6 C3-PAD alternate versions (Cronbach alpha coefficient=0.93). A total of 28 of 49 participants completed all at-home sessions correctly and 48 of 49 completed four out of five correctly. There were no significant differences in participant age, sex or education between complete and incomplete at-home assessments. A single in-clinic C3-PAD assessment and the at-home C3-PAD assessments were highly associated with each other (r2=0.508, p<0.0001), suggesting that at-home tests provide reliable data as in-clinic assessments. There was also a moderate association between the at-home C3-PAD assessments and the in-clinic standardized paper and pencil tests covering similar cognitive domains (r2= 0.168, p< 0.003). CONCLUSIONS: Reliable and valid cognitive data can be obtained from the C3-PAD assessments in the home environment. With initial in-clinic training, a high percentage of older individuals completed at-home assessments correctly. At-home cognitive testing shows promise for inclusion into clinical trial designs.

The Harvard Automated Phone Task: new performance-based activities of daily living tests for early Alzheimer's disease.

BACKGROUND: Impairment in activities of daily living is a major burden for Alzheimer's disease dementia patients and caregivers. Multiple subjective scales and a few performance-based instruments have been validated and proven to be reliable in measuring instrumental activities of daily living in Alzheimer's disease dementia but less so in amnestic mild cognitive impairment and preclinical Alzheimer's disease. OBJECTIVE: To validate the Harvard Automated Phone Task, a new performance-based activities of daily living test for early Alzheimer's disease, which assesses high level tasks that challenge seniors in daily life. DESIGN: In a cross-sectional study, the Harvard Automated Phone Task was associated with demographics and cognitive measures through univariate and multivariate analyses; ability to discriminate across diagnostic groups was assessed; test-retest reliability with the same and alternate versions was assessed in a subset of participants; and the relationship with regional cortical thickness was assessed in a subset of participants. SETTING: Academic clinical research center. PARTICIPANTS: One hundred and eighty two participants were recruited from the community (127 clinically normal elderly and 45 young normal participants) and memory disorders clinics at Brigham and Women's Hospital and Massachusetts General Hospital (10 participants with mild cognitive impairment). MEASUREMENTS: As part of the Harvard Automated Phone Task, participants navigated an interactive voice response system to refill a prescription (APT-Script), select a new primary care physician (APT-PCP), and make a bank account transfer and payment (APT-Bank). The 3 tasks were scored based on time, errors, and repetitions from which composite z-scores were derived, as well as a separate report of correct completion of the task. RESULTS: We found that the Harvard Automated Phone Task discriminated well between diagnostic groups (APT-Script: p=0.002; APT-PCP: p<0.001; APT-Bank: p=0.02), had an incremental level of difficulty, and had excellent test-retest reliability (Cronbach's α values of 0.81 to 0.87). Within the clinically normal elderly, there were significant associations in multivariate models between performance on the Harvard Automated Phone Task and executive function (APT-PCP: p<0.001), processing speed (APT-Script: p=0.005), and regional cortical atrophy (APT-PCP: p=0.001; no significant association with APT-Script) independent of hearing acuity, motor speed, age, race, education, and premorbid intelligence. CONCLUSIONS: Our initial experience with the Harvard Automated Phone Task, which consists of ecologically valid, easily-administered measures of daily activities, suggests that these tasks could be useful for screening and tracking the earliest functional alterations in preclinical and early prodromal AD.

Cognitive activity relates to cognitive performance but not to Alzheimer disease biomarkers.

OBJECTIVE: We aimed to determine whether there was a relationship between lifestyle factors and Alzheimer disease biomarkers. METHODS: In a cross-sectional study, we evaluated self-reported histories of recent and past cognitive activity, self-reported history of recent physical activity, and objective recent walking activity in 186 clinically normal individuals with mean age of 74 ± 6 years. Using backward elimination general linear models, we tested the hypotheses that greater cognitive or physical activity would be associated with lower Pittsburgh compound B-PET retention, greater (18)F-fluorodeoxyglucose-PET metabolism, and larger hippocampal volume, as well as better cognitive performance on neuropsychological testing. RESULTS: Linear regression demonstrated that history of greater cognitive activity was correlated with greater estimated IQ and education, as well as better neuropsychological testing performance. Self-reported recent physical activity was related to objective exercise monitoring. However, contrary to hypotheses, we did not find evidence of an association of Pittsburgh compound B retention, (18)F-fluorodeoxyglucose uptake, or hippocampal volume with past or current levels of cognitive activity, or with current physical activity. CONCLUSIONS: We conclude that a history of lifelong cognitive activity may support better cognitive performance by a mechanism that is independent of brain ß-amyloid burden, brain glucose metabolism, or hippocampal volume.

Development of a psychometrically equivalent short form of the Face-Name Associative Memory Exam for use along the early Alzheimer's disease trajectory.

Neuropsychologists are developing more challenging and specific tests to detect early and subtle changes in cognition related to preclinical Alzheimer's disease (AD). The 16-item Face-Name Associative Memory Exam (FNAME-16) is a challenging paired associative memory test able to detect subtle memory changes associated with biomarker evidence of preclinical AD. However, as individuals progress along the AD trajectory, measures that are sensitive at the preclinical stage may become too challenging by the stage of Mild Cognitive Impairment (MCI). Our goal was to develop a modified version of the face-name and face-occupation paired associative memory task (FNAME-12) with fewer stimuli and additional learning trials suitable for use in MCI. We administered the FNAME-12A, an alternate version FNAME 12B, the original FNAME-16, and a series of other neuropsychological measures to 65 clinically normal (CN) older adults (aged 65 to 85) and a subsample characterized by MCI (n = 18). The FNAME-12 exhibited psychometric equivalence with the FNAME-16 (r = .77, p < .001) and was correlated with other measures of episodic and semantic memory. The alternate form, FNAME-12B, was highly correlated with FNAME-12A (r = .76, p < .001). Mean performance on the FNAME 12A, stratified by education, was generated. The task could be completed by our MCI group yet remained challenging in the CN group, providing evidence for its utility along the AD trajectory.