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There are minimal data directly comparing plasma neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in aging and neurodegenerative disease research. We evaluated associations of plasma NfL and plasma GFAP with brain volume and cognition in two independent cohorts of older adults diagnosed as clinically normal (CN), mild cognitive impairment (MCI), or Alzheimer’s dementia.
We studied 121 total participants (Cohort 1: n = 50, age 71.6 ± 6.9 years, 78% CN, 22% MCI; Cohort 2: n = 71, age 72.2 ± 9.2 years, 45% CN, 25% MCI, 30% dementia). Gray and white matter volumes were obtained for total brain and broad subregions of interest (ROIs). Neuropsychological testing evaluated memory, executive functioning, language, and visuospatial abilities. Plasma samples were analyzed in duplicate for NfL and GFAP using single molecule array assays (Quanterix Simoa). Linear regression models with structural MRI and cognitive outcomes included plasma NfL and GFAP simultaneously along with relevant covariates.
Higher plasma GFAP was associated with lower white matter volume in both cohorts for temporal (Cohort 1: β = −0.33, p = .002; Cohort 2: β = −0.36, p = .03) and parietal ROIs (Cohort 1: β = −0.31, p = .01; Cohort 2: β = −0.35, p = .04). No consistent findings emerged for gray matter volumes. Higher plasma GFAP was associated with lower executive function scores (Cohort 1: β = −0.38, p = .01; Cohort 2: β = −0.36, p = .007). Plasma NfL was not associated with gray or white matter volumes, or cognition after adjusting for plasma GFAP.
Plasma GFAP may be more sensitive to white matter and cognitive changes than plasma NfL. Biomarkers reflecting astroglial pathophysiology may capture complex dynamics of aging and neurodegenerative disease.
Objective: We evaluated whether memory recall following an extended (1 week) delay predicts cognitive and brain structural trajectories in older adults
Clinically normal older adults (52–92 years old) were followed longitudinally for up to 8 years after completing a memory paradigm at baseline [Story Recall Test (SRT)] that assessed delayed recall at 30 min and 1 week. Subsets of the cohort underwent neuroimaging (N = 134, mean age = 75) and neuropsychological testing (N = 178–207, mean ages = 74–76) at annual study visits occurring approximately 15–18 months apart. Mixed-effects regression models evaluated if baseline SRT performance predicted longitudinal changes in gray matter volumes and cognitive composite scores, controlling for demographics.
Worse SRT 1-week recall was associated with more precipitous rates of longitudinal decline in medial temporal lobe volumes (p = .037), episodic memory (p = .003), and executive functioning (p = .011), but not occipital lobe or total gray matter volumes (demonstrating neuroanatomical specificity; p > .58). By contrast, SRT 30-min recall was only associated with longitudinal decline in executive functioning (p = .044).
Memory paradigms that capture longer-term recall may be particularly sensitive to age-related medial temporal lobe changes and neurodegenerative disease trajectories. (JINS, 2020, xx, xx-xx)
Objective: White matter (WM) microstructural changes are
increasingly recognized as a mechanism of age-related cognitive differences.
This study examined the associations between patterns of WM microstructure and
cognitive performance on the University of California, San Francisco (UCSF)
Brain Health Assessment (BHA) subtests of memory (Favorites), executive
functions and speed (Match), and visuospatial skills (Line Orientation) within a
sample of older adults. Method: Fractional anisotropy (FA) in WM
tracts and BHA performance were examined in 84 older adults diagnosed as
neurologically healthy (47), with mild cognitive impairment (19), or with
dementia (18). The relationships between FA and subtest performances were
evaluated using regression analyses. We then explored whether regional WM
predicted performance after accounting for variance explained by global FA.
Results: Memory performance was associated with FA of the
fornix and the superior cerebellar peduncle; and executive functions and speed,
with the body of the corpus callosum. The fornix–memory association and
the corpus callosum–executive association remained significant after
accounting for global FA. Neither tract-based nor global FA was associated with
visuospatial performance. Conclusions: Memory and executive
functions are associated with different patterns of WM diffusivity. Findings add
insight into WM alterations underlying age- and disease-related cognitive
Neuropsychological assessment tools are the staple of our field. The development of standardized metrics sensitive to brain-behavior relationships has shaped the neuropsychological questions we can ask, our understanding of discrete brain functions, and has informed the detection and treatment of neurological disorders. We identify key turning points and innovations in neuropsychological assessment over the past 40–50 years that highlight how the tools used in common practice today came to be. Also selected for emphasis are several exciting lines of research and novel approaches that are underway to further probe and characterize brain functions to enhance diagnostic and treatment outcomes. We provide a brief historical review of different clinical neuropsychological assessment approaches (Lurian, Flexible and Fixed Batteries, Boston Process Approach) and critical developments that have influenced their interpretation (normative standards, cultural considerations, longitudinal change, common metric batteries, and translational assessment constructs). Lastly, we discuss growing trends in assessment including technological advances, efforts to integrate neuropsychology across disciplines (e.g., primary care), and changes in neuropsychological assessment infrastructure. Neuropsychological assessment has undergone massive growth in the past several decades. Nonetheless, there remain many unanswered questions and future challenges to better support measurement tools and translate assessment findings into meaningful recommendations and treatments. As technology and our understanding of brain function advance, efforts to support infrastructure for both traditional and novel assessment approaches and integration of complementary brain assessment tools from other disciplines will be integral to inform brain health treatments and promote the growth of our field. (JINS, 2017, 23, 778–790)
Hispanics are the fastest growing ethnicity in the United States, yet there are limited well-validated neuropsychological tools in Spanish, and an even greater paucity of normative standards representing this population. The Spanish NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neurocognitive screener; however, the original norms were developed combining Spanish- and English-versions of the battery. We developed normative standards for the Spanish NIHTB-CB, fully adjusting for demographic variables and based entirely on a Spanish-speaking sample. A total of 408 Spanish-speaking neurologically healthy adults (ages 18–85 years) and 496 children (ages 3–7 years) completed the NIH Toolbox norming project. We developed three types of scores: uncorrected based on the entire Spanish-speaking cohort, age-corrected, and fully demographically corrected (age, education, sex) scores for each of the seven NIHTB-CB tests and three composites (Fluid, Crystallized, Total Composites). Corrected scores were developed using polynomial regression models. Demographic factors demonstrated medium-to-large effects on uncorrected NIHTB-CB scores in a pattern that differed from that observed on the English NIHTB-CB. For example, in Spanish-speaking adults, education was more strongly associated with Fluid scores, but showed the strongest association with Crystallized scores among English-speaking adults. Demographic factors were no longer associated with fully corrected scores. The original norms were not successful in eliminating demographic effects, overestimating children’s performances, and underestimating adults’ performances on the Spanish NIHTB-CB. The disparate pattern of demographic associations on the Spanish versus English NIHTB-CB supports the need for distinct normative standards developed separately for each population. Fully adjusted scores presented here will aid in more accurately characterizing acquired brain dysfunction among U.S. Spanish-speakers. (JINS, 2016, 21, 364–374)
Demographic factors impact neuropsychological test performances and accounting for them may help to better elucidate current brain functioning. The NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neuropsychological tool, yet the original norms developed for the battery did not adequately account for important demographic/cultural factors known to impact test performances. We developed norms fully adjusting for all demographic variables within each language group (English and Spanish) separately. The current study describes the standards for individuals tested in English. Neurologically healthy adults (n=1038) and children (n=2917) who completed the NIH Toolbox norming project in English were included. We created uncorrected scores weighted to the 2010 Census demographics, and applied polynomial regression models to develop age-corrected and fully demographically adjusted (age, education, sex, race/ethnicity) scores for each NIHTB-CB test and composite (i.e., Fluid, Crystallized, and Total Composites). On uncorrected NIHTB-CB scores, age and education demonstrated significant, medium-to-large associations, while sex showed smaller, but statistically significant effects. In terms of race/ethnicity, a significant stair-step effect on uncorrected NIHTB-CB scores was observed (African American<Hispanic<White). After applying normative corrections, NIHTB-CB no longer demonstrated any significant associations with demographic factors. The previously developed norms still maintained significant associations with demographic factors, and demonstrated more variable impairment rates in segments of the healthy normative sample. Similar to other neuropsychological tests, demographic factors demonstrated significant associations with unadjusted NIHTB-CB scores. Application of fully corrected scores will help account for unwanted variance that is associated with non-clinical factors to more accurately reflect effects of disease-related changes in brain function. (JINS, 2015, 21, 378–391)
This study describes psychometric properties of the NIH Toolbox Cognition Battery (NIHTB-CB) Composite Scores in an adult sample. The NIHTB-CB was designed for use in epidemiologic studies and clinical trials for ages 3 to 85. A total of 268 self-described healthy adults were recruited at four university-based sites, using stratified sampling guidelines to target demographic variability for age (20–85 years), gender, education, and ethnicity. The NIHTB-CB contains seven computer-based instruments assessing five cognitive sub-domains: Language, Executive Function, Episodic Memory, Processing Speed, and Working Memory. Participants completed the NIHTB-CB, corresponding gold standard validation measures selected to tap the same cognitive abilities, and sociodemographic questionnaires. Three Composite Scores were derived for both the NIHTB-CB and gold standard batteries: “Crystallized Cognition Composite,” “Fluid Cognition Composite,” and “Total Cognition Composite” scores. NIHTB Composite Scores showed acceptable internal consistency (Cronbach’s alphas=0.84 Crystallized, 0.83 Fluid, 0.77 Total), excellent test–retest reliability (r: 0.86–0.92), strong convergent (r: 0.78–0.90) and discriminant (r: 0.19–0.39) validities versus gold standard composites, and expected age effects (r=0.18 crystallized, r=−0.68 fluid, r=−0.26 total). Significant relationships with self-reported prior school difficulties and current health status, employment, and presence of a disability provided evidence of external validity. The NIH Toolbox Cognition Battery Composite Scores have excellent reliability and validity, suggesting they can be used effectively in epidemiologic and clinical studies. (JINS, 2014, 20, 1–11)
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