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Associations between NIH Toolbox Cognition Battery and in vivo brain amyloid and tau pathology in non‐demented older adults

The National Institutes of Health (NIH) Toolbox Cognition Battery (NIHTB‐CB) was developed to be a common assessment metric across a broad array of research studies. We investigated associations between NIHTB‐CB and brain amyloid and tau deposition in cognitively unimpaired older adults.

efficient, psychometrically sound, and accessible assessment measures for research use. These goals included the use of nonproprietary instruments, availability of both English and Spanish administration, and suitability for measuring constructs across the lifespan (ages 3 to 85). 1,2 Since its release in 2012, and migration to an iPad appadministered format in 2016, adoption into research communities has increased. There are currently 206 studies on ClinicalTrials.gov using NIHTB, more than 260 peer-reviewed publications, and active translation efforts in multiple languages. Of note: There is now an annual fee for the app subscription of approximately $500.00.
The National Institutes of Health (NIH) Toolbox Cognition Battery (NIHTB-CB) comprises seven primary tasks tapping sub-domains of attention/executive functions, language, processing speed, working memory, and episodic memory. Composite scores are computed for (1) crystallized abilities, reflecting tasks of semantic knowledge, such as vocabulary and word reading, thought to "hold" as relatively stable abilities in aging and disease; and (2) fluid abilities, reflecting tasks of novel problem solving, reasoning, processing speed, and memory, processes more vulnerable to decline in aging and disease. In addition, a total cognition composite is calculated. Previous work has shown good reliability for tasks 3 and composites scores, 4 with intraclass correlations for test-retest reliability ranging from .73 to .90. Construct validity for each task measure as well as composite scores has been evaluated and reported as metrics of convergent and divergent validity.
Values for convergent validity range from .50 to .92, similar to construct validity for gold standard traditional neuropsychological (NP) measures. 2,[5][6][7][8] The NIHTB-CB is used increasingly in a multitude of studies of behavioral and neurologic conditions across settings and ages. [9][10][11] This includes several studies of aging and in the Alzheimer's disease (AD) spectrum of risk, 12,13 although the number is limited.
There are especially limited studies, to date, of utility and validity of the NIHTB-CB in pre-symptomatic and early symptomatic AD, or in association with AD biomarkers. 14 This is the case despite recognized need for novel sensitive cognitive measures in this disease stage 15,16 when AD pathologic change is present, including amyloid beta (A ) and possibly tau deposition. 17 The goal of the present study was to begin to address the literature gap by investigating associations between current NIHTB-CB measures and AD neuroimaging biomarkers of A and tau in older adults without clinically significant cognitive impairment. In particular, the need to identify cognitive measures with improved sensitivity to preclinical AD for use in early screening and prevention trials has been discussed widely in the literature. 18,19 In this study, we also compared the pattern and strength of AD biomarker associations with NIHTB-CB to those with traditional pencil-and-paper NP tests.

Participants
Three ongoing neuroimaging studies contributed data to these analyses. The Monongahela-Youghiogheny Healthy Aging Team-

Diagnostic methods
All three neuroimaging studies included a comprehensive NP evaluation and the interviewer-based CDR scale, capturing cognitively driven daily function in the home and community. Both Heart SCORE- as regionally PiB-positive if any one composite region SUVR exceeded the corresponding regional cutoff.

Analysis
Descriptive statistics were computed for cognitive and demographic providing information about statistical reliability.

RESULTS
In the present analyses, n = 63 participants from the MYHAT-NI study, n = 36 participants from Heart SCORE-A and n = 19 from Heart SCORE-B studies contributed data, yielding a total combined sample of n = 118.   compared to its association with A or with tau in other brain regions, although the effect was not statistically reliable. Table 4 shows associations between neuropsychological paper and pencil measures and PET biomarkers, adjusted for age, sex, race, and education. Effect sizes can be compared to those presented in Table 3 with NIHTB-CB measures. Association effects were close to zero across most tests and PET biomarkers and none were statistically reliable.

Sensitivity analyses
Three models with one potential outlier were identified for Braak 5/  Table 2; the influence of the outlier on the Braak 5/6 tau-Pattern Comparison Processing Speed association is illustrated in Supplemental Figure 2.

F I G U R E 1 Association between Braak region 3/4 tau (AV-1451 retention) and Pattern Comparison Processing Speed Test performance.
Scatterplot on the left shows raw data points. Scatterplot on the right shows standardized model estimates with age, sex, education, and race as covariates

DISCUSSION
The aim of this study was to investigate associations between NIH  Speed. Present results are also strongest for this test in its association with tau deposition, albeit in brain regions outside the hippocampus.

Toolbox Cognition Battery and AD biomarkers
Although most studies of novel computerized tasks sensitive to preclinical AD focus on memory and associative learning paradigms, 16,18 there is a smaller but longstanding literature on computerized measures of reaction time, processing speed, and attentional control. [51][52][53] More recently, Kochan et al. 54  With regard to differential associations with cognition between A and tau pathologies, the latter is more proximally related to neurodegeneration and cognitive impairment in the theoretical AD biomarker model 59 across the disease spectrum, and this is empirically supported by postmortem studies. 60 Among cognitively unimpaired individuals, however, the extant literature of cross-sectional studies is mixed. In a large multi-cohort data set of 907 participants ages 40 and older, most traditional neuropsychological tests were associated with A status and none with tau, regardless of biomarker method (cerebrospinal fluid [CSF] or PET). 61 In contrast, an earlier smaller CSF study showed that both total-tau and phosphorylated-tau were associated with episodic memory, whereas A was not associated with any cognitive domain performance. 62 Rentz et al. 63 recently reported that both inferotemporal tau and global A imaging predicted MMSE scores in models controlling for verbal IQ (a proxy for cognitive reserve). It is clear from the past 10 to 15 years of amyloid imaging research that cross-sectional A -cognition association effect sizes in cognitively unimpaired cohorts are small and require power for detection, relative to larger effects of association with longitudinal cognitive change. 56 The present analyses were limited in that data were combined from three separate studies, with some minor differences in exclusion criteria, as well as in traditional NP test batteries. As a result, there was no episodic list-learning memory test in common as a traditional comparison measure, which may have been more sensitive to A or tau biomarkers in this cohort. A strength of this study is that the combined study samples have a somewhat higher proportion of under-represented minorities than do typical AD biomarker studies, as well as a more broadly representative distribution of education. 64,65 Because this study was exploratory in nature, replication and confirmation of findings is needed. Future research might also include tra- In summary, in this initial report characterizing NIHTB-CB relation-
Avid Radiopharmaceuticals, Inc., a wholly owned subsidiary of Eli Lilly and Company, enabled use of the 18F-flortaucipir tracer by providing precursor, but did not provide direct funding and was not involved in data analysis or interpretation.