The cross-sectional association of cognition with diabetic peripheral and autonomic neuropathy-The GRADE study

Abstract

Background: Studies examining whether measures of cognition are related to the presence of diabetic peripheral neuropathy (DPN) and/or cardiovascular autonomic neuropathy (CAN) are lacking, as are data regarding factors potentially explaining such associations.

Methods: Participants were from the Glycemia Reduction Approaches in Diabetes Study (GRADE) that examined 5047 middle-aged people with type 2 diabetes of <10 years of known duration. Verbal learning and immediate and delayed recall (memory) were assessed with the Spanish English Verbal Learning Test; frontal executive function and processing speed with the Digit Symbol Substitution Test; and ability to concentrate and organize data with word and animal fluency tests. DPN was assessed with the Michigan Neuropathy Screening Instrument and CAN by indices of heart rate variability (standard deviation of normal beat to beat variation [SDNN] and root mean square of successive differences [RMSSD]).

Results: DPN was significantly inversely related to measures of immediate recall and processing speed. The percent of cognitive variation explained by DPN was small. Tests of CAN had an inconsistent or absent association with measures of cognition. Higher waist circumference and urine albumin creatinine (UACR) levels were the strongest correlates in the relationship between DPN and cognitive impairment.

Conclusion: DPN, but not CAN, was cross-sectionally associated with lower performance in measures of cognition in people with type 2 diabetes of <10 years of known duration. Greater waist circumference and UACR were important variables in this association. The mechanisms underlying the cross-sectional association of DPN with cognitive impairment are unknown. Clinicaltrials.gov: NCT01794143.

Keywords: Cardiovascular autonomic neuropathy; Cognitive tests; Diabetes; Diabetic peripheral neuropathy.

Conflict of interest statement

None of the authors has an intellectual or financial conflict of interest regarding the contents of this paper.

Conflicts of Interest: RPB reports grants from National Institute of Diabetes and Digestive and Kidney Diseases, NIH (U34 DK088043 and U01 DK098246), during the conduct of the study; grants from Astra Zeneca, personal fees from Novo Nordisk, personal fees from Bayer, personal fees from Boehringer Ingelheim, outside the submitted work. AA reports personal fees from Novo Nordisk, and Lilly, during the conduct of the study; and personal fees from Medtronic outside the submitted work. JG reports grants from NIDDK, during the conduct of the study; grants and personal fees from Boehringer Ingelheim/Lilly, personal fees from NovoNordisk, grants from Roche, personal fees from Hawthorne Effect/Omada, grants and personal fees from Sanofi/Lexicon, personal fees from Pfizer, grants from Glaxo SmithKline, grants from Merck, grants and personal fees from AstraZeneca, outside the submitted work. ES reports “other” support from MannKind, “other” support from Zucara, ABIM, Web MD and Sanofi, outside the submitted work; and grants and other from Lilly outside the submitted work. JAL reports personal fees from vTV Therapeutics, and “other” support from Wolters Kluwer, outside the submitted work. JIB, AG, AB, MAB, RMC, FIB, and CLM have nothing to disclose.

Copyright © 2021. Published by Elsevier Inc.

Figures

Figure 1:

Analytic cohort from the GRADE study.

Figure 2:

Percent change of tests of cognition with peripheral diabetic neuropathy as a continuous and as a dichotomous variable (Definite DPN). Open circles are not statistically significant. The tests of cognition were the immediate (trials 1–3) and delayed recall (trial 4) in the Spanish English Verbal Learning Test (SEVLT), the digit symbol substitution test (DSST), and the letter and animal fluency tests. Model 1: no adjustments; Model 2: age, race, and female sex; Model 3: in addition, waist circumference, diabetes duration, current smoking, alcohol status, history of stroke, depression, hypertension, highest education level, and hyperlipidemia.

Figure 3:

Percent change of tests of cognition with SDNN, RMSSD and as a dichotomous variable (Definite CAN). Open circles are not statistically significant. The tests of cognition were the immediate (trials 1–3) and delayed recall (trial 4) in the Spanish English Verbal Learning Test (SEVLT), the digit symbol substitution test (DSST), and the letter and animal fluency tests. Model 1: no adjustments; Model 2: age, race, and female sex; Model 3: in addition, waist circumference, diabetes duration, current smoking, alcohol status, history of stroke, depression, hypertension, highest education level, and hyperlipidemia.