Increased plasma brain-derived neurotrophic factor (BDNF) as a potential biomarker for and compensatory mechanism in mild cognitive impairment: a case-control study

Background: Previous meta-analyses examining the continuum of Alzheimer’s disease (AD) concluded significantly decreased peripheral brain-derived neurotrophic factor (BDNF) in AD. However, across different meta-analyses, there remain inconsistent findings on peripheral BDNF levels in individuals with mild cognitive impairment (MCI). This issue has been attributed to the highly heterogenous clinical and laboratory factors. Thus, BDNF’s level, discriminative accuracy for identifying all-cause MCI and its subtypes, and its associations with other biomarkers and neurocognitive domains, remain largely unknown. Methods: To address this heterogeneity, we compared a healthy control cohort (n=56, 45 female) to an MCI cohort (n=40, 28 female), to determine whether plasma BDNF, hs-CRP, and DHEA-S can differentiate healthy from MCI individuals, including two MCI subtypes (amnestic [aMCI] and non-amnestic [non-aMCI]). The associations between BDNF with other biomarkers and neurocognitive tests were examined. Adults with cerebral palsy were included as sensitivity analyses. Results: Compared to healthy controls, BDNF was significantly higher in all-cause MCI, aMCI, and non-aMCI. Furthermore, BDNF had good (AUC=0.84, 95% CI=0.74 to 0.95, p<0.001) and excellent discriminative accuracies (AUC=0.92, 95% CI=0.84 to 1.00, p<0.001) for all-cause MCI and non-amnestic MCI, respectively. BDNF was significantly and positively associated with plasma hs-CRP (β=0.26, 95% CI=0.02 to 0.50, p=0.038), despite attenuated association upon controlling for BMI (β=0.15, 95% CI=-0.08 to 0.38, p=0.186). Multiple inverse associations between BDNF and detailed neurocognitive tests were also detected. Conclusions: These findings suggest BDNF is increased as a compensatory mechanism in preclinical dementia, supporting the neurotrophic and partially the inflammatory hypotheses of cognitive impairment.

Footnote: in contrast to MCI and probable MDD (higher values for discriminating the conditions) and similar to probable GAD, AUC curves were generated with the lower values of the biomarkers discriminating CP from other conditions. DHEA-S was not examined in the CP cohort and hence was not presented in this table. AGING Supplementary Table 3. Neurocognitive test and its associated cognitive domain(s) and task description.

RAVLT [1]
Declarative verbal learning and memory (immediate, delayed, and recognition) Participants were given a list of 15 unrelated words (list A) to learn and immediately recall aloud over five learning trials (Immediate Recall). Subsequently, an interference list of 15 unrelated words (list B) was presented only once for the participants to learn and recall immediately. After which, participants were instructed to recall aloud the words from list A. Approximately 30 minutes later, they were again asked to recall aloud the words from list A (Delayed Recall). Finally, participants were given a list of 50 words, comprising list A, list B, and 20 new distractor words, from which they had to identify the original 15 words (Recognition). Eight outcome measures were used in RAVLT. RAVLT T1 and RAVLT T5 referred to the total number of words correctly recalled in the first and fifth learning trials from list A during Immediate Recall. RAVLT B referred to the total number of words correctly recalled from the interference list. RAVLT T6 referred to the total number of words correctly recalled from list A during Delayed Recall. Lastly, RAVLT Recognition Trial and RAVLT Recognition Trail -False Positive referred to the total number of words correctly identified and falsely identified from list A during Recognition.

Digit Span Forward and Backward Task
Attention and working memory The Digit Span Forward and Backward Task are subtests from the Wechsler Adult Intelligence Scale III (WAIS-III) [2]. A series of numbers were read aloud by the assessor, of which participants were required to repeat the series of numbers in the same (forward) or reverse (backward) order. The forward trial measures working memory span specifically, while the backward trial involved manipulation of information in the working memory. Two outcome measures were used in the Digit Span Task. Forward and Backward scores were obtained from the total number of forward and backward trials successfully repeated by the participants, respectively.

CTT [3] Divided attention
The CTT consists of two parts. In the first (CTT1), participants connected a series of numbers that were printed within pink and yellow circles, sequentially from 1 to 25. In the second part (CTT2), participants similarly connected the numbers from 1 to 25, but alternated between choosing numbers in either pink or yellow circles. Three outcome measures were obtained from CTTcompletion time for CTT1 and CTT2, and interference effect (i.e. CTT interference), which was calculated as the difference in completion times between CTT1 and CTT2, divided by CTT1.

Block Design Test Visuospatial function
The Block Design Test is a subtest from the WAIS-III [2]. Here, participants were instructed to arrange blocks with red and white patterns on different sides to match the required block patterns in each trial. Scoring for the block design test depended on both the accuracy in matching the patterns and speed. Additional points were awarded to participants if they completed the trials within various time limits.

Semantic Fluency (Animal) Test [4] Verbal fluency
Participants were instructed to name as many different animals as they could in one minute. The total score was indicated by the total number of correct and unique animal names.