Interaction Between BDNF Val66Met and APOE4 on Biomarkers of Alzheimer's Disease and Cognitive Decline.

BACKGROUND: Whether brain-derived neurotrophic factor (BDNF) Met carriage impacts the risk or progression of Alzheimer's disease (AD) is unknown. OBJECTIVE: To evaluate the interaction of BDNF Met and APOE4 carriage on cerebral metabolic rate for glucose (CMRgl), amyloid burden, hippocampus volume, and cognitive decline among cognitively unimpaired (CU) adults enrolled in the Arizona APOE cohort study. METHODS: 114 CU adults (mean age 56.85 years, 38% male) with longitudinal FDG PET, magnetic resonance imaging, and cognitive measures were BDNF and APOE genotyped. A subgroup of 58 individuals also had Pittsburgh B (PiB) PET imaging. We examined baseline CMRgl, PiB PET amyloid burden, CMRgl, and hippocampus volume change over time, and rate of change in cognition over an average of 15 years. RESULTS: Among APOE4 carriers, BDNF Met carriers had significantly increased amyloid deposition and accelerated CMRgl decline in regions typically affected by AD, but without accompanying acceleration of cognitive decline or hippocampal volume changes and with higher baseline frontal CMRgl and slower frontal decline relative to the Val/Val group. The BDNF effects were not found among APOE4 non-carriers. CONCLUSION: Our preliminary studies suggest that there is a weak interaction between BDNF Met and APOE4 on amyloid-ß plaque burden and longitudinal PET measurements of AD-related CMRgl decline in cognitively unimpaired late-middle-aged and older adults, but with no apparent effect upon rate of cognitive decline. We suggest that cognitive effects of BDNF variants may be mitigated by compensatory increases in frontal brain activity-findings that would need to be confirmed in larger studies.

Deep Brain Stimulation and Cognitive Outcomes Among Patients With Parkinson's Disease: A Historical Cohort Study.

OBJECTIVE: Deep brain stimulation (DBS) is an effective treatment for motor symptoms of Parkinson's disease; however, there is conflicting literature about the effect of DBS on cognitive function. The authors conducted a historical cohort study involving patients with Parkinson's disease who underwent DBS of the globus pallidus pars interna (GPi; N=12) or subthalamic nucleus (STN; N=17). METHODS: The authors investigated differences in four neuropsychological test scores at 6 months post-DBS (follow-up) as compared with baseline (i.e., Boston Naming Test, WAIS Verbal Comprehension Index [WAIS-VCI], Working Memory Index [WAIS-WMI], and Processing Speed Index [WAIS-PSI]). RESULTS: GPi DBS patients showed no difference between baseline and follow-up on any neuropsychological test. STN DBS patients had lower scores indicating decreased performance at follow-up as compared with baseline on WAIS-PSI (mean [SD], 91.47 [10.42] versus 81.65 [12.03]; p=0.03). There was a significant (p=0.008) difference between the change in baseline to follow-up scores on the WAIS-VCI for the STN DBS and GPi DBS groups (i.e., STN DBS patients scored lower at the 6-month follow-up compared with baseline, whereas GPi DBS patients scored higher). CONCLUSIONS: GPi may be a preferred target for DBS in patients with Parkinson's disease when considering cognitive outcomes.

Brain MR Radiomics to Differentiate Cognitive Disorders.

OBJECTIVE: Subtle and gradual changes occur in the brain years before cognitive impairment due to age-related neurodegenerative disorders. The authors examined the utility of hippocampal texture analysis and volumetric features extracted from brain magnetic resonance (MR) data to differentiate between three cognitive groups (cognitively normal individuals, individuals with mild cognitive impairment, and individuals with Alzheimer's disease) and neuropsychological scores on the Clinical Dementia Rating (CDR) scale. METHODS: Data from 173 unique patients with 3-T T1-weighted MR images from the Alzheimer's Disease Neuroimaging Initiative database were analyzed. A variety of texture and volumetric features were extracted from bilateral hippocampal regions and were used to perform binary classification of cognitive groups and CDR scores. The authors used diagonal quadratic discriminant analysis in a leave-one-out cross-validation scheme. Sensitivity, specificity, and area under the receiver operating characteristic curve were used to assess the performance of models. RESULTS: The results show promise for hippocampal texture analysis to distinguish between no impairment and early stages of impairment. Volumetric features were more successful at differentiating between no impairment and advanced stages of impairment. CONCLUSIONS: MR radiomics may be a promising tool to classify various cognitive groups.

Association of Pancreatic Polypeptide with Mild Cognitive Impairment Varies by APOE ε4 Allele.

We conducted a preliminary case-control investigation of the association of pancreatic polypeptide (PP) with mild cognitive impairment (MCI) in 202 MCI cases (mean age, 81.6 years) and 202 age- and sex-matched cognitively normal controls in the Mayo Clinic Study of Aging. Plasma PP was measured and examined as the natural logarithm (continuous) and dichotomized at the median. The OR (95% CI) of MCI increased with increasing PP [1.46 (1.04-2.05)]. There was a negative interaction of PP with apolipoprotein E (APOE) ε4 allele; compared to the reference group (no APOE ε4 allele and low PP), the OR (95% CI) for combinations of ε4 and PP were: 2.64 (1.39-5.04) for APOE ε4 plus low PP; 2.09 (1.27-3.45) for no APOE ε4 plus high PP; and 1.91 (1.04-3.53) for no APOE ε4 plus high PP (P for interaction = 0.017). There was also a trend toward a negative interaction with type 2 diabetes (P for interaction = 0.058). Compared to no diabetes and low PP, the OR (95% CI) was 3.02 (1.22-7.46) for low PP plus diabetes but 1.80 (1.01-3.22) for high PP plus diabetes. Participants with high PP had a greater mean (SD) weight loss (kilograms per decade) than persons with low PP [-2.27 (4.07) vs. -1.61 (5.24); P = 0.016]. MCI cases had a non-significantly greater weight loss per decade compared to controls. These findings suggest that high PP alone or jointly with APOE ε4 allele or type 2 diabetes is associated with MCI, and that high PP may mitigate some effects of APOE ε4 allele and type 2 diabetes on cognition. Potential mechanisms may involve PP-related weight loss and centrally mediated effects of PP on cognition. These findings remain to be validated in other studies.

Probing Antibody-Antigen Interactions.

Antibodies are biological molecules generated by the host immune system in response to the invasion of foreign bodies or antigens. Therefore, antibodies must possess high specificity toward target antigens in order for the antigen to be recognized and subsequently destroyed. Because of this specificity, antibodies or antibody fragments that maintain binding specificity are heavily used in diagnostic assays and are becoming increasingly important in many therapeutic applications. Classical immunoassays such as radioimmunoassay and enzyme-linked immunosorbent assay are effective analytical techniques that have been widely used to screen and determine antibody specificity. Because of increased demands for antibodies with well-defined specificities, other techniques have been developed that facilitate generation and characterization of antibody-binding specificities under different conditions, such as when the protein is expressed on a cell surface or the target antigen is hard to isolate. Here, we describe three alternate techniques that provide unique abilities to characterize antibody-antigen binding events: (i) surface plasmon resonance, (ii) fluorescence activated cell sorting, and (iii) atomic force microscopy. These different techniques take advantage of various changes in physical and/or chemical properties of the analytes that occur upon binding, such as refractive index, surface charge, and changes in structure. These techniques provide unique powerful advantages over traditional immunoassays including real-time and label-free detection, low sample volume and concentration requirements, and molecular-level detection sensitivity. This article provides an overview of how these alternate approaches to studying antibody-antigen interactions can be used to facilitate rapid development of new antibody-based reagents for diagnostic and therapeutic applications.