Development and Validation of a Nutrition-Related Genetic–Clinical–Radiological Nomogram Associated with Behavioral and Psychological Symptoms in Alzheimer’s Disease
Alzheimer’s disease (AD) is the leading cause of dementia among older adults, with an estimated global prevalence projected to increase dramatically by 2050. Behavioral and psychological symptoms of dementia (BPSD) are a significant component of AD, affecting approximately 80% of patients. These symptoms, which include agitation, aggression, anxiety, depression, and sleep and appetite disturbances, contribute to clinical deterioration and increase caregiver burden. Despite their prevalence, BPSD are not included in the diagnostic criteria for AD, and current treatments, including antidepressants and antipsychotics, show high heterogeneity in efficacy and are associated with safety concerns. Non-pharmacological interventions, such as music therapy, have shown promise but require further research to establish their effectiveness. The complex pathogenesis of BPSD, influenced by biopsychosocial factors, presents challenges for developing effective interventions. Recent research highlights the potential role of dietary nutrition in AD and BPSD, suggesting that nutrition could influence brain health through various biological pathways.
This study aimed to develop and validate a novel genetic–clinical–radiological nomogram for evaluating BPSD in patients with AD, incorporating factors related to lipid metabolism, nutritional status, and brain structure. The study was conducted using data from the Chinese Imaging, Biomarkers, and Lifestyle (CIBL) cohort, a large-scale prospective study evaluating risk factors, biomarkers, and neuroimaging in individuals with AD in the Chinese population. The study included 165 patients with AD, with data collected between June 1, 2021, and March 31, 2022, for model development and between June 1, 2022, and February 1, 2023, for external validation.
The inclusion criteria for the study were age between 55 and 85 years, meeting the 2011 or 2018 National Institute on Aging Alzheimer’s Association diagnostic criteria for probable AD, objective cognitive impairment based on the Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA), and significant decline in daily living abilities based on the Activities of Daily Living (ADL) scale. Exclusion criteria included other central neurodegenerative diseases, concomitant central nervous system diseases, history of mental disorders, cognitive impairment due to traumatic brain injury, history of drug abuse or toxic exposure, systemic diseases, and lack of clinical, genetic, or imaging data.
The study used a nested case-control design, with 110 patients with AD and BPSD matched by age and sex to 55 patients with AD without BPSD. Data on demographics, neuropsychological assessments, single-nucleotide polymorphisms (SNPs) of AD risk genes, and regional brain volumes were collected. Neuropsychological assessments included the MMSE, MoCA, Neuropsychiatric Inventory (NPI), ADL scale, Mini-Nutritional Assessment (MNA), and Caregiver Burden Inventory (CBI). Genetic data were assessed using a customized Illumina WeGene V3 Array, and structural magnetic resonance imaging (MRI) was performed to measure brain volumes.
Univariate and multivariate analyses were used to identify factors associated with BPSD. Univariate analysis identified significant differences in MMSE, MoCA, ADL, MNA, and CBI scores between the BPSD and control groups. SNPs in the COMT rs4680, CETP rs708272, and CETP rs1800775 genes were also significantly associated with BPSD. Brain volumes in regions of interest (ROIs), including the insula, brain stem, putamen, amygdala, nucleus accumbens (NAc), and hypothalamus, showed significant differences between the groups.
Multivariate logistic regression analysis identified four factors independently associated with BPSD: carrier status for the CETP rs1800775 variant, lower MNA score, higher CBI score, and decreased brain stem volume. These factors were incorporated into a nomogram for evaluating the probability of BPSD in patients with AD. The nomogram was internally validated using 1000-bootstrap resampling, showing an area under the receiver operating characteristic (ROC) curve of 0.925, indicating excellent discrimination. External validation using a time-series split showed an area under the ROC curve of 0.791, confirming the model’s generalizability. Calibration curves and decision curve analysis (DCA) demonstrated good calibration and clinical applicability of the nomogram.
The CETP rs1800775 variant, a key determinant in lipid metabolism, was found to increase the risk of BPSD in patients with AD. Although no direct mediating effect of malnutrition was observed, previous studies have shown that CETP polymorphisms influence lipid metabolism and energy expenditure, suggesting a potential role in the regulation of nutrition and BPSD. Brain stem atrophy was also identified as a significant risk factor for BPSD. The brain stem contains several subregions involved in feeding behavior, energy balance, and psychological symptoms, including the nucleus of the tractus solitarius (NTS), raphe nuclei, locus coeruleus (LC), and ventral tegmental area (VTA). These regions play roles in regulating food intake, stress responses, and emotional behaviors, suggesting a potential link between brain stem function and BPSD.
The study’s findings highlight the potential multidimensional impact of nutrition on BPSD, with nutrition- and metabolism-related genes and brain regions participating in the regulation of nutritional status and BPSD. The nomogram provides a tool for early detection and intervention in patients with AD and BPSD, offering a critical time window for personalized management. However, the study has limitations, including the use of a nested case-control design, which limits predictive value, and the lack of genome-wide association studies and serum lipid metabolism biomarkers to confirm the regulatory mechanisms of BPSD. Additionally, the study analyzed only the volume changes of the entire brain stem, and further research is needed to investigate changes in specific subregions.
In conclusion, this study developed and validated a novel genetic–clinical–radiological nomogram for evaluating BPSD in patients with AD, incorporating factors related to lipid metabolism, nutritional status, and brain structure. The nomogram demonstrated excellent discrimination, calibration, and clinical applicability, providing a tool for early detection and intervention. The study’s findings underscore the potential role of nutrition in BPSD and suggest new insights into the nutritional management of BPSD in patients with AD. Further research is needed to validate the nomogram in multicenter studies and investigate the functional characteristics of nutrition- and metabolism-related brain regions.
doi.org/10.1097/CM9.0000000000002914
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