“MULTIMODAL PHYSIOLOGICAL BIOMARKERS OF COGNITIVE DYSFUNCTION IN MAJOR DEPRESSIVE DISORDER: FROM NEUROPHYSIOLOGY TO AUTONOMIC AND PERIPHERAL BIOMARKERS”.

Abstract

Major Depressive Disorder (MDD) and early neurocognitive disorders (such as mild cognitive impairment, or MCI) present massive global public health challenges, particularly among aging populations. Cognitive dysfunction represents a core, highly debilitating dimension of these conditions, persisting even during clinical remission. Traditional diagnostic strategies rely heavily on subjective screening tools and clinical interviews. However, a profound "subjective objective paradox" exists: subjective memory complaints (SMCs) often reflect acute psychosocial distress, anxiety, and current depressive symptom severity rather than objective neural or memory decline. There is an urgent clinical need to transition from subjective proxies to objective, non-invasive brain-body biotypes that span multiple physiological systems to achieve early risk stratification and precise therapeutic monitoring. Objective: This review synthesizes recent evidence to establish a systems-based, multimodal physiological framework for mapping cognitive homeostasis and autonomic dyshomeostasis. By integrating neuroelectrophysiological, cardiac, endocrine, and neuromuscular markers, we outline a definitive roadmap for predicting clinical transitions (such as MDD-to-MCI conversion) and characterizing central-autonomic-peripheral communication in older adults. Methods A comprehensive synthesis was performed across 38 recent clinical trials, prospective cohort studies, neuroimaging datasets, systematic reviews, and Mendelian randomization (MR) analyses. This review systematically evaluates: (1) neuroelectrophysiological indices of cognitive processing (event-related potentials [ERPs] such as the P300, N170, and LRP); (2) cardiac autonomic biomarkers (resting and task-reactive heart rate variability [HRV] and respiratory oscillations); (3) neuroendocrine markers (hypothalamic-pituitary-adrenal [HPA] axis dynamics and cortisol diurnal profiles); and (4) peripheral somatic indicators (isometrically measured handgrip strength, sarcopenia indices, and segmental bioelectrical impedance analysis [BIA]). Results & Synthesis: 1.Neurophysiological Processing (The P300 Paradigm): ERP studies establish the P300 wave as an objective indicator of cognitive resource allocation (P3b amplitude) and information processing speed (P3b latency). Active depression is robustly characterised by significantly reduced P300 amplitude and prolonged latency, correlating with impaired verbal memory and executive dysfunction in older adults [8]. Conversely, a history of MDD is associated with a hyper-reactive novelty P3 (P3a) and accelerated target P3 (P3b) latency, suggesting persistent sensory distractibility even after clinical remission [9]. 2.Cardiac-Autonomic Dysregulation: While resting HRV (e.g., RMSSD, HF, LF, and non-linear SD1) is widely used to index parasympathetic (vagal) tone, large-scale umbrella reviews indicate that while reduced HRV is highly suggestive in dementia, PTSD, and schizophrenia, evidence for overall HRV reduction in adult MDD is weaker [4]. However, task reactive HRV assessments reveal that depression disrupts the normal physiological coupling between autonomic vagal tone and executive performance (e.g., inhibitory control during continuous performance tests) [5]. 3.The Non-Linear Compensation Paradigm: In early-stage mild neurocognitive disorder (mNCD), resting vagally mediated HRV (specifically HF-HRV) exhibits a paradoxical compensatory increase due to prefrontal and anterior cingulate cortex (ACC) hyperactivation [10]. This compensatory mechanism becomes exhausted as neurodegeneration progresses, leading to a profound decline in total and parasympathetic resting HRV in frank dementia [15]. 4.Stress-Induced Neuroendocrine cascades: Chronic stress induces HPA axis hyperactivity and glucocorticoid receptor (GR) desensitisation (glucocorticoid resistance) in 40–60% of MDD patients. Chronic hypercortisolemia flattens diurnal cortisol rhythms, triggers neuroinflammation via hippocampal microglial activation, suppresses adult neurogenesis, and impairs synaptic plasticity (attenuating BDNF signaling), culminating in irreversible hippocampal and prefrontal dendritic atrophy [39]. 5.Peripheral Neuromuscular & Body Composition Biomarkers: Handgrip strength (HGS) and sarcopenia indices (such as appendicular lean mass [ALM] and gait speed) exhibit a robust, bidirectional causal relationship with general cognitive function, heavily mediated by moderate-to-vigorous physical activity and regional gray matter volume (GMV) within the subcortical nuclei and temporal cortices [44]. Furthermore, segmental BIA demonstrates that early cognitive decline (MCI and AD dementia) is characterized by reduced reactance and phase angle in the lower extremities, reflecting diminished body cell mass, compromised cell membrane strength, and abnormal cellular fluid distribution [43]. 6.Humoral and Network Dyshomeostasis: Adipomyokine network mapping in poorly managed hypertension (PMHTN) reveals systemic homeostatic collapse: the positive, neuroprotective coupling between adiponectin and verbal delayed memory, as well as IGF-1/IGFBP-3 and cognitive activity, is completely severed [51]. Elevated vaspin levels correlate with cognitive inefficiency (poorer MMSE and Trail Making Test Part B scores) and physical frailty [52]. Conclusions & Clinical Implications Single-channel physiological variables are fundamentally insufficient for capturing the complex, bidirectional brain heart-body interactions that govern cognitive homeostasis. Integrating electrophysiological, autonomic, neuroendocrine, and somatic markers into advanced machine learning and sensor-fusion models (such as combining video-based facial expressiveness with rPPG-derived HRV and quantitative EEG) significantly enhances diagnostic and prognostic accuracy. A validated multi-channel biotype predicts subsequent cognitive decline and MCI transition with up to 80.6% precision. Incorporating non-pharmacological interventions (such as resistance training, hatha yoga, and HRV biofeedback) offers a definitive clinical roadmap to actively restore HPA axis equilibrium, expand grey matter volume, enhance neurogenesis, and preserve cognitive autonomy in older adults.