Depression Before Degeneration: A Thiamine-Dependent Dynamic-Reserve Hypothesis of the Long Neuropsychiatric Prodrome

Depression can be an early clinically recognized manifestation of an evolving neurological process. Population and registry studies document depression, anxiety, and other nonmotor features years before clinical Parkinson disease (PD) diagnosis. Repeated-measurement cohorts also identify increasing depressive symptoms before dementia diagnosis. Disease-specific pathology can already be present during these prediagnostic intervals. We propose that, in a prospectively identifiable subgroup, progressive constraint of effective thiamine-dependent cerebral metabolic capacity relative to physiological demand contributes to this long neuropsychiatric trajectory. The Dynamic-Reserve framework expresses the margin as R_T(t) = C_T(t) − D_T(t), with regional demand, compensation, and susceptibility allowing sleep, affective, cognitive, autonomic, and motor abnormalities to emerge asynchronously. Experimental thiamine deficiency produces unequal regional metabolic changes; inherited transport and cofactor-activation disorders establish selective human neurological vulnerability; and PD and Alzheimer disease (AD) tissues show abnormalities involving thiamine pyrophosphate (TPP)-dependent pathways. The model distinguishes insufficient TPP availability or engagement (H4a) from impairment of a TPP-dependent enzyme system despite adequate cofactor (H4b). The latter identifies pathway dysfunction, not by itself a thiamine-specific defect. Controlled human studies document context-dependent mood or functional observations and sometimes preserved performance despite biochemical depletion. Eight falsifiable predictions assess prospective clinical change, objective tremor, regionally selective dysfunction, neurological risk, pathway specificity, demand and recovery, controlled correction, and medication exposure. The decisive studies require independent assay validation, incremental value beyond generic energetic and disease-specific biomarkers, and appropriate causal tests of verified metabolic correction. The model proposes an experimentally discriminable explanation for depression preceding recognizable neurological deterioration.