Severe thalamic injury can determine a particular type of vascular dementia affecting multiple network dysfunctions, considered the central role of thalamus as a hub for afferent and efferent stimuli. A 67-year-old male patient with bilateral thalamic stroke was studied with positron emission tomography, magnetic resonance imaging, and cognitive assessment, performed at baseline and at two follow-up evaluations. A pattern primarily involving thalamo-frontal connections was observed by both PET and tractography analyses. All significant differences between the patient and controls involved the anterior thalamic radiation, one of the major fiber tracts in the fronto-thalamic circuitry. In particular, altered tractography indices of higher radial diffusivity and apparent diffusion coefficient and reduced fractional anisotropy values for the anterior thalamic radiation were reported. In accordance with imaging findings, neuropsychological evaluation demonstrated a multidomain impairment including memory, executive functions, and attention. Additionally, the patients displayed behavioral symptoms, in absence of mood alterations. Multimodal imaging assessment, revealing the metabolic and microstructural alterations that attend to multidomain neuropsychological impairment, demonstrated multiple levels of adaptations to bilateral vascular thalamic injury.