Aim: The study aims to investigate the correlation between anatomical changes in the brain and neuropathological disorders, including Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Multiple Sclerosis (MS), and stroke-related neurodegeneration. Materials and Methods: This prospective, observational study included 90 patients recruited from a tertiary care hospital. Participants were aged ≥18 years and diagnosed or suspected to have a neuropathological disorder. Exclusion criteria included major traumatic brain injury, neurosurgical interventions, and systemic diseases affecting neurological function. Neuroimaging assessments included Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) to analyze structural and functional changes. Cognitive and neurological evaluations were conducted using Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), Unified Parkinson’s Disease Rating Scale (UPDRS), and Clinical Dementia Rating (CDR) scale. Biomarker analysis from cerebrospinal fluid (CSF) and blood included β-amyloid (Aβ42), Tau, phosphorylated Tau, α-synuclein, and Neurofilament Light Chain (NfL). Results: The study cohort had a mean age of 65.4 ± 9.8 years, with 55.6% males and 44.4% females. AD was the most prevalent disorder (33.3%), followed by PD (27.8%), stroke-related neurodegeneration (22.2%), and MS (16.7%). Cortical atrophy (44.4%) and PET hypometabolism (55.6%) were the most common neuroimaging findings. Cognitive assessment scores indicated mild to moderate impairment, with a mean MMSE of 22.3 ± 4.5 and MoCA of 19.6 ± 5.2. Biomarker analysis showed reduced Aβ42 and increased Tau levels in AD, while elevated α-synuclein was noted in PD patients. Significant correlations were found between cortical atrophy and MMSE (-0.58, p<0.01), white matter lesions and MoCA (-0.62, p<0.01), and PET hypometabolism and CDR (0.72, p<0.01). Conclusion: This study establishes a strong correlation between anatomical brain changes and neuropathological disorders, emphasizing the role of neuroimaging and biomarker analysis in diagnosis and disease monitoring. Structural abnormalities such as cortical atrophy, white matter lesions, and basal ganglia changes are significantly associated with cognitive and motor dysfunction. The findings support the integration of MRI, PET, and biomarker analysis in early detection and management of neurodegenerative diseases.