Abstract: This document provides methods and materials related to determining whether or not a mammal (e.g., a human) has a neurodegenerative disease (e.g., frontotemporal dementia, AD, or amyotrophic lateral sclerosis (ALS)). For example, methods and materials for using the levels of TDP-43 polypeptides and/or TDP-43 polypeptide cleavage products (e.g., 25 kD and 35 kD TDP-43 polypeptide cleavage products) in a biological fluid (e.g., cerebrospinal fluid) to determine whether or not a mammal has a neurodegenerative disease (e.g., frontotemporal dementia, AD, or ALS) are provided.