CLN2 disease is caused by inherited mutations in tripeptidyl peptidase 1 (TPP1). Most studies of CLN2 pathogenesis and testing of therapies has been performed in TPP1 deficient mice. However, these mice have small, simple brains and studies are further complicated by their vulnerability to lethal spontaneous seizures. Larger animal species offer more human-like pathology, and a CLN2 Dachshund was pivotal in the pre-clinical development of enzyme replacement therapy. Recently a TPP1 deficient cynomolgus macaque was identified with a homozygous single-base deletion (c.42delC) of the CLN2/TPP1 gene, resulting in a frameshifted premature stop codon. Initial characterization of this non-human primate confirmed TPP1 deficiency, autosomal recessive inheritance, progressive neuronal clinical symptoms and regional brain atrophy evident via MRI imaging and characteristic disease-associated neuropathology. We have now undertaken a more detailed analysis of the extent and nature of these neuropathological changes throughout the CNS at disease end stage, compared to age-matched unaffected control samples. These analyses revealed pronounced cortical atrophy, that differs in extent between regions. This is more pronounced in sensory cortical areas where neuron loss is especially pronounced, including populations of GABAergic interneurons. This is accompanied by pronounced activation of both astrocytes (GFAP) and microglia (Iba1), and autofluorescent storage material accumulation that is also detectable immunohistochemically (SCMAS). Pronounced regional atrophy, reactive changes and neuron loss is also evident in the cerebellum, and at multiple levels of the spinal cord. In general, neuropathological changes are more pronounced in brain and spinal grey matter. However, white matter also displays reactive changes and demyelination to a far greater extent than in TPP1 deficient mice. Further analyses are under way, but our data so far confirm this cynomolgus macaque as an important new model that exhibits pronounced neuropathological changes that resemble human CLN2 disease.