This study investigates the types, locations, numbers, forms, and compositions of huntingtin aggregates in brain tissues from humans with different grades of Huntington's disease (HD). The researchers developed a fusion protein antibody that specifically recognizes aggregated huntingtin and labels more aggregates in neuronal nuclei, perikarya, and processes than previously described. Using this antibody, they compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. They found that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. Neuropil aggregates, identified by electron microscopy to occur in dendrites and dendritic spines, may play a role in the dendritic pathology observed in HD. Aggregates increase in size in advanced grades, suggesting they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, indicating that ubiquitin-mediated proteolysis of aggregates may be late or variable. The study also highlights the distribution of nuclear aggregates does not correspond to the neuropathology of HD, suggesting that nuclear aggregates may not be the primary cause of neuronal death in HD.This study investigates the types, locations, numbers, forms, and compositions of huntingtin aggregates in brain tissues from humans with different grades of Huntington's disease (HD). The researchers developed a fusion protein antibody that specifically recognizes aggregated huntingtin and labels more aggregates in neuronal nuclei, perikarya, and processes than previously described. Using this antibody, they compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. They found that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. Neuropil aggregates, identified by electron microscopy to occur in dendrites and dendritic spines, may play a role in the dendritic pathology observed in HD. Aggregates increase in size in advanced grades, suggesting they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, indicating that ubiquitin-mediated proteolysis of aggregates may be late or variable. The study also highlights the distribution of nuclear aggregates does not correspond to the neuropathology of HD, suggesting that nuclear aggregates may not be the primary cause of neuronal death in HD.