Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by movement disorders, psychiatric symptoms, and dementia. The disease is caused by an expansion of CAG repeats in the huntingtin (Htt) gene, leading to the accumulation of mutant Htt protein. This study investigates the types, locations, numbers, forms, and composition of microscopic Htt aggregates in brain tissues from HD patients of different grades. A new fusion protein antibody, EM48, was developed to specifically recognize aggregated Htt and label more aggregates in neuronal nuclei, perikarya, and processes than previously described antibodies. The study compared the numbers and locations of nuclear and neuropil aggregates with known patterns of neuronal death in HD. It found that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before clinical symptoms appear. Neuropil aggregates, identified by electron microscopy in dendrites and dendritic spines, may play a role in dendritic pathology in HD. Aggregates increase in size in advanced grades, suggesting they may persist in neurons that survive longer. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis may be late or variable. The study also examined the distribution and types of aggregates in HD brains. EM48 labeled many more aggregates than previously reported antibodies, providing a more complete picture of their morphology and distribution. Aggregates were primarily found in gray matter, especially in layers V and VI of the cerebral cortex. They were less frequent in white matter and other regions such as the caudate, putamen, substantia nigra, and brainstem nuclei. In the striatum, aggregates were widely scattered without groupings. In the substantia nigra, most aggregates were in the pars compacta neuropil. Ultrastructural analysis showed that neuropil aggregates were intracellular and often located within dendrites. They were composed of granular and filamentous material resembling filaments in intranuclear aggregates. Nuclear aggregates were round to fusiform in shape and were less common than neuropil aggregates. The study found that neuropil aggregates were more frequent in the cerebral cortex than in the striatum, even when cortical cell loss had not been identified. The relationship between aggregates and neuropathology was examined. In a presymptomatic HD case, a high density of neuropil aggregates was found in the cerebral cortex, while nuclear aggregates were rare. This suggests that neuropil aggregates may be more common in the brain before the development of neurological symptoms. The study also found that the density of aggregates in the striatum was much lower than in the cortex, despite significant neuronal loss. The study concluded that neuropil aggregates are more common than nuclear aggregates in HD and may play a role in dendritic pathology. The findings suggest that neuropil aggregates may represent storage of Htt fragments in neurons resistant to degeneration and that aggregate ubiquitination may be late or variable. The resultsHuntington's disease (HD) is a progressive neurodegenerative disorder characterized by movement disorders, psychiatric symptoms, and dementia. The disease is caused by an expansion of CAG repeats in the huntingtin (Htt) gene, leading to the accumulation of mutant Htt protein. This study investigates the types, locations, numbers, forms, and composition of microscopic Htt aggregates in brain tissues from HD patients of different grades. A new fusion protein antibody, EM48, was developed to specifically recognize aggregated Htt and label more aggregates in neuronal nuclei, perikarya, and processes than previously described antibodies. The study compared the numbers and locations of nuclear and neuropil aggregates with known patterns of neuronal death in HD. It found that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before clinical symptoms appear. Neuropil aggregates, identified by electron microscopy in dendrites and dendritic spines, may play a role in dendritic pathology in HD. Aggregates increase in size in advanced grades, suggesting they may persist in neurons that survive longer. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis may be late or variable. The study also examined the distribution and types of aggregates in HD brains. EM48 labeled many more aggregates than previously reported antibodies, providing a more complete picture of their morphology and distribution. Aggregates were primarily found in gray matter, especially in layers V and VI of the cerebral cortex. They were less frequent in white matter and other regions such as the caudate, putamen, substantia nigra, and brainstem nuclei. In the striatum, aggregates were widely scattered without groupings. In the substantia nigra, most aggregates were in the pars compacta neuropil. Ultrastructural analysis showed that neuropil aggregates were intracellular and often located within dendrites. They were composed of granular and filamentous material resembling filaments in intranuclear aggregates. Nuclear aggregates were round to fusiform in shape and were less common than neuropil aggregates. The study found that neuropil aggregates were more frequent in the cerebral cortex than in the striatum, even when cortical cell loss had not been identified. The relationship between aggregates and neuropathology was examined. In a presymptomatic HD case, a high density of neuropil aggregates was found in the cerebral cortex, while nuclear aggregates were rare. This suggests that neuropil aggregates may be more common in the brain before the development of neurological symptoms. The study also found that the density of aggregates in the striatum was much lower than in the cortex, despite significant neuronal loss. The study concluded that neuropil aggregates are more common than nuclear aggregates in HD and may play a role in dendritic pathology. The findings suggest that neuropil aggregates may represent storage of Htt fragments in neurons resistant to degeneration and that aggregate ubiquitination may be late or variable. The results