The data we report in this study concern the types, location, numbers, forms, and composition of microscopic huntingtin aggregates in brain tissues from humans with different grades of Huntington’s disease (HD). We have developed a fusion protein antibody against the first 256 amino acids that preferentially recognizes aggregated huntingtin and labels many more aggregates in neuronal nuclei, perikarya, and processes in human brain than have been described previously. Using this antibody and human brain tissue ranging from presymptomatic to grade 4, we have compared the numbers and locations of nuclear and neuropil aggregates with the known patterns of neuronal death in HD. We show that neuropil aggregates are much more common than nuclear aggregates and can be present in large numbers before the onset of clinical symptoms. There are also many more aggregates in cortex than in striatum, where they are actually uncommon. Although the striatum is the most affected region in HD, only 1–4% of striatal neurons in all grades of HD have nuclear aggregates. Neuropil aggregates, which we have identified by electron microscopy to occur in dendrites and dendritic spines, could play a role in the known dendritic pathology that occurs in HD. Aggregates increase in size in advanced grades, suggesting that they may persist in neurons that are more likely to survive. Ubiquitination is apparent in only a subset of aggregates, suggesting that ubiquitin-mediated proteolysis of aggregates may be late or variable.

https://www.jneurosci.org/content/jneuro/19/7/2522.full.pdf

Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology

Two different compensatory mechanisms are engaged when the nervous system senses errors during a reaching movement. First, on-line feedback control mechanisms produce in-flight corrections to reduce errors in the on-going movement. Second, these errors modify the internal model with which the motor plan is transformed into motor commands for the subsequent movements. What are the neural mechanisms of these compensatory systems? In a previous study, we reported that while on-line error correction was disturbed in patients with Huntington's disease (HD), it was largely intact in patients with cerebellar degeneration. Here we altered dynamics of reaching and studied the effect of error in one trial on the motor commands that initiated the subsequent trial. We observed that in patients with cerebellar degeneration, motor commands changed from trial-to-trial by an amount that was comparable to control subjects. However, these changes were random and were uninformed by the error in the preceding trial. In contrast, the change in motor commands of HD patients was strongly related to the error in the preceding trial. This error-dependent change had a sensitivity that was comparable to healthy controls. As a result, HD patients exhibited no significant deficits in adapting to novel arm dynamics, whereas cerebellar subjects were profoundly impaired. These results demonstrate a double dissociation between on-line and trial-to-trial error correction suggesting that these compensatory mechanisms have distinct neural bases that can be differentially affected by disease.

/pdf/intact-ability-to-learn-internal-models-of-arm-dynamics-in-bdrgblrhgb.pdf

Intact ability to learn internal models of arm dynamics in Huntington's disease but not cerebellar degeneration.

Objective: To determine whether volumes of hippocampus and amygdala are abnormal in people with autism. Background: Neuropathologic studies of the limbic system in autism have found decreased neuronal size, increased neuronal packing density, and decreased complexity of dendritic arbors in hippocampus, amygdala, and other limbic structures. These findings are suggestive of a developmental curtailment in the maturation of the neurons and neuropil. Methods: Measurement of hippocampus, amygdala, and total brain volumes from 1.5-mm coronal, spoiled gradient-recalled echo MRI scans in 14 non–mentally retarded autistic male adolescents and young adults and 14 individually matched, healthy community volunteers. Results: Amygdala volume was significantly smaller in the autistic subjects, both with ( p = 0.006) and without ( p = 0.01) correcting for total brain volume. Total brain volume and absolute hippocampal volume did not differ significantly between groups, but hippocampal volume, when corrected for total brain volume, was significantly reduced ( p = 0.04) in the autistic subjects. Conclusions: There is a reduction in the volume of amygdala and hippocampus in people with autism, particularly in relation to total brain volume. The histopathology of autism suggests that these volume reductions are related to a reduction in dendritic tree and neuropil development, and likely reflect the underdevelopment of the neural connections of limbic structures with other parts of the brain, particularly cerebral cortex.

MRI volumes of amygdala and hippocampus in non-mentally retarded autistic adolescents and adults.

The purpose of our study was to determine the relationship between mutant huntingtin (Htt) and mitochondrial dynamics in the progression of Huntington's disease (HD). We measured the mRNA levels of electron transport chain genes, and mitochondrial structural genes, Drp1 (dynamin-related protein 1), Fis1 (fission 1), Mfn1 (mitofusin 1), Mfn2 (mitofusin 2), Opa1 (optric atrophy 1), Tomm40 (translocase of outermembrane 40) and CypD (cyclophilin D) in grade III and grade IV HD patients and controls. The mutant Htt oligomers and the mitochondrial structural proteins were quantified in the striatum and frontal cortex of HD patients. Changes in expressions of the electron transport chain genes were found in HD patients and may represent a compensatory response to mitochondrial damage caused by mutant Htt. Increased expression of Drp1 and Fis1 and decreased expression of Mfn1, Mfn2, Opa1 and Tomm40 were found in HD patients relative to the controls. CypD was upregulated in HD patients, and this upregulation increased as HD progressed. Significantly increased immunoreactivity of 8-hydroxy-guanosine was found in the cortical specimens from stage III and IV HD patients relative to controls, suggesting increased oxidative DNA damage in HD patients. In contrast, significantly decreased immunoreactivities of cytochrome oxidase 1 and cytochrome b were found in HD patients relative to controls, indicating a loss of mitochondrial function in HD patients. Immunoblotting analysis revealed 15, 25 and 50 kDa mutant Htt oligomers in the brain specimens of HD patients. All oligomeric forms of mutant Htt were significantly increased in the cortical tissues of HD patients, and mutant Htt oligomers were found in the nucleus and in mitochondria. The increase in Drp1, Fis1 and CypD and the decrease in Mfn1 and Mfn2 may be responsible for abnormal mitochondrial dynamics that we found in the cortex of HD patients, and may contribute to neuronal damage in HD patients. The presence of mutant Htt oligomers in the nucleus of HD neurons and in mitochondria may disrupt neuronal functions. Based on these findings, we propose that mutant Htt in association with mitochondria imbalance and mitochondrial dynamics impairs axonal transport of mitochondria, decreases mitochondrial function and damages neurons in affected brain regions of HD patients.

/pdf/abnormal-mitochondrial-dynamics-mitochondrial-loss-and-4aj1s52kxz.pdf

Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage

The basal ganglia are a highly interconnected set of subcortical nuclei and major atrophy in one or more regions may have major effects on other regions of the brain. Therefore, the striatum which is preferentially degenerated and receives projections from the entire cortex also affects the regions to which it targets, especially the globus pallidus and substantia nigra pars reticulata. Additionally, the cerebral cortex is itself severely affected as are many other regions of the brain, especially in more advanced cases. The cell loss in the basal ganglia and the cerebral cortex is extensive. The most important new findings in Huntington’s disease pathology is the highly variable nature of the degeneration in the brain. Most interestingly, this variable pattern of pathology appears to reflect the highly variable symptomatology of cases with Huntington’s disease even among cases possessing the same number of CAG repeats.

The Neuropathology of Huntington’s Disease

Neuropathologic and neuroimaging studies have suggested that frontal lobes are affected in Huntington's disease (HD), and that atrophy in this region may be associated with some of the cognitive impairment and clinical decline observed in patients with HD. We measured gray and white matter volumes within the frontal lobes on MRI for 20 patients with HD (10 mildly affected and 10 moderately affected) and 20 age- and sex-matched control subjects. We also correlated frontal lobe measurements with measures of symptom severity and cognitive function. Patients who were mildly affected had frontal lobe volumes (both gray and white matter) essentially identical to those of control subjects, despite clearly abnormal basal ganglia. Patients who were moderately affected demonstrated significant reductions in total frontal lobe volume (17%) and frontal white matter volume (28%). Frontal lobe white matter volume reductions, but not total frontal lobe volume reductions, were disproportionately greater than overall brain volume reductions (17%). Frontal lobe volume correlated with symptom severity and general cognitive function, but these correlations did not remain significant after taking into account total brain volume. We conclude that cognitive impairment and symptom severity are associated with frontal lobe atrophy, but this association is not specific to the frontal lobes. Frontal lobe atrophy (like total brain atrophy) occurs in later stages of increasing HD symptom severity and this atrophy primarily involves white matter.

Frontal lobe volume in patients with Huntington's disease

389. Brain MRI changes in schizophrenia - Effects of sex and specificity

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Frontal lobe volume in patients with Huntington's disease

389. Brain MRI changes in schizophrenia - Effects of sex and specificity