Virginia M. Hogg

Cell loss in the motor and cingulate cortex correlates with symptomatology in Huntington’s disease

Huntingtons disease is an autosomal dominant inherited neurodegenerative disease with motor symptoms that are variably co-expressed with mood and cognitive symptoms, and in which variable neuronal degeneration is also observed in the basal ganglia and the cerebral cortex. We have recently shown that the variable symptomatology in Huntingtons disease correlates with the variable compartmental pattern of GABAA receptor and cell loss in the striatum. To determine whether the phenotypic variability in Huntingtons disease is also related to variable neuronal degeneration in the cerebral cortex, we undertook a double-blind study using unbiased stereological cell counting methods to determine the pattern of cell loss in the primary motor and anterior cingulate cortices in the brains of 12 cases of Huntingtons disease and 15 controls, and collected detailed data on the clinical symptomatology of the patients with Huntingtons disease from family members and clinical records. The results showed a significant association between: (i) pronounced motor dysfunction and cell loss in the primary motor cortex; and (ii) major mood symptomatology and cell loss in the anterior cingulate cortex. This association held for both total neuronal loss (neuronal N staining) and pyramidal cell loss (SMI32 staining), and also correlated with marked dystrophic changes in the remaining cortical neurons. There was also an association between cortical cell loss and striatal neuropathological grade, but no significant association with CAG repeat length in the Huntingtons disease gene. These findings suggest that the heterogeneity in clinical symptomatology that characterizes Huntingtons disease is associated with variation in the extent of cell loss in the corresponding functional regions of the cerebral cortex whereby motor dysfunction correlates with primary motor cortex cell loss and mood symptomatology is associated with cell loss in the cingulate cortex.

A retrospective study of the impact of lifestyle on age at onset of Huntington disease

In transgenic mouse models of Huntington disease (HD) environmental enrichment significantly delays disease onset. A questionnaire‐based survey of 154 adults with diagnosed HD (mean 4.2 years postdiagnosis) and a known IT15 CAG repeat length, explored whether premorbid lifestyle may relate to age‐at‐onset (AO). Participants were drawn from HD outpatient clinics in Australia and New Zealand. Premorbid physical, intellectual, and passive activity levels were used to generate scores in the categories of leisure, nonleisure (education, occupation and domestic duties) and total lifestyle. AO was associated with increased CAG repeat length as expected (r = −0.72, P < 0.001), but also with a lifestyle that included higher levels of passive activity (r = −0.38, P < 0.001). Multiple linear regression modeling showed lifestyle passivity to be a variable independent of CAG repeat length in predicting AO (R2 = 0.54, b = −0.22, P = 0.005). Comparison of the mean AO across tertiles of lifestyle passivity scores showed onset 4.6 years (95% CI = 1.3–7.9) later in the least compared with the most passive tertile. CAG repeat length was also shown to predict lifestyle passivity (R2 = 0.12, b = 1.08, P < 0.0005). Neither intellectual nor physical activity showed significant relationships to AO or CAG repeat length in this cohort. Our study leads to two conclusions: that a passive lifestyle may be a preclinical expression of HD, and that it actually contributes to the earlier onset of symptoms. Overcoming the tendency to be passive may substantially delay onset of HD.

Striatal parvalbuminergic neurons are lost in Huntington's disease: implications for dystonia

Although dystonia represents a major source of motor disability in Huntingtons disease (HD), its pathophysiology remains unknown. Because recent animal studies indicate that loss of parvalbuminergic (PARV+) striatal interneurons can cause dystonia, we investigated if loss of PARV+ striatal interneurons occurs during human HD progression, and thus might contribute to dystonia in HD. We used immunolabeling to detect PARV+ interneurons in fixed sections, and corrected for disease‐related striatal atrophy by expressing PARV+ interneuron counts in ratio to interneurons co‐containing somatostatin and neuropeptide Y (whose numbers are unaffected in HD). At all symptomatic HD grades, PARV+ interneurons were reduced to less than 26% of normal abundance in rostral caudate. In putamen rostral to the level of globus pallidus, loss of PARV+ interneurons was more gradual, not dropping off to less than 20% of control until grade 2. Loss of PARV+ interneurons was even more gradual in motor putamen at globus pallidus levels, with no loss at grade 1, and steady grade‐wise decline thereafter. A large decrease in striatal PARV+ interneurons, thus, occurs in HD with advancing disease grade, with regional variation in the loss per grade. Given the findings of animal studies and the grade‐wise loss of PARV+ striatal interneurons in motor striatum in parallel with the grade‐wise appearance and worsening of dystonia, our results raise the possibility that loss of PARV+ striatal interneurons is a contributor to dystonia in HD.

Cortical Interneuron Loss and Symptom Heterogeneity in Huntington Disease

The cellular basis of variable symptoms in Huntington disease (HD) is unclear. One important possibility is that degeneration of the interneurons in the cerebral cortex, which play a critical role in modulating cortical output to the basal ganglia, might play a significant role in the development of variable symptomatology in HD. This study aimed to examine whether symptom variability in HD is specifically associated with variable degeneration of cortical interneurons.

Widespread Heterogeneous Neuronal Loss Across the Cerebral Cortex in Huntington's Disease

Huntingtons disease is an autosomal dominant neurodegenerative disease characterized by neuronal degeneration in the basal ganglia and cerebral cortex, and a variable symptom profile. Although progressive striatal degeneration is known to occur and is related to symptom profile, little is known about the cellular basis of symptom heterogeneity across the entire cerebral cortex. To investigate this, we have undertaken a double blind study using unbiased stereological cell counting techniques to determine the pattern of cell loss in six representative cortical regions from the frontal, parietal, temporal, and occipital lobes in the brains of 14 Huntingtons disease cases and 15 controls. The results clearly demonstrate a widespread loss of total neurons and pyramidal cells across all cortical regions studied, except for the primary visual cortex. Importantly, the results show that cell loss is remarkably variable both within and between Huntingtons disease cases. The results also show that neuronal loss in the primary sensory and secondary visual cortices relate to Huntingtons disease motor symptom profiles, and neuronal loss across the associational cortices in the frontal, parietal and temporal lobes is related to both Huntingtons disease motor and to mood symptom profiles. This finding considerably extends a previous study (Thu et al., Brain, 2010; 133:1094-1110) which showed that neuronal loss in the primary motor cortex was related specifically to the motor symptom profiles while neuronal loss in the anterior cingulate cortex was related specifically to mood symptom profiles. The extent of cortical cell loss in the current study was generally related to the striatal neuropathological grade, but not to CAG repeat length on the HTT gene. Overall our findings show that Huntingtons disease is characterized by a heterogeneous pattern of neuronal cell loss across the entire cerebrum which varies with symptom profile.

Aggregate distribution in frontal and motor cortex in Huntington's disease brain

Insoluble protein aggregates have been considered a pathological hallmark of Huntingtons disease and other polyglutamine disorders. In this study the number of aggregates was assessed in the superior frontal gyrus and motor cortex of seven Huntingtons disease patients and was compared with the symptoms (motor/mood) these patients displayed during the course of the disease. Regardless of the pattern of symptoms present in the patients, there was a consistently higher number of nuclear and non-nuclear aggregates in the superior frontal gyrus than in the motor cortex. This suggests that there is a consistent regional difference in the density of aggregates and that this consistency is not reflected in the variable symptomatology between cases.

Selective Neurodegeneration, Neuropathology and Symptom Profiles in Huntington’s Disease

Huntingtons disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the Huntington gene (HD) also known as IT15. Despite the disease being caused by dysfunction ofa single gene, expressed as an expanded polyglutamine in the huntingtin protein, there is a major variability in the symptom profile of patients with Huntingtons disease as well as great variability in the neuropathology. The symptoms vary throughout the course of the disease and vary greatly between cases. These symptoms present as varying degrees of involuntary movements, mood, personality changes, cognitive changes and dementia. To determine whether there is a morphological basis for this symptom variability, recent studies have investigated the cellular and neurochemical changes in the striatum and cerebral cortex in the human brain to determine whether there is a link between the pathology in these regions and the symptomatology shown by individual cases. These studies together revealed that cases showing mainly mood symptom profiles correlated with marked degeneration in the striosomal compartment of the striatum, or in the anterior cingulate gyrus of the cerebral cortex. In contrast, in cases with mainly motor symptoms neurodegeneration was especially marked in the primary motor cortex with variable degeneration in both the striosomes and matrix compartments of the striatum. These studies suggest that the variable degeneration of the striatum and cerebral cortex correlates with the variable profiles of Huntingtons disease.

Globus pallidus degeneration and clinicopathological features of Huntington disease.

Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology.

Globus pallidus degeneration and clinico-pathological features of Huntington's disease

Numerous studies have focused on striatal neurodegeneration in Huntington disease (HD). In comparison, the globus pallidus (GP), a main striatal output nucleus, has received less focus in HD research. This study characterizes the pattern of neurodegeneration in 3 subdivisions of the human GP, and its relation to clinical symptomatology.

Young children's ability to find objects reflected in mirrors

Recent, well-controlled studies have reported that children as young as 2 years of age do not show reliable use of mirrors to localise reflected objects. A new method was used to test the ability of 2-, 3- and 4-year-old children to use a mirror to search for a hidden object. A toy reflected in a mirror was hidden randomly behind one of two identical small screens placed in front of the children. Despite the difficulty of the task, spatially accurate searching for the toy emerged in the 4-year-old group. The possible relationship of this development in the use of mirror reflection to other age changes in representational abilities is discussed, although the mechanisms underlying the age change remain to be clarified.