The paper reviewed here is ‘Striosomes and Mood Dysfunction in Huntington’s Disease’ by Tippett and colleagues and freely available here. The authors write in their abstract that
‘we report here a significant association between pronounced mood dysfunction in Huntington’s Disease patients and differential loss of the GABAa receptor marker in striosomes of the striatum‘
In the introduction, the authors describe the importance of the GABAergic projection neurons in the striatum in the pathogenesis of Huntington’s Disease (HD) as well as noting the initial involvement of those neurons that project to the external pallidum.
In order to arrive at the above conclusions, the researchers compared 35 people with Huntington’s Disease with 13 control cases. This was a post-mortem study, retrospective in nature. The preparation of brains is described in the methodology section and the researchers state that the pathological grading was conducted by a pathologist with expertise in HD. For subjects with HD, the number of CAG repeats (associated with disease severity) in the gene region was assessed. The staining method for the specimens is then described.
As this is a retrospective study and the researchers were interested in correlating clinical features with pathological findings they required an instrument that was capable of capturing clinical features retrospectively. For this purpose they designed questionnaire for assessing motor, mood and cognitive components of the disease. The details surrounding the construction of this questionnaire are given in the supplementary material. The questionnaire is administered to family members who recall information retrospectively. They validated this questionnaire by testing it in a family with HD who had also undergone testing on other clinical measures including the HADS for depression and anxiety.
Pathological specimens were divided into predominantly striatal loss, predominantly matrix or loss or a mixture of both. The researchers reported that ‘mood dysfunction indices again were significantly higher in the striosome-damaged group at clinical onset’. The striosome damage in this case refers to the loss of GABAa receptor immunostaining in these regions. Although the CAG repeat correlations reproduced some previously well-established findings, the researchers also found that the average number of CAG repeats was significantly lower in the striosome-damaged group and further that the striosome-damaged group had a later-onset of disease.
This is a difficult paper to read as it covers a number of specialised areas including in particular the preparation and assessment of the pathological specimens. Nevertheless multidisciplinary studies of this type are essential in gaining a better understanding of the illness and correlating pathology with certain clinical features. I didn’t understand the finer points of the preparation of the specimens. I would argue though that striatal loss should be a continuous rather than discrete process and for the purposes of data-analysis there were three groupings (e.g. predominantly striatal loss). However, when it came to the assessment of clinical features, I think it’s not unreasonable to say that there are obvious methodological difficulties with retrospective assessment of clinical features particularly as in Huntington’s Disease they manifest in several different areas including motor functions and cognition. There are well established measures for assessment of motor function in HD in living patients and a prospective design would be much better placed to test the hypothesis generated in the study. In such a design, clinical measures would be repeated at intervals and the most recent could be used in any post-mortem correlational analysis. In this study, one obvious objection would be a recall bias by informants in favour of their understanding of how the disease progresses. This might not tally up with the actual disease progression. However the researchers support their use of this method by the inclusion of a validation study in the supplemental material in a family with HD although even here large replication studies would improve confidence.
The study has generated a number of testable hypotheses. Furthermore these hypotheses place the structure of the striatum squarely in the centre of they hypothesis.
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