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Updated: Jul 26, 2025
Whole-brain Segmentation and Change-point Analysis of Anatomical Brain MRI—Application in Premanifest Huntington's Disease
Published on: June 9, 2018
Selective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields
Pierre Wibawa1,2,3, Mark Walterfang1,2,4, Charles B Malpas1,2
1Neuropsychiatry, Royal Melbourne Hospital, Parkville, Victoria, Australia.
Insights
Huntington disease (HD) causes memory loss due to hippocampal subfield atrophy, particularly in the perforant pathway. This atrophy correlates with disease progression and genetic markers in early symptomatic individuals.
Area of Science:
- Neuroimaging
- Neurodegeneration
- Human Genetics
Background:
- Huntington disease (HD) is characterized by memory impairment suggesting hippocampal dysfunction.
- Previous studies lack consistent structural evidence implicating the entire hippocampus, suggesting localized atrophy in specific subregions.
Purpose of the Study:
- To investigate structural changes in hippocampal subfields in early symptomatic (symp-HD), pre-symptomatic (pre-HD), and control individuals.
- To correlate hippocampal subfield volumes with genetic and clinical markers of HD progression.
Main Methods:
- T1-weighted MRI scans from the IMAGE-HD study were analyzed using FreeSurfer 7.0.
- Volumes of hippocampal subfields were compared across 36 symp-HD, 40 pre-HD, and 36 control participants over 36 months.
- Mixed-model analyses were employed to assess group differences and longitudinal changes.
Main Results:
- Significantly lower subfield volumes were observed in symp-HD compared to pre-HD and control groups, specifically in the presubiculum, subiculum, dentate gyrus, tail, and right molecular layer.
- These adjoining subfields formed a principal component showing accelerated atrophy in symp-HD.
- No significant volume differences were found between pre-HD and control groups.
- CAG repeat length and disease burden score correlated with volumes in the presubiculum, molecular layer, tail, and perforant pathway subfields in combined HD groups.
- Left tail and perforant pathway subfield volumes correlated with motor onset in the pre-HD group.
Conclusions:
- Atrophy in specific hippocampal subfields, particularly within the perforant pathway, is evident in early symptomatic HD.
- This selective atrophy may explain the memory deficits observed at this stage of the illness.
- The association of these subfield volumes with genetic and clinical markers highlights their susceptibility to mutant Huntingtin and disease progression.
Introduction:
While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions.
Methods:
We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months.
Results:
Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group.
Conclusions:
Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.
