Subcortical Volumetric Reductions in Adult Niemann-Pick Disease Type C: A Cross-Sectional Study

BACKGROUND AND PURPOSE:Voxel-based analysis has suggested that deep gray matter rather than cortical regions is initially affected in adult Niemann-Pick type C. We sought to examine a range of deep gray matter structures in adults with NPC and relate these to clinical variables.MATERIALS AND METHODS:Ten adult patients with NPC (18–49 years of age) were compared with 27 age- and sex-matched controls, and subcortical structures were automatically segmented from normalized T1-weighted MR images. Absolute volumes (in cubic millimeters) were generated for a range of deep gray matter structures and were compared between groups and correlated with illness variables.RESULTS:Most structures were smaller in patients with NPC compared with controls. The thalamus, hippocampus, and striatum showed the greatest and most significant reductions, and left hippocampal volume correlated with symptom score and cognition. Vertex analysis of the thalamus, hippocampus, and caudate implicated regions involved in memory, executive function, and motor control.CONCLUSIONS:Thalamic and hippocampal reductions may underpin the memory and executive deficits seen in adult NPC. Volume losses in other subcortical regions may also be involved in the characteristic range of motor, psychiatric, and cognitive deficits seen in the disease.

Niemann-Pick disease type C (Online Mendelian Inheritance in Man 257220 and 607625; http://www.ncbi.nlm.nih.gov/omim) is a progressive neurogenetic disorder, resulting from mutations to the genes encoding for the NPC1/NPC2 proteins. Impaired function of NPC1/NPC2 results in altered intracellular sterol trafficking and accumulation of gangliosides and other glycosphingolipids.¹ While most patients present with neurovisceral signs in childhood, in 20% of cases, the illness presents in adults.¹ Adults demonstrate a range of central nervous system symptoms, including ataxia, dystonia, vertical supranuclear ophthalmoplegia, cognitive impairment, and psychotic illness.^2,3 Because of the rarity of adult patients, few studies have examined brain changes in the disease at a group level and their relationship with clinical variables.^4,5We previously used VBM to demonstrate that gray matter changes in NPC were most significant in basal and subcortical regions, with reductions in volume in the hippocampus, thalamus, cerebellum, and striatum.⁵ These findings matched both animal and human models of NPC, where these regions show the greatest ganglioside accumulation,⁶ and where humans develop NFTs.⁷ Given that the most significant reductions were in medial and subcortical gray matter regions, we aimed to both validate and extend on our previous findings by using a subcortical segmentation approach. This provided regional volumetric data for a range of subcortical structures, which were then correlated with illness variables. We subsequently used vertex analysis to examine localized changes in brain structures that showed significant volumetric change.