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

Discussion

These findings in gray matter nuclei are broadly in accordance with but expand the limited findings from the neuroimaging literature in NPC. The initial case series in which MR imaging was included had based analyses on visual inspection and generally reported anterior cortical and cerebellar atrophy and callosal thinning,^2,3 though hippocampal atrophy has been reported.^3,14 Our previous voxel-based study described reductions in volume in the thalamus, hippocampus, striatum, and cerebellum,⁵ though it did not implicate all striatal nuclei. Tedeschi et al¹⁵ described proton MR spectroscopy parameters in 10 (mostly adult) patients compared with controls and showed reduced NAA/creatine ratios in the caudate. Battisti et al¹⁶ described significant frontal cortex, thalamic, and cerebellar hypoperfusion on FDG-PET associated with illness progression. Zaaraoui et al¹⁷ compared 2 patients individually against a group of controls by using magnetization transfer ratio and found reductions in the thalamus, putamen and globus pallidus, and cerebellum. The current study confirms the findings from these small series that volumetric changes occur in thalamic, hippocampal, and striatal regions in NPC and suggests that these changes progress with illness.

These findings also correlate with changes described in animal models of NPC and the limited number of human neuropathologic studies. In feline NPC models, the formation of axonal spheroids occurs in gamma-aminobutyric acid–ergic neuronal populations in the cerebellum, brain stem, hippocampus, and basal ganglia.¹⁸ In murine NPC models, intracellular storage of gangliosides occurs maximally in large pyramidal neurons, Purkinje cells in the cerebellum, and neurons in the lateral thalamus, hippocampus, and brain stem^6,19; and maximal neuronal loss occurs in the thalamus and cerebellum.^19⇓–21 The earliest human neuropathologic studies showed that neuroaxonal dystrophy was maximal in the thalamus and cerebellum.²² In humans, neuropathologic studies demonstrated that noncerebellar brain regions develop NFTs in the basal ganglia, thalamus, brain stem, cerebral cortex, and hippocampus.^7,23,24 The convergent animal and human data suggest that in addition to notable cerebellar Purkinje cell loss, significant changes also occur in the thalamus and hippocampus. While most visually rated MR imaging reports in NPC disease focus on atrophy in surface regions such as the cerebral cortex and cerebellum, which are more obvious on T1-weighted imaging, the atrophy of deeper nuclei may be less obvious.

Neuronal loss in the hippocampus and thalamus, the subcortical regions of greatest and most significant volume loss in this study, would be expected to cause marked neuropsychological impairment in NPC. The hippocampus plays a key role in episodic and declarative memory, and because the hippocampus projects to the anterior thalamus via the fornix (to the mammillary bodies) and then via the mamillothalamic tract, pathology in the thalamus is known to cause significant impairment in both new memory encoding and executive function. Cognitive impairment is a core symptom cluster in adult NPC, in addition to movement disturbance, gaze palsy, and psychiatric illness,^2,3 and is present, to some degree, in all adult patients at diagnosis and progresses with time.² Significant memory and executive impairment have been described in a number of adult patients in case reports^2,3,14,25; however, few studies have systematically examined cognitive function in adult patients with NPC. Klarner et al²⁶ demonstrated that verbal memory impairment was present in most adult patients with moderate progression, whereas executive impairment occurred early. Hinton et al²⁷ also showed that verbal memory impairment was present in 13/14 adolescent and adult patients, and all patients had demonstrably impaired executive function. These findings suggest that the memory impairment in adult NPC is related to the primacy of pathology affecting the hippocampus in particular and the thalamus.

Results of the vertex analyses for the hippocampus showed significant reductions in the CA1 region, a zone vulnerable to metabolic stress and where NFT formation is regionally concentrated in human patients with NPC.²³ The CA1 region is crucial for autobiographic memory retrieval and spatial learning.²⁸ The subiculum, where particular reductions were seen on the left (and where NFTs are also found but are less numerous than in CA1²³), is principally concerned with spatial navigation and mnemonic processing.²⁹ These findings consolidate the assertion that memory impairment in adult NPC is driven by hippocampal pathology.

In addition, the regional reductions seen in the thalamus implicated the anterior and lateral dorsal nuclei and the pulvinar. The anterior nucleus receives input from the hippocampus, cingulate, and hypothalamus, projecting back to these regions, and is involved in recognition memory; pathology in this nucleus results in varying levels of verbal and spatial memory impairment.³⁰ The lateral dorsal nucleus has similar connections and appears to act in concert with it in spatial learning and memory.³¹ The pulvinar plays a key role in stimulus-driven visual attention and has reciprocal connections throughout the cortex, particularly the frontal and visual cortices.³² It may also integrate cortical control of voluntary eye movements from the frontal cortex with reflexive movements that originate in the superior colliculus,³³ and pathology may thus contribute to the deficits seen in self-generated saccades and antisaccade performance in adult NPC.³³ It is possible that the thalamic volume loss is primary, related to both altered neuronal ultrastructure and NFT formation in this region,²³ but given the close functional relationship with the hippocampus, there may be a contribution of trans-synaptic degeneration secondary to deafferentation, which is known to affect the anterior thalamic nuclei in hippocampal sclerosis.³⁴

The volumetric reductions in the basal ganglia, though not significant when corrected for multiple comparisons, are consistent with the motor findings in adult NPC. Whereas ataxia follows early loss of cerebellar Purkinje neurons, dystonia is also common, with Parkinsonism and chorea occurring in a small group of patients.² Only a small group of studies has specifically examined dystonia in NPC. Floyd et al³⁵ examined 15 adult patients with NPC by using accelerometry and surface electromyography; 13/15 showed physiologic evidence of action tremor; 6/15, of dystonia; and 2/15, of myoclonus. In 14 adolescent/adult patients and 14 matched controls, spiral analysis of upper limb kinematics found tremor in most patients but also showed abnormal pressure-time relationships consistent with focal dystonia.³⁶ Dystonia occurs in concert with the pathology of the basal ganglia, the putamen in particular. This study showed the greatest volumetric loss in the putamen, followed by caudate and pallidal volumes. The basal ganglia is a known site of neurofibrillary tangle formation in human patients with NPC^7,23 and of marked neuroaxonal dystrophy in the feline NPC model.³⁷

Cerebellar dysfunction may also play a role in contributing to dystonia, via cerebellar-basal ganglia connections through the thalamus, red nucleus, and zona incerta³⁸; the interaction of both cerebellar and basal ganglia pathology may thus underpin the high rate of dystonia in adult patients with NPC. The vertex analysis of the caudate showed that dorsolateral regions were particularly affected; this region of the caudate is a central node in the dorsolateral prefrontal cortical loop, which reciprocally connects this region of the caudate to the dorsolateral prefrontal cortex. This circuit subserves executive function, such as problem-solving, self-direction and judgment, and shifting behavioral set. The executive impairment frequently described in the illness^26,27 may thus also be increased by dysfunction in this frontostriatal circuitry. The caudate also plays a role in inhibiting saccade neurons in the superior colliculus³⁹; damage to this pathway leads to errors on the antisaccade task, a task that patients with NPC perform poorly if at all.⁴⁰

The nucleus accumbens showed modest nonsignificant volumetric reductions in our study. The accumbens is thought to function as the interface between limbic and motor systems and to play a significant role in goal-directed behavior, the reward system, and addiction.⁴¹ Abnormalities in the accumbens have also been implicated in schizophrenia,⁴² and if function of the accumbens is impaired in NPC, it may be related to the high prevalence of schizophrenia-like psychosis in the disorder.^2,3 The only study to examine the accumbens in NPC, however, found no reductions in number but did find abnormal morphology in accumbal cholinergic neurons.¹⁹

Finally, modest reductions were seen in amygdala size in our adult NPC cohort. The amygdala is known to play a role in emotional regulation and social cognition; bilateral amygdala lesions are known to result in the lack of awareness of threat and in social disinhibition.⁴³ Social disinhibition and a lack of interpersonal “distance” have frequently been described in adult patients with NPC.^3,14 Neurofibrillary tangles and distended neurons have been described in the amygdala in human patients with NPC ^7,23; thus, it may be that disruptions to the normal amygdalar function of modulating social interactions may underpin the phenomenon of impaired social inhibition in adult patients with NPC.

An intriguing interpretation of our findings is that the neuropathology intrinsic to NPC preferentially affects brain regions that serve as large “connection hubs” (ie, regions that are most highly anatomically connected to other brain regions, such as the hippocampus, striatum, and thalamus).⁴⁴ As described, these regions are in areas where there is significant overlap between regional toxic ganglioside excess and NFT accumulation. It is also possible that given the widespread white matter changes in NPC,^4,5 volumetric loss in these regions is reflective of pathology in their attenuated anatomic interconnections. If these hub regions are preferentially affected, then this potential suggests that select neocortical regions that are similarly attenuated, such as entorhinal and retrosplenial cortices and frontal regions such as orbitofrontal and dorsolateral prefrontal zones,^44⇓–46 may also show regional vulnerability. We have extended our initial exploratory VBM approach with a specific examination of subcortical structures, and the role of neocortical regions in NPC pathology warrants testing by using specific cortically based analysis methods.

The key limitation of this study is its sample size, which, despite the rarity of adult NPC, remains modest. This size limits the generalizability of our findings to all patients, particularly pediatric patients. However, this limitation is mitigated by the broad age range of our patient group, from early adulthood to middle age, which affords significant variance in our sample as seen in Table 1. Sample size also limits our statistical approach, preventing more sophisticated analyses such as multivariate regression. Given the high number of between-group comparisons and correlations for this sample size, we have attempted to control for multiple comparisons by using a method that aims to balance type I and II errors. In addition, volumetric analysis is limited in its capacity to inform us about brain function; only when significant neuronal loss has already occurred would volumetric changes follow. Thus our method is relatively insensitive to early neuronal changes that cause functional but not gross anatomic disruption to the deep gray matter regions involved in this study. Other MR imaging–based measures that probe function and microstructure, such as MR spectroscopy or magnetization transfer ratio, may be more sensitive to early changes but can be limited by voxel size and placement.