Clinical and Molecular Correlates of Abnormal Changes in the Cerebellum and Globus Pallidus in Fragile X Premutation

Abstract

BackgroundFragile X premutation carriers (55–200 CGG triplets) may develop a progressive neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), after the age of 50. The neuroradiologic markers of FXTAS are hyperintense T2-signals in the middle cerebellar peduncle—the MCP sign. We recently noticed abnormal T2-signals in the globus pallidus in male premutation carriers and controls but the prevalence and clinical significance were unknown.MethodsWe estimated the prevalence of the MCP sign and pallidal T2-abnormalities in 230 male premutation carriers and 144 controls (aged 8–86), and examined the associations with FXTAS symptoms, CGG repeat length, and iron content in the cerebellar dentate nucleus and globus pallidus.ResultsAmong participants aged ≥45 years (175 premutation carriers and 82 controls), MCP sign was observed only in premutation carriers (52 vs. 0%) whereas the prevalence of pallidal T2-abnormalities approached significance in premutation carriers compared with controls after age-adjustment (25.1 vs. 13.4%, p = 0.069). MCP sign was associated with impaired motor and executive functioning, and the additional presence of pallidal T2-abnormalities was associated with greater impaired executive functioning. Among premutation carriers, significant iron accumulation was observed in the dentate nucleus, and neither pallidal or MCP T2-abnormalities affected measures of the dentate nucleus. While the MCP sign was associated with CGG repeat length >75 and dentate nucleus volume correlated negatively with CGG repeat length, pallidal T2-abnormalities did not correlate with CGG repeat length. However, pallidal signal changes were associated with age-related accelerated iron depletion and variability and having both MCP and pallidal signs further increased iron variability in the globus pallidus.ConclusionsOnly the MCP sign, not pallidal abnormalities, revealed independent associations with motor and cognitive impairment; however, the occurrence of combined MCP and pallidal T2-abnormalities may present a risk for greater cognitive impairment and increased iron variability in the globus pallidus.

Artificial neural network applied to fragile X-associated tremor/ataxia syndrome stage diagnosis based on peripheral mitochondrial bioenergetics and brain imaging outcomes

“…The other three were the volumes of the WMHs, whole brain, and ventricles normalized by intracranial volume. These outcomes are supported by previous studies on brain MRI imaging changes associated with FXTAS progression, which include white matter lesions, generalized brain atrophy, ventricular enlargement, and accumulation of iron deposits in the subcortical nuclei 16 , 51 – 54 . While some of these changes can be detected before overt development of FXTAS symptoms, including loss of cerebellar and brain stem volume 55 , 56 , changes in white matter tracts 57 , and modifications in functional MRI recordings 58 , microstructural white matter disease in the middle cerebellar peduncles and the genu of the corpus callosum correlates with the severity of executive dysfunction and impairments in processing speed in carriers 59 .…”

“…Intriguingly, the two binary variables, the presence of WMHs in the middle cerebellar peduncles and the cerebellum-brainstem, were not selected by ANN for FXTAS stage classification. In our recent study of 175 carriers and 82 controls aged ≥ 45 years 54 , the WMHs presence in the middle cerebellar peduncles was detected only in the premutation carriers (52%) with significant correlations with impaired motor and executive function in those carriers with > 75 CGG repeats. In the current study of 111 carriers, the prevalence of WMHs in the middle cerebellar peduncles and WMHs in the cerebellum and brainstem increased with FXTAS stage (middle cerebellar peduncles/cerebellum and brainstem: Stage 0–1, 6.1%/57.6%; Stage 2, 25%/80%; Stage 3, 42.1%/94.7; Stages 4–5, 80%/100%).…”

A postmortem MRI study of cerebrovascular disease and iron content at end-stage of fragile X-associated tremor/ataxia syndrome

“…The prominence of the MCP sign in FXTAS pathophysiology was demonstrated by its independent associations with cerebellar ataxia, intention tremor, and executive function de cits. Although the pallidal sign was not associated with motor or cognitive de cits independently, having both MCP and pallidal signs was associated with greater impairment in executive function and iron content variability in the globus pallidus 11 .…”

“…We recently expanded T2 ndings in FXTAS to include abnormal signals in the globus pallidus ("pallidal sign") displaying hyperintensities in the center surrounded by hypointensive T2 signals. We explored clinical signi cance of both MCP and pallidal signs 11 . The prominence of the MCP sign in FXTAS pathophysiology was demonstrated by its independent associations with cerebellar ataxia, intention tremor, and executive function de cits.…”

Cerebellum neuropathology and motor skill deficits in fragile X syndrome

“…Thus, structural abnormalities in the cerebellum of FXTAS patients can be clinically observed on microtubule‐associated protein hyperintensities, which is employed as the primary diagnostic criterion (Brunberg et al, 2002). The cerebellar peduncle hypersignal T2‐MCP is a neuroradiologic marker of FXTAS (Wang et al, 2022). Consistent with the neuropathological and MRI of FXTAS, these studies suggest an association between cerebellar degeneration and neuromotor skill deficits and cognitive impairment.…”