MRI and SPECT of midbrain and striatal degeneration in fragile X-associated tremor/ataxia syndrome

Abstract

Sirs: Fragile X-associated tremor/ataxia syndrome (FXTAS) is an inclusion disorder with an estimated prevalence among men > 50 years of age up to 1 in 3000 in the general population [16]. The neurologic phenotype of FXTAS is variable and includes intention tremor, ataxia, parkinsonism, and cognitive decline [7–10]. We report evidence from MRI and SPECT that the fragile X premutation determines a subcortical gray matter degeneration involving the midbrain and striatum associated with parkinsonian signs. We studied five men with FXTAS and documentation of the premutation by DNA testing whose genetic and clinical data are detailed in Table 1. In all patients prior MRI showed characteristic symmetric areas of signal changes in the peridentate, middle cerebellar peduncle and cerebral white matter and diffuse brain atrophy [2, 5]. MRI was obtained in patients 1, 2, 4 and 5 at 1.5 T with a protocol including 1 mm thick T1-weighted 3D gradient echo images and 5 mm thick T2-weighted spin-echo (SE) images for evaluation of hypointensities suggestive for possible iron deposits in the basal ganglia [6, 14]. Bulk and shape of the midbrain were evaluated subjectively [12] and midbrain anteroposterior diameter was measured in patients and in 12 healthy subjects [15]. Basal ganglia signals in T2-weighted SE images were visually assessed. Midbrain evaluation in case 4 was performed on hard copies of prior MRI. SPECT examinations were obtained in patients 1, 3–5. They were injected with 111–185 MBq of [123I]FP-CIT for evaluation of striatal dopamine transporter (DAT) density. Patient 3 was also injected with 160 MBq of [123I] idobenzamide (IBZM) for evaluation of striatal dopamine D2 receptors. SPECT examinations were evaluated visually [1]. MRI and SPECT findings are reported in Table 1. Atrophy of the midbrain with an AP diameter smaller than 17 mm [15] was observed in all patients. The superior profile of the midbrain was concave in two patients (Fig. 1) and linear in three. Symmetric hypointensity in the putamen and caudate in T2-weighted SE images was present in all four patients examined with the protocol. DATscan SPECT in patients 3, 4 and 5 showed an asymmetric decrease of the striatum tracer uptake which was mild in cases 4 and 5 and marked in case 3 (Fig. 1). IBZM SPECT in patient 3 revealed almost complete absence of striatal tracer uptake (Fig. 1) Parkinsonism is one of the most common other diagnoses given to FXTAS patients which also include tremor, ataxia, dementia or stroke [9] and fragile X premutation is found in 4 % of patients with diagnosis of probable multi-system atrophy cerebellar type (MSA-C) [10]. Neuropathological examination in FXTAS demonstrates, along with spongiosis of the white matter, nuclear eosinophilic inclusions in the neurons and astrocytes of the cortical and subcortical gray matter, including the substantia nigra and putamen, of possible pathogenetic role [7]. We found MRI evidence of midbrain and striatal neurodegeneration in five patients with FXTAS who showed extra-pyramidal signs. Three patients had vertical gaze palsy, namely a feature of midbrain involvement which is not observed in Parkinson disease (PD) and is characteristic of progressive supranuclear palsy (PSP). In particular, we measured atrophy of the midbrain in all five FXTAS patients that was accompanied by a concave or linear superior profile of the midbrain, instead of the convex profile observed in healthy subjects [12]. These features were emphasized as distinctive of PSP [12, 15]. It is noteworthy that also in LETTER TO THE EDITORS