The Added Diagnostic Value of ¹⁸F-FDG PET/CT in Suspected CreutzfeldtJakob Disease: A Retrospective Case Series

INTRODUCTION

The diagnosis of Creutzfeldt-Jakob disease (CJD), a fatal and rapidly progressive prionopathy, presents a significant clinical challenge, relying on clinical symptoms, electroencephalogram (EEG) findings, and cerebrospinal fluid (CSF) biomarkers. Within this diagnostic arsenal, neuroimaging plays a pivotal role. Magnetic Resonance Imaging (MRI), particularly Diffusion-Weighted Imaging (DWI), is considered the cornerstone, revealing characteristic patterns of cortical ribboning and basal ganglia hyperintensities that are central to modern diagnostic criteria.

Despite its established utility, MRI has recognised limitations. Findings may be subtle or absent in the early stages of the disease, can be mimicked by other acute encephalopathies such as autoimmune or metabolic conditions, and image quality is often degraded by motion artefacts - a frequent complication in patients with CJD.

¹⁸F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (¹⁸F-FDG PET/CT) offers a complementary approach by visualising regional cerebral glucose metabolism, providing a direct measure of neuronal function. Previous studies have sporadically reported distinct patterns of cerebral hypometabolism in CJD, suggesting that these functional changes may precede or be more widespread than the structural abnormalities seen on MRI.

However, the precise role of ¹⁸F-FDG PET/CT in the diagnostic pathway, particularly in relation to MRI findings, remains to be fully elucidated. In this retrospective case series, we aim to illustrate the added diagnostic value of ¹⁸F-FDG PET/CT by presenting four cases of suspected CJD where PET provided crucial information beyond that available from MRI, thereby enhancing diagnostic confidence and providing a more comprehensive assessment of disease topography.

CASE REPORTS

This is a retrospective review of four patients referred to our institution for evaluation of rapidly progressive dementia. The cases were identified from institutional records spanning 2019-2025. All patients had a high clinical suspicion of CJD and underwent a standardised diagnostic workup including EEG, brain MRI, and a subsequent ¹⁸F-FDG PET/CT scan. MRI was performed on a scanner and included DWI, T2/FLAIR sequences. ¹⁸F-FDG PET/CT was performed after injection of ¹⁸F-FDG and an uptake period of 60 minutes. CortexID images (normalised to age) were generated. ¹⁸F-FDG PET/CT images were interpreted by an experienced nuclear medicine physician for patterns of hypometabolism visually as well as quantitatively using CortexID software.

The cohort consisted of three females and one male, with an age range of 45-76 years. All patients presented with rapidly progressive cognitive and motor symptoms. Key findings are summarised in [Table 1]. In all four patients, ¹⁸F-FDG PET/CT confirmed hypometabolism in regions showing diffusion restriction on MRI. More importantly, in every case, ¹⁸F-FDG PET/CT identified additional areas of hypometabolism in regions that appeared structurally normal on MRI. For instance, in Case 2, PET revealed left striatal hypometabolism, where MRI was unremarkable. In Case 1, extensive brainstem and cerebellar hypometabolism was seen on PET, corresponding well with the patient's ataxia but exceeding the changes seen on MRI. Asymmetric hypometabolism was a consistent finding (3 left-predominant, 1 right-predominant), and all patients demonstrated hypometabolism in the frontal lobes, precuneus, striatum and posterior cingulate cortex. Two patients also had temporal, occipital, cerebellar, and midbrain hypometabolism, while one had pons involvement.

CASE 1

A 76-year-old female, a gynaecologist by profession, presented with rapid onset dementia, ataxia and Parkinsonism for 6 months. Mini mental state examination (MMSE) was 22/30. EEG was normal. MRI brain showed symmetric areas of restricted diffusion seen involving the entire caudate nucleus, bilateral putamen, bilateral pulvinar of thalamus, bilateral high frontal parafalcine cortical region and to a lesser extent in right posterior parietal cortex, which appeared hyperintense on T2Wt images. Overall findings raised suspicion of creutzfeldt Jakob Disease. ¹⁸F-FDG PET/CT was advised. It showed areas of hypometabolism in the areas corresponding to the diffusion restriction on MRI. Also, there were other areas of hypometabolism noted in cerebellum, pons, midbrain and bilateral medial frontal lobes [Fig 1]. There was a very mild asymmetry noted, with more hypometabolism in the left cerebral hemisphere. Mild relative sensorimotor cortex sparing was seen. Serum autoimmune encephalitis panel, CSF culture and meningoencephalitis panel were done, which came out to be negative.

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Fig. 1:

¹⁸F-FDG PET + MRI (A) images show multiple areas of hypometabolism (marked by blue arrows) seen corresponding to the areas of cortical thickening and restricted diffusion on MRI - bilateral high frontal parafalcine cortical region, entire caudate nucleus and most of putamen on either side, and pulvinar of thalamus on either side; (B) as well as additional areas of hypometabolism (marked by white arrows) - cerebellum, pons, mid brain and bilateral medial frontal lobes on CortexID images of ¹⁸F-FDG.

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CASE 2

A 72-year-old male presented with rapid worsening of forgetfulness and fine tremors (with no side predilection) for 1 year. EEG showed mild generalised slowing. MRI brain showed asymmetrical involvement of both cerebral hemispheres by cortical thickening and T2 and FLAIR hyperintensities, along with restricted diffusion. There was predominant involvement of bilateral temporal-occipital lobes, bilateral mid-frontal, left central gyrus, left insular cortex and left posterior parietal lobe. Areas of diffusion restriction were seen in the left fronto-parietal parasagittal gyri and the right posterior parietal lobe. Findings raised the possibility of creutzfeldt Jakob Disease. ¹⁸F-FDG PET/CT showed multiple areas of hypometabolism corresponding to the areas of cortical thickening and diffusion restriction on MRI. Sensorimotor cortex sparing was noted. There was significant asymmetry noted, with significant involvement of the left cerebral hemisphere. In addition, there was mild hypometabolism seen in the left striatum, cerebellum and midbrain, which showed no MRI abnormality [Fig 2].

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Fig. 2:

¹⁸F-FDG PET + MRI (A) images show multiple areas of hypometabolism (marked by blue arrows) seen corresponding to the areas of cortical thickening and restricted diffusion on MRI - bilateral frontal, left cingulate gyri, left insular cortex, left posterior parietal lobe, and bilateral temporo occipital lobes; (B) as well as additional areas of hypometabolism (marked by white arrows) - left striatum, cerebellum and mid brain seen on CortexID images of ¹⁸F-FDG.

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CASE 3

A 45-year-old female presented with tremors, dropping objects, imbalance, speech difficulty and slowness in activities. MMSE was 20/30. On examination, there was no bradykinesia or tremors. There was finger-nose finger ataxia and dysdiadochokinesia in the bilateral upper limbs. EEG was normal. MRI brain showed diffusion restriction in bilateral putamen, caudate and cortical ribbon sign -suggestive of changes of CJD. Areas of hypometabolism on ¹⁸F-FDG PET/CT were noted corresponding to the areas of diffusion restriction on MRI. There were additional areas of hypometabolism in the bilateral frontal, temporal, parietal lobes, midbrain and cerebellum [Fig 3].

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Fig. 3:

¹⁸F-FDG PET + MRI (A) images show multiple areas of hypometabolism (marked by blue arrows) seen corresponding to the areas of cortical thickening and restricted diffusion on MRI - cortical ribbon sign along bilateral parafalcine region, bilateral putamen and caudate; (B) as well as additional areas of hypometabolism (marked by white arrows) - bilateral frontal, temporal and parietal lobes, midbrain and cerebellum seen on CortexID images of ¹⁸F-FDG.

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CASE 4

A 48-year-old female presented with rapidly progressive dementia for one month with significant mental function impairment, gait imbalance and slowness of movements. EEG revealed a periodic pattern of sharp waves, triphasic and biphasic. MRI found intracortical ribbon-like restricted diffusion in cerebellar cortex on both sides – suggestive of CJD. ¹⁸F-FDG PET/CT showed hypometabolism in bilateral frontal, parietal lobes, precuneus and posterior cingulate cortex. Mild hypometabolism was also seen in the right caudate nucleus and the right occipital lobe.

DISCUSSION

The principal finding of this case series is that ¹⁸F-FDG PET/CT provides significant diagnostic information complementary to MRI in the workup of suspected CJD. In all four of our patients, ¹⁸F-FDG PET/CT not only corroborated the regions of diffusion restriction seen on MRI but, more importantly, consistently identified a wider topography of neuronal dysfunction. This was demonstrated by additional areas of hypometabolism in regions that appeared structurally normal on MRI, thereby providing a more complete picture of the disease's extent.

Our observations align with and extend the existing literature. The general pattern of widespread, asymmetric cortical hypometabolism with relative sparing of the sensorimotor cortex, seen in our cohort, is consistent with the findings reported by Damian et al. and others.^[1,2] Furthermore, our cases lend support to emerging efforts to correlate metabolic patterns with clinical subtypes. Renard et al.^[3] described distinct metabolic signatures for different CJD phenotypes (with cerebellar ataxia, visual signs, pyramidal signs, myoclonus, corticobasal syndrome, etc.), including cerebellar and brainstem hypometabolism in patients with ataxia. Notably, our first case, who presented with prominent ataxia and Parkinsonism, demonstrated significant hypometabolism in the cerebellum, pons, and midbrain on PET, supporting the phenotype-metabolic correlation proposed by Renard's group.

A key observation across all four cases was the discordance between metabolic and structural findings. This phenomenon is likely rooted in the underlying pathophysiology of neurodegeneration, where synaptic dysfunction and metabolic decline precede the eventual neuronal loss, gliosis, and spongiform changes that result in DWI restriction on MRI.^[4] High-intensity signal on DWI typically appears in the grey matter regions (first cortex, then basal ganglia, and finally thalamus).

This concept is strongly supported by longitudinal studies in genetic CJD, which show that metabolic abnormalities appear in asymptomatic stages, well before structural MRI changes or clinical onset.^[5] The high concordance (80.6%) between hypometabolism and definitive histopathological changes reported by Mente et al.^[2] further validates that PET visualises the core disease process While both modalities are crucial, studies suggest that in cases of discordance, ¹⁸F-FDG PET/CT is often more sensitive for cortical pathology, whereas MRI may be more sensitive for abnormalities in the basal ganglia.^[2,6,7] These findings have direct clinical implications.

In clinical practice, MRI shows a high-intensity signal on DWI, which typically appears in the grey matter regions (first cortex, then basal ganglia, and finally thalamus). Although MRI is the most important imaging tool for the diagnosis of CJD, there are drawbacks associated with it. Some of them are missing the early stages of CJD, considerable overlap with other conditions (autoimmune encephalitis, hypoxic ischemic encephalopathy, etc.), image quality being degraded by movement artefacts (common in CJD patients) due to longer acquisition times and other known contraindications (claustrophobia, pacemakers, etc.)^[4]

In such scenarios, an ¹⁸F-FDG PET/CT scan showing a classic metabolic pattern can substantially increase diagnostic confidence. For example, Kim et al.^[7] reported predominantly bilateral occipital hypometabolism in the Heidenhain variant. Moreover, ¹⁸F-FDG PET/CT can be pivotal in the complex differential diagnosis of rapidly progressive dementia. The metabolic signature of CJD is distinct from the typical posterior-predominant pattern of Alzheimer's disease and can help differentiate it from autoimmune encephalitis, which often presents with hypermetabolism rather than hypometabolism. In addition, hypometabolism can be quantified using SUVs and SPM software, which can further reduce operator dependence. It can be done as a part of multimodal imaging when findings (EEG, MRI or biomarkers like CSF 14-14-3) are inconclusive with high suspicion of disease clinically. Apart from all these, it can help in guiding research applications in providing insights into the mechanisms of neurodegeneration and also possibly in therapeutic monitoring clinical trials for new treatments.^[8] This makes PET a powerful problem-solving tool when other tests are inconclusive.

We acknowledge the limitations of this study. Its retrospective design and small cohort size (n=4) preclude generalisation. The diagnosis of CJD was probable, not definitive, as histopathological confirmation - the gold standard was not available.

Further prospective, longitudinal studies are warranted to systematically evaluate the temporal evolution of PET and MRI changes in CJD. Such studies could help solidify the role of ¹⁸F-FDG PET/CT not only as a complementary diagnostic tool but also as a potential biomarker for tracking disease progression in future therapeutic trials.

CONCLUSION

In conclusion, ¹⁸F-FDG PET/CT is a valuable and powerful adjunct to MRI in the diagnostic workup of CreutzfeldtJakob disease. It enhances diagnostic precision by confirming structural abnormalities while simultaneously revealing a more extensive landscape of neuronal dysfunction not visible on MRI. Its ability to identify a distinct metabolic signature helps differentiate CJD from other rapidly progressive dementias, particularly when MRI findings are atypical or non-specific. While MRI remains the primary structural imaging modality, the integration of ¹⁸F-FDG PET/CT provides crucial functional insights that increase diagnostic confidence and improve our understanding of the disease. Future prospective studies are warranted to formally establish its role in the clinical diagnostic algorithm for CJD.