Keywords
Huntington's disease - DaTSCAN - dopamine transporter imaging - neurodegeneration
- [
123I] Ioflupane
Introduction
Huntington's disease (HD) is an autosomal dominant disorder caused by an expansion
of CAG repeats in the HD gene, leading to a mutant protein accumulation and subsequent
degeneration mainly of the postsynaptic striatal medium-spiny GABAergic neurons. It's
characterized by a gradual onset of involuntary movements, cognitive difficulties,
and behavioral or emotional disturbances.[1] The average age of onset is typically between 30 and 50 years, but cases have been
reported from as young as 2 to as old as 85 years.[2] It is diagnosed primarily through genetic testing, which confirms the presence of
an expanded CAG repeat in the HTT gene. This test is definitive and can identify the disease even before symptoms appear.[1]
While genetic testing remains the definitive method for diagnosing HD, nuclear imaging
scans can offer valuable insights into the functional and molecular changes in HD.
A Dopamine Transporter scan (DaT) is a nuclear imaging scan using single-photon emission
computed tomography (SPECT) to visualize dopamine transporter levels in the brain,
particularly in the striatum. The tracer used is [123I] Ioflupane (radiolabeled cocaine analogue) which binds specifically to dopamine
transporters in presynaptic neurons. It is primarily indicated for evaluation of patients
with suspected parkinsonian syndromes and for differentiation of presynaptic parkinsonian
syndromes from parkinsonism without presynaptic dopaminergic loss.[3]
Here, we present a case of a patient with reduced presynaptic dopamine uptake on [123I] Ioflupane SPECT-CT (DaTSCAN), with subsequent genetic testing confirming HD.
Case Report
A 68-year-old right-handed male patient with a past medical history of hypothyroidism
and hypertension presented with increased anxiety, depression, auditory hallucinations,
nightmares, and suicidal thoughts. He reported that his symptoms began 2 years ago,
and he had no prior psychiatric history. His social history was notable for alcohol
dependence, abstaining since 1989 and no documented family history for neurodegenerative
diseases.
The patient was hospitalized and started on antipsychotics (olanzapine, quetiapine).
Over time, his condition progressed, and he began experiencing involuntary movements
(jerky limb movements, poor coordination, unsteadiness, multiple falls, orofacial
dyskinesia, and foot drop). Antipsychotics were discontinued as they exacerbated these
involuntary movements. On neurological examination, findings were largely unremarkable,
aside from unsteadiness on the heel-to-toe test, past-pointing in the left arm, and
mild dysdiadochokinesia.
A brain magnetic resonance imaging (MRI) showed cerebral and cerebellar hemispheric
atrophy. A subsequent DaTSCAN was conducted. The patient was pretreated with a thyroid
blocking agent approximately an hour before the intravenous administration of 185
MBq of [123I] Ioflupane. Three hours after the administration, SPECT-CT imaging was performed
using a dual-head SPECT gamma camera model Symbia Intevo (SIEMENS Healthineers) with
integrated CT (16 slices/rotation). Striatal binding ratios were calculated using
DaTQuant software by GE Healthcare, to semiquantify striatum to background (occipital
region) ratios of SPECT counts within the predefined volume of interests.
DaTSCAN revealed borderline reduced putaminal binding ratios bilaterally (more prominent
on the left) and left putamen-to-caudate asymmetry ([Figs. 1A, B]; [Fig. 2]). These findings were suggestive of a dopamine transporter deficit at the presynaptic
level, so degenerative parkinsonism (Idiopathic Parkinson’s disease/Parkinsonian syndromes
[IPD/PS]) was suspected.
Fig. 1 (A, B) DaTSCAN SPECT/CT axial images showing slightly reduced uptake in bilateral putamina,
left slightly greater than the right. Uptake in the caudate heads seems normal. SPECT/CT,
single-photon emission computed tomography–computed tomography.
Fig. 2 Semiquantitative analysis showing reduced putaminal binding ratios bilaterally (more
prominent on the left) with Putamen/Caudate ratio below 2 standard deviation.
Due to persistent nightmares and involuntary movements, Huntington's disease (HD)
was strongly considered. Genetic testing confirmed the diagnosis, revealing one pathogenic
allele with 40 (± 1) CAG repeats and one nonpathogenic allele with 17 CAG repeats.
Discussion
This case presents several diagnostic challenges, including atypical DaTSCAN findings,
a lack of documented family history, and the impact of antipsychotic therapy on symptomatology.
Postsynaptic dopaminergic involvement has been described in several postmortem and
imaging studies.[4]
[5]
[6] There is also evolving in vivo imaging evidence of presynaptic dopaminergic involvement.[4] From imaging perspective, several reported cases have shown that HD may present
with reduced presynaptic dopamine uptake on DaT imaging ([Table 1]).[6]
[7]
[8]
[9]
[10]
[11]
[12]
Table 1
Previous studies reporting abnormal DAT imaging in Huntington's disease
|
Study ID
|
Study design
|
Number of patients
|
Tracer
|
CAG repeats
|
Main findings on DAT imaging
|
Conclusion
|
|
Gamez-2010[7]
|
Observational study
|
12 HD
|
[123I]-FP-CIT
|
45.2 (3.7)
*mean/SD
|
8 abnormal visual analysis
4 abnormal semiquantitative analysis
|
Reduced striatal uptake observed in HD patients suggests pre-synaptic dopaminergic
involvement
|
|
Hwang-2013[6]
|
Observational study
|
4 HD
7 controls
|
[99ᵐTc] TRODAT-1
[123I] IBZM
|
17/18
17/49
17/48
17/46
|
1 Reduced DAT binding
3 Reduced striatal D2 receptor binding
|
The postsynaptic nigrostriatal pathway is involved, while the presynaptic part is
generally unaffected but may be in advanced cases
|
|
Kiferle-2013[8]
|
Observational study
|
12 HD
12 Controls
|
[123I]-FP-CIT
|
37–47
|
Striatal, caudate, and putaminal uptake was significantly lower in HD compared with
controls
|
Nigrostriatal degeneration may occur in symptomatic HD but doesn't play a central
role in in the pathogenesis of cognitive and motor features
|
|
Gamez-2014[9]
|
Observational study
|
4 HD
|
[123I]-FP-CIT
|
Not stated
|
Progressive uptake reduction in the caudate and putamen average annual decline of
5.8% in the caudate and 9.6% in the putamen over a 2-y follow-up
|
[123I]-FP-CIT/SPECT is useful for investigating presynaptic dopaminergic degeneration
in HD and may serve as a biomarker for disease progression
|
|
Larson-2021[10]
|
Case report
|
1
|
Tracer not stated
|
51
|
Dopamine transporter SPECT showed abnormal dopamine uptake bilaterally
|
This case highlights an atypical presentation of HD with parkinsonism and the need
for specialized genetic testing for repeat expansion disorders
|
|
Mulroy-2020[11]
|
Case report
|
1
|
Tracer not stated
|
52
*HDL-2
|
Bilateral asymmetric reduction in striatal uptake more in the right putamen
|
DAT-SPECT imaging can be abnormal in HDL-2
|
|
Chun-2022[12]
|
Case report
|
1
|
[18F]-FP-CIT PET/CT
[99ᵐTc]-ECD SPECT
|
18/43
|
[18F]-FP-CIT PET/CT showed reduced uptake in the basal ganglia, frontal, and parietotemporal lobes, with
decreased DAT binding in the ventral and posterior putamen. [99ᵐTc]-ECD SPECT revealed reduced perfusion in the basal ganglia, frontal, and temporal
lobes
|
A multimodal imaging approach is recommended for tracking HD progression since no
single technique is optimal. A single-tracer, dual-phase 18F-FP-CIT PET test may help differentiate HD while reducing costs and radiation exposure
|
Abbreviations: HD, Huntington's disease; SPECT/CT, single-photon emission computed
tomography–computed tomography.
DaTSCAN findings may be variable. Gamez et al. observed reduced [123I]-FP-CIT (DaTSCAN) uptake in 8 out of 12 HD patients based on visual analysis, with
4 showing abnormal semiquantitative results, suggesting presynaptic dopaminergic involvement.
They also found no linear correlation with disease severity, but they found that the
patients with severe symptoms had more severe reductions in radioligand uptake.[7] In a 2-year follow-up study, Gamez et al. noted progressive uptake reductions of
[123I]-FP-CIT in the caudate and putamen nuclei, with average annual declines of 5.8 and
9.6%, respectively. Similarly, Larson described a HD patient with abnormal dopamine
uptake bilaterally.[10]
Kiferle et al. also reported significantly reduced caudate, putamen, and overall striatal
uptake in HD patients compared with controls, supporting potential presynaptic dysfunction.[8] Mulroy et al. proposed that striatal atrophy could account for the reduced DaT uptake,
aligning with the observations of Gamez et al. and Kiferle et al., suggesting that
structural degeneration may contribute to the DaTSCAN findings.[7]
[8]
[9]
[11] However, MRI findings in our case indicated global cerebral atrophy with no prominent
striatal atrophy identified.
In contrast, Hwang et al. using both [99ᵐTc] TRODAT-1 and [123I] IBZM, reported reduced DAT binding in only one out of four HD patients and more
prominent reductions in D2 receptor binding, suggesting predominant postsynaptic involvement.[6] They concluded that presynaptic component is usually not affected but could happen
in very advanced disease.
Several studies have also contributed to our understanding of DAT imaging in HD using
other modalities. Chun demonstrated that early-phase [18F]-FP-CIT PET/CT perfusion imaging showed patterns similar to [99ᵐTc]-ECD SPECT, whereas late-phase imaging revealed decreased DAT binding in the ventral
and posterior putamen. Based on these findings, the study proposed that a dual-phase
[18F]-FP-CIT PET protocol may serve as a single-tracer alternative for assessing both
perfusion and dopaminergic function in HD.[12] Other PET radioligands have been developed to target key aspects of HD pathology,
including microglial activation, C-11 β-CIT and phosphodiesterase 10A (PDE10A) expression.[5]
[13]
The possibility of concomitant HD and Parkinson's disease (PD), as described in a
case by Hadden et al., could also explain the imaging findings.[14] The lack of documented family history and possible antipsychotic-induced effects
added to the diagnostic uncertainty. Early antipsychotic use led to parkinsonism-like
symptoms, as managing HD chorea by reducing dopaminergic transmission can worsen involuntary
movements and induce drug-related parkinsonism.
Conclusion
Abnormal DaTSCAN does not necessarily indicate degenerative parkinsonism. Other neurodegenerative
conditions, such as HD, should be considered, especially when clinical symptoms are
unclear, and family history is undocumented. This case underscores the importance
of increased awareness of HD presenting with abnormal DaTSCAN findings.
Further comparative studies are needed to correlate genetic findings, MRI, disease
severity, and DaTSCAN results. While genetic testing remains the definitive diagnostic
tool for HD, DaTSCAN may serve as a complementary modality to evaluate presynaptic
dopaminergic involvement and potentially monitor disease progression. Future comparative
studies are essential to correlate genetic findings, MRI, disease severity, and DaTSCAN
results.
