Ioflupane [I-123] 185MBq/2.5ml solution for injection vials

Abstract Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an unstable expansion of CAG trinucleotide repeats that lead to progressive degeneration of postsynaptic striatal medium-spiny GABAergic neurons. We report a case of abnormal [123I] Ioflupane single-photon emission computed tomography/computed tomography (DaTSCAN) and a subsequent genetic test confirming HD. A 68-year-old man presented with progressive memory difficulties, auditory hallucinations, nightmares, suicidal thoughts, low mood, and involuntary limb movements. DaTSCAN showed borderline reduced putaminal binding ratios bilaterally, more prominent on the left side, and a low putamen-to-caudate ratio suggesting degenerative parkinsonism. Genetic testing revealed one pathogenic expansion (40/17 CAG repeats), confirming HD. Postsynaptic dopaminergic involvement has previously been documented in postmortem studies. However, an emerging in vivo research also suggests presynaptic dopaminergic involvement. While genetic testing remains the gold standard for diagnosis of HD, DaTSCAN may play a role in assessing dopamine transporter activity and tracking the progression of neurodegeneration in HD.

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Traumatic brain injury commonly impairs attention and executive function and disrupts the large-scale brain networks that support these cognitive functions. Abnormalities of functional connectivity are seen in corticostriatal networks, which are associated with executive dysfunction and damage to neuromodulatory catecholaminergic systems caused by head injury. Methylphenidate, a stimulant medication that increases extracellular dopamine and noradrenaline, can improve cognitive function following traumatic brain injury. In this experimental medicine add-on study to a randomized, double-blind, placebo-controlled clinical trial, we test whether administration of methylphenidate alters corticostriatal network function and influences drug response. Forty-three moderate-severe traumatic brain injury patients received 0.3 mg/kg of methylphenidate or placebo twice a day in 2-week blocks. Twenty-eight patients were included in the neuropsychological and functional imaging analysis (four females, mean age 40.9 ± 12.7 years, range 20-65 years) and underwent functional MRI and neuropsychological assessment after each block. 123I-Ioflupane single-photon emission computed tomography dopamine transporter scans were performed, and specific binding ratios were extracted from caudate subdivisions. Functional connectivity and the relationship to cognition were compared between drug and placebo conditions. Methylphenidate increased caudate to anterior cingulate cortex functional connectivity compared with placebo and decreased connectivity from the caudate to the default mode network. Connectivity within the default mode network was also decreased by methylphenidate administration, and there was a significant relationship between caudate functional connectivity and dopamine transporter binding during methylphenidate administration. Methylphenidate significantly improved executive function in traumatic brain injury patients, and this was associated with alterations in the relationship between executive function and right anterior caudate functional connectivity. Functional connectivity is strengthened to brain regions, including the anterior cingulate, that are activated when attention is focused externally. These results show that methylphenidate alters caudate interactions with cortical brain networks involved in executive control. In contrast, caudate functional connectivity reduces to default mode network regions involved in internally focused attention and that deactivate during tasks that require externally focused attention. These results suggest that the beneficial cognitive effects of methylphenidate might be mediated through its impact on the caudate. Methylphenidate differentially influences how the caudate interacts with large-scale functional brain networks that exhibit co-ordinated but distinct patterns of activity required for attentionally demanding tasks.

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Abstract Frontotemporal dementia is a group of neurodegenerative disorders mainly characterized by behavioural and language impairments. While the precise pathophysiology remains elusive, emerging evidence points to an important role of dopamine dysfunction, particularly within the caudate nucleus. Moreover, a theoretical model proposes that frontotemporal dementia manifestations result from a deficit in goal-directed behaviour, which may be related to altered dopamine control of the frontostriatal circuitry. However, no study has investigated the gradient of striatal dopamine transporter levels in frontotemporal dementia using neuroimaging and their correlation with clinical features. This study used 123I-Ioflupane Single Photon Emission Computed Tomography imaging to measure striatal dopamine transporter levels and their distribution patterns in frontotemporal dementia, compared to Parkinson’s disease and healthy controls. Additionally, we explored the correlation between dopamine transporter uptake and two key domains affected in frontotemporal dementia: social cognition and language abilities. We hypothesized that frontotemporal dementia would show a predominant dopaminergic deficit in the caudate, and that this would correlate with the severity of clinical core features. The study comprised 139 participants, including 34 sporadic and genetic frontotemporal dementia, 68 Parkinson’s disease individuals, and 37 age- and sex-matched healthy controls. Among the frontotemporal dementia group, 22 cases had clinically probable behavioural variant frontotemporal dementia, and 12 had primary progressive aphasia. Social cognition was assessed with the abbreviated version of the Social and Emotional Assessment, which includes a Theory of Mind test and a Facial Emotion Recognition Task. Language skills were evaluated with the Screening for Aphasia in NeuroDegeneration battery. We found that dopamine transporter levels were reduced in frontotemporal dementia compared to healthy controls (P < 0.001) and that frontotemporal dementia showed a higher putamen-to-caudate ratio than Parkinson’s disease (P < 0.001), particularly notable in patients with identified disease-causing mutation. We also found that dopamine transporter levels were correlated with parkinsonian motor features and general cognition in frontotemporal dementia. Notably, both social cognition—especially facial emotion recognition—and language abilities exhibited associations with dopamine transporter levels in both the putamen and the caudate. These findings suggest that the pattern of dopamine transporter uptake could serve as a valuable biomarker for frontotemporal dementia, shedding light on the role of the dopaminergic system and the striatum in some fundamental clinical aspects. This opens new avenues for further investigating the underlying mechanisms and potential therapeutic targets of the dopaminergic projections in frontotemporal dementia.

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INTRODUCTION: I-ioflupane single-photon emission computed tomography (SPECT) striatal binding ratio (SBR) correlated with parkinsonian motor symptoms in dementia with Lewy bodies (DLB) and if SBR predicts worsening of parkinsonism over time. METHODS: I-ioflupane SPECT analyzed with DaTQUANT and baseline and 24-month Movement Disorder Society Unified Parkinson's Disease Rating Scale-Part III (MDS-UPDRS-III). A subset had cerebrospinal fluid α-synuclein seed amplification assay (SAA) evaluation. RESULTS: Baseline mean SBRs were significant predictors of baseline and 24-month MDS-UPDRS-III scores, although they did not predict meaningful worsening over time. SAA positivity was associated with lower SBRs; Z score cut-off values are provided. DISCUSSION: I-ioflupane SPECT, at diagnosis, could be used to confirm underlying dopamine deficiency; it does not predict meaningful worsening of motor parkinsonism. More severe dopamine deficiency increases confidence in presence of synucleinopathy. HIGHLIGHTS: I-ioflupane single-photon emission computed tomography (SPECT) can confirm underlying dopamine deficiency. Striatal binding ratio (SBR) Z scores predicted 24-month Unified Parkinson's Disease Rating Scale-Part III (UPDRS-III) scores. SBR Z scores are not predictive of subsequent meaningful worsening of parkinsonism. More severe dopamine dysfunction on SPECT is associated with presence of seed amplification assay (SAA). SBR Z score cut-offs that indicate cerebrospinal fluid SAA positivity are provided.

Abstract licence: CC BY-NC-ND

Abstract Purpose Due to new advances in molecular and imaging biomarkers, a biological classification of Parkinson’s disease (PD) called SyNeurGe (Hoglinger et al. Lancet Neurol 2024;23:191-204) has been proposed for research use recently. [ 123 I]ioflupane dopamine transporter single-photon-emission-computed tomography (DaT-SPECT) and cardiac [ 123 I]meta-iodobenzylguanidine (MIBG) scintigraphy are included in this biological classification scheme together with 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG-PET) as central imaging biomarkers for the assessment of dopaminergic function, cardiac sympathetic denervation, and metabolic patterns in brain. In order to facilitate this prospectively high imaging demand and optimize diagnostic workup in PD we propose a single-day protocol. Methods First, we excluded relevant binding of MIBG in the brain as well as DaT in the heart by acquisition of brain scans in patients that received MIBG as well as by acquisition of chest scans in patients that received DaT. Then, we performed a single-day protocol including DaT-SPECT and cardiac MIBG scintigraphy in ten patients with clinically suspected α-synucleinopathies (9 male, 1 female; 68.2 ± 7.3 years). Both radiotracers were injected simultaneously and cardiac imaging was performed at 3.5 h after injection followed by brain imaging at 4 h after injection using standard protocols for MIBG-scintigraphy and DaT-SPECT. Additionally, five patients of the dual tracer protocol group received brain FDG-PET after DaT and MIBG imaging. Results Single tracer imaging confirmed no relevant uptake of [ 123 I]ioflupane in the heart or [ 123 I]MIBG in the brain. Six out of the ten dual tracer protocol patients (PD or multiple system atrophy with Parkinsonian phenotype (MSA-P)) showed a significantly reduced DaT-SPECT binding (z-score < -2) in at least one hemisphere (mean putaminal z-score -4.01 ± 1.39) while seven patients had a pathological heart-to-mediastinum ratio in the MIBG scan (mean H/M-ratio: 1.12 ± 0.08). Both DaT and MIBG scans could visually be interpreted without any signs of image artifacts or decrease in imaging quality and also quantitatively did not reveal significant differences to the single tracer scans. FDG-PET brain scans of the triple tracer protocol patients also showed no relevant interference in regard to image quality as well was generation of surface projections and z-scores. Conclusion A single day protocol for DaT-SPECT, MIBG, and FDG-PET facilitates biomarker assessments needed for efficient biological characterization of Parkinsonian syndromes according to the SyNeurGe criteria.

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