Dopamine Transporter Single-photon Emission Computed Tomography Research Articles

Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Biomarkers of neurodegeneration in isolated and antidepressant-related rapid eye movement sleep behavior disorder.

This study compared the features of isolated rapid eye movement (REM) sleep behavior disorder (iRBD) and antidepressant-related REM sleep behaviour disorder (RBD) with the aim of highlighting markers that might distinguish the two entities. The observational cohort study included RBD patients with and without antidepressant use (antiD+ and antiD- patients, respectively), without cognitive impairment and parkinsonism. Clinical features of RBD, subtle motor and non-motor symptoms of parkinsonism, sleep architecture, REM atonia index, dopamine transporter-single photon emission computed tomography (DAT-SPECT) and skin biopsies for the intraneuronal alpha-synuclein (α-syn), were evaluated in the baseline work-up. Thirty-nine patients, 10 antiD+ and 29 antiD-, were included. AntiD+ patients (more frequently female) reported more psychiatric symptoms, less violent dream enactment, and less frequent hyposmia. Dermal α-syn was detected in 93.1% of antiD- versus 30% of antiD+ patients (p = 0.00024). No differences appeared in other motor and non-motor symptoms, Movement Disorder Society-Unified Parkinson's Disease Rating Scale part III score, DAT-SPECT, or polysomnographic features. Patients with antidepressant-related RBD have clinical and neuropathological features suggesting a lower risk of evolution than those with iRBD.

Synthesis and initial evaluation of radioiodine-labelled deuterated tropane derivatives targeting dopamine transporter

The dopamine transporter (DAT) is closely related to a variety of neurological disorders including Parkinson’s disease (PD) and other neurodegenerative diseases. In vivo imaging of DAT with radio-labelled tracers has become a powerful technique in related disorders. The radioiodine-labelled tropane derivative [123I]FP-CIT ([123I]1a) is widely used in clinical single photon emission computed tomography (SPECT) imaging as a DAT imaging agent. To develop more metabolically stable DAT radioligands for accurate imaging, this work compared two novel deuterated tropane derivatives ([131I]1c-d) with non-deuterated tropane derivatives ([131I]1a-b). [131I]1a-d were obtained in high radiochemical purity (RCP) above 99 % with molar activities of 7.0–10.0 GBq/μmol. The [131I]1a and [131I]1c exhibited relatively higher affinity to DAT (Ki: 2.0–3.12 nM) than [131I]1b and [131I]1d. Biodistribution results showed that [131I]1c consistently exhibited a higher ratio of the target to non-target (striatum/cerebellum) than [131I]1a. Furthermore, metabolism studies indicated that the in vivo metabolic stability of [131I]1c was superior to that of [131I]1a. Ex vivo autoradiography showed that [131I]1c selectively localized on DAT-rich striatal regions and the specific signal could be blocked by DAT inhibitor. These results indicated that [131I]1c might be a potential probe for DAT SPECT imaging in the brain.

Harmonizing multisite data with the ComBat method for enhanced Parkinson's disease diagnosis via DAT-SPECT.

Dopamine transporter single-photon emission computed tomography (DAT-SPECT) is a crucial tool for evaluating patients with Parkinson's disease (PD). However, its implication is limited by inter-site variability in large multisite clinical trials. To overcome the limitation, a conventional prospective correction method employs linear regression with phantom scanning, which is effective yet available only in a prospective manner. An alternative, although relatively underexplored, involves retrospective modeling using a statistical method known as "combatting batch effects when combining batches of gene expression microarray data" (ComBat). We analyzed DAT-SPECT-specific binding ratios (SBRs) derived from 72 healthy older adults and 81 patients with PD registered in four clinical sites. We applied both the prospective correction and the retrospective ComBat correction to the original SBRs. Next, we compared the performance of the original and two corrected SBRs to differentiate the PD patients from the healthy controls. Diagnostic accuracy was assessed using the area under the receiver operating characteristic curve (AUC-ROC). The original SBRs were 6.13 ± 1.54 (mean ± standard deviation) and 2.03 ± 1.41 in the control and PD groups, respectively. After the prospective correction, the mean SBRs were 6.52 ± 1.06 and 2.40 ± 0.99 in the control and PD groups, respectively. After the retrospective ComBat correction, the SBRs were 5.25 ± 0.89 and 2.01 ± 0.73 in the control and PD groups, respectively, resulting in substantial changes in mean values with fewer variances. The original SBRs demonstrated fair performance in differentiating PD from controls (Hedges's g = 2.76; AUC-ROC = 0.936). Both correction methods improved discrimination performance. The ComBat-corrected SBR demonstrated comparable performance (g = 3.99 and AUC-ROC = 0.987) to the prospectively corrected SBR (g = 4.32 and AUC-ROC = 0.992) for discrimination. Although we confirmed that SBRs fairly discriminated PD from healthy older adults without any correction, the correction methods improved their discrimination performance in a multisite setting. Our results support the utility of harmonization methods with ComBat for consolidating SBR-based diagnosis or stratification of PD in multisite studies. Nonetheless, given the substantial changes in the mean values of ComBat-corrected SBRs, caution is advised when interpreting them.

Potential dopaminergic deficit in patients with geriatric psychiatric disorders as revealed by DAT-SPECT: a cross-sectional study

BackgroundIt has been reported that patients with geriatric psychiatric disorders include many cases of the prodromal stages of neurodegenerative diseases. Abnormal 123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane dopamine transporter single-photon emission computed tomography (DAT-SPECT)...

Contribution of amyloid and putative Lewy body pathologies in neuropsychiatric symptoms.

Neuropsychiatric symptom could be useful for detecting patients with prodromal dementia. Similarities and differences in the NPSs between preclinical/prodromal Alzheimer's disease (AD) and prodromal Parkinson's disease dementia (PDD)/Dementia with Lewy bodies (DLB) may exist. This study aimed to compare the NPSs between preclinical/prodromal AD and prodromal PDD/DLB. One hundred and three participants without dementia aged ≥50years were included in this study. The mild behavioral impairment (MBI) total score and the MBI scores for each domain were calculated using the neuropsychiatric inventory questionnaire score. Participants were divided into five groups based on the clinical diagnosis by neurologists or psychiatrists in each institution based on the results of the amyloid positron emission tomography and dopamine transporter single photon emission computed tomography (DAT-SPECT): Group 1: amyloid-positive and abnormal DAT-SPECT, Group 2: amyloid-negative and abnormal DAT-SPECT, Group 3: amyloid-positive and normal DAT-SPECT, Group 4: mild cognitive impairment unlikely due to AD with normal DAT-SPECT, and Group 5: cognitively normal with amyloid-negative and normal DAT-SPECT. The MBI abnormal perception or thought content scores were significantly higher in Group 1 than Group 5 (Bonferroni-corrected p=0.012). The MBI total score (Bonferroni-corrected p=0.011) and MBI impulse dyscontrol score (Bonferroni-corrected p=0.033) in Group 4 were significantly higher than those in Group 5. The presence of both amyloid and putative Lewy body pathologies may be associated with psychotic symptoms.

Clinical and dopaminergic imaging characteristics of the FARPRESTO cohort of trial-ready idiopathic rapid eye movement sleep behavior patients.

Idiopathic/isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is considered the prodromal stage of alpha-synucleinopathies. Thus, iRBD patients are the ideal target for disease-modifying therapy. The risk FActoRs PREdictive of phenoconversion in iRBD Italian STudy (FARPRESTO) is an ongoing Italian database aimed at identifying risk factors of phenoconversion, and eventually to ease clinical trial enrollment of well-characterized subjects. Polysomnography-confirmed iRBD patients were retrospectively and prospectively enrolled. Baseline harmonized clinical and nigrostriatal functioning data were collected at baseline. Nigrostriatal functioning was evaluated by dopamine transporter-single-photon emission computed tomography (DaT-SPECT) and categorized with visual semi-quantification. Longitudinal data were evaluated to assess phenoconversion. Cox regressions were applied to calculate hazard ratios. 365 patients were enrolled, and 289 patients with follow-up (age 67.7 ± 7.3 years, 237 males, mean follow-up 40 ± 37 months) were included in this study. At follow-up, 97 iRBD patients (33.6%) phenoconverted to an overt synucleinopathy. Older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression, and visual semi-quantification of nigrostriatal functioning predicted phenoconversion. The remaining 268 patients are in follow-up within the FARPRESTO project. Clinical data (older age, motor and cognitive impairment, constipation, urinary and sexual dysfunction, depression) predicted phenoconversion in this multicenter, longitudinal, observational study. A standardized visual approach for semi-quantification of DaT-SPECT is proposed as a practical risk factor for phenoconversion in iRBD patients. Of note, non-converted and newly diagnosed iRBD patients, who represent a trial-ready cohort for upcoming disease-modification trials, are currently being enrolled and followed in the FARPRESTO study. New data are expected to allow better risk characterization.

Serum but not cerebrospinal fluid levels of allantoin are increased in de novo Parkinson’s disease

Oxidative stress supposedly plays a role in the pathogenesis of Parkinson’s disease (PD). Uric acid (UA), a powerful antioxidant, is lowered in PD while allantoin, the oxidation product of UA and known biomarker of oxidative stress, was not systematically studied in PD. We aim to compare serum and cerebrospinal fluid (CSF) levels of UA, allantoin, and allantoin/UA ratio in de novo PD patients and controls, and evaluate their associations with clinical severity and the degree of substantia nigra degeneration in PD. We measured serum and CSF levels of UA, allantoin, and allantoin/UA ratio in 86 PD patients (33 females, mean age 57.9 (SD 12.6) years; CSF levels were assessed in 51 patients) and in 40 controls (19 females, 56.7 (14.1) years). PD patients were examined using Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), Montreal Cognitive Assessment (MoCA), Scales for Outcomes in Parkinson Disease-Autonomic (SCOPA-AUT), the University of Pennsylvania Smell Identification Test (UPSIT), one-night video-polysomnography, and dopamine transporter single-photon emission computed tomography (DAT-SPECT). Serum allantoin and allantoin/UA ratio were significantly increased in the PD group compared to controls (p < 0.001 and p = 0.002, respectively). Allantoin/UA ratios in serum and CSF were positively associated with the SCOPA-AUT score (p = 0.005 and 0.031, respectively) and RBD presence (p = 0.044 and 0.028, respectively). In conclusion, serum allantoin and allantoin/UA ratio are elevated in patients with de novo PD. Allantoin/UA ratio in serum and CSF is associated with autonomic dysfunction and RBD presence, indicating that higher systemic oxidative stress occurs in PD patients with more diffuse neurodegenerative changes.

Quantified Striatal Dopaminergic Denervation as Predictor for Motor Outcomes in Parkinson's Disease.

A hallmark of Parkinson's disease (PD) is progressive loss of dopamine terminals in the basal ganglia, with clinical symptoms including motor and non-motor manifestations such as bradykinesia, rigidity, and cognitive impairment. Dopamine transporter single-photon emission computed tomography (DaT-SPECT) can be used to assess dopaminergic denervation by detecting loss of striatal dopamine transporters (DaT). We examined DaT binding scores' (DaTbs) association with motor outcomes in PD and explored its usefulness as a predictor of disease progression. Faster dopaminergic denervation in the basal ganglia was hypothesized to have stronger correlation and predictive value for poor motor outcomes. Data was analyzed from the Parkinson's Progression Markers Initiative. DaTbs in the putamen and caudate nucleus were correlated with Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) scores for walking and balance difficulties, gait difficulties, and presence of dyskinesias. A predictive model using baseline speed of drop in DaT binding score was performed for each motor outcome. All motor outcomes had mild, significantly negative correlation with DaTbs in the putamen and caudate nucleus, with similar degree of correlation per region. Speed of drop was predictive of only substantial gait difficulties when evaluated in the putamen but not the caudate. These findings suggest that analyzing speed of drop in DaTbs, which occurs early in the motor phase of the disease, may be helpful for predicting clinical outcomes in PD. Longer observation of this cohort may provide further data to investigate DaTbs as a prognostic marker in PD.

Same same but different: dopamine transporter SPECT on scanners with CZT vs. NaI detectors

BackgroundThe aims of this study were to establish a normal database (NDB) for semiquantification of dopamine transporter (DAT) single-photon emission computed tomography (SPECT) with [123I]FP-CIT on a cadmium zinc telluride (CZT) camera, test the preexisting NaI-derived NDB for use in CZT scans, and compare the diagnostic findings in subjects imaged with a CZT scanner with either the preexisting NaI-based NDB or our newly defined CZT NDB.MethodsThe sample comprised 73 subjects with clinically uncertain parkinsonian syndrome (PS) who prospectively underwent [123I]FP-CIT SPECT on a CZT camera according to standard guidelines with identical acquisition and reconstruction protocols (DaTQUANT). Two experienced readers visually assessed the images and binarized the subjects into “non-neurodegenerative PS” and “neurodegenerative PS”. Twenty-five subjects from the “non-neurodegenerative PS” subgroup were randomly selected to establish a CZT NDB. The remaining 48 subjects were defined as “test group”. DaTQUANT was used to determine the specific binding ratio (SBR). For the test group, SBR values were transformed to z-scores for the putamen utilizing both the CZT NDB and the manufacturer-provided NaI-based NDB (GE NDB). A predefined fixed cut-off of -2 was used for dichotomization of z-scores to classify neurodegenerative and non-neurodegenerative PS. Performance of semiquantification using the two NDB to identify subjects with neurodegenerative PS was assessed in comparison with the visual rating. Furthermore, a randomized head-to-head comparison of both detector systems was performed semiquantitatively in a subset of 32 out of all 73 subjects.ResultsCompared to the visual rating as reference, semiquantification based on the dedicated CZT NDB led to fewer discordant ratings than the GE NDB in CZT scans (3 vs. 8 out of 48 subjects). This can be attributed to the putaminal z-scores being consistently higher with the GE NDB on a CZT camera (median absolute difference of 1.68), suggesting an optimal cut-off of -0.5 for the GE NDB instead of -2.0. Average binding ratios and z-scores were significantly lower in CZT compared to NaI data.ConclusionsUse of a dedicated, CZT-derived NDB is recommended in [123I]FP-CIT SPECT with a CZT camera since it improves agreement between semiquantification and visual assessment.

Correlations between cerebrospinal fluid homovanillic acid and dopamine transporter SPECT in degenerative parkinsonian syndromes

Both cerebrospinal fluid (CSF) homovanillic acid (HVA) and striatal dopamine transporter (DAT) binding on single-photon emission computed tomography (SPECT) reflect nigrostriatal dopaminergic function, but studies on the relationship between the two have been limited. It is also unknown whether the reported variance in striatal DAT binding among diseases reflects the pathophysiology or characteristics of the subjects. We included 70 patients with Parkinson’s disease (PD), 12 with progressive supranuclear palsy (PSP), 12 with multiple system atrophy, six with corticobasal syndrome, and nine with Alzheimer’s disease as disease control, who underwent both CSF analysis and 123I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane (123I-ioflupane) SPECT. We evaluated the correlation between CSF HVA concentration and the specific binding ratio (SBR) of striatal DAT binding. We also compared the SBR for each diagnosis, controlling for CSF HVA concentration. The correlations between the two were significant in patients with PD (r = 0.34, p = 0.004) and PSP (r = 0.77, p = 0.004). The mean SBR value was the lowest in patients with PSP and was significantly lower in patients with PSP than in those with PD (p = 0.037) after adjusting for CSF HVA concentration. Our study demonstrates that striatal DAT binding correlates with CSF HVA concentration in both PD and PSP, and striatal DAT reduction would be more advanced in PSP than in PD at an equivalent dopamine level. Striatal DAT binding may correlate with dopamine levels in the brain. The pathophysiology of each diagnosis may explain this difference.

Radiomics insight into the neurodegenerative “hot” brain: A narrative review from the nuclear medicine perspective

The application of radiomics for non-oncologic diseases is currently emerging. Despite its relative infancy state, the evidence highlights the potential of radiomics approaches to serve as neuroimaging biomarkers in the field of the neurodegenerative brain. This systematic review presents the last progress and potential application of radiomics in the field of neurodegenerative nuclear imaging applied to positron-emission tomography (PET) and single-photon emission computed tomography (SPECT) by focusing mainly on the two most common neurodegenerative disorders, Alzheimer's (AD) and Parkinson's disease (PD). A comprehensive review of the current literature was performed using the PubMed and Web of Science databases up to November 2022. The final collection of eighteen relevant publications was grouped as AD-related and PD-related. The main efforts in the field of AD dealt with radiomics-based early diagnosis of preclinical AD and the prediction of MCI to AD conversion, meanwhile, in the setting of PD, the radiomics techniques have been used in the attempt to improve the assessment of PD diagnosis, the differential diagnosis between PD and other parkinsonism, severity assessment, and outcome prediction. Although limited evidence with relatively small cohort studies, it seems that radiomics-based analysis using nuclear medicine tools, mainly [18F]Fluorodeoxyglucose (FDG) and β-amyloid (Aβ) PET, and dopamine transporter (DAT) SPECT, can be used for computer-aided diagnoses in AD-continuum and parkinsonian disorders. Combining nuclear radiomics analysis with clinical factors and introducing a multimodality approach can significantly improve classification and prediction efficiency in neurodegenerative disorders.

Dopamine transporter single photon emission computed tomography (DaT-SPECT) use in the diagnosis and clinical management of parkinsonism: an 8-year retrospective study

IntroductionParkinson’s disease (PD) is a neurodegenerative movement disorder that is typically diagnosed clinically. DaT-SPECT scanning (DaT Scan) can be used when there is diagnostic difficulty differentiating from non-neurodegenerative Parkinsonism. This study assessed the effect of DaT Scan imaging on diagnosis and subsequent clinical management of these disorders.MethodsThis single-trust retrospective study involved 455 patients who had undergone DaT scans for investigation for Parkinsonism, between 01/01/2014 and 31/12/2021. Data collected included patient demographics, date of clinical assessment, scan report, pre-scan and post-scan diagnosis, and clinical management.ResultsThe mean age at scan was 70.5 years and 57% were male. The percentage of patients who had an abnormal scan result was 40% (n = 184), whilst 53% (n = 239) had a normal scan result, and 7% (n = 32) had an equivocal scan. Pre-scan diagnosis was consistent with scan results in 71% of cases of neurodegenerative Parkinsonism, whereas this figure was 64% for cases of non-neurodegenerative Parkinsonism. For all DaT scans, the diagnosis was changed in 37% of patients (n = 168), whilst the clinical management was changed in 42% of patients (n = 190). Change in management involved 63% starting dopaminergic medication, 5% stopping dopaminergic medications, and 31% undergoing other changes in management.ConclusionDaT imaging is useful for confirming the correct diagnosis and clinical management for patients with clinically indeterminate Parkinsonism. Pre-scan diagnoses were generally consistent with scan results.

Accurate Detection of α-Synuclein Seeds in Cerebrospinal Fluid from Isolated Rapid Eye Movement Sleep Behavior Disorder and Patients with Parkinson's Disease in the DeNovo Parkinson (DeNoPa) Cohort.

Misfolded α-synuclein (αSyn) aggregates (αSyn-seeds) in cerebrospinal fluid (CSF) are biomarkers for synucleinopathies such as Parkinson's disease (PD). αSyn-seeds have been detected in prodromal cases with isolated rapid eye movement sleep behavior disorder (iRBD). The objective of this study was to determine the accuracy of the αSyn-seed amplification assay (αS-SAA) in a comprehensively characterized cohort with a high proportion of PD and iRBD CSF samples collected at baseline. We used a high-throughput αS-SAA to analyze 233 blinded CSF samples from 206 participants of the DeNovo Parkinson Cohort (DeNoPa) (113 de novo PD, 64 healthy controls, 29 iRBD confirmed by video polysomnography). Results were compared with the final diagnosis, which was determined after up to 10 years of longitudinal clinical evaluations, including dopamine-transporter-single-photon emission computed tomography (DAT-SPECT) at baseline, CSF proteins, Movement Disorder Society-Unified Parkinson's Disease Rating Scale, and various cognitive and nonmotor scales. αS-SAA detected αSyn-seeds in baseline PD-CSF with 98% accuracy. αSyn-seeds were detected in 93% of the iRBD cases. αS-SAA results showed higher agreement with the final than the initial diagnosis, as 14 patients were rediagnosed as non-αSyn aggregation disorder. For synucleinopathies, αS-SAA showed higher concordance with the final diagnosis than DAT-SPECT. Statistically significant correlations were found between assay parameters and disease progression. Our results confirm αS-SAA accuracy at the first clinical evaluation when a definite diagnosis is most consequential. αS-SAA conditions reported here are highly sensitive, enabling the detection of αSyn-seeds in CSF from iRBD just months after the first symptoms, suggesting that αSyn-seeds are present in the very early prodromal phase of synucleinopathies. Therefore, αSyn-seeds are clear risk markers for synuclein-related disorders, but not for time of phenoconversion. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Differential serum microRNAs in premotor LRRK2 G2019S carriers from Parkinson’s disease

The LRRK2 G2019S pathogenic mutation causes LRRK2-associated Parkinson’s disease (L2PD) with incomplete penetrance. LRRK2 non-manifesting carriers (L2NMC) are at PD high risk but predicting pheno-conversion is challenging given the lack of progression biomarkers. To investigate novel biomarkers for PD premotor stages, we performed a longitudinal microRNA (miRNA) assessment of serum samples from G2019S L2NMC followed-up over 8 years. Our cohort consisted of G2019S L2NMC stratified by dopamine transporter single-photon emission computed tomography (DaT-SPECT) into DaT-negative (n = 20) and DaT-positive L2NMC (n = 20), pheno-converted G2019S L2PD patients (n = 20), idiopathic PD (iPD) (n = 19), and controls (n = 40). We also screened a second cohort of L2PD patients (n = 19) and controls (n = 20) (Total n = 158). Compared to healthy controls, we identified eight deregulated miRNAs in DaT-negative L2NMC, six in DaT-positive L2NMC, and one in L2PD. Between groups, the highest miRNA differences, 24 candidate miRNAs, occurred between DaT-positive L2NMC and L2PD. Longitudinally, we found 11 common miRNAs with sustained variation in DaT-negative and DaT-positive L2NMCs compared to their baselines. Our study identifies novel miRNA alterations in premotor stages of PD co-occurring with progressive DaT-SPECT decline before motor manifestation, whose deregulation seems to attenuate after the diagnosis of L2PD. Moreover, we identified four miRNAs with relatively high discriminative ability (AUC = 0.82) between non-pheno-converted DaT-positive G2019S carriers and pheno-converted L2PD patients (miR-4505, miR-8069, miR-6125, and miR-451a), which hold potential as early progression biomarkers for PD.

A case of non-fluent/agrammatic variant of primary progressive aphasia with logoclonia

We report a case of non-fluent/agrammatic variant of primary progressive aphasia in a 79-year-old right-handed man who was admitted with a 5-year history of non-fluent speech and apraxia of speech. He also presented with agrammatism and logoclonia (the meaningless repetition of the middle or final syllable of a word). Furthermore, brain MRI revealed atrophy of the bilateral frontal and temporal lobes, while N-isopropyl-p-123I-iodoamphetamine single-photon emission computed tomography (SPECT) revealed relative hypoperfusion in the right basal ganglia. In addition, dopamine transporter SPECT revealed a decrease in specific binding ratio values, indicating neural dopamine dysfunction, which led to his diagnosis of progressive non-fluent aphasia with logoclonia. Logoclonia is a severe linguistic dysfunction usually observed in the advanced stages of Alzheimer's disease. However, based on the clinical course and cerebrospinal fluid evaluation results, our patient did not show any features of Alzheimer's disease. Thus, logoclonia might be associated with lesions involving the basal ganglia, right hemisphere, and left frontotemporal lobe.

Use of 99mTc-Trodat-1 SPECT to evaluate the efficacy of deep brain stimulation in Parkinson's disease.

This study aimed to explore the availability of striatal dopamine transporter (DAT) after deep brain stimulation (DBS) by single photon emission computed tomography (SPECT) using technetium-99m-labeled tropane derivative (99mTc-Trodat-1). In this cohort, 28 patients with PD were enrolled (including 18 males and 10 females). Among these patients, the age range was 55-75 years. All patients referred for optimized DBS programming were recruited for 99mTc-Trodat-1 imaging and symptom assessment. Dopamine transporter SPECT was performed under medication-off state before DBS and at the 6th month after DBS, respectively. The clinical scales including Unified Parkinson Disease Rating Scale (UPDRS), Modified Hoehn & Yahr Scale (MHYS) and Ability of Daily Life Scale (ADLS) were carried out before DBS and at 6 months after DBS under medication-on and medication-off, respectively. Dopamine transporter availability was assessed based on DAT SPECT. In addition, the correlation between DAT availability and clinical scales was investigated. The data were analyzed using SPSS 23.0. The mean UPDRS total, MHYS and ADLS scores were 62.36, 2.23 and 42.07 under medication-on, respectively. The medication improvement rate of UPDRS total, MHYS and ADLS scores were 27.55%, 21.88% and 54.19%, respectively. Interestingly, we found PD patients with MHYS grade I usually presented unilateral symptoms, but DAT imaging showed that DAT uptake of the bilateral striatum was lower than that of the normal and the S-value of the contralateral side was significantly lower than that of the ipsilateral side. Furthermore, we found that DBS can improve the laterality of symptoms. The DBS improvement rate of UPDRS total scores, ADLS scores and DAT S-value were 37.65%, 72.51% and 18.21%, respectively. The symptom laterality was significantly correlated with the DAT S-value at baseline and at 6 months after DBS (r=0.63, 0.69 and 0.66, 0.75). The dosage of levodopa was 696.43±146.52 and was 455.36±107.44 before DBS surgery and at DBS-on, respectively. Deep brain stimulation can significantly improve the symptom of PD. Dopamine transporter S-value was well correlated with the change of symptoms laterality. Therefore, DAT imaging can be used to diagnose PD in the early stage and to evaluate the curative effect of DBS. However, the validation of this result requires further study.

Multi-Modal Synergistic 99mTc-TRODAT-1 SPECT and MRI for Evaluation of the Efficacy of Hyperbaric Oxygen Therapy in CO-Induced Delayed Parkinsonian and Non-Parkinsonian Syndromes.

Delayed neuropsychiatric syndrome (DNS) is characterized by motor dysfunction after acute carbon monoxide (CO) poisoning. We examined the relationship between dopamine transporter (DAT) loss using kit-based Tc-99m-TRODAT-1 (DAT single-photon emission-computed tomography (SPECT) radioligand) and globus pallidus necrosis on MRI, DAT availability before and after hyperbaric oxygen therapy (HBOT), and feasibility of Tc-99m-TRODAT-1 as an index for parkinsonian syndrome in CO poisoning. Twenty-one CO-intoxicated patients (mean ± SD age, 38.6 ± 11.4; range, 20-68 years) with DNS underwent Tc-99m-TRODAT-1 SPECT and MRI before HBOT and follow-up Tc-99m-TRODAT-1 SPECT to assess DAT recovery. Neurological examinations for Parkinsonism were performed after development of DNS. Over 70% (15/21) of DNS patients showed globus pallidus necrosis on MRI. Significantly lower bilateral striatal DAT availability was associated with globus pallidus necrosis (p &lt; 0.005). Moreover, 68.4% (13/19) of DNS subjects with Parkinsonian syndrome had lower bilateral striatal DAT availability vs. non-parkinsonian subjects pre- or post-HBOT. The SURs for both striata increased by ~11% post-HBOT in the Parkinsonian group; however, the left striatum presented a significantly higher DAT recovery rate than the right (*** p &lt; 0.005). Coupled Tc-99m TRODAT-1 SPECT and MRI could assist evaluation of Parkinsonism risk and indicate DAT availability after HBOT in CO-poisoned patients with DNS.

Trial of Cinpanemab in Early Parkinson’s Disease

BackgroundAggregated α-synuclein plays an important role in Parkinson’s disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson’s disease.MethodsIn a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson’s disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society–sponsored revision of the Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT).ResultsOf the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, −0.3 points [95% confidence interval {CI}, −4.9 to 4.3], P=0.90; 0.5 points [95% CI, −3.3 to 4.3], P=0.80; and 0.1 point [95% CI, −3.8 to 4.0], P=0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was −0.9 points (95% CI, −5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, −3.3 to 4.4) for the 1250-mg dose, and −0.8 points (95% CI, −4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls.ConclusionsIn participants with early Parkinson’s disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.)

A tissue-fraction estimation-based segmentation method for quantitative dopamine transporter SPECT.

Quantitative measures of dopamine transporter (DaT) uptake in caudate, putamen, and globus pallidus (GP) derived from dopamine transporter-single-photon emission computed tomography (DaT-SPECT) images have potential as biomarkers for measuring the severity of Parkinson's disease. Reliable quantification of this uptake requires accurate segmentation of the considered regions. However, segmentation of these regions from DaT-SPECT images is challenging, a major reason being partial-volume effects (PVEs) in SPECT. The PVEs arise from two sources, namely the limited system resolution and reconstruction of images over finite-sized voxel grids. The limited system resolution results in blurred boundaries of the different regions. The finite voxel size leads to TFEs, that is, voxels contain a mixture of regions. Thus, there is an important need for methods that can account for the PVEs, including the TFEs, and accurately segment the caudate, putamen, and GP, from DaT-SPECTimages. Design and objectively evaluate a fully automated tissue-fraction estimation-based segmentation method that segments the caudate, putamen, and GP from DaT-SPECTimages. The proposed method estimates the posterior mean of the fractional volumes occupied by the caudate, putamen, and GP within each voxel of a three-dimensional DaT-SPECT image. The estimate is obtained by minimizing a cost function based on the binary cross-entropy loss between the true and estimated fractional volumes over a population of SPECT images, where the distribution of true fractional volumes is obtained from existing populations of clinical magnetic resonance images. The method is implemented using a supervised deep-learning-basedapproach. Evaluations using clinically guided highly realistic simulation studies show that the proposed method accurately segmented the caudate, putamen, and GP with high mean Dice similarity coefficients of ∼ 0.80 and significantly outperformed ( ) all other considered segmentation methods. Further, an objective evaluation of the proposed method on the task of quantifying regional uptake shows that the method yielded reliable quantification with low ensemble normalized root mean square error (NRMSE) < 20% for all the considered regions. In particular, the method yielded an even lower ensemble NRMSE of ∼ 10% for the caudate andputamen. The proposed tissue-fraction estimation-based segmentation method for DaT-SPECT images demonstrated the ability to accurately segment the caudate, putamen, and GP, and reliably quantify the uptake within these regions. The results motivate further evaluation of the method with physical-phantom and patientstudies.