Rest tremor correlates with reduced contralateral striatal dopamine transporter binding in Parkinson's disease.

INTRODUCTION: In vivo dopamine transporter imaging is a useful tool for distinguishing nigrostriatal pathologies (e.g. Parkinson's disease) from other causes of tremor. However, while many of the motoric features of Parkinson's disease (e.g. bradykinesia, rigidity, hypomimia) correlate well with reduced striatal dopamine transporter binding, the same relationship has not been demonstrated for tremor. We investigated the relationship between striatal dopamine transporter binding and quantitative measures of tremor. METHODS: 23 participants with Parkinson's disease underwent standardised clinical assessment including structured, videotaped clinical examination, tremor neurophysiology study of both upper limbs using accelerometry and surface EMG, and Technitium-99 m TRODAT-1 brain SPECT imaging. Normalised striatal uptake values were calculated. Tremor EMG and accelerometry time series were processed with Fourier transformation to identify peak tremor power within a window of 3-10Hz and to calculate the tremor stability index (TSI). RESULTS: Spearman correlation analyses revealed an association between tremor power and contralaterally reduced striatal uptake in a number of recording conditions. This association was strongest for rest tremor, followed by postural tremor, with the weakest association observed for kinetic tremor. Lower TSI was also associated with lower contralateral striatal uptake in a number of rest and postural conditions. CONCLUSION: These data suggest a relationship between Parkinsonian rest tremor and contralateral reduction in striatal dopamine binding. Use of quantitative neurophysiology techniques may allow the demonstration of clinico-pathophysiological relationships in tremor that have remained occult to previous studies.

White matter hyperintensities mediate the impact of amyloid ß on future freezing of gait in Parkinson's disease.

BACKGROUND: Freezing of gait (FOG) is a common symptom in Parkinson's Disease (PD) patients. Previous studies have reported relationships between FOG, substantia nigra (SN) degeneration, dopamine transporter (DAT) concentration, as well as amyloid ß deposition. However, there is a paucity of research on the concurrent impact of white matter damage. OBJECTIVES: To assess the inter-relationships between these different co-morbidities, their impact on future FOG and whether they act independently of each other. METHODS: We used baseline MRI and longitudinal gait data from 423 de novo PD patients from the Parkinson's Progression Markers Initiative (PPMI). We used deformation based morphometry (DBM) from T1-weighted MRI to measure SN atrophy, and segmentation of white matter hyperintensities (WMH) as a measure of WM pathological load. Putamen and caudate DAT levels from SPECT as well as cerebrospinal fluid (CSF) amyloid ß were obtained directly from the PPMI. Following correlation analyses, we investigated whether WMH burden mediates the impact of amyloid ß on future FOG. RESULTS: SN DBM, WMH load, putamen and caudate DAT activity and CSF amyloid ß levels were significantly different between PD patients with and without future FOG (p < 0.008). Mediation analysis demonstrated an effect of CSF amyloid ß levels on future FOG via WMH load, independent of SN atrophy and striatal DAT activity levels. CONCLUSIONS: Amyloid ß might impact future FOG in PD patients through an increase in WMH burden, in a pathway independent of Lewy body pathology.

Automated assessment of the substantia nigra on susceptibility map-weighted imaging using deep convolutional neural networks for diagnosis of Idiopathic Parkinson's disease.

OBJECTIVES: Despite its use in determining nigrostriatal degeneration, the lack of a consistent interpretation of nigrosome 1 susceptibility map-weighted imaging (SMwI) limits its generalized applicability. To implement and evaluate a diagnostic algorithm based on convolutional neural networks for interpreting nigrosome 1 SMwI for determining nigrostriatal degeneration in idiopathic Parkinson's disease (IPD). METHODS: In this retrospective study, we enrolled 267 IPD patients and 160 control subjects (125 patients with drug-induced parkinsonism and 35 healthy subjects) at our institute, and 24 IPD patients and 27 control subjects at three other institutes on approval of the local institutional review boards. Dopamine transporter imaging served as the reference standard for the presence or absence of abnormalities of nigrosome 1 on SMwI. Diagnostic performance was compared between visual assessment by an experienced neuroradiologist and the developed deep learning-based diagnostic algorithm in both internal and external datasets using a bootstrapping method with 10000 re-samples by the "pROC" package of R (version 1.16.2). RESULTS: The area under the receiver operating characteristics curve (AUC) (95% confidence interval [CI]) per participant by the bootstrap method was not significantly different between visual assessment and the deep learning-based algorithm (internal validation, .9622 [0.8912-1.0000] versus 0.9534 [0.8779-0.9956], P = .1511; external validation, 0.9367 [0.8843-0.9802] versus 0.9208 [0.8634-0.9693], P = .6267), indicative of a comparable performance to visual assessment. CONCLUSIONS: Our deep learning-based algorithm for assessing abnormalities of nigrosome 1 on SMwI was found to have a comparable performance to that of an experienced neuroradiologist.

Serum NFL levels predict progression of motor impairment and reduction in putamen dopamine transporter binding ratios in de novo Parkinson's disease: An 8-year longitudinal study.

Neurofilament light chain (NFL) level in biofluids is a sensitive measure of axonal damage and a promising biomarker in neurodegenerative diseases. In Parkinson's disease (PD), NFL can distinguish PD from other parkinsonian disorders, and NFL concentration is associated with disease severity, risk of progression, and survival. To determine whether serum NFL at baseline in de novo PD predicts motor decline, differentially impacts specific motor features, predicts cognitive decline, and predicts loss of dopamine terminals, here we evaluated 376 de novo PD patients from the PPMI database and analyzed the effect of baseline serum NFL levels on progression over eight years of motor impairment measured with the UPDRS, cognitive function measured with the MoCA, and putamen dopamine transporter (DAT) binding ratio measured with DaTscan. In longitudinal mixed effects models that controlled for age, gender, disease duration, and levodopa equivalent drug dose, higher levels of serum NFL at baseline were associated with greater increases of UPDRS-III and total UPDRS scores, with greater worsening of postural instability and gait disorder (PIGD) scores but not tremor scores over time. In contrast, baseline serum NFL was not associated with significant progression of MoCA scores in this de novo PD cohort. Higher baseline serum NFL was associated with greater reduction of putamen DAT binding ratio over time. Together, these findings show that baseline serum NFL levels predict the rate of motor decline, the accumulation of PIGD clinical features, and the progression of dopamine transporter loss in the early stage of PD.

Impact of the apolipoprotein E ε4 allele on early Parkinson's disease progression.

OBJECTIVE: Emerging evidence shows that apolipoprotein E (APOE) ε4 exacerbates alpha-synuclein pathology. We aimed to investigate whether the APOE ε4 allele contributes to early Parkinson's disease (PD) progression. METHODS: This cohort study included 361 early PD patients who were classified as APOE ε4 carriers (n = 90) and noncarriers (n = 271). The patients underwent yearly motor and nonmotor assessments covering neuropsychiatric, sleep-related, and autonomic symptoms over 5 years of follow-up. Dopamine transporter (DAT) imaging was conducted at baseline and the 1-, 2-, and 4-year follow-up visits. RESULTS: The APOE ε4 carriers had steeper declines in the Montreal Cognitive Assessment score (p=0.005) and the semantic fluency test score (p=0.012) than the noncarriers. No significant between-group differences in the longitudinal changes in motor, other nonmotor, and DAT imaging variables were observed. CONCLUSIONS: Our exploratory analyses show that only cognitive performance was negatively affected by the APOE ε4 allele in the progression of early PD. More specifically, this allele was associated with poorer performance in semantic verbal fluency among cognitive domains.

Non-motor symptoms and striatal dopamine transporter binding in early Parkinson's disease.

BACKGROUND: Non-motor symptoms (NMS) are common in Parkinson's disease (PD), but their relationships to nigrostriatal degeneration remain largely unexplored. METHODS: We evaluated 18 NMS scores covering 5 major domains in relation to concurrent and future dopamine transporter (DAT) imaging in 344 PD patients from the Parkinson's Progression and Markers Initiative (PPMI). We standardized NMS assessments into z-scores for side-by-side comparisons. Patients underwent sequential DaTSCAN imaging at enrollment and at months 12, 24, and 48. Specific binding ratios (SBR) were calculated using the occipital lobe reference region. We evaluated the association of striatal DAT binding at the four time points with each baseline NMS using mixed-effects regression models. RESULTS: Multiple baseline NMS were significantly associated with DAT binding at baseline and at follow-up scans. REM sleep behavior disorder (RBD) symptoms showed the strongest association - mean striatal SBR declined with increasing RBD symptom z-score (average of time-point-specific slopes per unit change in z-score: ßAVG = -0.083, SE = 0.017; p < 0.0001). In addition, striatal DAT binding was linearly associated with increasing baseline z-scores: positively for the memory (ßAVG=0.055, SE = 0.022; p = 0.01) and visuospatial (ßAVG=0.044, SE = 0.020; p = 0.03) cognitive domains, and negatively for total anxiety (ßAVG= -0.059, SE = 0.018; p = 0.001). Striatal DAT binding showed curvilinear associations with odor identification, verbal discrimination recognition, and autonomic dysfunction z-scores (p = 0.001, p = 0.0009, and p = 0.0002, respectively). Other NMS were not associated with DAT binding. CONCLUSIONS: Multiple NMS, RBD symptoms in particular, are associated with nigrostriatal dopaminergic changes in early PD.

The longitudinal associations between cognition, mood and striatal dopaminergic binding in Parkinson's Disease.

Cognitive decline and mood symptoms are common in Parkinson's disease (PD). Reductions in striatal dopaminergic binding have been associated with worse cognition and mood. We investigated whether this association persists throughout the disease progression in newly diagnosed PD. Four-year data from Parkinson's Progression Markers Initiative (PPMI) were used. Groups consisted of left and right limb dominantly affected PD patients, and controls. Longitudinal relationships between cognition, mood and striatal binding ratios were assessed by repeated measures correlations. Reduced binding was associated with general cognitive decline in controls, reduced processing speed and increased mood symptoms in PD. Anxiety was associated with striatum only in left limb dominantly affected PD. Dominantly affected limb side did not impact striatum and cognition association. There are longitudinal associations between striatum, processing speed and anxiety. Dopamine transporter availability imaging may have some prognostic value for cognition and mood in PD.

Progressive dopaminergic defect in a patient with primary progressive multiple sclerosis.

Dopamine has a modulatory role in a number of autoimmune diseases, but there are no published cases of longitudinal dopaminergic imaging in multiple sclerosis (MS). Here we report a patient with primary progressive multiple sclerosis (PPMS) who was scanned twice with brain dopamine transporter single photon emission computed tomography (SPECT) with an interval of four years. The results showed a loss of tracer binding that corresponded to a 4-7 fold steeper decline than in normal ageing. The finding points to a relevant role of nigrostriatal dopaminergic degeneration in the pathological process of PPMS.

Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies.

BACKGROUND: Dopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage. METHODS: We recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2ß-carbomethoxy-3ß-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal. RESULTS: The sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2-68.6], with a specificity of 89.0% (95% CI 70.8-97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5-77.4) and in possible MCI-LB was 40.0% (95% CI 16.4-67.7). CONCLUSIONS: Dopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.

Relation of overactive bladder with motor symptoms and dopamine transporter imaging in drug-naïve Parkinson's disease.

OBJECTIVES: The aim of the present study was to determine the relation of urinary dysfunction with motor symptoms and nigrostriatal neuron loss in drug-naïve patients with Parkinson's disease (PD). We therefore examined the relation of overactive bladder (OAB) symptoms with motor symptoms and striatal dopamine transporter (DAT) binding measured by [123-Iodine]-fluoropropyl-2beta-carbomethoxy-3beta-(4-iodophenylnortropane) dopamine transporter single-photon emission computed tomography (123I-FP-CIT SPECT). PATIENTS AND METHODS: Thirty-one untreated PD patients (12 men and 19 women with a mean age of 71.2 ±â€¯6.7 years) were included in this study. Patients were evaluated with overactive bladder symptom score (OABSS) and divided into an OAB group and Non-OAB group. They underwent clinical assessments and 123I-FP-CIT SPECT imaging. Motor symptoms were assessed using Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The results showed that UPDRS motor score (p = 0.01) and akinetic-rigid score (p = 0.002) were higher and that striatal DAT availability (p = 0.01) was lower in the OAB group than in the Non-OAB group. However, tremor score, age, and duration of PD showed no significant differences between the OAB group and Non-OAB group. CONCLUSIONS: Urinary dysfunction in untreated PD is related with increase in motor symptoms (especially bradykinesia and axial symptoms) and reduction of striatal DAT availability.

Membrane-permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release.

The dopamine transporter (DAT) is responsible for sequestration of extracellular dopamine (DA). The psychostimulant amphetamine (AMPH) is a DAT substrate, which is actively transported into the nerve terminal, eliciting vesicular depletion and reversal of DA transport via DAT. Here, we investigate the role of the DAT C terminus in AMPH-evoked DA efflux using cell-permeant dominant-negative peptides. A peptide, which corresponded to the last 24 C-terminal residues of DAT (TAT-C24 DAT) and thereby contained the Ca(2+)-calmodulin-dependent protein kinase IIα (CaMKIIα) binding domain and the PSD-95/Discs-large/ZO-1 (PDZ)-binding sequence of DAT, was made membrane-permeable by fusing it to the cell membrane transduction domain of the HIV-1 Tat protein (TAT-C24WT). The ability of TAT-C24WT but not a scrambled peptide (TAT-C24Scr) to block the CaMKIIα-DAT interaction was supported by co-immunoprecipitation experiments in heterologous cells. In heterologous cells, we also found that TAT-C24WT, but not TAT-C24Scr, decreased AMPH-evoked 1-methyl-4-phenylpyridinium efflux. Moreover, chronoamperometric recordings in striatum revealed diminished AMPH-evoked DA efflux in mice preinjected with TAT-C24WT. Both in heterologous cells and in striatum, the peptide did not further inhibit efflux upon KN-93-mediated inhibition of CaMKIIα activity, consistent with a dominant-negative action preventing binding of CaMKIIα to the DAT C terminus. This was further supported by the ability of a peptide with perturbed PDZ-binding sequence, but preserved CaMKIIα binding (TAT-C24AAA), to diminish AMPH-evoked DA efflux in vivo to the same extent as TAT-C24WT. Finally, AMPH-induced locomotor hyperactivity was attenuated following systemic administration of TAT-C24WT but not TAT-C24Scr. Summarized, our findings substantiate that DAT C-terminal protein-protein interactions are critical for AMPH-evoked DA efflux and suggest that it may be possible to target protein-protein interactions to modulate transporter function and interfere with psychostimulant effects.

A basic smell test is as sensitive as a dopamine transporter scan: comparison of olfaction, taste and DaTSCAN in the diagnosis of Parkinson's disease.

AIM: To evaluate relationship between odour identification, taste threshold, dopamine transporter scan (DaTSCAN) and motor function in early Parkinson's disease (PD) and their diagnostic accuracy. METHODS: Seventy-three patients with early parkinsonism were evaluated by the Unified Parkinson's Disease Rating Scale (UPDRS), DaTSCAN, electrogustometry (EGM) threshold and University of Pennsylvania Smell Identification Test (UPSIT). Olfactory Event-Related potentials (OERP) were performed on 49 patients. At follow-up (mean 15.3 months), patients were diagnosed as 'PD' or 'non-PD'. DaTSCAN images were assessed visually and semi-quantitatively by QuantiSPECT. RESULTS: The sensitivity of UPSIT (86%) was not significantly different from that of the DaTSCAN (92%). UPSIT correlated moderately with DaTSCAN uptake (r = 0.44; P < 0.005) and UPDRS score (r = 0.43; P < 0.05) and weakly with symptom duration (r = 0.25; P < 0.05). In the PD group, OERP showed increased latency but no change in amplitude and no correlation with DaTSCAN. EGM thresholds were impaired in 22% of the PD group but they did not correlate with any other test parameters. DaTSCAN-UPSIT discordance was found in nine patients with PD, but neither was diagnostically superior. CONCLUSION: Our patients with early PD have a frequent and severe olfactory deficit that correlates with disease severity, symptom duration and DaTSCAN but not EGM. The sensitivities of UPSIT and DaTSCAN are high at 86% and 92%, respectively. Although DaTSCAN is superior for 'localization', UPSIT is considerably 'cheaper', and neither is disease specific. EGM threshold impairment in PD is independent of the smell deficit, and probably signifies advanced disease.