Magnetic Resonance-Guided Focused Ultrasound (MRgFUS)-Thalamotomy for Essential Tremor: Lesion Location and Clinical Outcomes.

BACKGROUND: Factors predicting clinical outcomes after MR-guided focused ultrasound (MRgFUS)-thalamotomy in patients with essential tremor (ET) are not well known. OBJECTIVE: To examine the clinical outcomes and their relationship with patients' baseline demographic and clinical features and lesion characteristics at 6-month follow-up in ET patients. METHODS: A total of 127 patients were prospectively evaluated at 1 (n = 122), 3 (n = 102), and 6 months (n = 78) after MRgFUS-thalamotomy. Magnetic resonance imaging (MRI) was obtained at 6 months (n = 60). Primary outcomes included: (1) change in the Clinical Rating Scale of Tremor (CRST)-A+B score in the treated hand and (2) frequency and severity of adverse events (AEs) at 6 months. Secondary outcomes included changes in all subitems of the CRST scale in the treated hand, CRST-C, axial tremor (face, head, voice, tongue), AEs, and correlation of primary outcomes at 6 months with lesion characteristics. Statistical analysis included linear mixed, standard, and logistic regression models. RESULTS: Scores for CRST-A+B, CRST-A, CRST-B in the treated hand, CRST-C, and axial tremor were improved at each evaluation (P < 0.001). Five patients had severe AEs at 1 month that became mild throughout the follow-up. Mild AEs occurred in 71%, 45%, and 34% of patients at 1, 3, and 6 months, respectively. Lesion volume was associated with the reduction in the CRST-A (P = 0.003) and its overlapping with the ventralis intermedius nucleus (Vim) nucleus with the reduction in CRST-A+B (P = 0.02) and CRST-B (P = 0.008) at 6 months. CONCLUSIONS: MRgFUS-thalamotomy improves hand and axial tremor in ET patients. Transient and mild AEs are frequent. Lesion volume and location are associated with tremor reduction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Astrogliosis in aging and Parkinson's disease dementia: a new clinical study with 11C-BU99008 PET.

The role of astrogliosis in the pathology of brain aging and neurodegenerative diseases has recently drawn great attention. Imidazoline-2 binding sites represent a possible target to map the distribution of reactive astrocytes. In this study, we use 11C-BU99008, an imidazoline-2 binding sites-specific PET radioligand, to image reactive astrocytes in vivo in healthy controls and patients with established Parkinson's disease dementia. Eighteen healthy controls (age: 45-78 years) and six patients with Parkinson's disease dementia (age: 64-77 years) had one 11C-BU99008 PET-CT scan with arterial input function. All subjects underwent one 3 T MRI brain scan to facilitate the analysis of the PET data and to capture individual cerebral atrophy. Regional 11C-BU99008 volumes of distribution were calculated for each subject by the two-tissue compartmental modelling. Positive correlations between 11C-BU99008 volumes of distribution values and age were found for all tested regions across the brain within healthy controls (P < 0.05); furthermore, multiple regression indicated that aging affects 11C-BU99008 volumes of distribution values in a region-specific manner. Independent samples t-test indicated that there was no significant group difference in 11C-BU99008 volumes of distribution values between Parkinson's disease dementia (n = 6; mean age = 71.97 ± 4.66 years) and older healthy controls (n = 9; mean age = 71.90 ± 5.51 years). Our data set shows that astrogliosis is common with aging in a region-specific manner. However, in this set-up, 11C-BU99008 PET cannot differentiate patients with Parkinson's disease dementia from healthy controls of similar age.

Neuromelanin-MRI to Quantify and Track Nigral Depigmentation in Parkinson's Disease: A Multicenter Longitudinal Study Using Template-Based Standardized Analysis.

BACKGROUND: Clinical diagnosis and monitoring of Parkinson's disease (PD) remain challenging because of the lack of an established biomarker. Neuromelanin-magnetic resonance imaging (NM-MRI) is an emerging biomarker of nigral depigmentation indexing the loss of melanized neurons but has unknown prospective diagnostic and tracking performance in multicenter settings. OBJECTIVES: The aim was to investigate the diagnostic accuracy of NM-MRI in early PD in a multiprotocol setting and to determine and compare serial NM-MRI changes in PD and controls. METHODS: In this longitudinal case-control 3 T MRI study, 148 patients and 97 controls were included from six UK clinical centers, of whom 140 underwent a second scan after 1.5 to 3 years. An automated template-based analysis was applied for subregional substantia nigra NM-MRI contrast and volume assessment. A point estimate of the period of prediagnostic depigmentation was computed. RESULTS: All NM metrics performed well to discriminate patients from controls, with receiver operating characteristic showing 85% accuracy for ventral NM contrast and 83% for volume. Generalizability using a priori volume cutoff was good (79% accuracy). Serial MRI demonstrated accelerated NM loss in patients compared to controls. Ventral NM contrast loss was point estimated to start 5 to 6 years before clinical diagnosis. Ventral nigral depigmentation was greater in the most affected side, more severe cases, and nigral NM volume change correlated with change in motor severity. CONCLUSIONS: We demonstrate that NM-MRI provides clinically useful diagnostic information in early PD across protocols, platforms, and sites. It provides methods and estimated depigmentation rates that highlight the potential to detect preclinical PD and track progression for biomarker-enabled clinical trials. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Multimodal brain and retinal imaging of dopaminergic degeneration in Parkinson disease.

Parkinson disease (PD) is a progressive disorder characterized by dopaminergic neurodegeneration in the brain. The development of parkinsonism is preceded by a long prodromal phase, and >50% of dopaminergic neurons can be lost from the substantia nigra by the time of the initial diagnosis. Therefore, validation of in vivo imaging biomarkers for early diagnosis and monitoring of disease progression is essential for future therapeutic developments. PET and single-photon emission CT targeting the presynaptic terminals of dopaminergic neurons can be used for early diagnosis by detecting axonal degeneration in the striatum. However, these techniques poorly differentiate atypical parkinsonian syndromes from PD, and their availability is limited in clinical settings. Advanced MRI in which pathological changes in the substantia nigra are visualized with diffusion, iron-sensitive susceptibility and neuromelanin-sensitive sequences potentially represents a more accessible imaging tool. Although these techniques can visualize the classic degenerative changes in PD, they might be insufficient for phenotyping or prognostication of heterogeneous aspects of PD resulting from extranigral pathologies. The retina is an emerging imaging target owing to its pathological involvement early in PD, which correlates with brain pathology. Retinal optical coherence tomography (OCT) is a non-invasive technique to visualize structural changes in the retina. Progressive parafoveal thinning and fovea avascular zone remodelling, as revealed by OCT, provide potential biomarkers for early diagnosis and prognostication in PD. As we discuss in this Review, multimodal imaging of the substantia nigra and retina is a promising tool to aid diagnosis and management of PD.

Imaging Cognitive Impairment and Impulse Control Disorders in Parkinson's Disease.

Dementia and mild forms of cognitive impairment as well as neuropsychiatric symptoms (i. e., impulse control disorders) are frequent and disabling non-motor symptoms of Parkinson's disease (PD). The identification of changes in neuroimaging studies for the early diagnosis and monitoring of the cognitive and neuropsychiatric symptoms associated with Parkinson's disease, as well as their pathophysiological understanding, are critical for the development of an optimal therapeutic approach. In the current literature review, we present an update on the latest structural and functional neuroimaging findings, including high magnetic field resonance and radionuclide imaging, assessing cognitive dysfunction and impulse control disorders in PD.

Dissociable effects of age and Parkinson's disease on instruction-based learning.

The cognitive deficits associated with Parkinson's disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson's disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson's disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson's might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson's Disease. Seventeen participants with Parkinson's disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson's group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson's show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.

Frequency and Characterization of Movement Disorders in Anti-IgLON5 Disease.

OBJECTIVE: Anti-IgLON5 disease is a recently described neurological disease that shares features of autoimmunity and neurodegeneration. Abnormal movements appear to be frequent and important but have not been characterized and are under-reported. Here we describe the frequency and types of movement disorders in a series of consecutive patients with this disease. METHODS: In this retrospective, observational study, the presence and phenomenology of movement disorders were assessed with a standardized clinical questionnaire. Available videos were centrally reviewed by three experts in movement disorders. RESULTS: Seventy two patients were included. In 41 (57%) the main reason for initial consultation was difficulty walking along with one or several concurrent movement disorders. At the time of anti-IgLON5 diagnosis, 63 (87%) patients had at least one movement disorder with a median of three per patient. The most frequent abnormal movements were gait and balance disturbances (52 patients, 72%), chorea (24, 33%), bradykinesia (20, 28%), dystonia (19, 26%), abnormal body postures or rigidity (18, 25%), and tremor (15, 21%). Other hyperkinetic movements (myoclonus, akathisia, myorhythmia, myokymia, or abdominal dyskinesias) occurred in 26 (36%) patients. The craniofacial region was one of the most frequently affected by multiple concurrent movement disorders (23 patients, 32%) including dystonia (13), myorhythmia (6), chorea (4) or myokymia (4). Considering any body region, the most frequent combination of multiple movement disorders consisted of gait instability or ataxia associated with craniofacial dyskinesias or generalized chorea observed in 31(43%) of patients. In addition to abnormal movements, 87% of patients had sleep alterations, 74% bulbar dysfunction, and 53% cognitive impairment. Fifty-five (76%) patients were treated with immunotherapy, resulting in important and sustained improvement of the movement disorders in only seven (13%) cases. CONCLUSIONS: Movement disorders are a frequent and leading cause of initial neurological consultation in patients with anti-IgLON5 disease. Although multiple types of abnormal movements can occur, the most prevalent are disorders of gait, generalized chorea, and dystonia and other dyskinesias that frequently affect craniofacial muscles. Overall, anti-IgLON5 disease should be considered in patients with multiple movement disorders, particularly if they occur in association with sleep alterations, bulbar dysfunction, or cognitive impairment.

Longitudinal changes in movement-related functional MRI activity in Parkinson's disease patients.

INTRODUCTION: Functional brain imaging has shown alterations in the basal ganglia, cortex and cerebellum in Parkinson's disease patients. However, few functional imaging studies have tested how these changes evolve over time. Our study aimed to test the longitudinal progression of movement-related functional activity in Parkinson's disease patients. METHODS: At baseline, 48 Parkinson's disease patients and 16 healthy controls underwent structural and functional magnetic resonance imaging during a joystick motor task. Patients had repeated imaging after 18-months (n = 42) and 36-months (n = 32). T-tests compared functional responses between Parkinson's disease patients and controls, and linear mixed effects models examined longitudinal differences within Parkinson's disease. Correlations of motor-activity with bradykinesia, rigidity and tremor were undertaken. All contrasts used whole-brain analyses, thresholded at Z > 3.1 with a cluster-wise P < 0.05. RESULTS: Baseline activation was significantly greater in patients than controls across contralateral parietal and occipital regions, ipsilateral precentral gyrus and thalamus. Longitudinally, patients showed significant increases in cerebellar activity at successive visits following baseline. Task-related activity also increased in the contralateral motor, parietal and temporal areas at 36 months compared to baseline, however this was reduced when controlling for motor task performance. CONCLUSION: We have shown that there are changes over time in the blood-activation level dependent response of patients with Parkinson's disease undertaking a simple motor task. These changes are observed primarily in the ipsilateral cerebellum and may be compensatory in nature.

Is Chelation Therapy a Potential Treatment for Parkinson's Disease?

Iron loading in some brain regions occurs in Parkinson's Disease (PD), and it has been considered that its removal by iron chelators could be an appropriate therapeutic approach. Since neuroinflammation with microgliosis is also a common feature of PD, it is possible that iron is sequestered within cells as a result of the "anaemia of chronic disease" and remains unavailable to the chelator. In this review, the extent of neuroinflammation in PD is discussed together with the role played by glia cells, specifically microglia and astrocytes, in controlling iron metabolism during inflammation, together with the results of MRI studies. The current use of chelators in clinical medicine is presented together with a discussion of two clinical trials of PD patients where an iron chelator was administered and showed encouraging results. It is proposed that the use of anti-inflammatory drugs combined with an iron chelator might be a better approach to increase chelator efficacy.

Iron and inflammation: in vivo and post-mortem studies in Parkinson's disease.

In these present studies, in vivo and and post-mortem studies have investigated the association between iron and inflammation. Early-stage Parkinson's disease (PD) patients, of less than 5 years disease duration, showed associations of plasmatic ferritin concentrations with both proinflammatory cytokine interleukin-6 and hepcidin, a regulator of iron metabolism as well as clinical measures. In addition ratios of plasmatic ferritin and iron accumulation in deep grey matter nuclei assessed with relaxometry T2* inversely correlated with disease severity and duration of PD. On the hand, post-mortem material of the substantia nigra compacta (SNc) divided according to Braak and Braak scores, III-IV and V-VI staging, exhibited comparable microgliosis, with a variety of phenotypes present. There was an association between the intensity of microgliosis and iron accumulation as assayed by Perl's staining in the SNc sections. In conclusion, markers of inflammation and iron metabolism in both systemic and brain systems are closely linked in PD, thus offering a potential biomarker for progression of the disease.

Parkinson's disease laterality: a 11C-PE2I PET imaging study.

Asymmetry of striatal dopaminergic deficits and motor symptoms is a typical characteristic of idiopathic Parkinson's disease (PD). This study aims to characterise the trend of asymmetry in moderate-stage PD. We performed a 19-month longitudinal study in 27 patients with PET-CT imaging and appropriate clinical assessments. 11C-PE2I non-displaceable binding potential (BPND) was calculated bilaterally for the striatum at baseline and follow-up to estimate the in vivo density of striatal dopamine transporters (DAT). Changes in striatal 11C-PE2I BPND over time were more prominent in the ipsilateral as compared to contralateral side. Changes in MDS-UPDRS-III (motor component of the Movement Disorders Society Unified PD Rating Scale) were not different between the clinically most and least affected body sides. Our data support that the asymmetry in striatal dopaminergic degeneration becomes less prominent in moderate-stage PD. In contrast, during the above period, the asymmetry of motor symptoms was maintained between the clinically most and least affected body sides.

Longitudinal functional connectivity changes related to dopaminergic decline in Parkinson's disease.

BACKGROUND: Resting-state functional magnetic resonance imaging (fMRI) studies have demonstrated that basal ganglia functional connectivity is altered in Parkinson's disease (PD) as compared to healthy controls. However, such functional connectivity alterations have not been related to the dopaminergic deficits that occurs in PD over time. OBJECTIVES: To examine whether functional connectivity impairments are correlated with dopaminergic deficits across basal ganglia subdivisions in patients with PD both cross-sectionally and longitudinally. METHODS: We assessed resting-state functional connectivity of basal ganglia subdivisions and dopamine transporter density using 11C-PE2I PET in thirty-four PD patients at baseline. Of these, twenty PD patients were rescanned after 19.9 ± 3.8 months. A seed-based approach was used to analyze resting-state fMRI data. 11C-PE2I binding potential (BPND) was calculated for each participant. PD patients were assessed for disease severity. RESULTS: At baseline, PD patients with greater dopaminergic deficits, as measured with 11C-PE2I PET, showed larger decreases in posterior putamen functional connectivity with the midbrain and pallidum. Reduced functional connectivity of the posterior putamen with the thalamus, midbrain, supplementary motor area and sensorimotor cortex over time were significantly associated with changes in DAT density over the same period. Furthermore, increased motor disability was associated with lower intraregional functional connectivity of the posterior putamen. CONCLUSIONS: Our findings suggest that basal ganglia functional connectivity is related to integrity of dopaminergic system in patients with PD. Application of resting-state fMRI in a large cohort and longitudinal scanning may be a powerful tool for assessing underlying PD pathology and its progression.

Relationship between neuromelanin and dopamine terminals within the Parkinson's nigrostriatal system.

Parkinson's disease is characterized by the progressive loss of pigmented dopaminergic neurons in the substantia nigra and associated striatal deafferentation. Neuromelanin content is thought to reflect the loss of pigmented neurons, but available data characterizing its relationship with striatal dopaminergic integrity are not comprehensive or consistent, and predominantly involve heterogeneous samples. In this cross-sectional study, we used neuromelanin-sensitive MRI and the highly specific dopamine transporter PET radioligand, 11C-PE2I, to assess the association between neuromelanin-containing cell levels in the substantia nigra pars compacta and nigrostriatal terminal density in vivo, in 30 patients with bilateral Parkinson's disease. Fifteen healthy control subjects also underwent neuromelanin-sensitive imaging. We used a novel approach taking into account the anatomical and functional subdivision of substantia nigra into dorsal and ventral tiers and striatal nuclei into pre- and post-commissural subregions, in accordance with previous animal and post-mortem studies, and consider the clinically asymmetric disease presentation. In vivo, Parkinson's disease subjects displayed reduced neuromelanin levels in the ventral (-30 ± 28%) and dorsal tiers (-21 ± 24%) as compared to the control group [F(1,43) = 11.95, P = 0.001]. Within the Parkinson's disease group, nigral pigmentation was lower in the ventral tier as compared to the dorsal tier [F(1,29) = 36.19, P < 0.001] and lower in the clinically-defined most affected side [F(1,29) = 4.85, P = 0.036]. Similarly, lower dopamine transporter density was observed in the ventral tier [F(1,29) = 76.39, P < 0.001] and clinically-defined most affected side [F(1,29) = 4.21, P = 0.049]. Despite similar patterns, regression analysis showed no significant association between nigral pigmentation and nigral dopamine transporter density. However, for the clinically-defined most affected side, significant relationships were observed between pigmentation of the ventral nigral tier with striatal dopamine transporter binding in pre-commissural and post-commissural striatal subregions known to receive nigrostriatal projections from this tier, while the dorsal tier correlated with striatal projection sites in the pre-commissural striatum (P < 0.05, Benjamini-Hochberg corrected). In contrast, there were no statistically significant relationships between these two measures in the clinically-defined least affected side. These findings provide important insights into the topography of nigrostriatal neurodegeneration in Parkinson's disease, indicating that the characteristics of disease progression may fundamentally differ across hemispheres and support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus tyrosine hydroxylase positive nigral cells.

11 C-PE2I and 18 F-Dopa PET for assessing progression rate in Parkinson's: A longitudinal study.

BACKGROUND: 18 F-dopa PET measuring aromatic l-amino acid decarboxylase activity is regarded as the gold standard for evaluating dopaminergic function in Parkinson's disease. Radioligands for dopamine transporters are also used in clinical trials and for confirming PD diagnosis. Currently, it is not clear which imaging marker is more reliable for assessing clinical severity and rate of progression. The objective of this study was to directly compare 18 F-dopa with the highly selective dopamine transporter radioligand 11 C-PE2I for the assessment of motor severity and rate of progression in PD. METHODS: Thirty-three mild-moderate PD patients underwent 18 F-dopa and 11 C-PE2I PET at baseline. Twenty-three were followed up for 18.8 ± 3.4 months. RESULTS: Standard multiple regression at baseline indicated that 11 C-PE2I BPND predicted UPDRS-III and bradykinesia-rigidity scores (P < 0.05), whereas 18 F-dopa Ki did not make significant unique explanatory contributions. Voxel-wise analysis showed negative correlations between 11 C-PE2I BPND and motor severity across the whole striatum bilaterally. 18 F-Dopa Ki clusters were restricted to the most affected putamen and caudate. Longitudinally, negative correlations were found between striatal Δ11 C-PE2I BPND , ΔUPDRS-III, and Δbradykinesia-rigidity, whereas no significant associations were found for Δ18 F-dopa Ki . One cluster in the most affected putamen was identified in the longitudinal voxel-wise analysis showing a negative relationship between Δ11 C-PE2I BPND and Δbradykinesia-rigidity. CONCLUSIONS: Striatal 11 C-PE2I appears to show greater sensitivity for detecting differences in motor severity than 18 F-dopa. Furthermore, dopamine transporter decline is closely associated with motor progression over time, whereas no such relationship was found with aromatic l-amino acid decarboxylase. 11 C-PE2I may be more effective for evaluating the efficacy of neuroprotective treatments in PD. © 2017 International Parkinson and Movement Disorder Society.

Patterns of grey matter loss associated with motor subscores in early Parkinson's disease.

Classical motor symptoms of Parkinson's disease (PD) such as tremor, rigidity, bradykinesia, and axial symptoms are graded in the Movement Disorders Society Unified Parkinson's Disease Rating Scale (MDS-UPDRS) III. It is yet to be ascertained whether parkinsonian motor symptoms are associated with different anatomical patterns of neurodegeneration as reflected by brain grey matter (GM) alteration. This study aimed to investigate associations between motor subscores and brain GM at voxel level. High resolution structural MRI T1 scans from the Parkinson's Progression Markers Initiative (PPMI) repository were employed to estimate brain GM intensity of PD subjects. Correlations between GM intensity and total MDS-UPDRS III and its four subscores were computed. The total MDS-UPDRS III score was significantly negatively correlated bilaterally with putamen and caudate GM density. Lower anterior striatal GM intensity was significantly associated with higher rigidity subscores, whereas left-sided anterior striatal and precentral cortical GM reduction were correlated with severity of axial symptoms. No significant morphometric associations were demonstrated for tremor subscores. In conclusion, we provide evidence for neuroanatomical patterns underpinning motor symptoms in early PD.

Protocol of a single group prospective observational study on the diagnostic value of 3T susceptibility weighted MRI of nigrosome-1 in patients with parkinsonian symptoms: the N3iPD study (nigrosomal iron imaging in Parkinson's disease).

INTRODUCTION: Parkinson's disease (PD) is the most common movement disorder in the elderly and is characterised clinically by bradykinesia, tremor and rigidity. Diagnosing Parkinson's can be difficult especially in the early stages. High-resolution nigrosome MRI offers promising diagnostic accuracy of patients with established clinical symptoms; however, it is unclear whether this may help to establish the diagnosis in the early stages of PD, when there is diagnostic uncertainty. In this scenario, a single photon emission CT scan using a radioactive dopamine transporter ligand can help to establish the diagnosis, or clinical follow-up may eventually clarify the diagnosis. A non-invasive, cost-effective diagnostic test that could replace this would be desirable. We therefore aim to prospectively test whether nigrosome MRI is as useful as DaTSCAN to establish the correct diagnosis in people with minor or unclear symptoms suspicious for PD. METHODS AND ANALYSIS: In a prospective study we will recruit 145 patients with unclear symptoms possibly caused by Parkinson's from three movement disorder centres in the UK to take part in the study. We will record the Movement Disorder Society - Unified Parkinson's Disease Rating Scale, and participants will undergo DaTSCAN and high-resolution susceptibility weighted MRI at a field strength of 3T. DaTSCANs will be assessed visually and semiquantitatively; MRI scans will be visually assessed for signal loss in nigrosome-1 by blinded investigators. We will compare how the diagnosis suggested by MRI compares with the diagnosis based on DaTSCAN and will also validate the diagnosis based on the two tests with a clinical examination performed at least 1 year after the initial presentation as a surrogate gold standard diagnostic test. ETHICS AND DISSEMINATION: The local ethics commission (Health Research Authority East Midlands - Derby Research Ethics Committee) has approved this study (REC ref.: 16/EM/0229). The study is being carried out under the principles of the Declaration of Helsinki (64th, 2013) and Good Clinical Practice standards. We have included a number of 15 research-funded DaTSCAN in the research protocol. This is to compensate for study site-specific National Health Service funding for this investigation in affected patients. We therefore have also obtained approval from the Administration of Radioactive Substances Administration Committee (ARSAC Ref 253/3629/35864). All findings will be presented at relevant scientific meetings and published in peer-reviewed journals, on the study website, and disseminated in lay and social media where appropriate. TRIAL REGISTRATION NUMBER: NCT03022357; Pre-results.

Iron metabolism and its detection through MRI in parkinsonian disorders: a systematic review.

Iron deposition in the brain normally increase with age, but its accumulation in certain regions is observed in a number of neurodegenerative diseases including Parkinson's disease (PD) and other parkinsonisms. Whether iron overload leads to dopaminergic neuronal death in the SN of PD patients or is instead simply a by-product of the neurodegenerative progression is still yet to be ascertained. Magnetic resonance imaging (MRI) is a non-invasive method to assess brain iron content in PD patients. In PD, accurate radiologic visualization of basal ganglia is required. Deep gray matter nuclei are well presented in T2- and T2*-weighted images. T2*-weighted gradient-echo (GRE) is widely used to assess calcifications and also for iron detection. On the other hand, new methods specifically designed for detecting iron-induced susceptibility differences can be further improved by sequences like susceptibility-weighted imaging (SWI). In the present review, we aim to summarize the available data on brain iron deposition in PD.

Brain iron chelation by deferiprone in a phase 2 randomised double-blinded placebo controlled clinical trial in Parkinson's disease.

Parkinson's disease (PD) is associated with increased iron levels in the substantia nigra (SNc). This study evaluated whether the iron chelator, deferiprone, is well tolerated, able to chelate iron from various brain regions and improve PD symptomology. In a randomised double-blind, placebo controlled trial, 22 early onset PD patients, were administered deferiprone, 10 or 15 mg/kg BID or placebo, for 6 months. Patients were evaluated for PD severity, cognitive function, depression rating and quality of life. Iron concentrations were assessed in the substantia nigra (SNc), dentate and caudate nucleus, red nucleus, putamen and globus pallidus by T2* MRI at baseline and after 3 and 6 months of treatment. Deferiprone therapy was well tolerated and was associated with a reduced dentate and caudate nucleus iron content compared to placebo. Reductions in iron content of the SNc occurred in only 3 patients, with no changes being detected in the putamen or globus pallidus. Although 30 mg/kg deferiprone treated patients showed a trend for improvement in motor-UPDRS scores and quality of life, this did not reach significance. Cognitive function and mood were not adversely affected by deferiprone therapy. Such data supports more extensive clinical trials into the potential benefits of iron chelation in PD.

Neuromelanin in parkinsonian disorders: an update.

Neuromelanin (NM) is a dark pigment that accumulates linearly with aging in substantia nigra (SN) and locus coeruleus (LC). The dual protective and toxic role of NM has been hypothesized according to its intraneuronal or extraneuronal deposition. The melanized dopaminergic neurons in SN and LC seem to have special vulnerability to neurodegeneration in Parkinson's disease (PD). The paramagnetic properties of NM due to its association to metals like iron induce T1 prolongation; hence the measurement of SN-sensitive contrast could be a useful diagnostic biomarker in neurodegenerative disease like PD and other atypical parkinsonisms. This paper will review NM histopathology and neurochemistry studies in health and diseases and the role of imaging targeting NM load in parkinsonian disorders.