Chapter 1 : Imaging Approaches to Parkinson Disease The diagnosis of idiopathic Parkinson's disease (PD) can often be made on clinical grounds with a high degree of accuracy particularly in cases with full expression of the classical motor features of the illness. Multiple-system atrophy patient shows significant striatal reduction of glucose metabolism. Parkin gene mutations are the most commonly known cause of young-onset recessive parkinsonism. Parkin is a ubiquitin ligase, and many mutations of the gene have been described. Most clinically affected cases are compound heterozygote gene carriers a different mutation on the 2 chromosome 6s rather than homozygous for the same mutation. Clinically affected compound heterozygote gene carriers show severe reductions of striatal 18F-dopa uptake even when disability is mild, suggesting that adaptive processes develop to compensate for their dopamine deficiency 57, The pattern of dopaminergic deficit in symptomatic parkin patients mimics that of idiopathic PD, putamen being targeted, but the caudate and midbrain are relatively more involved Asymptomatic heterozygote parkin gene carriers also show a mild but significant reduction in putamen 18F-dopa uptake This dopaminergic deficit could conceivably make heterozygote carriers more susceptible to late-onset PD. Two asymptomatic mutation carriers showed reduced putamen 11C-methylphenidate but normal 18F-dopa uptake suggesting a selective reduction of DAT binding. This finding is in line with findings in idiopathic PD, in which putamen DAT binding is known to be relatively more depressed than 18F-dopa uptake Another 2 asymptomatic mutation carriers had DAT binding that was normal at baseline but subsequently fell over 4 y of follow-up while 18F-dopa uptake remained normal. The authors concluded that the neurochemical phenotype of LRRK2 mutations was indistinguishable from that of sporadic PD. Asymptomatic gene carriers, however, can show downregulation of DAT binding and preservation of dopa decarboxylase activity, which will act to maintain levels of synaptic dopamine and delay the onset of parkinsonism. Relatives of PD patients with idiopathic hyposmia are at risk of PD. Four of these 7 subsequently converted to clinical PD over a 2-y period. Patients with idiopathic rapid-eye-movement sleep behavior disorder are at high risk of developing parkinsonism or dementia. Increased midbrain echogenicity has been reported in 5 of 7 asymptomatic parkin gene carriers 14 and 11 of 30 idiopathic hyposmic patients Three of the 5 parkin carriers with abnormal transcranial sonography findings showed reduced striatal 18F-dopa uptake, whereas 5 of the 11 hyposmic patients had reduced striatal FP-CIT binding. Midbrain hyperechogenicity detected by ultrasound in at-risk subjects, therefore, is associated with dopamine cell dysfunction in around half of the subjects. This finding again suggests that transcranial sonography is detecting nondopaminergic pathology present in PD such as midbrain iron deposition There is, however, considerable overlap of individual levels of putamen 18F-dopa uptake in fluctuator and nonfluctuator cohorts, and so, loss of putamen dopamine terminal function cannot be the sole factor responsible for determining the timing of onset of motor complications. Striatal dopamine D1 and D2 receptor availability has been compared in dyskinetic and nondyskinetic groups of PD patients with similar clinical disease duration and severity who were receiving a similar daily dose of levodopa Similar levels of D1 and D2 receptor binding were found, suggesting that onset of motor fluctuations and dyskinesias in PD is not driven by alterations in striatal postsynaptic dopamine receptor availability. The higher the extracellular dopamine level, the lower the dopamine D2 site availability to the tracer. When PD patients are given levodopa treatment they show a fall in striatal 11C-raclopride binding. The fall in striatal 11C-raclopride binding after levodopa is greater in the putamen of advanced-pd patients with fluctuations than in early cases, implying that higher levels of synaptic dopamine are generated by the former This reflects the compensatory increase in dopamine turnover in remaining dopamine terminals in advanced fluctuators and their failure to buffer the dopamine generated from exogenous levodopa because of the loss of DATs and vesicles. The failure to buffer dopamine levels by the striatum in advanced PD results in high nonphysiologic swings in synaptic dopamine levels. This, in turn, promotes excessive dopamine receptor internalization into neurons, the normal mechanism for dissociating Page 1
dopamine from the receptor, leading to fluctuating and unpredictable treatment responses. In support of this viewpoint, De la Fuente-Fernandez et al. These workers found that fluctuators showed transient 8-fold rises in synaptic dopamine levels whereas sustained responders generated only 2-fold rises, which then slowly further increased over the next 4 h. It is this phenomenon, rather than changes in postsynaptic dopamine D1 and D2 receptor availability, that results in the more rapid but short-lived response of advanced PD patients to oral levodopa. This finding implies that overstimulation of dopamine receptors is a major factor in generating peak-dose dyskinesias. However, studies on animal lesion models of PD have shown that changes in peptide transmission also play an important role Opioid receptors are located both presynaptically on dopamine terminals, where they regulate dopamine release, and postsynaptically on interneurons and medium spiny projection neurons. Significant reductions in 11C-diprenorphine binding in caudate, putamen, thalamus, and anterior cingulate have been reported in dyskinetic patients, compared with sustained responders Individual levels of putamen 11C-diprenorphine uptake correlated inversely with the severity of dyskinesia. These findings are compatible with the presence of raised basal ganglia levels of enkephalin and dynorphin in these dyskinetic PD patients. In a preliminary study, thalamic neurokinin 1 availability has been shown to be reduced in dyskinetic PD patients but normal in nondyskinetic patients These in vivo PET findings support the abnormal presence of elevated levels of endogenous peptides in the basal ganglia of dyskinetic PD patients. Because Lewy body pathology is known to affect serotonergic and noradrenergic as well as dopaminergic neurotransmission, dysfunction of any or all of these systems would seem to be a reasonable candidate for the functional substrate of depression To date, functional imaging has failed to demonstrate a correlation between serotonergic dysfunction and depression in PD. They found no difference between uptake in depressed and nondepressed patients and no correlation between radiotracer uptake and Hamilton Depression Rating Scale scores The serotonin 5-hydroxytryptamine receptor 1A 5-HT1A is found as an autoreceptor on 5-HT cell bodies in the midbrain raphe nuclei, where it acts to inhibit serotonin release, and also postsynaptically on cortical pyramidal neurons. However, the level of reduction is similar in PD patients whether a history of depression features or not They also provide no rationale for the use of selective serotonin reuptake inhibitors to treat PD depression. Nondepressed PD patients show reduced putamen 11C-RTI 32 uptake, but patients with a history of depression show additional reductions of 11C-RTI 32 binding in the noradrenergic locus coeruleus, the thalamus, and the limbic system amygdala, ventral striatum, and anterior cingulate Severity of anxiety inversely correlates with 11C-RTI 32 binding in these regions. These results suggest that depression and anxiety in PD are associated with loss of noradrenergic and limbic dopaminergic innervation additional to the striatal dopamine deficiency present. The use of nonselective inhibitors of monoamine transporters boosting synaptic levels of dopamine and noradrenaline would, therefore, seem a rational approach for treating depression in PD rather than the use of selective serotonin reuptake inhibitors. Impulse control disorders can devastate the quality of life of PD patients and their families; affected patients have gambled away their life savings before the problem has come to light. The mechanisms underlying the development of these behavioral disturbances in PD are currently under extensive investigation. Using 99mTc-ethylcysteinate dimer bicisate SPECT, a marker of regional cerebral blood flow, it has been reported that PD patients with pathologic gambling show resting overactivity of a right hemisphere network involved in reward processing that includes the orbitofrontal cortex, hippocampus, amygdala, insula, and ventral pallidum PD patients with pathologic gambling have also been studied with 11C-raclopride PET during performance of a gambling task. The pathologic gamblers demonstrated greater decreases in ventral striatum D2 binding during gambling Factors contributing to the cognitive dysfunction include direct involvement of the cortex by Lewy body pathology, loss of cholinergic projections from the nucleus basalis of Meynert, degeneration of mesofrontal and mesolimbic dopaminergic projections, coexistent Alzheimer disease, and small-vessel pathology. The presence of these various contributors can be detected with a combination of structural and functional imaging. MRI Volumetry Voxel-based morphometry can be applied to volumetric MRI to localize significant regional brain volume reductions in patients at a voxel level. When Page 2
PDD patients are studied with voxel-based morphometry, significant hippocampal, thalamic, and anterior cingulate atrophy can be detected Subclinical volume loss in these areas can also be detected in nondemented PD patients. As PDD progresses, a further volume loss occurs from cortical association areas The boundary-shift integral approach applied to volumetric MRI allows whole-brain volume changes to be quantitated. With this approach, Burton et al. These workers concluded that MRI may provide a useful tool for following progression of PD with dementia. Metabolic Imaging In PD patients who develop dementia, 18F-FDG PET has demonstrated a characteristic pattern of reduced resting regional cerebral glucose metabolism targeting the posterior cingulate, parietal, and temporal association regions, with lesser involvement of the prefrontal cortex 93, Primary motor and visual areas and the basal ganglia are spared. This pattern of reduced glucose metabolism is similar to that reported in Alzheimer disease 95, suggesting that Lewy body and Alzheimer pathology are associated with overlapping patterns of cortical neuronal dysfunction. Temporoparietal cortical hypometabolism can also be observed in a minority of nondemented PD patients with established disease, suggesting that subclinical cortical Lewy body involvement may already be present It remains to be determined whether the observed glucose hypometabolism in these subjects is a predictor of late-onset dementia. DLB is characterized by onset of dementia associated with a combination of parkinsonism, visual hallucinations, psychosis, and fluctuating confusion. Again, the pattern of reduced 18F-FDG uptake resembles that seen in Alzheimer disease, though more severe involvement of the occipital cortex has been reported Dopaminergic Imaging Although Lewy body pathology targets the substantia nigra, this nucleus is spared in Alzheimer disease. In an initial series, Walker et al. This result compares favorably with the clinical impression, which diagnosed only 4 of the 9 cases of DLB correctly in life. Page 3
Chapter 2 : Dopaminergic Imaging in Parkinsonâ s Disease: SPECT - Oxford Scholarship Imaging in Parkinson's Disease provides up-to-date information concerning new applications of brain imaging to the study of Parkinson's disease. Written by experts in the field, the book focuses on structural and functional imaging methodologies that have recently been applied to study the natural history of Parkinson's disease, with emphasis on the development of the major motor. However, since striatal dopaminergic terminals are affected in all of those disease entities, evaluation of DAT binding or dopa decarboxylase activity by the ROI approach has limited value in discriminating between patients with IPD and atypical parkinsonian disorders Brooks et al. However, [18F]fluorodopa or DAT ligand uptake is not restricted to the striatum only. By applying statistical parametric mapping SPM to [18F]fluorodopa PET studies a technique that objectively localizes focal changes of the radiotracer throughout the entire brain volume without having to make an a priori hypothesis as to their location, several research groups were able to identify distinct alterations of the dopa decarboxylase activity in other brain regions than the striatum in different stages of IPD and related disorders Rakshi et al. Only patients ranging between 50 and 70 years of age with clinically probable disease according to established diagnostic criteria and a disease duration not exceeding 3 years were eligible for the study Hughes et al. Signs of dementia, vertical gaze palsy or cerebellar signs were absent in all patients in the MSA-P cohort. Disease duration ranged from 0. Patients with IPD were matched for age and disease duration mean disease duration 1. None of the patients was taking selective serotonin reuptake inhibitors. The group of healthy controls consisted of five patients with peripheral neurological disorders sensorimotor polyneuropathy in three cases and radial nerve pressure palsies in two cases and eight healthy volunteers without evidence of neurological disease. Radiolabelling, radiochemical purity, radiopharmaceutical safety and dosimetry of the tracers have been described previously Kuikka et al. Data acquisition started 18 h post tracer application and lasted 42 min and 40 s Laruelle et al. Camera heads were equipped with medium-energy collimators. For each scan a total of 64 projections 80 s per frame were collected in a step-and-shoot mode. The image data were reconstructed by standard filtered backprojection using a Gaussian-weighted Ramp filter cut-off frequency 0. Two methods of analysis were employed: This allowed exploratory voxel-by-voxel group comparisons throughout the entire brain volume without requiring an a priori hypothesis. V2 was estimated by placing a circular ROI diameter 32 mm on four consecutive transversal slices within each occipital lobe. These included the head of the caudate nucleus circle, diameter 10 mm, and the putamen two circles, diameter 10 mm each. Caudate and putaminal asymmetry indices AIs were calculated, reflecting the percentage difference between the SPECT signal in the respective region of higher tracer uptake compared with the contralateral region using the following formula: Parametric images transformed into MNI space enable comparisons across study groups in analogous voxel regions of the brain volume. Since DAT densities are known to be low in the occipital lobe and the cerebellum, a brain mask for those areas was created in order to minimize voxels of no-interest for multi-comparison corrections. A total of 61 voxels were analysed. For multiple comparisons between groups, a Bonferroni correction was applied. An F-value of 3. For group membership, the same a priori probability was assumed for all cases. For validation of the model we used a leave-one-out procedure. The cut-off value between two groups was determined as follows: Results Patients groups and control subjects were matched for age. Page 4
Chapter 3 : Publications Authored by Christoph Scherfler PubFacts Chapter 2: Dopaminergic Imaging in Parkinson's DiseaseD: SPECT, Christoph Scherfler and Werner Poewe Chapter 3: Cerebral Glucose Metabolism and Blood Flow in Parkinson's Disease, Yilong. Received Jan 14; Accepted Feb This article has been cited by other articles in PMC. To improve the accuracy of the clinical diagnosis, it is necessary to have a reliable and practical reference standard. Dopamine transporter single-photon emission computed tomography DAT SPECT imaging might have the potential high diagnostic accuracy and practical to use to act as reference standard in detecting nigrostriatal cell loss in patients with early stage parkinsonism. Studies were selected when they met the following criteria: In addition, studies needed to fulfill one of the two following criteria: The search identified 1, articles. Eight studies fulfilled our selection criteria and were included in this review. There was only one study including patients with diagnostic uncertainty. The other studies included patients with a diagnosis of PD in whom there was no uncertainty. Electronic supplementary material The online version of this article doi: However, parkinsonism is also a prominent feature in, for example, progressive supranuclear palsy PSP, multiple system atrophy MSA, psychogenic parkinsonism, dementia with Lewy bodies DLB, vascular parkinsonism, and drug-induced parkinsonism. There is no definite test to confirm the cause of parkinsonism in clinical practice, except for the vascular causes of parkinsonism. Although the diagnosis is straightforward when patients have a classic presentation, establishing the cause of parkinsonism can be challenging, especially in early stages [ 7, 8 ]. The different causes of parkinsonism can be classified into two distinct groups; diseases with nigrostriatal cell loss e. This classification is of clinical importance since the prognosis is considerably worse in parkinsonism characterized by loss of nigrostriatal cells [ 13 ]. Patients without nigrostriatal cell loss, except for dopa-responsive dystonia, do not benefit from treatment with dopaminomimetics and require different treatment [ 5, 13, 14 ]. The current reference standard or gold standard of parkinsonism is pathological evaluation. Although accurate, it is not a practical standard for the validation of new diagnostic tools because the time between diagnosis and death is often decades. Therefore, there is a need for an alternative in vivo reference standard to detect nigrostriatal dopaminergic cell loss in patients with parkinsonism. Several different diagnostic tools have been evaluated in their ability to detect nigrostriatal cell loss. Tests used in establishing the cause of Parkinsonism PET is a radiotracer-based method that can assess the in vivo function of the dopaminergic and other neurotransmitter systems. For example, people with subclinical and even preclinical PD already have clear deficits of the nigrostriatal pathway [ 21, 25-28 ]. Also, if the scan does not show a nigrostriatal deficit, it is highly unlikely that the patient suffers from symptoms caused by nigrostriatal cell loss [ 11, 29, 30 ]. To summarize, DAT SPECT imaging appears to be the most suitable candidate to act as reference standard in detecting nigrostriatal cell loss in patients with early stage parkinsonism. Both search strategies are included in Additional file 1. Furthermore, we searched the reference lists of all relevant articles to identify additional published studies for possible inclusion in the review. We did not impose any language restrictions. Studies were selected according to the following inclusion criteria: With an annual decline of 5. All study designs were included with the exception of case reports, case series less than five patients, and case-control studies. We did not impose restrictions regarding the type of radiotracer used e. If investigators published several reports based on data from a single study population, we selected the most complete report. Articles were excluded if information on diagnostic accuracy e. In all cases, disagreements about study selection were resolved by consensus and a third reviewer JB was consulted if disagreement persisted. Data extraction and risk of bias Data were extracted by the two reviewers SRS and CVB independently using an extraction form designed for this review. We extracted data on the diagnostic accuracy of the studies, the baseline characteristics of studied patients e. We also extracted data on the SPECT technique, which radiotracer was used, handling of DAT interfering medication, patient preparation, test interpretation, technical failures, and assessors e. Results were compared, and discrepancies Page 5
between the two reviewers were resolved in a meeting. Statistical analysis and data synthesis For each study, patient and study characteristics were summarized using descriptive statistics. We did not perform a meta-analysis because we included a heterogeneous group of patients with a clinical diagnosis of PD as well as with clinically uncertain parkinsonism in this review. This alters the spectrum of disease and non-disease in the population, which may have strong impact on test accuracy. We identified 2, articles. After duplicate removal, 1, articles remained. A total of 1, articles were excluded because they did not fulfill our selection criteria. Seventeen articles were selected for further review. Of these, five were excluded because the study population overlapped with more complete or more recent publications. We contacted the authors of five additional studies that had missing data [ 41-44 ]. One author responded [ 23 ]. The other four articles were excluded. In the end, eight studies fulfilled our selection criteria. Chapter 4 : Imaging in Parkinson's Disease : David Eidelberg : Dopaminergic imaging in Parkinson's disease: PET / A. Jon Stoessl and Biju Gopalakrishnan --Dopaminergic imaging in Parkinson's disease: SPECT / Christoph Scherfler and Werner Poewe --Cerebral glucose metabolism and blood flow in Parkinson's disease / Yilong Ma [and others] --Structural abnormalities in Parkinson's disease: MRI and related. Chapter 5 : Imaging in Parkinsonâ s Disease - Oxford Scholarship Chapter 2: Dopaminergic Imaging in Parkinson's DiseaseD: SPECT, Christoph Scherfler and Werner Poewe Chapter 3: Cerebral Glucose Metabolism and Blood Flow in Parkinson's Disease, Yilong Ma, Schichun Peng, Vijay Dhawan, and David Eidelberg. Chapter 6 : Imaging in parkinson's disease - literatura KsiÄ garnia BookMaster Contents: Dopaminergic imaging in Parkinson's disease: PET / A. Jon Stoessl and Biju Gopalakrishnan -- Dopaminergic imaging in Parkinson's disease: SPECT / Christoph Scherfler and Werner Poewe -- Cerebral glucose metabolism and blood flow in Parkinson's disease / Yilong Ma. Chapter 7 : Imaging in Parkinson's Disease Oxford University Press Abstract. We discuss the potential role of dopamine transporter (DAT) imaging by single photon emission computed tomography (SPECT) as a biological marker for differentiating among parkinsonian disorders in routine clinical practice, and the implication for disease progression assessment is considered. Chapter 8 : - NLM Catalog Result Small animal imaging using a conventional gamma camera exemplified in studies on the striatal dopaminergic system. C Decristoforo ; C Scherfler ; Prevalence and burden of gait disorders in elderly men and women aged years: a population-based study. Chapter 9 : Unilateral absence of swallow-tail sign in Parkinson disease Radiology Case blog.quintoapp. Introduction: The hummingbird sign and the morning glory flower sign, reflecting midbrain pathology on MRI, have previously been shown to separate patients with progressive supran. Page 6