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1.  Differentiation of dementia with Lewy bodies from Alzheimer's disease using a dopaminergic presynaptic ligand 
Background: Dementia with Lewy bodies (DLB) is one of the main differential diagnoses of Alzheimer's disease (AD). Key pathological features of patients with DLB are not only the presence of cerebral cortical neuronal loss, with Lewy bodies in surviving neurones, but also loss of nigrostriatal dopaminergic neurones, similar to that of Parkinson's disease (PD). In DLB there is 40–70% loss of striatal dopamine.
Objective: To determine if detection of this dopaminergic degeneration can help to distinguish DLB from AD during life.
Methods: The integrity of the nigrostriatal metabolism in 27 patients with DLB, 17 with AD, 19 drug naive patients with PD, and 16 controls was assessed using a dopaminergic presynaptic ligand, 123I-labelled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), and single photon emission tomography (SPET). A SPET scan was carried out with a single slice, brain dedicated tomograph (SME 810) 3.5 hours after intravenous injection of 185 MBq FP-CIT. With occipital cortex used as a radioactivity uptake reference, ratios for the caudate nucleus and the anterior and posterior putamen of both hemispheres were calculated. All scans were also rated by a simple visual method.
Results: Both DLB and PD patients had significantly lower uptake of radioactivity than patients with AD (p<0.001) and controls (p<0.001) in the caudate nucleus and the anterior and posterior putamen.
Conclusion: FP-CIT SPET provides a means of distinguishing DLB from AD during life.
doi:10.1136/jnnp.73.2.134
PMCID: PMC1737968  PMID: 12122169
2.  Dementia with Lewy bodies: a comparison of clinical diagnosis, FP‐CIT single photon emission computed tomography imaging and autopsy 
Background
Dementia with Lewy bodies (DLB) is a common form of dementia. The presence of Alzheimer's disease (AD) pathology modifies the clinical features of DLB, making it harder to distinguish DLB from AD clinically during life. Clinical diagnostic criteria for DLB applied at presentation can fail to identify up to 50% of cases. Our aim was to determine, in a series of patients with dementia in whom autopsy confirmation of diagnosis was available, whether functional imaging of the nigrostriatal pathway improves the accuracy of diagnosis compared with diagnosis by means of clinical criteria alone.
Methods
A single photon emission computed tomography (SPECT) scan was carried out with a dopaminergic presynaptic ligand [123I]‐2beta‐carbometoxy‐3beta‐(4‐iodophenyl)‐N‐(3‐fluoropropyl) nortropane (FP‐CIT; ioflupane) on a group of patients with a clinical diagnosis of DLB or other dementia. An abnormal scan was defined as one in which right and left posterior putamen binding, measured semiquantitatively, was more than 2 SDs below the mean of the controls.
Results
Over a 10 year period it was possible to collect 20 patients who had been followed from the time of first assessment and time of scan through to death and subsequent detailed neuropathological autopsy. Eight patients fulfilled neuropathological diagnostic criteria for DLB. Nine patients had AD, mostly with coexisting cerebrovascular disease. Three patients had other diagnoses. The sensitivity of an initial clinical diagnosis of DLB was 75% and specificity was 42%. The sensitivity of the FP‐CIT scan for the diagnosis of DLB was 88% and specificity was 100%.
Conclusion
FP‐CIT SPECT scans substantially enhanced the accuracy of diagnosis of DLB by comparison with clinical criteria alone.
doi:10.1136/jnnp.2006.110122
PMCID: PMC2117602  PMID: 17353255
3.  The role of 123I-ioflupane SPECT dopamine transporter imaging in the diagnosis and treatment of patients with dementia with Lewy bodies 
The diagnosis of dementia with Lewy bodies (DLB) is difficult if one relies solely on clinical features. Current International Consensus Criteria for DLB have high specificity but a significant percentage of patients might be misdiagnosed. Reasons for clinical uncertainty regard the presence of concomitant motor signs in patients with Alzheimer’s disease as well as the observation that cognitive abnormalities in DLB might develop with memory impairment without significant parkinsonism. This has clinical relevance as DLB patients may be particularly sensitive to antipsychotics and even the effectiveness of atypical neuroleptics such as quetiapine for the treatment of agitation and hallucinations has been questioned by double-blind, placebo-controlled, randomized studies. By contrast, acetyl-cholinesterase inhibitors such as rivastigmine have shown benefit not only on cognitive but also on psychiatric symptoms. Recent evidence shows that striatal dopamine transporter binding of 123I-ioflupane SPECT is reduced in DLB and this is consistent with a significant loss of nigral dopamine neurons in this disorder. Several studies have demonstrated the diagnostic accuracy of 123I-ioflupane in the differential diagnosis of parkinsonism. Given the availability of SPECT, this investigation represents a useful marker to support clinical diagnosis and can help establishing appropriate treatment for this disorder.
PMCID: PMC2654798  PMID: 19300562
dementia with Lewy bodies; 123I-ioflupane-SPECT; dopamine transporter; parkinsonism; Alzheimer’s disease
4.  Effects of l-DOPA on striatal iodine-123-FP-CIT binding and behavioral parameters in the rat 
Nuclear Medicine Communications  2013;34(12):1223-1232.
Purpose
The effect of clinical l-3,4-dihydroxyphenylalanine (l-DOPA) doses on the binding of [123I]N-Ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ([123I]FP-CIT) to the rat dopamine transporter (DAT) was investigated using small animal single-photon emission computed tomography.
Materials and methods
DAT binding was measured at baseline, after challenge with the aromatic l-amino acid decarboxylase inhibitor benserazide, and after challenge with either 5 or 10 mg/kg l-DOPA plus benserazide. For baseline and challenges, striatal equilibrium ratios (V3′′) were computed as an estimation of the binding potential. Moreover, striatal V3′′ values were correlated with parameters of motor and exploratory behavior.
Results
V3′′ differed significantly between baseline and either dose of l-DOPA/benserazide. Moreover, V3′′ differed significantly between l-DOPA treatment groups. After 5 mg/kg l-DOPA/benserazide, DAT binding was inversely correlated with sitting duration (1–5 min) and sitting frequency (10–15 min). After 10 mg/kg l-DOPA/benserazide, an inverse correlation was found between DAT binding and sitting duration (1–30 min), whereas DAT binding and duration of ambulatory activity (1–30 min) as well as head and shoulder motility (10–15 min) exhibited a positive correlation.
Conclusion
Challenge with 5 and 10 mg/kg l-DOPA/benserazide led to mean reductions in DAT binding by 34 and 20%, respectively. Results indicate a biphasic response with a higher effect on DAT after the lower dose of l-DOPA. The reduction in DAT binding may be interpreted in terms of competition between [123I]FP-CIT and endogenous dopamine. Moreover, there is preliminary evidence of an association between striatal DAT and motor and exploratory parameters.
doi:10.1097/MNM.0b013e3283657404
PMCID: PMC3815148  PMID: 23982164
dopamine transporter; l-3,4-dihydroxyphenylalanine methylester; motor behavior; Parkinson’s disease; small animal single-photon emission computed tomography
5.  How useful is [123I]ß-CIT SPECT in clinical practice? 
Objective: To assess the accuracy and clinical usefulness of [123I]ß-CIT (2ß-carbomethoxy-3ß-(4-iodophenyl)tropane) SPECT in the differential diagnosis of Parkinson's disease.
Subjects: 185 consecutive patients with symptoms of movement disorder were studied. The diagnoses were Parkinson's disease (92), essential tremor (16), vascular parkinsonism (15), various Parkinson plus syndromes (P+) (12), dementia with Lewy bodies (DLB) (5), dystonia (5), drug induced movement disorder (12), and other diagnoses (8). A reference group (psychogenic parkinsonism) comprised 20 subjects with complaints suggesting extrapyramidal disease but with no unequivocal signs on clinical examination and no abnormalities on brain imaging.
Results: ß-CIT uptake was significantly lower in the whole striatum as well as separately in the putamen and in the caudate nucleus in Parkinson's disease than in the reference group or in drug induced movement disorder, essential tremor, or dystonia. The uptake of ß-CIT in the vascular parkinsonism group was heterogeneous and mean ß-CIT uptake fell between the reference group and the Parkinson's disease group. In the P+ and DLB groups the striatal uptake ratios overlapped those of the Parkinson's disease group.
Conclusions: [123I]ß-CIT SPECT may not be as useful a tool in the clinical differential diagnosis of Parkinson's disease as was previously believed, but it was 100% sensitive and specific for the diagnosis in younger patients (age <55 years). In older patients (age >55 years) specificity was substantially lower (68.5%). This differential specificity reflected the different distribution of differential diagnostic disorders (P+, DLB, vascular parkinsonism) in the older and younger age groups.
doi:10.1136/jnnp.2004.045237
PMCID: PMC1739796  PMID: 16107353
6.  Positive FP-CIT SPECT (DaTSCAN) in Clinical Alzheimer's Disease – An Unexpected Finding? 
Clinically, Alzheimer's disease (AD) is by far the most common cause of dementia. Criteria for the diagnosis of dementia with Lewy bodies (DLB) are highly specific but not at all sensitive, which is reflected by the higher number of DLB cases detected histopathologically at autopsy. Imaging of dopamine transporter with FP-CIT SPECT is one possibility to increase sensitivity. Pathological confirmation was also included in the revised consensus criteria for the diagnosis of DLB. However, in the absence of parkinsonism, one of the core features, a clinical diagnosis of AD is more likely. The role of FP-CIT SPECT in DLB diagnosis remains to be clarified. Based on our 3 case reports and a review of the literature, the utility of this imaging method in the differential diagnosis of AD and DLB is highlighted.
doi:10.1159/000330470
PMCID: PMC3235939  PMID: 22545039
Alzheimer's disease; Dementia; Dopamine; Lewy bodies; FP-CIT SPECT
7.  Dopamine transporter imaging with [123I]-β-CIT demonstrates presynaptic nigrostriatal dopaminergic damage in Wilson's disease 
Jeon, B | Kim, J | Jeong, J | Kim, K | Chang, Y | Lee, D | Lee, M
OBJECTIVES—The most common neurological manifestations in Wilson's disease are parkinsonism and dystonia. These are assumed to be due to striatal injury, which has been repeatedly demonstrated by pathology and CT or MRI. The substantia nigra has not been shown to be damaged in pathological studies. However, there have been clinical and imaging studies suggesting presynaptic nigrostriatal injury. (1r)-2β-carbomethoxy-3β-(4-iodophenyl)tropane (β-CIT) is a specific ligand that binds to the dopamine transporter (DAT), and can examine the integrity of dopaminergic nerve terminals. Evidence for presynaptic nigrostriatal dopaminergic damage in Wilson's disease was searched for using [123I]-β-CIT SPECT.
METHODS—Six patients with Wilson's disease were studied, together with 15 healthy normal controls, and six patients with Parkinson's disease. After injection of [123I]-β-CIT, SPECT studies were done at 18 hours. Specific striatal/occipital binding ratio (S/O ratio) was calculated as (striatal binding−occipital binding)/occipital binding.
RESULTS—The specific S/O ratios were 6.22 (1.32) (mean (SD)) in normal volunteers, 3.78 (0.65) in Parkinson's disease, and 3.60 (0.49) in Wilson's disease.
CONCLUSION—There was severe loss of the DAT in the striatum suggesting significant damage in presynaptic nigrostriatal dopaminergic nerve terminals. Therefore, a presynaptic lesion may contribute to neurological manifestations in Wilson's disease.


PMCID: PMC2170169  PMID: 9667562
8.  [123I]FP-CIT SPECT shows a pronounced decline of striatal dopamine transporter labelling in early and advanced Parkinson's disease. 
OBJECTIVES: The main neuropathological feature in Parkinson's disease is a severe degeneration of the dopaminergic neurons in the substantia nigra resulting in a loss of dopamine (DA) transporters in the striatum. [123I]beta-CIT single photon emission computed tomography (SPECT) studies have demonstrated this loss of striatal DA transporter content in Parkinson's disease in vivo. However, studies with this radioligand also showed that an adequate imaging of the striatal DA transporter content could only be performed on the day after the injection of radioligand, which is not convenient for outpatient evaluations. Recently, a new radioligand [123I]FP-CIT, with faster kinetics than beta-CIT, became available for imaging of the DA transporter with SPECT, and the applicability of this ligand was tested in patients with early and advanced Parkinson's disease, using a one day protocol. METHODS: [123I]FP-CIT SPECT was performed in six patients with early and 12 patients with advanced Parkinson's disease, and in six age matched healthy volunteers. RESULTS: Compared with an age matched control group striatal [123I]FP-CIT uptake in patients with Parkinson's disease was decreased, and this result was measurable three hours after injection of the radioligand. In the Parkinson's disease group the uptake in the putamen was reduced more than in the caudate nucleus. The contralateral striatal uptake of [123I]FP-CIT was significantly lower than the ipsilateral striatal uptake in the Parkinson's disease group. Specific to non-specific striatal uptake ratios correlated with the Hoehn and Yahr stage. A subgroup of patients with early Parkinson's disease also showed significantly lower uptake in the putamen and lower putamen:caudate ratios than controls. CONCLUSION: [123I]FP-CIT SPECT allows a significant discrimination between patients with Parkinson's disease and age matched controls with a one day protocol, which will be to great advantage in outpatient evaluations.
Images
PMCID: PMC486723  PMID: 9048712
9.  Dopamine transporter SPECT in patients with mitochondrial disorders 
Objective : To investigate the dopaminergic system in patients with known mitochondrial disorders and complex I deficiency.
Methods: Dopamine transporter density was studied in 10 female patients with mitochondrial complex I deficiency by 123I-FP-CIT (N-ß-fluoropropyl-2ß-carbomethyl-3ß-(4-iodophenyl)-nortropane) SPECT.
Results: No differences in 123I-FP-CIT striatal binding ratios were observed and no correlation of the degree of complex I deficiency and striatal binding ratios could be detected.
Conclusions: These data argue against the possibility that mitochondrial complex I deficiency by itself is sufficient to elicit dopaminergic cell loss.
doi:10.1136/jnnp.2004.040220
PMCID: PMC1739307  PMID: 15608010
10.  Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study 
BMJ Open  2012;2(1):e000380.
Objectives
Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimer's disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future.
Design
In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures.
Setting
Patients were recruited from 40 European centres.
Participants
Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging.
Outcome measures
The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI).
Results
The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed.
Conclusions
DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.
Article summary
Article focus
Dementia with Lewy bodies (DLB) has distinct neuropsychiatric features.
At present, we do not know whether the poorer prognosis of DLB is due to a more rapid cognitive decline compared with Alzheimer's disease (AD).
Key messages
In this fairly large cohort of patients with DLB and AD, while there was no difference in level of cognitive impairment (Cambridge Cognitive Examination (CAMCOG) score) at baseline and at 12-month follow-up, DLB patients had significantly higher Neuropsychiatric Inventory (NPI) and NPI carer distress scores both at baseline and at 12-month follow-up.
Therefore, the worse prognosis of DLB is likely to be mediated by neuropsychiatric or other symptoms and not only by cognitive decline.
Strengths and limitations of this study
Inclusion of high number of subjects from 40 European clinical centres.
Well-characterised cases with both consensus panel clinical diagnosis (three clinical experts) and dopaminergic transporter single photon emission computed tomography imaging.
No autopsy data were available and therefore it is possible that more rapid cognitive decline may be present in pure DLB.
Only 1 year of follow-up.
There was higher attrition rate (no-follow-up assessment) in the DLB group, and DLB patients that did not return for follow-up were more impaired than AD patients.
doi:10.1136/bmjopen-2011-000380
PMCID: PMC3330257  PMID: 22318660
11.  A role for locus coeruleus in Parkinson tremor 
We analyzed rest tremor, one of the etiologically most elusive hallmarks of Parkinson disease (PD), in 12 consecutive PD patients during a specific task activating the locus coeruleus (LC) to investigate a putative role of noradrenaline (NA) in tremor generation and suppression. Clinical diagnosis was confirmed in all subjects by reduced dopamine reuptake transporter (DAT) binding values investigated by single photon computed tomography imaging (SPECT) with [123I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane (FP-CIT). The intensity of tremor (i.e., the power of Electromyography [EMG] signals), but not its frequency, significantly increased during the task. In six subjects, tremor appeared selectively during the task. In a second part of the study, we retrospectively reviewed SPECT with FP-CIT data and confirmed the lack of correlation between dopaminergic loss and tremor by comparing DAT binding values of 82 PD subjects with bilateral tremor (n = 27), unilateral tremor (n = 22), and no tremor (n = 33). This study suggests a role of the LC in Parkinson tremor.
doi:10.3389/fnhum.2011.00179
PMCID: PMC3250076  PMID: 22287946
Parkinson disease; tremor; locus coeruleus; noradrenaline
12.  High correlation between in vivo [123I]β-CIT SPECT/CT imaging and post-mortem immunohistochemical findings in the evaluation of lesions induced by 6-OHDA in rats 
EJNMMI Research  2013;3:46.
Background
6-Hydroxydopamine (6-OHDA) is widely used in pre-clinical animal studies to induce degeneration of midbrain dopamine neurons to create animal models of Parkinson's disease. The aim of our study was to evaluate the potential of combined single-photon emission computed tomography/computed tomography (SPECT/CT) for the detection of differences in 6-OHDA-induced partial lesions in a dose- and time-dependent manner using the dopamine transporter (DAT) ligand 2β-carbomethoxy-3β-(4-[123I]iodophenyl)tropane ([123I]β-CIT).
Methods
Rats were unilaterally lesioned with intrastriatal injections of 8 or 2 × 10 μg 6-OHDA. At 2 or 4 weeks post-lesion, 40 to 50 MBq [123I]β-CIT was administered intravenously and rats were imaged with small-animal SPECT/CT under isoflurane anesthesia. The striatum was delineated and mean striatal activity in the lesioned side was compared to the intact side. After the [123I]β-CIT SPECT/CT scan, the rats were tested for amphetamine-induced rotation asymmetry, and their brains were immunohistochemically stained for DAT and tyrosine hydroxylase (TH). The fiber density of DAT- and TH-stained striata was estimated, and TH-immunoreactive cells in the rat substantia nigra pars compacta (SNpc) were stereologically counted.
Results
The striatal uptake of [123I]β-CIT differed significantly between the lesion groups and the results were highly correlated to both striatal DAT- and TH-immunoreactive fiber densities and to TH-immunoreactive cell numbers in the rat SNpc. No clear progression of the lesion could be seen.
Conclusions
[123I]β-CIT SPECT/CT is a valuable tool in predicting the condition of the rat midbrain dopaminergic pathway in the unilateral partial 6-OHDA lesion model of Parkinson's disease and it offers many advantages, allowing repeated non-invasive analysis of living animals.
doi:10.1186/2191-219X-3-46
PMCID: PMC3689076  PMID: 23758882
6-OHDA; β-CIT; Rat; SPECT
13.  Brain Dopamine Transporter Binding and Glucose Metabolism in Progressive Supranuclear Palsy-Like Creutzfeldt-Jakob Disease 
Case Reports in Neurology  2014;6(1):28-33.
Here, we present a patient with Creutzfeldt-Jakob disease (CJD) who developed initial symptoms mimicking progressive supranuclear palsy (PSP). Before the development of typical CJD symptoms, functional imaging supported a diagnosis of PSP when [123I]-FP-CIT-SPECT showed a defect in striatal dopamine transporter binding, while [18F]-fluorodeoxyglucose PET showed cortical hypometabolism suggestive of Lewy body dementia. However, the postmortem neuropathological examination was indicative of CJD only, without tau protein or Lewy body findings. This case demonstrates that CJD should be taken into account in rapidly progressing atypical cases of parkinsonism, even when functional imaging supports a diagnosis of a movement disorder.
doi:10.1159/000358483
PMCID: PMC3934789  PMID: 24575030
Creutzfeldt-Jakob disease; Progressive supranuclear palsy; PET; MRI
14.  A clinical role for [123I]MIBG myocardial scintigraphy in the distinction between dementia of the Alzheimer's-type and dementia with Lewy bodies 
OBJECTIVE—Scintigraphy with [123I]metaiodobenzyl guanidine ([123I]MIBG) enables the quantification of postganglionic sympathetic cardiac innervation. Recently, myocardial [123I]MIBG scintigraphy has been found to be useful in distinguishing Parkinson's disease, a Lewy body disease, from other akinetic rigid syndromes. Some patients initially diagnosed with dementia of the Alzheimer's type (DAT) are discovered to have an alternative disease such as dementia with Lewy bodies (DLB), despite the application of stringent diagnostic criteria. In the present study, examinations were performed to clarify the usefulness of myocardial [123I]MIBG scintigraphy in improving the differential diagnosis between patients with DLB and DAT.
METHODS—Fourteen patients with DLB and 14 patients with DAT underwent scintigraphy with [123I]MIBG, combined with orthostatic tests and cardiac examinations.
RESULTS—In all patients with DLB, the heart to mediastinum (H/M) ratio of MIBG uptake was pathologically impaired in both early and delayed images, independently of the duration of disease and autonomic failure. All patients with DAT had successful MIBG uptake in the heart regardless of duration of disease and autonomic failure. Orthostatic hypotension was seen in four patients with DAT and 13 patients with DLB.
CONCLUSIONS—[123I]MIBG myocardial scintigraphy might detect early disturbances of the sympathetic nervous system in DLB and might provide useful diagnostic information to discriminate DLB from DAT. The distinction between DLB and DAT may be improved by greater emphasis on cardiac sympathetic disturbances.


doi:10.1136/jnnp.71.5.583
PMCID: PMC1737586  PMID: 11606666
15.  Serum urate and probability of dopaminergic deficit in early ‘Parkinson disease’ 
Objective
Investigate whether higher levels of urate, an antioxidant linked to a lower likelihood of developing Parkinson disease (PD), is also a predictor of having a dopamine transporter brain scan without evidence of dopaminergic deficit (SWEDD).
Methods
In a cross-sectional study of 797 mildly affected, untreated parkinsonian subjects diagnosed with early PD in the Parkinson Research Examination of CEP-1347 Trial (PRECEPT), we investigated the relationship at baseline between serum urate and striatal dopamine transporter density, determined by single-photon emission computed-tomography of iodine-123-labeled 2-β-carboxymethoxy-3-β-(4-iodophenyl)tropane ([123I]β-CIT) uptake. A SWEDD was defined as lowest putamen [123I]β-CIT > 80% age-expected putamen DAT density.
Results
Odds of having a SWEDD rose across increasing quintiles of urate level, with an age- and gender-adjusted odds ratio of 3.2 comparing the highest to the lowest urate quintile; 95% CI: 1.5 to 7.2; p for trend = 0.0003) and remained significant after adjusting for potential confounding factors. The association was significant in men but not women, regardless of whether common or sex-specific quintiles of urate were used.
Conclusions
Higher levels of urate were associated with a greater likelihood of a SWEDD amongst subjects with early untreated parkinsonism in the PRECEPT study. The findings support the diagnostic utility of urate in combination with other determinants.
doi:10.1002/mds.23741
PMCID: PMC3150627  PMID: 21538532
Parkinson disease; urate; dopamine transporter; neuroimaging; diagnosis; biomarker
16.  Imaging Improves Diagnosis of Dementia with Lewy Bodies 
Psychiatry Investigation  2009;6(4):233-240.
Dementia with Lewy bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD), and is clinically characterized by the progressive cognitive decline with fluctuations in cognition and alertness, recurrent visual hallucinations and Parkinsonism. Once these characteristic symptoms of DLB emerge, discriminating it from AD is relatively easy. However, in the early disease stages, the clinical symptoms of various types of dementias largely overlap and it is difficult to distinguish DLB from other neurodegenerative dementias based on clinical manifestations alone. To increase the accuracy of antemortem diagnosis of DLB, the latest diagnostic criteria incorporate findings from 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, or from neuroimaging such as computed tomography (CT), magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), and positron emission tomography (PET). In the present guidelines, decreased dopamine transporter uptake revealed by SPECT or PET receives the greatest importance among various neuroimaging findings and is listed as one of the suggestive features. Supportive features that commonly present but are not proven to have diagnostic specificity include relatively-preserved medial-temporal-lobe structures, occipital hypoperfusion, and abnormal MIBG myocardial scintigraphy. In this paper, we review the major findings on various neuroimaging modalities and discuss the clinical usefulness of them for the diagnosis of DLB. Although there is not enough evidence to reach the conclusion, considering the accessibility in clinical practice, in our personal views, we recommend the use of brain-perfusion SPECT and MIBG myocardial scintigraphy to improve the diagnosis of DLB.
doi:10.4306/pi.2009.6.4.233
PMCID: PMC2808791  PMID: 20140120
Dementia; Dementia with Lewy bodies; Magnetic resonance imaging; Single photon emission computed tomography; Positron emission tomography; 123I-metaiodobenzylguanidine myocardial scintigraphy
17.  Rivastigmine for the treatment of dementia associated with Parkinson’s disease 
Parkinson’s disease (PD) afflicts millions of people worldwide and leads to cognitive impairment or dementia in the majority of patients over time. Parkinson’s disease dementia (PDD) is characterized by deficits in attention, executive and visuospatial function, and memory. The clinical diagnostic criteria and neuropathology surrounding PDD remain controversial with evidence of overlap among PDD, dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). Cortical cholinergic deficits are greater in PDD than in AD, and are well-correlated with the cognitive and neuropsychiatric dysfunction that occurs in PDD. Inhibition of acetylcholine metabolism is therefore a practical therapeutic strategy in PDD.
This review examines current evidence for rivastigmine (a cholinesterase/butyrylcholinesterase inhibitor) treatment in PDD. In addition to its efficacy, we examine the safety profile, side effects, and cost effectiveness of rivastigmine in PDD. Rivastigmine provides modest benefit in PDD and further long-term studies are needed to determine the effectiveness and safety of rivastigmine over time. Tolerability is a problem for many PDD patients treated with rivastigmine. Future studies of rivastigmine in PDD should focus on pragmatic outcomes such as time to need for nursing home placement, pharmacoeconomic outcomes and simultaneous patient/caregiver quality of life assessments.
PMCID: PMC2656320  PMID: 19300613
Parkinson’s disease; dementia; rivastigmine; cholinesterase inhibitor
18.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
19.  SERT-to-DAT ratios in early Parkinson’s disease do not correlate with the development of dyskinesias 
EJNMMI Research  2013;3:44.
Background
Although the treatment of Parkinson’s disease (PD) is very effective, in the course of the disease, 40% to 60% of patients develop dyskinesias. The pathophysiology of dyskinesias is still unclear. Results of preclinical research suggest that uptake and uncontrolled release of dopamine by serotonergic neurons is an important factor. Based on this model, we hypothesized that dyskinesias will develop predominantly in PD patients with a relatively preserved serotonergic system.
Methods
Between 1995 and 1998, 50 patients with early-stage untreated PD, diagnosed according to clinical criteria, and reduced striatal [123I]β-carboxymethyoxy-3-beta-(4-iodophenyl) tropane (CIT) single-photon emission computed tomography (SPECT) binding were recruited. To test our hypothesis, we retrospectively assessed baseline [123I]β-CIT SPECT scans for striatal dopamine transporter (DAT) and midbrain serotonin transporter (SERT) availability as well as the SERT-to-DAT ratios. We compared these data between patients that developed dyskinesias and patients that did not develop dyskinesias during a mean follow-up of 14.2 years.
Results
Approximately half of the PD patients developed dyskinesias. No differences in baseline [123I]β-CIT DAT availability, SERT availability, or SERT-to-DAT ratios were found between the dyskinetic and non-dyskinetic group. The development of dyskinesias was most strongly associated with the age of onset (P = 0.002).
Conclusions
SERT-to-DAT ratios in early-stage untreated PD do not correlate with the future development of dyskinesias. However, our study does not exclude the possibility that SERT-to-DAT ratios increase with disease progression in patients that develop dyskinesias because of a slower rate of degeneration of the serotonergic system.
doi:10.1186/2191-219X-3-44
PMCID: PMC3680321  PMID: 23738774
Parkinson’s disease; Dopamine transporter; Serotonin transporter; [123I]β-CIT SPECT; Dyskinesias; Age of onset
20.  Enhanced catecholamine transporter binding in the locus coeruleus of patients with early Parkinson disease 
BMC Neurology  2011;11:88.
Background
Studies in animals suggest that the noradrenergic system arising from the locus coeruleus (LC) and dopaminergic pathways mutually influence each other. Little is known however, about the functional state of the LC in patients with Parkinson disease (PD).
Methods
We retrospectively reviewed clinical and imaging data of 94 subjects with PD at an early clinical stage (Hoehn and Yahr stage 1-2) who underwent single photon computed tomography imaging with FP-CIT ([123I] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl) tropane). FP-CIT binding values from the patients were compared with 15 healthy subjects: using both a voxel-based whole brain analysis and a volume of interest analysis of a priori defined brain regions.
Results
Average FP-CIT binding in the putamen and caudate nucleus was significantly reduced in PD subjects (43% and 57% on average, respectively; p < 0.001). In contrast, subjects with PD showed an increased binding in the LC (166% on average; p < 0.001) in both analyses. LC-binding correlated negatively with striatal FP-CIT binding values (caudate: contralateral, ρ = -0.28, p < 0.01 and ipsilateral ρ = -0.26, p < 0.01; putamen: contralateral, ρ = -0.29, p < 0.01 and ipsilateral ρ = -0.29, p < 0.01).
Conclusions
These findings are consistent with an up-regulation of noradrenaline reuptake in the LC area of patients with early stage PD, compatible with enhanced noradrenaline release, and a compensating activity for degeneration of dopaminergic nigrostriatal projections.
doi:10.1186/1471-2377-11-88
PMCID: PMC3146819  PMID: 21777421
21.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
22.  Persistence of Cholinesterase Inhibitor Treatment in Dementia: Insights from a Naturalistic Study 
Background
Cholinesterase inhibitors (ChEI) are widely used in dementia, but there is a lack of practice guidelines in case of intolerance or absence of perceived effect.
Methods
Two hundred and forty patients (mean age 77 years, SD 6.3, 66% female) with Alzheimer's disease or Lewy body dementia were prescribed a ChEI and evaluated annually under conditions of standard practice. Of these, 152 patients maintained, 36 switched, and 52 abandoned ChEI treatment.
Results
Less behavioural disturbance and less cognitive deterioration were observed, respectively, at the 3- and 4-year follow-up assessments in the patients who maintained the first prescribed ChEI (p < 0.05). Cognitive benefits were reinforced in the patients who experienced some adverse event, but no benefits were observed when the patient or caregiver did not perceive an effect.
Conclusions
Maintenance of the first prescribed ChEI was supported when some benefit was perceived by the patient or caregiver, even in cases of nonserious adverse events.
doi:10.1159/000345279
PMCID: PMC3617973  PMID: 23637699
Alzheimer's disease; Cholinesterase inhibitors; Lewy body dementia; Treatment persistence

23.  [123I]ß-CIT SPECT is a useful method for monitoring dopaminergic degeneration in early stage Parkinson's disease 
Objectives:To examine the validity of [123I]ß-CIT SPECT for monitoring the progression of dopaminergic degeneration in Parkinson's disease; to investigate the influence of short term treatment with D2receptor agonists on striatal [123I]ß-CIT binding; and to determine the sample size and frequency of SPECT imaging required to demonstrate a significant effect of a putative neuroprotective agent.
Methods:A group of 50 early stage Parkinson's disease patients was examined. Two SPECT imaging series were obtained, 12 months apart. The mean annual change in the ratio of specific to non-specific [123I]ß-CIT binding to the striatum, putamen, and caudate nucleus was used as the outcome measure.
Results:A decrease in [123I]ß-CIT binding ratios between the two images was found in all regions of interest. The average decrease in [123I]ß-CIT binding ratios was about 8% in the whole striatum, 8% in the putaminal region, and 4% in the caudate region. Comparison of scans done in nine patients under two different conditions—in the off state and while on drug treatment—showed no significant alterations in the expression of striatal dopamine transporters as measured using [123I]ß-CIT SPECT. Power analysis indicated that to detect a significant (p < 0.05) effect of a neuroprotective agent with 0.80 power and 30% of predicted protection within two years, 216 patients are required in each group when the effects are measured in the whole putamen.
Conclusions:[123I]ß-CIT SPECT seems to be a useful tool to investigate the progression of dopaminergic degeneration in Parkinson's disease and may provide an objective method of measuring the effectiveness of neuroprotective treatments. Short term treatment with a D2agonist does not have a significant influence on [123I]ß-CIT binding to dopamine transporters. If the latter finding is replicated in larger groups of patients, it supports the suitability of [123I]ß-CIT SPECT for examining the progression of neurodegeneration in patients being treated with D2receptor agonists.
doi:10.1136/jnnp.74.3.294
PMCID: PMC1738309  PMID: 12588911
24.  Performance on the dementia rating scale in Parkinson's disease with dementia and dementia with Lewy bodies: comparison with progressive supranuclear palsy and Alzheimer's disease 
Background: The relation between dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD) is unknown.
Objectives: To compare the cognitive profiles of patients with DLB and PDD, and compare those with the performance of patients with a subcortical dementia (progressive supranuclear palsy) and a cortical dementia (Alzheimer's disease).
Design: Survey of cognitive features.
Setting: General community in Rogaland county, Norway, and a university dementia and movement disorder research centre in the USA.
Patients: 60 patients with DLB, 35 with PDD, 49 with progressive supranuclear palsy, and 29 with Alzheimer's disease, diagnosed by either standardised clinical procedures and criteria (all PDD and Alzheimer cases and 76% of cases of progressive supranuclear palsy), or necropsy (all DLB cases and 24% of cases of progressive supranuclear palsy). Level of dementia severity was matched using the total score on the dementia rating scale adjusted for age and education.
Main outcome measures: Dementia rating scale subscores corrected for age.
Results: No significant differences between the dementia rating scale subscores in the PDD and DLB groups were found in the severely demented patients; in patients with mild to moderate dementia the conceptualisation subscore was higher in PDD than in DLB (p = 0.03). Compared with Alzheimer's disease, PDD and DLB had higher memory subscores (p < 0.001) but lower initiation and perseveration (p = 0.008 and p=0.021) and construction subscores (p = 0.009 and p = 0.001). DLB patients had a lower conceptualisation subscore (p = 0.004). Compared with progressive supranuclear palsy, PDD and DLB patients had lower memory subscores (p < 0.001).
Conclusions: The cognitive profiles of patients with DLB and PDD were similar, but they differed from those of patients with Alzheimer's disease and progressive supranuclear palsy. The cognitive pattern in DLB and PDD probably reflects the superimposition of subcortical deficits upon deficits typically associated with Alzheimer's disease.
doi:10.1136/jnnp.74.9.1215
PMCID: PMC1738667  PMID: 12933921
25.  Cerebral and Extracranial Neurodegeneration are Strongly Coupled in Parkinson’s Disease 
In idiopathic Parkinson’s disease (PD), a generalized Lewy body type-degeneration in the brain as well as extracranial organs was identified. It is unclear, whether cerebral and extracranial Lewy body type-degeneration in PD are coupled or not. To address this question, cerebral [123I]FP-CIT SPECT – to quantify cerebral nigrostriatal dopaminergic degeneration – and myocardial [123I]MIBG scintigraphy – to quantify extracranial myocardial sympathetic degeneration – were performed in 95 PD patients and 20 healthy controls. At each Hoehn and Yahr stage separately, myocardial MIBG uptake correlated significantly with striatal FP-CIT uptake. No such correlation was found in the controls. Cerebral and extracranial Lewy body type-degeneration in PD do not develop independently from each other but develop in a strongly coupled manner. Obviously cerebral and extracranial changes are driven by at least similar pathomechanisms. Our findings in controls contradict a physiological correlation between nigrostriatal dopaminergic and myocardial sympathetic function.
doi:10.2174/1874205X00701010001
PMCID: PMC2577926  PMID: 19018276
Parkinson’s disease; FP-CIT SPECT; MIBG scintigraphy

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