123I-FP-CIT SPECT in dementia with Lewy bodies, Parkinson's disease and Alzheimer's disease: a new quantitative analysis of autopsy confirmed cases.

PURPOSE: The aim of this study was to re-evaluate the differentiation of patients with dementia with Lewy bodies (DLB) from Alzheimer's disease (AD) and Parkinson's disease (PD) using a quantitative analysis of 123I-FP-CIT SPECT scans. METHODS: Thirty-six patients with in vivo 123I-FP-CIT SPECT and neuropathological diagnoses were included. Based on neuropathological criteria, patients were further subclassified into nine AD, eight DLB, ten PD and nine with other diagnoses. An additional 16 healthy controls (HC) scanned with 123I-FP-CIT SPECT were also included. All images were visually assessed as normal versus abnormal uptake by consensus of five nuclear medicine physicians. Bihemispheric mean was calculated for caudate binding potential (CBP), putamen binding potential (PBP) and putamen-to-caudate ratio (PCR). RESULTS: Patients with DLB had significantly lower CBP and PBP than patients with AD and significantly higher PCR than patients with PD. Qualitative visual analysis of the images gave an accuracy of 88% in the evaluation of the status of the nigrostriatal pathway considering all individuals, and 96% considering only the patients with PD, AD and DLB. Quantitative analyses provided a balanced accuracy of 94%, 94% and 100% in binary classifications DLB versus AD, DLB versus PD and PD versus AD, respectively, and an accuracy of 93% in the differentiation among patients with DLB, AD and PD simultaneously. No statistically significant differences were observed between the AD and HC. CONCLUSIONS: This study demonstrates a very high diagnostic accuracy of the quantitative analysis of(123I-FP-CIT SPECT data to differentiate among patients with DLB, PD and AD.

Autopsy validation of 123I-FP-CIT dopaminergic neuroimaging for the diagnosis of DLB.

OBJECTIVE: To conduct a validation study of 123I-N-fluoropropyl-2b-carbomethoxy-3b-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT dopaminergic imaging in the clinical diagnosis of dementia with Lewy bodies (DLB) with autopsy as the gold standard. METHODS: Patients >60 years of age with dementia who had undergone 123I-FP-CIT imaging in research studies and who had donated their brain tissue to the Newcastle Brain Tissue Resource were included. All had structured clinical research assessments, and clinical diagnoses were applied by consensus panels using international diagnostic criteria. All underwent 123I-FP-CIT imaging at baseline, and scans were rated as normal or abnormal by blinded raters. Patients were reviewed in prospective studies and after death underwent detailed autopsy assessment, and neuropathologic diagnoses were applied with the use of standard international criteria. RESULTS: Fifty-five patients (33 with DLB and 22 with Alzheimer disease) were included. Against autopsy diagnosis, 123I-FP-CIT had a balanced diagnostic accuracy of 86% (sensitivity 80%, specificity 92%) compared with clinical diagnosis, which had an accuracy of 79% (sensitivity 87%, specificity 72%). Among patients with DLB, 10% (3 patients) met pathologic criteria for Lewy body disease but had normal 123I-FP-CIT imaging. CONCLUSIONS: This large autopsy analysis of 123I-FP-CIT imaging in dementia demonstrates that it is a valid and accurate biomarker for DLB, and the high specificity compared with clinical diagnosis (20% higher) is clinically important. The results need to be replicated with patients recruited from a wider range of settings, including movement disorder clinics and general practice. While an abnormal 123I-FP-CIT scan strongly supports Lewy body disease, a normal scan does not exclude DLB with minimal brainstem involvement. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that 123I-FP-CIT dopaminergic neuroimaging accurately identifies patients with DLB.

Dopamine transporter single photon emission computerized tomography in the diagnosis of dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is part of the spectrum of Lewy body disorders. However, it may be difficult to diagnose patients who have dementia but no Parkinsonism. Visual and semiquantitative assessment of the nigrostriatal dopaminergic nerve terminals in the putamen and caudate nuclei can be obtained with single photon emission computerized tomography (SPECT) using ligands that bind to the dopamine transporter molecule in the membranes of the nigrostriatal nerve terminals. This can be employed as a means of identifying subclinical degeneration of nigrostriatal neurones in patients with suspected DLB, increasing the probability of the diagnosis. In several studies, the sensitivity and specificity of abnormal dopamine transporter scans with regard to diagnosing probable DLB are better than 75 and 90%, respectively. This communication outlines the evidence for this and discusses some of the advantages, potential disadvantages, and areas of uncertainty with regard to the use of dopamine transporter SPECT in DLB diagnosis.

An fMRI study of verbal episodic memory encoding in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment (aMCI) is a high-risk and often prodromal state for the development of Alzheimer's disease (AD) and is characterised by isolated episodic memory impairment. Functional neuroimaging studies in healthy subjects consistently report left prefrontal cortex (PFC) activation during verbal episodic memory encoding. The PFC activation at encoding is related to semantic processing which enhances memory. The purpose of this study was to ascertain whether impaired verbal episodic memory in aMCI is related to PFC dysfunction. Using functional magnetic resonance imaging (fMRI) we compared 10 aMCI patients with 10 elderly controls during verbal encoding. The encoding task was sensitive to the effects of semantic processing. Subsequent recognition was tested to measure encoding success. Behavioural results revealed impaired recognition and a lower false recognition rate for semantically related distracters (lures) in aMCI, which suggest impaired semantic processing at encoding. Both groups activated left hemispheric PFC, insula, premotor cortex and cerebellum, but group comparisons revealed decreased activation in left ventrolateral PFC in the aMCI group. The magnitude of activation in left ventrolateral PFC during encoding was positively correlated with recognition accuracy in the control group but not in the aMCI group. We propose that verbal episodic memory impairment in aMCI is related to PFC dysfunction which affects semantic processing at encoding.

Occurrence of hepatocellular carcinoma in an adult male Nile lechwe (Kobus megaceros).

A 14-yr-old male Nile lechwe (Kobus megaceros) from the Jackson Zoo (Mississippi, USA) had chronic weight loss that was associated with elevated serum alkaline phosphatase levels. Approximately 4 yr after the first clinical signs of weight loss, the animal fractured its left rear femur and was subsequently euthanized; on the same day necropsy was performed. The liver was grossly enlarged and contained a smooth-surfaced nodular mass that occupied the majority of the right lobe of the liver. The mass had a liver-like appearance exhibiting a tan-red coloration but having a soft consistency. A single, approximately 0.6 cm, round, slightly elevated discrete red nodule was present in the left anterior lung. Microscopically, the hepatic mass and pulmonary nodule diffusely consisted of irregular cords of cells exhibiting hepatoid features, but containing no evidence of normal portal bile duct or portal triad development. To our knowledge, this is the first report in the scientific literature of a naturally occurring case of hepatocellular carcinoma in a Nile lechwe or in any antelope species.

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.

Imaging in neurodegenerative disorders: recent studies.

PURPOSE OF REVIEW: Advances in neuroimaging have expanded its already central role in neurodegenerative disorders. RECENT FINDINGS: The main advances we emphasize are imaging of amyloid in Alzheimer's disease, serial co-registered magnetic resonance imaging in frontotemporal lobar degeneration and imaging of nigrostriatal dysfunction in dementia with Lewy bodies. SUMMARY: All of these techniques offer ways of improving diagnosis.

Connexin 32 promoter P2 mutations: a mechanism of peripheral nerve dysfunction.

We identified a large Charcot-Marie-Tooth disease family with a novel mutation in the Connexin 32 (Cx32) P2 promoter region at position -526bp. This mutation was in a highly conserved SOX10 binding site. Functional studies were conducted on the Cx32 promoter that showed that this mutation reduced the activity of the Cx32 promoter and the affinity for SOX10 binding. These data suggest that interaction between the Cx32 P2 promoter, SOX10, and EGR2 highlight a mechanism of peripheral nerve dysfunction.

Dementia with Lewy bodies versus Alzheimer's disease: role of dopamine transporter imaging.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are the common forms of dementia at post-mortem, but distinguishing between these two types of dementia is often very difficult during life. Ioflupane significantly improves the differentiation during life between DLB and AD patients. However, there is a trend for lower caudate uptake in DLB than PD and lower posterior/caudal putamen uptake in PD than in DLB. Further research is needed to test the hypothesis that dopaminergic degeneration may be different, at least regarding anatomical distribution, in DLB and PD. Furthermore, it is important to consider and discuss the potential for ioflupane in the diagnostic workup of patients with DLB.

Mortality associated with melarsomine dihydrochloride administration in two North American river otters (Lontra canadensis) and a red panda (Ailurus fulgens fulgens).

Two adult North American river otters (Lontra canadensis) and an adult red panda (Ailurus fulgens fulgens) at three separate institutions died within 22 hr after receiving single 2.5- to 2.7-mg/kg doses of melarsomine dihydrochloride administered in the epaxial musculature as a treatment for filarid nematodes. One otter had a suspected Dirofilaria immitis infection, the other had a confirmed D. lutrae infection, and the red panda had a confirmed Dirofilaria sp. infection, presumably with D. immitis. Postmortem examinations revealed similar gross lesions, although they were less severe in the red panda. The trachea and primary bronchi contained abundant foamy fluid, the lungs were mottled with areas of consolidation, and the pulmonary parenchyma exuded abundant fluid at the cut section. Histologic evaluation revealed acute pulmonary edema, which resulted in respiratory failure and death. There may have been direct pulmonary cellular toxicity of melarsomine dihydrochloride or a severe systemic anaphylactic reaction to antigens released after parasite death. An idiosyncratic drug reaction or a low therapeutic index of melarsomine probably caused the death of the three individuals. Melarsomine dihydrochloride use should be avoided in North American river otters and red pandas.