D. C. Costa

Diagnosis and management of dementia with Lewy bodies Third report of the DLB consortium

The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in ∼50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

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 Alzheimers 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 Parkinsons 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 2β-carbomethoxy-3β-(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.

Clinical role of positron emission tomography in oncology

Positron emission tomography (PET) is now in routine use in oncology, through the success of metabolic imaging, mainly with fluorodeoxyglucose (FDG). Clear benefit is obtained with FDG PET in the assessment of patients with recurrent or residual disease, especially colorectal cancer and lymphoma. Preoperative staging of non-small-cell lung cancer with FDG PET is of proven benefit. Staging and restaging of patients with melanoma of stage II or greater is useful, and FDG PET has also been successfully used to investigate single pulmonary nodules. Tumour grading has been assessed, especially in the brain, but an important and emerging indication is the evaluation of tumour response with PET. Rapid decline of FDG uptake has been observed in responsive cancers. Further advances are being made with other fluorine-18-labelled and generator-based PET tracers, the only ones that can be used in units without dedicated cyclotrons.

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.

Pathophysiology of Chronic Left Ventricular Dysfunction New Insights From the Measurement of Absolute Myocardial Blood Flow and Glucose Utilization

BACKGROUND Chronically dysfunctional myocardium may improve after coronary revascularization. This condition was thought to be due to a chronically reduced myocardial blood flow (MBF). Recently, however, it has been shown that in patients without previous infarction but with chronic left ventricular dysfunction, baseline MBF was normal. METHODS AND RESULTS To study the pathophysiology of chronic left ventricular dysfunction in patients with previous infarction, regional MBF (milliliter per minute per gram of water-perfusable tissue) and glucose utilization (MRG; micromoles per minute per gram) during hyperinsulinemic euglycemic clamp were measured with positron emission tomography in 30 patients before bypass. At baseline, 133 myocardial segments were normal, and 107 were dysfunctional. After revascularization, 59 of 107 segments improved, while 48 of 107 were unchanged. MBF was 0.92 +/- 0.25 mL.min-1.g-1 in normal segments, 0.87 +/- 0.31 mL.min-1.g-1 in improved segments (P = NS versus normal), and 0.82 +/- 0.40 mL.min-1.g-1 in unchanged segments (P < .05 versus normal). In 90% of the dysfunctional segments, MBF was > 0.42 mL.min-1.g-1, a cutoff value corresponding to the mean MBF minus 2 SD in normal segments. The MRG was 0.71 +/- 0.14 mumol.min-1.g-1 in 9 age-matched normal subjects, 0.45 +/- 0.19 mumol.min-1.g-1 (P < .01) in normal segments, 0.44 +/- 0.14 mumol.min-1.g-1 in improved segments (P = NS versus normal), and 0.34 +/- 0.17 mumol.min-1.g-1 in unchanged segments (P < .01 versus normal and improved). CONCLUSIONS The results suggest that resting MBF measured with 15O-labeled water in chronically dysfunctional segments is not reduced and that the myocardium of these patients is less sensitive to insulin than that of normal subjects.

Clozapine, single photon emission tomography, and the D2 dopamine receptor blockade hypothesis of schizophrenia

According to the dopamine hypothesis of schizophrenia, D2 receptor blockade is essential for a drug to have antipsychotic potency, and antipsychotic potency and D2 blockade are linearly related in vitro. To test this assumption in vivo, we have compared clinical response with central D2 dopamine receptor availability measured by 123I-iodobenzamide single photon emission tomography in two groups of schizophrenic patients. 6 patients were on typical antipsychotic drugs and 10 were on the atypical antipsychotic clozapine, including 2 patients from the first group. The patients on typical antipsychotics showed poor therapeutic response despite D2 receptor blockade. Significant clinical improvement occurred in all patients on clozapine, but at a lower level of D2 blockade by the drug. These findings suggest a more complex relation between D2 blockade and clinical efficacy than was previously thought.

A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the ROBUST study.

Abstract. There are no large studies available to guide the selection of thallium (Tl), methoxyisobutylisonitrile (MIBI) or tetrofosmin (Tf) for myocardial perfusion imaging. Our objective was to compare the technical and clinical performance of the three in routine clinical practice. We randomised 2,560 patients to receive Tl, MIBI or Tf. A 1-day stress/rest protocol was used for MIBI and Tf. Tracer uptake was scored using a 17-segment model, quality and artefact scores were assigned, and ratios of heart (H), liver (L), subdiaphragmatic (S) and lung activity were measured. Mean quality scores (stress/rest) were Tl 2.13/2.16, MIBI 2.18/2.39, Tf 2.18/2.42 (P=ns stress and <0.00001 rest). For attenuation artefact, Tl>MIBI=Tf (P<0.05) and for low-count artefact Tl>MIBI>Tf (P<0.001). For H/S, Tl>MIBI=Tf, for H/L Tl>MIBI=Tf, and for H/lung Tl<MIBI=Tf. Stress defects in the patients with reversible or mixed perfusion defects were more severe for Tl than for the other tracers (mean summed score out of 68: Tl 52.3, MIBI 55.7, Tf 54.4, P<0.01), but mean rest scores were more similar (Tl 58.7, MIBI 60.7, Tf 59.4, P=0.02). In the subset of 137 patients undergoing diagnostic perfusion studies without prior infarction, angiography or revascularisation, overall sensitivity for the detection of coronary disease defined by subsequent angiography was 91% with a specificity of 87%. There were no significant differences between the tracers with regard to sensitivity and specificity. In conclusion: There are technical differences between the tracers. Overall image quality score is superior using technetium, with less low-count artefact and less attenuation. Stress defect depth and extent are slightly greater using thallium, with no difference between MIBI and tetrofosmin. All three tracers perform well in clinical terms, with high sensitivity and specificity for angiographic stenosis and no differences in accuracy between the tracers.

Limbic selectivity of clozapine

6motile sperm cells per mL, the inclusion criterion for the use of ICSI in the Netherlands. Both oligozoospermic (n=69) and azoospermic (n=11) men were included. All patients were karyotyped, and a consecutive subgroup (n=58) was also tested for Y-chromosomal deletions and CFTR mutations. We found an abnormal karyotype in peripheral blood lymphocytes in seven (8·8%) of 80 patients, ten-fold more than the overall population incidence of 0·85% 2 (p<0·001, 2 test; table). We analysed Y-chromosomal deletions with a multiplex PCR system with markers for the AZF-a, AZF-b, and AZF-c regions. 3 With markers sY254 and sY255, three (5%) of 58 patients were found to have an AZF-c deletion associated with the deleted-in-azoospermia (DAZ) gene. No AZF deletions were detected with this assay in a study of 100 fertile male controls. 3

Parkinson's disease is overdiagnosed clinically at baseline in diagnostically uncertain cases: a 3-year European multicenter study with repeat [123I]FP-CIT SPECT

Overdiagnosis of Parkinsons disease (PD) is suggested by specialist review of community diagnosis, and in postmortem studies. In specialist centers 4 to 15% of patients entered into clinical trials as early PD do not have functional imaging support for a PD diagnosis. In a European multicenter, prospective, longitudinal study, we compared clinical diagnosis with functional SPECT imaging using [123I]FP‐CIT (DaTSCAN™, GE Healthcare). Repeat observations were performed over 3 years in patients with tremor and/or parkinsonism in whom there was initial diagnostic uncertainty between degenerative parkinsonism and nondegenerative tremor disorders. Video‐recording of clinical features was scored independently of functional imaging results by two blinded clinicians at 36 months (= gold standard clinical diagnosis). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The main endpoint was the sensitivity and specificity of SPECT imaging at baseline compared with the gold standard. In 99 patients completing the three serial assessments, on‐site clinical diagnosis overdiagnosed degenerative parkinsonism at baseline in diagnostically uncertain cases compared with the gold standard clinical diagnosis (at 36 months), the latter giving a sensitivity of 93% and specificity of 46%. The corresponding baseline [123I]FP‐CIT SPECT results showed a mean sensitivity of 78% and a specificity of 97%. Inter‐reader agreement for rating scans as normal or abnormal was high (Cohens

The investigation of Alzheimer's disease with single photon emission tomography.

\hat{\kappa}