Alzheimer Disease: Minoshima S

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: 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 approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Minoshima S, Cross D. · Departments of Radiology and Bioengineering, University of Washington, 1959 N.E. Pacific Street,Seattle, WA 98195-7115, USA. · Eur J Nucl Med Mol Imaging. · Pubmed #18204931 No free full text.

Abstract: PURPOSE: MRI using manganese as a trans-synaptic axonal tracing agent can unveil dynamics of axonal transport in living subjects. We use this technology to test the hypotheses if impaired axonal transport is a significant pathophysiological process in aging and early Alzheimer's disease (AD) and in part accounting for "selective vulnerability" of projection neurons in AD. METHODS: To allow quantitative assessment of axonal transport in vivo, we developed voxel-based statistical mapping technology as well as a tracer kinetic modeling method based on mass transport for manganese-enhanced MRI to estimate axonal transport rates in aging rats and AD transgenic mice. RESULTS: These techniques demonstrated manganese-enhanced signal changes in axonal projections of the olfactory tract and decreased axonal transport rates in rodent models of aging and AD. CONCLUSION: Altered axonal transport may be a critical pathophysiological process in aging and AD. Manganese-enhanced MRI provides exciting opportunities for the investigations of altered axonal transport in AD and related disorders.

Minoshima S. · Departments of Radiology and Bioengineering, University of Washington, 1959 North East Pacific Street, Seattle, WA 98195-6004, USA. · Neuroimaging Clin N Am. · Pubmed #15024960 No free full text.

Abstract: Extensive PET imaging research on AD has been conducted since PET scanners became available in the early 1980s. PET imaging using FDG, now commercially available, can detect early metabolic changes in AD and differential metabolic features of various dementing disorders. Image analysis techniques have also advanced in the field of functional brain imaging and permit accurate and consistent scan interpretation. PET studies that involve autopsy-confirmed cases suggest that the PET diagnosis of AD is no worse or may even be better than clinical diagnosis. Limited prospective studies demonstrated the effects of PET imaging in dementia management, which precludes the approval of FDG PET for more widespread, reimbursable use. Further evidence for the efficacy of PET imaging through well-organized clinical studies, as well as continuing efforts in technologic development and basic research to characterize functional alterations in dementing disorders in living patients, are equally important to achieve the goal of better dementia care.

Minoshima S, Frey KA, Cross DJ, Kuhl DE. · Department of Radiology, University of Washington, Seattle 98195-6004, USA. · Semin Nucl Med. · Pubmed #14735460 No free full text.

Abstract: Neurochemical imaging is one of the most established "molecular" imaging techniques. There have been tremendous efforts expended to develop radioligands specific to each neurochemical system. Investigational applications of neurochemical imaging in dementing disorders are extensive. Cholinergic, dopaminergic, and serotonergic systems, as well as benzodiazepine receptors, opioid receptors, and glutamatergic receptors have been imaged in Alzheimer disease and other dementing disorders. These investigations have provided important insights into disease processes in living human patients. The clinical diagnostic use of neurochemical imaging for dementing disorders is currently limited, but this technique is used to help develop therapeutic drugs at multiple levels.

Tang BN, Minoshima S, George J, Robert A, Swine C, Laloux P, Borght TV. · Department of Nuclear Medicine, Mont-Godinne University Hospital, UCL-Université Catholique de Louvain, Yvoir, Belgium. · Eur J Nucl Med Mol Imaging. · Pubmed #15232656 No free full text.

Abstract: PURPOSE: Accurate diagnosis of Alzheimer's disease (AD), the most common form of dementia, remains difficult. In order to assess whether fully automated stereotactic surface projection (3D-SSP) presentation contributes to the diagnosis of AD by single-photon emission computed tomography (SPECT), we investigated the diagnostic accuracy of transaxial display with and without 3D-SSP analysis as well as the correlation between cerebral perfusion in different cortical areas and the mini mental score (MMS). METHODS: Seventy-two patients referred because of cognitive impairment were included in the study. According to the National Institute of Neurological and Communicative Disorders and Stroke (NINCDS) and the Alzheimer's disease and Related Disorders Association (ADRDA) criteria, 27 patients were diagnosed as having probable AD while 45 were classified as non-AD patients. 3D-SSP was used to quantify the regional cerebral blood flow (rCBF) acquired from SPECT imaging. RESULTS: Compared with the transaxial section presentation alone, 3D-SSP presentation improved the area under the receiver operating curve (p<0.05) as well as intra-observer (k=0.73 vs 0.88) and inter-observer (k=0.50 vs 0.84) reproducibility. Upon normalisation of regional to thalamic activity, multiple regression analysis revealed a strong correlation between the MMS and rCBF in the right parietal cortex (p=0.002). CONCLUSION: Addition of 3D-SSP to the transaxial section display of ECD-SPECT studies improves the reproducibility and the diagnostic performance in respect of AD in patients with cognitive impairment and provides a valid tool for assessment of the severity of cortical perfusion abnormalities in such patients.

Higdon R, Foster NL, Koeppe RA, DeCarli CS, Jagust WJ, Clark CM, Barbas NR, Arnold SE, Turner RS, Heidebrink JL, Minoshima S. · University of Washington, Seattle, USA. · Stat Med. · Pubmed #14716732 No free full text.

Abstract: Flurodeoxyglucose positron emission tomography (FDG-PET) is being explored to determine its ability to differentiate between a diagnosis of Alzheimer's disease (AD) and fronto-temporal dementia (FTD). We have examined statistical discrimination procedures to help achieve this purpose and compared the results to visual ratings of FDG-PET images. The methods are applied to a data set of 48 subjects with autopsy confirmed diagnoses of AD or FTD (these subjects come from a multi-centre collaborative study funded by the National Alzheimer's Coordinating Center). FDG-PET images are composed of thousands of voxels (volume elements) so one is left with a situation where there are vastly more variables than subjects. Therefore, it is necessary to perform a data reduction before a statistical procedure can be applied. Approaches using both the entire image and summary statistics calculated on a number of volumes of interest (VOI) are examined. We performed the data reduction techniques of principal components analysis (PCA) and partial least-squares (PLS) on the entire image and then used linear discriminant analysis (LDA), quadratic (QDA) or logistic regression (LR) to classify subjects as having AD or FTD. Some of these methods achieve diagnostic accuracy (as assessed by leave-one-out cross-validation) that is similar to visual ratings by expert raters. Methods using PLS appear to be more successful. Averaging or using VOI data may also be helpful.

Drzezga A, Lautenschlager N, Siebner H, Riemenschneider M, Willoch F, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, 81675, München, Germany, · Eur J Nucl Med Mol Imaging. · Pubmed #12764551 No free full text.

Abstract: A high percentage of patients with mild cognitive impairment (MCI) develop clinical dementia of the Alzheimer type (AD) within 1 year. The aim of this longitudinal study was to identify characteristic patterns of cerebral metabolism at baseline in patients converting from MCI to AD, and to evaluate the changes in these patterns over time. Baseline and follow-up examinations after 1 year were performed in 22 MCI patients (12 males, 10 females, aged 69.8+/-5.8 years); these examinations included neuropsychological testing, structural cranial magnetic resonance imaging and fluorine-18 fluorodeoxyglucose positron emission tomography (PET) evaluation of relative cerebral glucose metabolic rate (rCMRglc). Individual PET scans were stereotactically normalised with NEUROSTAT software (Univ. of Michigan, Ann Arbor, USA). Subsequently, statistical comparison of PET data with an age-matched healthy control population and between patient subgroups was performed using SPM 99 (Wellcome Dept. of Neuroimaging Sciences, London, UK). After 1 year, eight patients (36%) had developed probable AD (referred to as MCI(AD)), whereas 12 (55%) were still classified as having stable MCI (referred to as MCI(MCI)). Compared with the healthy control group, a reduced rCMRglc in AD-typical regions, including the temporoparietal and posterior cingulate cortex, was detected at baseline in patients with MCI(AD). Abnormalities in the posterior cingulate cortex reached significance even in comparison with the MCI(MCI) group. After 1 year, MCI(AD) patients demonstrated an additional bilateral reduction of rCMRglc in prefrontal areas, along with a further progression of the abnormalities in the parietal and posterior cingulate cortex. No such changes were observed in the MCI(MCI) group. In patients with MCI, characteristic cerebral metabolic differences can be delineated at the time of initial presentation, which helps to define prognostic subgroups. A newly emerging reduction of rCMRglc in prefrontal cortical areas is associated with the transition from MCI to AD.

Petrie EC, Cross DJ, Galasko D, Schellenberg GD, Raskind MA, Peskind ER, Minoshima S. · Mail Code S-182-GRECC, Veterans Affairs Puget Sound Health Care System, 1660 S Columbian Way, Seattle, WA 98108, USA. · Arch Neurol. · Pubmed #19433663 No free full text.

Abstract: BACKGROUND: Alterations in cerebrospinal fluid (CSF) tau and beta-amyloid peptide 1-42 (Abeta(42)) levels and rates of cerebral glucose metabolism (CMRglu) on fluorodeoxyglucose positron emission tomography (FDG-PET) occur years before clinical symptoms of Alzheimer disease (AD) become manifest, but their relationship remains unclear. OBJECTIVE: To determine whether CSF AD biomarker levels and CMRglu in healthy individuals correlate in brain structures affected early in AD. DESIGN: Cohort study. SETTING: Alzheimer disease research center. PARTICIPANTS: Twenty individuals without dementia aged 46 to 83 years. INTERVENTIONS: Lumbar CSF sampling and FDG-PET imaging of CMRglu. The CSF Abeta(42), tau, and tau phosphorylated at threonine 181 (ptau(181)) levels were measured using immunobead-based multiplex assays. MAIN OUTCOME MEASURES: Correlations between CMRglu and CSF biomarker levels were analyzed via voxel-based and volume-of-interest approaches. RESULTS: Voxel-based analyses demonstrated significant negative correlations between CSF tau and ptau(181) levels and CMRglu in the posterior cingulate, precuneus, and parahippocampal regions. In contrast, a limited positive correlation was found between CSF Abeta(42) levels and CMRglu in the inferior temporal cortex. Volume-of-interest analyses confirmed negative associations between CSF tau and ptau(181) levels and CMRglu in the parietal and medial parietal lobes and a positive association between CSF Abeta(42) levels and CMRglu in the parahippocampal gyrus. CONCLUSIONS: In healthy individuals, higher CSF tau and ptau(181) concentrations were associated with more severe hypometabolism in several brain regions affected very early in AD, whereas lower CSF Abeta(42) concentrations were associated with hypometabolism only in the medial temporal lobe. This suggests that early tau and Abeta abnormalities may be associated with subtle synaptic changes in brain regions vulnerable to AD. A longitudinal assessment of CSF and FDG-PET biomarkers is needed to determine whether these changes predict cognitive impairment and incipient AD.

Ishii K, Kanda T, Uemura T, Miyamoto N, Yoshikawa T, Shimada K, Ohkawa S, Minoshima S. · Department of Radiology and Nuclear Medicine, Hyogo Brain and Heart Center, Himeji, Hyogo, Japan. · Eur J Nucl Med Mol Imaging. · Pubmed #19148640 No free full text.

Abstract: PURPOSE: To develop a computer-assisted automated diagnostic system to distinguish among Alzheimer disease (AD), dementia with Lewy bodies (DLB), and other degenerative disorders in patients with mild dementia. METHODS: Single photon emission computed tomography (SPECT) images with injection of N-Isopropyl-p-[(123)I]iodoamphetamine (IMP) were obtained from patients with mild degenerative dementia. First, datasets from 20 patients mild AD, 15 patients with dementia with DLB, and 17 healthy controls were used to develop an automated diagnosing system based on three-dimensional stereotactic surface projections (3D-SSP). AD- and DLB-specific regional templates were created using 3D-SSP, and critical Z scores in the templates were established. Datasets from 50 AD patients, 8 DLB patients, and 10 patients with non-AD/DLB type degenerative dementia (5 with frontotemporal dementia and 5 with progressive supranuclear palsy) were then used to test the diagnostic accuracy of the optimized automated system in comparison to the diagnostic interpretation of conventional IMP-SPECT images. These comparisons were performed to differentiate AD and DLB from non-AD/DLB and to distinguish AD from DLB. A receiver operating characteristic (ROC) analysis was performed. RESULTS: The area under the ROC curve (Az) and the accuracy of the automated diagnosis system were 0.89 and 82%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the visual inspection were 0.84 and 77%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 65%, respectively, for AD vs. DLB patients. The mean Az and the accuracy of the combination of visual inspection and this system were 0.96 and 91%, respectively, for AD/DLB vs. non-AD/DLB patients, and 0.70 and 66%, respectively, for AD vs. DLB patients. CONCLUSION: The system developed in the present study achieved as good discrimination of AD, DLB, and other degenerative disorders in patients with mild dementia as the commonly performed visual inspection of conventional SPECT images. A combination of visual inspection and this system is helpful in the differential diagnosis of patients with mild dementia.

Mosconi L, Tsui WH, Herholz K, Pupi A, Drzezga A, Lucignani G, Reiman EM, Holthoff V, Kalbe E, Sorbi S, Diehl-Schmid J, Perneczky R, Clerici F, Caselli R, Beuthien-Baumann B, Kurz A, Minoshima S, de Leon MJ. · Center for Brain Health, New York University School of Medicine, New York, New York 10016, USA. · J Nucl Med. · Pubmed #18287270 links to  free full text

Abstract: This multicenter study examined (18)F-FDG PET measures in the differential diagnosis of Alzheimer's disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB) from normal aging and from each other and the relation of disease-specific patterns to mild cognitive impairment (MCI). METHODS: We examined the (18)F-FDG PET scans of 548 subjects, including 110 healthy elderly individuals ("normals" or NLs), 114 MCI, 199 AD, 98 FTD, and 27 DLB patients, collected at 7 participating centers. Individual PET scans were Z scored using automated voxel-based comparison with generation of disease-specific patterns of cortical and hippocampal (18)F-FDG uptake that were then applied to characterize MCI. RESULTS: Standardized disease-specific PET patterns were developed that correctly classified 95% AD, 92% DLB, 94% FTD, and 94% NL. MCI patients showed primarily posterior cingulate cortex and hippocampal hypometabolism (81%), whereas neocortical abnormalities varied according to neuropsychological profiles. An AD PET pattern was observed in 79% MCI with deficits in multiple cognitive domains and 31% amnesic MCI. (18)F-FDG PET heterogeneity in MCI with nonmemory deficits ranged from absent hypometabolism to FTD and DLB PET patterns. CONCLUSION: Standardized automated analysis of (18)F-FDG PET scans may provide an objective and sensitive support to the clinical diagnosis in early dementia.

Foster NL, Heidebrink JL, Clark CM, Jagust WJ, Arnold SE, Barbas NR, DeCarli CS, Turner RS, Koeppe RA, Higdon R, Minoshima S. · Center for Alzheimer's Care, Imaging and Research and Department of Neurology, University of Utah, USA. · Brain. · Pubmed #17704526 links to  free full text

Abstract: Distinguishing Alzheimer's disease (AD) and frontotemporal dementia (FTD) currently relies on a clinical history and examination, but positron emission tomography with [(18)F] fluorodeoxyglucose (FDG-PET) shows different patterns of hypometabolism in these disorders that might aid differential diagnosis. Six dementia experts with variable FDG-PET experience made independent, forced choice, diagnostic decisions in 45 patients with pathologically confirmed AD (n = 31) or FTD (n = 14) using five separate methods: (1) review of clinical summaries, (2) a diagnostic checklist alone, (3) summary and checklist, (4) transaxial FDG-PET scans and (5) FDG-PET stereotactic surface projection (SSP) metabolic and statistical maps. In addition, we evaluated the effect of the sequential review of a clinical summary followed by SSP. Visual interpretation of SSP images was superior to clinical assessment and had the best inter-rater reliability (mean kappa = 0.78) and diagnostic accuracy (89.6%). It also had the highest specificity (97.6%) and sensitivity (86%), and positive likelihood ratio for FTD (36.5). The addition of FDG-PET to clinical summaries increased diagnostic accuracy and confidence for both AD and FTD. It was particularly helpful when raters were uncertain in their clinical diagnosis. Visual interpretation of FDG-PET after brief training is more reliable and accurate in distinguishing FTD from AD than clinical methods alone. FDG-PET adds important information that appropriately increases diagnostic confidence, even among experienced dementia specialists.

Mosconi L, Tsui WH, Pupi A, De Santi S, Drzezga A, Minoshima S, de Leon MJ. · New York University School of Medicine, New York, New York 10016, USA. · J Nucl Med. · Pubmed #17574982 links to  free full text

Abstract: The normative reference sample is crucial for the diagnosis of Alzheimer's disease (AD) with automated (18)F-FDG PET analysis. We tested whether an (18)F-FDG PET database of longitudinally confirmed healthy elderly individuals ("normals," or NLs) would improve diagnosis of AD and mild cognitive impairment (MCI). METHODS: Two (18)F-FDG PET databases of 55 NLs with 4-y clinical follow-up examinations were created: one of NLs who remained NL, and the other including a fraction of NLs who declined to MCI at follow-up. Each (18)F-FDG PET scan of 19 NLs, 37 MCI patients, and 33 AD patients was z scored using automated voxel-based comparison to both databases and examined for AD-related abnormalities. RESULTS: Our database of longitudinally confirmed NLs yielded 1.4- to 2-fold higher z scores than did the mixed database in detecting (18)F-FDG PET abnormalities in both the MCI and the AD groups. (18)F-FDG PET diagnosis using the longitudinal NL database identified 100% NLs, 100% MCI patients, and 100% AD patients, which was significantly more accurate for MCI patients than with the mixed database (100% NLs, 68% MCI patients, and 94% AD patients identified). CONCLUSION: Our longitudinally confirmed NL database constitutes reliable (18)F-FDG PET normative values for MCI and AD.

Uchida Y, Minoshima S, Okada S, Kawata T, Ito H. · Department of Radiology, Chiba University School of Medicine, Chiba, Japan. · Clin Nucl Med. · Pubmed #17117070 No free full text.

Abstract: PURPOSE: This study was performed to evaluate the diagnostic accuracy of brain perfusion SPECT in patients visiting the cognitive disorder clinic for initial evaluation using 3D-SSP compared with using standard transaxial section. MATERIALS AND METHODS: Standard transaxial section displays and 3D-SSP z-score maps obtained after administration of Tc-99m ECD or I-123 IMP were randomly interpreted in 315 patients who visited initially to the cognitive disorder clinic (age 46-88 years; 162 women, 153 men). Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were calculated and receiver operating characteristic (ROC) analysis was performed. RESULTS: One hundred thirty-seven patients were clinically diagnosed with Alzheimer disease and 178 patients were diagnosed with other disorders and age-associated cognitive decline. Sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy calculated using standard transaxial display were 61%, 70%, 61%, 70%, and 66%, respectively, and using the 3D-SSP z-score map were 90%, 74%, 73%, 90%, and 81%, respectively. Particularly, the sensitivity value improved in mild cases compared with severe cases using 3D-SSP. Diagnostic performance with 3D-SSP was superior in both mild dementia (Az = 0.64 [section] vs 0.81 [3D-SSP], P = 0.001) and severe dementia (Az = 0.75 [section] vs 0.90 [3D-SSP], P = 0.002). CONCLUSIONS: Brain perfusion SPECT was useful for diagnosis in patients who come to the cognitive disorder clinic for initial evaluation using 3D-SSP.

Ishiwata A, Sakayori O, Minoshima S, Mizumura S, Kitamura S, Katayama Y. · Department of Neurology, Nippon Medical School, Tokyo, Japan. · Acta Neurol Scand. · Pubmed #16867030 No free full text.

Abstract: OBJECTIVES: Baseline brain single-photon emission computed tomography (SPECT) can predict mild cognitive impairment (MCI) patients at risk for progressive MCI (PMCI). METHODS: Twenty-eight subjects [12 MCI, 6 with probable Alzheimer's Disease (AD), and 10 normal subjects] underwent baseline brain SPECT and were clinically followed for a mean period of 36 months. RESULTS: Of 12 MCI patients, 6 progressed to PMCI and 6 remained stable. Baseline SPECT identified asymmetric perfusion reduction in the parahippocampus (-5%), lateral parietal (-8%), and posterior cingulate (-11%) cortices--reductions consistent with that of mild AD--in five of the six PMCI patients. Significant perfusion reduction was observed particularly in the frontal cortices of probable AD when compared with PMCI (P < 0.05). CONCLUSION: Baseline SPECT can identify brain perfusion abnormalities among patients with MCI for progression to PMCI. This imaging modality may aid in MCI treatment stratification.

Ishii K, Minoshima S. · Department of Radiology and Nuclear Medicine, Hyogo Brain and Heart Center, 520 Saisho-Ko, Himeji, Hyogo 670-0981, Japan. · Eur J Nucl Med Mol Imaging. · Pubmed #16283181 No free full text.

This publication has no abstract.

Kuhl DE, Koeppe RA, Snyder SE, Minoshima S, Frey KA, Kilbourn MR. · Division of Nuclear Medicine, Department of Radiology, University of Michigan Medical Center, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA. · Ann Neurol. · Pubmed #16278840 No free full text.

Abstract: OBJECTIVE: We tested the premise that cholinesterase inhibitor therapy should target butyrylcholinesterase (BuChE) in Alzheimer's disease (AD), not acetylcholinesterase (AChE) alone, because both enzymes hydrolyze acetylcholine, and BuChE is increased in AD cerebral cortex. METHODS: To examine this issue in vivo, we quantified human cerebral cortical BuChE activity using tracer kinetic estimates (k(3)) of 1-[(11)C]methyl-4-piperidinyl n-butyrate ([(11)C]BMP) hydrolysis determined by positron emission tomography. Validation of the putative positron emission tomography method included regional distribution, positive correlation with age, and attenuation by the nonselective cholinesterase inhibitor physostigmine, but no attenuation by the AChE-selective inhibitor donepezil. Positron emission tomography scans in AD patients (n = 15) and control subjects (n = 12) measured both BuChE (using [(11)C]BMP) and AChE activity (using N-[(11)C] methylpiperidin-4-yl propionate, an established method). RESULTS: As expected, AChE activity in AD cerebral cortex was decreased to 75 +/- 13% of normal (p = 0.00001). Contrary to prediction, accompanying BuChE activity also was decreased to 82 +/- 14% of normal (p = 0.001). INTERPRETATION: Failure to observe increased [(11)C]BMP hydrolysis in vivo makes it less likely that incremental BuChE contributes importantly to acetylcholine hydrolysis in AD. The findings do not support the premise that inhibitor therapy should target BuChE so as to prevent increased levels of BuChE from hydrolyzing acetylcholine in AD cerebral cortex.

Chen WP, Matsunari I, Noda A, Yanase D, Yajima K, Takeda N, Yamada M, Minoshima S, Nishimura S. · Ishikawa Sunrise Industries Creation Organization, Kanazawa, Japan. · J Nucl Med. · Pubmed #16204713 links to  free full text

Abstract: Although (18)F-FDG PET is an established technique to assess brain glucose use, a shorter imaging time is preferable for patient convenience and increased throughput. The aim of this study was to validate a brain (18)F-FDG PET protocol more rapid than the conventional protocol. METHODS: For comparison of normalized metabolic activities, brain (18)F-FDG PET was performed on 60 healthy subjects and 25 patients with probable Alzheimer's disease (AD), and an additional 20 healthy subjects served as a control group to assess diagnostic performance between the conventional and rapid scanning protocols. Conventional scans were acquired for a total of 20 min (a 10-min emission and a 10-min transmission). Immediately after conventional scanning, rapid scanning was performed for a total of 4 min (a 3-min emission and a 1-min transmission). PET images were anatomically standardized using NEUROSTAT, with pixel values normalized to the individual global value. Two database sets, from the 2 protocols, were compared by regional values and pixel-by-pixel analysis. A receiver-operating-characteristic analysis was performed for comparison of diagnostic accuracy between the 2 protocols. A kinetic simulation study was also performed to examine the possible difference due to the time lag between the protocols. RESULTS: Although small differences in normalized activity were found in several regions in the healthy subjects between the 2 protocols, no significant difference was found in any region in the patient group. The coefficients of variation of the normalized activity were 20%-30% larger in the rapidly scanned images, but the mean z images and their coefficient-of-variation images did not differ. The kinetic simulation study suggested that the differences were caused by the time lag between the 2 protocols. No significant differences were found in area under the receiver-operating-characteristic curves, and the diagnostic accuracies for the detection of AD were virtually equal between the 2 protocols. CONCLUSION: The rapid scanning protocol used in the present study could provide results nearly equivalent to data from the conventional protocol. Thus, it is feasible to use this rapid protocol to detect AD, without losing diagnostic accuracy.

Drzezga A, Grimmer T, Riemenschneider M, Lautenschlager N, Siebner H, Alexopoulus P, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Technische Universität, München, Munich, Germany. · J Nucl Med. · Pubmed #16204712 links to  free full text

Abstract: Patients with mild cognitive impairment (MCI) represent a risk population for progressing to dementia of the Alzheimer type (DAT). However, clinical criteria do not ensure reliable individual prognosis in these patients. The objective of this longitudinal, prospective study was to examine the value of (18)F-FDG PET of cerebral glucose metabolism and of genetic susceptibility, as defined by an APOEepsilon4-positive genotype, with regard to the early diagnosis of DAT in patients with MCI. METHODS: In 30 patients with the diagnosis of MCI (16 female, 14 male; age, 70 +/- 8 y), baseline and follow-up examinations (mean observation period, 16 mo) were performed. In all patients, the APOE genotype was assessed and cerebral glucose metabolism was evaluated at baseline using cranial (18)F-FDG PET. Individual PET data were screened for findings suggestive of Alzheimer's disease (AD), with the help of an automated computer program. After stereotactical normalization of the PET images, this program performs an observer-independent statistical comparison with an age-matched reference database (n = 22). RESULTS: In 43% of all MCI subjects, a PET scan suggestive of AD pathology according to our predefined criteria was observed at baseline (PET+); 57% of all MCI patients were carriers of the APOE epsilon4 allele (e4+). In 40% of all patients, progression of symptoms within the observation period justified the clinical diagnosis of probable DAT at the time of follow-up reevaluation. Statistical evaluation revealed the best results for PET with regard to early diagnosis of DAT in MCI patients (sensitivity, 92%; specificity, 89%). Classification according to the APOE genotype was significantly less successful (sensitivity, 75%; specificity, 56%). However, a combination of both diagnostic tests allowed early diagnosis with either very high specificity (PET+ AND e4+: sensitivity, 67%; specificity, 100%) or very high sensitivity (PET+ OR e4+: sensitivity, 100%; specificity, 44%). CONCLUSION: (18)F-FDG PET of cerebral glucose metabolism is a valuable diagnostic tool for the prediction of clinical outcome in individual MCI patients. Results are superior to the exclusive assessment of the APOE genotype. A combination of both functional imaging and genotyping may allow an early high-risk or low-risk stratification of patients with either very high sensitivity or very high specificity. This may be valuable, for example, for patient selection in scientific studies.

Drzezga A, Riemenschneider M, Strassner B, Grimmer T, Peller M, Knoll A, Wagenpfeil S, Minoshima S, Schwaiger M, Kurz A. · Department of Nuclear Medicine, Technische Universität München, Munich, Germany. · Neurology. · Pubmed #15642911 No free full text.

Abstract: OBJECTIVE: To examine the influence of the APOE epsilon4 allele on cerebral glucose metabolism in a large series of patients with Alzheimer disease (AD). METHODS: Eighty-three patients (41 APOE epsilon4 positive and 42 epsilon4 negative) were selected from a pre-existing databank of patients with AD (n > 1,000). The patients were carefully matched for age, age at onset, approximate disease duration, educational level, and overall degree of cognitive impairment. Cerebral [18F]fluorodeoxyglucose PET imaging was performed in all patients by a standardized protocol. Statistical comparison of patient PET data vs a healthy control population was performed as well as an analysis of differences between groups (SPM99; Wellcome Department of Cognitive Imaging, London, UK). RESULTS: A similar pattern of cerebral hypometabolism was detected in the epsilon4-positive and -negative patient groups vs healthy volunteers in regions typically affected by AD (bilateral temporal, parietal, posterior cingulate, and prefrontal cortical areas). The comparison between epsilon4-positive and -negative patients additionally revealed stronger abnormalities in epsilon4 carriers in parietal, temporal, and posterior cingulate cortical regions. CONCLUSIONS: A generally similar pattern of cerebral hypometabolism was detected in APOE epsilon4-positive and -negative patients with Alzheimer disease. However, in direct comparison of the two matched groups, the abnormalities in the epsilon4-positive group were demonstrated to be more pronounced.

Moretti P, Lieberman AP, Wilde EA, Giordani BI, Kluin KJ, Koeppe RA, Minoshima S, Kuhl DE, Seltzer WK, Foster NL. · Departments of Neurology, University of Michigan, Ann Arbor 48109, USA. · Neurology. · Pubmed #15159497 No free full text.

Abstract: A four-generation pedigree exhibiting early-onset autosomal dominant Alzheimer disease (AD) with spastic paraplegia, dystonia, and dysarthria due to a novel 6-nucleotide insertional mutation in exon 3 of the presenilin 1 gene (PS1) is described. Serial examinations, PET scans, and autopsy revealed that the mutation in this highly conserved portion of PS1 causes an aggressive dementia that maintains the usual regional hierarchy of disease pathology while extending abnormalities into more widespread brain areas than typically seen in AD.

Uchida Y, Ito H, Iimori T, Kigawa T, Okada S, Minoshima S. · No affiliation provided · Nippon Hoshasen Gijutsu Gakkai Zasshi. · Pubmed #12577014 links to  free full text

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Minoshima S, Foster NL, Sima AA, Frey KA, Albin RL, Kuhl DE. · Department of Internal Medicine, University of Michigan Medical School, Geriatrics Research, Education, and Clinical Center, Ann Arbor, USA. · Ann Neurol. · Pubmed #11558792 No free full text.

Abstract: Seeking antemortem markers to distinguish Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD), we examined brain glucose metabolism of DLB and AD. Eleven DLB patients (7 Lewy body variant of AD [LBVAD] and 4 pure diffuse Lewy body disease [DLBD]) who had antemortem position emission tomography imaging and autopsy confirmation were compared to 10 autopsy-confirmed pure AD patients. In addition, 53 patients with clinically-diagnosed probable AD, 13 of whom later fulfilled clinical diagnoses of DLB, were examined. Autopsy-confirmed AD and DLB patients showed significant metabolic reductions involving parietotemporal association, posterior cingulate, and frontal association cortices. Only DLB patients showed significant metabolic reductions in the occipital cortex, particularly in the primary visual cortex (LBVAD -23% and DLBD -29% vs AD -8%), which distinguished DLB versus AD with 90% sensitivity and 80% specificity. Multivariate analysis revealed that occipital metabolic changes in DLB were independent from those in the adjacent parietotemporal cortices. Analysis of clinically diagnosed probable AD patients showed a significantly higher frequency of primary visual metabolic reduction among patients who fulfilled later dinical criteria for DLB. In these patients, occipital hypometabolism preceded some clinical features of DLB. Occipital hypometabolism is a potential antemortem marker to distinguish DLB versus AD.

Ishii K, Willoch F, Minoshima S, Drzezga A, Ficaro EP, Cross DJ, Kuhl DE, Schwaiger M. · Nuklearmedizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, München, Germany. · J Nucl Med. · Pubmed #11337540 links to  free full text

Abstract: Despite the increased use of statistical mapping to detect brain functional changes in Alzheimer's disease (AD), potential artifacts introduced by stereotactic anatomic standardization of atrophied brains have not been examined carefully. We investigated the effects of anatomic standardization by Statistical Parametric Mapping (SPM) and NEUROSTAT. METHODS: First, 10 AD patients and 10 age-matched healthy volunteers underwent 18F-FDG brain PET imaging. Each image set was standardized to a stereotactic brain template using SPM or NEUROSTAT, followed by pixel normalization to the global or cerebellar activity. Within-group comparisons of standardized image sets by each method and a between-group comparison of healthy volunteers and AD patients were performed using the statistical analysis routines of SPM. Second, simulated PET image sets were generated from segmented MR image sets of 5 healthy volunteers and 5 AD patients. Using the anatomic standardization parameters estimated on the simulated image sets, original gray matter MR image sets were transformed to the stereotactic coordinate system. Between-group subtraction analyses of the transformed gray matter image sets between healthy volunteers and AD groups were performed to examine the accuracy of cortical gray matter matching. RESULTS: Between-group comparison by SPM or NEUROSTAT showed generally similar areas of hypometabolism in bilateral temporoparietal, posterior cingulate, and left frontal cortices. Both methods showed possible deformation artifacts in the anterior part of the corpus callosum. The localization of the peak hypometabolism varied considerably between the two methods when global normalization was applied. The use of a common brain template for standardization resulted in asymmetric differences in cortical margins, indicating systematic differences in the deformation algorithms. The realistic simulation study revealed gray matter mismatches to be 20% greater with SPM than with NEUROSTAT. CONCLUSION: Although different statistical mapping methods may yield grossly similar patterns of hypometabolism in AD, the extent, severity, and peak location of metabolic changes can be inconsistent. Deformation accuracy appears to be more prone to atrophy. These limitations need to be considered carefully in the application and interpretation of brain mapping analysis in atrophied brains.

Kuhl DE, Minoshima S, Frey KA, Foster NL, Kilbourn MR, Koeppe RA. · Department of Internal Medicine, University of Michigan, Ann Arbor, USA. · Ann Neurol. · Pubmed #10976649 No free full text.

Abstract: Based on surrogate assays of peripheral red blood cells, reports state that widely prescribed doses of donepezil hydrochloride provide nearly complete inhibition of cerebral cortical acetylcholinesterase activity in the treatment of Alzheimer's disease (AD). To test this, direct positron emission tomography measures of cerebral acetylcholinesterase activity were made in AD patients before and after treatment with donepezil (5 and 10 mg/day) for at least 5 weeks and compared with similar measures in normal controls who were untreated or after acute administration of another AChE inhibitor, physostigmine salicylate (1.5 mg/hr). After physostigmine, acetylcholinesterase inhibition averaged 52% in normal cerebral cortex. After donepezil, cerebral cortical inhibition in AD brain averaged only 27%. Clinical trials of this donepezil dose schedule are not testing the effect of nearly complete cerebral cortical inhibition.

Shimura H, Hattori N, Kubo S, Mizuno Y, Asakawa S, Minoshima S, Shimizu N, Iwai K, Chiba T, Tanaka K, Suzuki T. · Department of Neurology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan. · Nat Genet. · Pubmed #10888878 No free full text.

Abstract: Autosomal recessive juvenile parkinsonism (AR-JP), one of the most common familial forms of Parkinson disease, is characterized by selective dopaminergic neural cell death and the absence of the Lewy body, a cytoplasmic inclusion body consisting of aggregates of abnormally accumulated proteins. We previously cloned PARK2, mutations of which cause AR-JP (ref. 2), but the function of the gene product, parkin, remains unknown. We report here that parkin is involved in protein degradation as a ubiquitin-protein ligase collaborating with the ubiquitin-conjugating enzyme UbcH7, and that mutant parkins from AR-JP patients show loss of the ubiquitin-protein ligase activity. Our findings indicate that accumulation of proteins that have yet to be identified causes a selective neural cell death without formation of Lewy bodies. Our findings should enhance the exploration of the molecular mechanisms of neurodegeneration in Parkinson disease as well as in other neurodegenerative diseases that are characterized by involvement of abnormal protein ubiquitination, including Alzheimer disease, other tauopathies, CAG triplet repeat disorders and amyotrophic lateral sclerosis.