Biomarkers Differentiating Dementia with Lewy Bodies from Other Dementias: A Meta-Analysis.

BACKGROUND: Several nuclear imaging and cerebrospinal fluid (CSF) biomarkers are under investigation, aimed at facilitating the differential diagnosis of dementias. OBJECTIVE: To quantitatively synthesize data on test performance in differentiating dementia with Lewy bodies (DLB) from other dementias. METHODS: We searched PubMed (January 2000- March 2015) for English-language publications that assessed a selected set of five imaging and three CSF biomarkers for this purpose. We meta-analyzed measures of agreement between biomarker results and clinical diagnosis. RESULTS: Forty-five publications were eligible. The majority of evidence was based on studies that enrolled representative disease populations. For differentiating between DLB and Alzheimer's disease (AD) or other dementias, metaiodobenzylguanidine scintigraphy and dopamine transporter (DAT) single photon emission computed tomography (SPECT) showed, respectively, excellent (summary kappa = 0.85; 95% confidence interval [95% CI], 0.74-0.96) and good (summary kappa = 0.71; 95% CI, 0.43-0.99) agreement. Metaiodobenzylguanidine scintigraphy appeared superior to fluorodeoxyglucose- positron emission tomography (summary kappa = 0.53; 95% CI, 0.36-0.69) and cerebral blood flow SPECT (summary kappa = 0.40; 95% CI, 0.33-0.47). For differentiating DLB from AD, CSF t-tau levels (summary kappa = 0.68; 95% CI, 0.55-0.82) performed comparably to metaiodobenzylguanidine scintigraphy and DAT SPECT. Sparse direct comparative evidence failed to corroborate these indirect comparisons. CONCLUSION: Metaiodobenzylguanidine scintigraphy and DAT SPECT are highly concordant with clinical diagnosis in differentiating DLB from other dementias. However, given the limitations in the study design, the applicability of these results to real-world differential diagnosis remains unclear. Prospective studies targeting patients with atypical presentations that adopt gold standard tests would reliably estimate the true test performance of these promising biomarkers.

Comparison of (123)I-MIBG myocardial scintigraphy, brain perfusion SPECT, and voxel-based MRI morphometry for distinguishing between dementia with Lewy bodies and Alzheimer's disease.

OBJECTIVE: This study aimed to compare the diagnostic value of (123)I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy, N-isopropyl-p[(123)I]iodoamphetamine (IMP) brain perfusion single-photon emission computed tomography (SPECT), and brain magnetic resonance imaging (MRI) voxel-based morphometry (VBM) for the differentiation of dementia with Lewy bodies (DLB) and Alzheimer's disease (AD). METHODS: Thirty-five and 34 patients with probable DLB and probable AD, respectively, were enrolled. All patients underwent (123)I-MIBG myocardial scintigraphy, (123)I-IMP brain perfusion SPECT, and brain MRI. For (123)I-MIBG imaging, we calculated early and delayed heart-to-mediastinum (H/M) uptake ratios. Three-dimensional stereotactic surface projections (3D-SSP) were used to analyze the results of (123)I-IMP SPECT. VBM with statistical parametric mapping 8 plus diffeomorphic anatomical registration using exponentiated Lie algebra (DARTEL) was used to analyze the brain MRI data. RESULTS: The area under the receiver operating characteristic curves (AUC) for discriminating DLB and AD was highest (0.882) for the delayed H/M ratio on (123)I-MIBG scintigraphy. AUC for z-score measurement in the occipital lobe was 0.818 and that for the extent of gray matter (GM) atrophy in the whole brain was 0.788. AUC for the combination of 3D-SSP and VBM analysis was 0.836. The respective sensitivities and specificities for distinguishing DLB from AD were 97.1 and 100 % for the delayed H/M ratio using (123)I-MIBG scintigraphy; 88.6 and 73.5 % for the occipital lobe z-score using 3D-SSP analysis; 85.7 and 64.7 % for the extent of whole brain GM atrophy using voxel-based MRI morphometry; and 91.4 and 76.5 % for the combination of 3D-SSP analysis and VBM. CONCLUSIONS: (123)I-MIBG myocardial scintigraphy was superior to brain perfusion SPECT and brain MRI using an advanced statistical technique to differentiate DLB and AD.

Multivariate spatial covariance analysis of 99mTc-exametazime SPECT images in dementia with Lewy bodies and Alzheimer's disease: utility in differential diagnosis.

We examined (99m)Tc-exametazime brain blood flow single-photon emission computed tomography (SPECT) images using a spatial covariance analysis (SCA) approach to assess its diagnostic value in distinguishing dementia with Lewy bodies (DLB) from Alzheimer's disease (AD). Voxel SCA was simultaneously applied to a set of preprocessed images (AD, n=40; DLB, n=26), generating a series of eigenimages representing common intercorrelated voxels in AD and DLB. Linear regression derived a spatial covariance pattern (SCP) that discriminated DLB from AD. To investigate the diagnostic value of the model SCP, the SCP was validated by applying it to a second, independent, AD and DLB cohort (AD, n=34; DLB, n=29). Mean SCP expressions differed between AD and DLB (F(1,64)=36.2, P<0.001) with good diagnostic accuracy (receiver operating characteristic (ROC) curve area 0.87, sensitivity 81%, specificity 88%). Forward application of the model SCP to the independent cohort revealed similar differences between groups (F(1,61)=38.4, P<0.001), also with good diagnostic accuracy (ROC 0.86, sensitivity 80%, specificity 80%). Multivariate analysis of blood flow SPECT data appears to be robust and shows good diagnostic accuracy in two independent cohorts for distinguishing DLB from AD.

[The clinical significance of MIBG myocardial scintigraphy in Parkinson disease].

Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy can assess postganglionic presynaptic cardiac sympathetic nerve endings. Reduced cardiac MIBG uptake on MIBG myocardial scintigraphy has been reported in patients with Parkinson disease (PD), dementia with Lewy bodies (DLB), pure autonomic failure (PAF), and familial PD linked to SNCA duplication. This imaging procedure is a sensitive diagnostic tool that might differentiate PD and DLB from other movement disorders from Alzheimer disease (AD). We recently reported cardiac sympathetic denervation in PD, DLB, PAF, and familial PD linked to SNCA duplication which accounts for the reduced cardiac MIBG uptake in these disorders. The patients with PD, DLB, PAF and familial PD linked to SNCA duplication have Lewy bodies in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration, AD, and parkin-associated PD do not. However, in patients with MSA or PSP, cardiac sympathetic denervation was associated with the presence of Lewy bodies in the nervous system. Therefore, cardiac sympathetic denervation is closely related to the presence of Lewy bodies in the wide range of neurodegenerative processes. Thus, we conclude that reduced cardiac MIBG uptake is a potential biomarker for the presence of Lewy bodies in the nervous system. We infer that MIBG myocardial scintigraphy is a noninvasive tool for detecting Lewy bodies during life.

Amyloid imaging with (18)F-florbetaben in Alzheimer disease and other dementias.

UNLABELLED: Amyloid imaging with (18)F-labeled radiotracers will allow widespread use, facilitating research, diagnosis, and therapeutic development for Alzheimer disease. The purpose of the study program was to compare cortical amyloid deposition using (18)F-florbetaben and PET in controls and subjects with mild cognitive impairment (MCI), frontotemporal lobar degeneration (FTLD), dementia with Lewy bodies (DLB), vascular dementia (VaD), Parkinson disease (PD), and Alzheimer disease (AD). METHODS: One hundred nine subjects in 3 clinical studies at Austin Health were reviewed: 32 controls, 20 subjects with MCI, and 30 patients with AD, 11 with FTLD, 7 with DLB, 5 with PD, and 4 with VaD underwent PET after intravenous injection of 300 MBq of (18)F-florbetaben. Standardized uptake value ratios (SUVR) using the cerebellar cortex as a reference region were calculated between 90 and 110 min after injection. RESULTS: When compared with the other groups, AD patients demonstrated significantly higher SUVRs (P < 0.0001) in neocortical areas. Most AD patients (96%) and 60% of MCI subjects showed diffuse cortical (18)F-florbetaben retention. In contrast, only 9% of FTLD, 25% of VaD, 29% of DLB, and no PD patients and 16% of controls showed cortical binding. Although there was a correlation between Mini Mental State Examination and ß-amyloid burden in the MCI group, no correlation was observed in controls, FTLD or AD. CONCLUSION: (18)F-florbetaben had high sensitivity for AD, clearly distinguished patients with FTLD from AD, and provided results comparable to those reported with (11)C-Pittsburgh Compound B in a variety of neurodegenerative diseases.

Amyloid imaging of Lewy body-associated disorders.

Clinicopathologic studies of Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) commonly reveal abnormal ß-amyloid deposition in addition to diffuse Lewy bodies (α-synuclein aggregates), but the relationship among these neuropathologic features and the development of dementia in these disorders remains uncertain. The purpose of this study was to determine whether amyloid-ß deposition detected by PET imaging with Pittsburgh Compound B (PIB) distinguishes clinical subtypes of Lewy body-associated disorders. Nine healthy controls, 8 PD with no cognitive impairment, 9 PD with mild cognitive impairment, 6 DLB, and 15 PDD patients underwent [(11)C]-PIB positron emission tomography imaging, clinical examination, and cognitive testing. The binding potential (BP) of PIB for predefined regions and the mean cortical BP (MCBP) were calculated for each participant. Annual longitudinal follow-up and postmortem examinations were performed on a subset of participants. Regional PIB BPs and the proportion of individuals with abnormally elevated MCBP were not significantly different across participant groups. Elevated PIB binding was associated with worse global cognitive impairment in participants with Lewy body disorders but was not associated with any other clinical or neuropsychological features, including earlier onset or faster rate of progression of cognitive impairment. These results suggest that the presence of fibrillar amyloid-ß does not distinguish between clinical subtypes of Lewy body-associated disorders, although larger numbers are needed to more definitively rule out this association. Amyloid-ß may modify the severity of global cognitive impairment in individuals with Lewy body-associated dementia.

Recent developments in innervation imaging using iodine-123-metaiodobenzylguanidine scintigraphy in Lewy body diseases.

Radiolabeled metaiodobenzylguanidine (MIBG) is an analog of guanethidine and is taken up by the postganglionic presynaptic nerve endings. MIBG uptake in the heart correlates with adrenergic function, which can be reduced in Lewy body diseases. We described the recent developments in innervation imaging using (123)I-MIBG scintigraphy in Lewy body diseases including Parkinson's disease and dementia with Lewy bodies. Particularly, we underlined the role of MIBG scintigraphy in differential diagnosis of movement disorders. As described by recent studies, MIBG scintigraphy is a valuable diagnostic tool for differentiation between Lewy body diseases and parkinsonian syndromes or other movement disorders with parkinsonism. Furthermore, this method may provide a powerful differential diagnostic tool between dementia with Lewy bodies and Alzheimer's disease. We also reported the results of clinical investigations about the correlation between characteristics of Parkinson's disease and myocardial MIBG uptake.

Neurotransmitter changes in dementia with Lewy bodies and Parkinson disease dementia in vivo.

OBJECTIVE: Although Parkinson disease with dementia (PDD) and dementia with Lewy bodies (DLB) show a wide clinical and neuropathologic overlap, they are differentiated according to the order and latency of cognitive and motor symptom appearance. Whether both are distinct disease entities is an ongoing controversy. Therefore, we directly compared patients with DLB and PDD with multitracer PET. METHODS: PET with (18)fluorodopa (FDOPA), N-(11)C-methyl-4-piperidyl acetate (MP4A), and (18)fluorodeoxyglucose (FDG) was performed in 8 patients with PDD, 6 patients with DLB, and 9 patients with PD without dementia vs age-matched controls. Data were analyzed with voxel-based statistical parametric mapping and region of interest-based statistics. RESULTS: We found a reduced FDOPA uptake in the striatum and in limbic and associative prefrontal areas in all patient groups. Patients with PDD and patients with DLB showed a severe MP4A and FDG binding reduction in the neocortex with increasing signal diminution from frontal to occipital regions. Significant differences between PDD and DLB were not found in any of the radioligands used. Patients with PD without dementia had a mild cholinergic deficit and no FDG reductions vs controls. CONCLUSIONS: Patients with dementia with Lewy bodies and Parkinson disease dementia share the same dopaminergic and cholinergic deficit profile in the brain and seem to represent 2 sides of the same coin in a continuum of Lewy body diseases. Cholinergic deficits seem to be crucial for the development of dementia in addition to motor symptoms. The spatial congruence of cholinergic deficits and energy hypometabolism argues for cortical deafferentation due to the degeneration of projection fibers from the basal forebrain.

In vivo amyloid imaging in autopsy-confirmed Parkinson disease with dementia.

OBJECTIVE: To investigate the specificity of in vivo amyloid imaging with [(11)C]-Pittsburgh Compound B (PIB) in Parkinson disease dementia (PDD). METHODS: We performed detailed neuropathologic examination for 3 individuals with PDD who had PIB PET imaging within 15 months of death. RESULTS: We observed elevated cortical uptake of [(11)C]-PIB on in vivo PET imaging in 2 of the 3 cases. At autopsy, all 3 individuals had abundant cortical Lewy bodies (Braak PD stage 6), and were classified as low-probability Alzheimer disease (AD) based on NIA-Reagan criteria. The 2 PIB-positive individuals had abundant diffuse Abeta plaques but only sparse neuritic plaques and intermediate neurofibrillary tangle pathology. The PIB-negative individual had rare diffuse plaques, no neuritic plaques, and low neurofibrillary tangle burden. CONCLUSIONS: [(11)C]-Pittsburgh Compound B (PIB) PET is specific for fibrillar Abeta molecular pathology but not for pathologic diagnosis of comorbid Alzheimer disease in individuals with Parkinson disease dementia. The ability to specifically identify fibrillar Abeta amyloid in the setting of alpha-synucleinopathy makes [(11)C]-PIB PET a valuable tool for prospectively evaluating how the presence of Abeta amyloid influences the clinical course of dementia in patients with Lewy body disorders.

Phase contrast radiography of Lewy bodies in Parkinson disease.

Parkinson's disease (PD), defined as a neurodegenerative disorder, is characterized by the loss of dopaminergic neurons and the presence of Lewy bodies in neurons. Morphological study of Lewy bodies is important to identify the causes and the processes of PD. Here, we investigate a possibility of phase contrast radiography using coherent synchrotron X-rays to explore the microscopic details of Lewy bodies in thick (approximately 3 mm) midbrain tissues. Autopsied midbrain tissues of a PD patient were sliced in 3 mm thickness and then examined using synchrotron X-rays from the 7B2 beamline of the Pohang Light Source. Refraction-enhanced phase contrast radiography and microtomography were adopted to identify dark core and dim edge of Lewy bodies in neurons. The morphology of Lewy bodies was clearly revealed by the phase contrast radiography in very thick (3 mm) midbrain tissues without any staining treatment. Three-dimensional volume rendered microtomography of the autopsied midbrain tissues demonstrates striking evidence that several Lewy bodies are agglomerated by dim edges in a neuron. We suggest that the phase contrast radiography could be a useful tool to morphologically investigate the causes or the processes in PD.

Regional cerebral blood flow difference between dementia with Lewy bodies and AD.

The authors studied 14 patients with dementia with Lewy bodies (DLB), 14 patients with AD, and 14 healthy control subjects with N-isopropyl-p-[123I]iodoamphetamine SPECT. Comparison with the statistical parametric mappings revealed that relative cerebral blood flow was lower in the occipital lobes and higher in the right medial temporal lobe in the DLB group than in the AD group. Decreased occipital perfusion and relatively well preserved medial temporal perfusion are features that distinguish DLB from AD.

[Clinical diagnosis of dementia associated with cortical Lewy bodies]. / Diagnóstico clínico de la demencia asociada a cuerpos de Lewy corticales.

8 cases of dementia associated with cortical Lewy bodies are dealt with, that were diagnosed in 1993 in examinations for dementia, using the Nottingham's clinical criteria. They make up 15.4% of primary degenerative dementias diagnosed in this examination. All developed a predominantly cortical dementia with variable bradiphrenia and a parkinsonian syndrome which was predominantly of the rigid-bradikinetic type. The dementia established itself rapidly -between 1 and 3 weeks- in 3 cases (37.5%). 50% of patients (4 cases) showed marked psychiatric symptoms. In 2 cases stiffness was predominantly axial and another had supranuclear paralysis of vertical gaze. 3 patients had no tremor, and 2 of the 5 remaining patients showed postural tremor. CT and axial MR images of the encephalon were similar to those observed in dementia of the Alzheimer type. The coronal MR carried out on 3 patients revealed less atrophy of the hypocampus than is normally observed in patients with dementia of the Alzheimer type who are at the same stage of development.

[Relation between cerebral white matter damage on CT and MRI and clinical data in DRPLA (pseudo-Huntington form)].

We studied the relation between cerebral white matter damage and clinical data in nine patients with dentatorubropallidoluysian atrophy (DRPLA). All patients showed pseudo-Huntington form. The study produced five results. (1) The four of the nine patients showed diffuse hypodensity of the cerebral white matter on CT. We studied one of this four patients by MRI. The hypodensity area on CT showed marked high signal intensity by T2-weighted image on MRI. (2) The onset age was later in the patients with cerebral white matter damage as compared with the patients without this damage. (3) All patients showed subcortical dementia, which was more remarkable in the patient with white matter damage. This suggests the relation between cerebral white matter damage and progression rate of subcortical dementia in DRPLA. (4) Gait disturbance progressed more rapidly in the patients with cerebral white matter damage. (5) The homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA) concentration in CSF decreased more remarkably in the patients with white matter damage.