Dementia With Lewy Bodies

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 ϳ50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors. NEUROLOGY 2005;65:1863-1872 Clinical diagnostic criteria for DLB. Since the publication of Consensus criteria for clinical and pathologic diagnosis of dementia with Lewy bodies (DLB), 1,2 new information indicates that clinical criteria for probable DLB have acceptable specificity, but suboptimal sensitivity. Reasons identified in-clude difficulties in recognition of the core feature fluctuation 5,6 and a low rate of all core features (fluctuation, visual hallucinations, parkinsonism) in the presence of neocortical, neurofibrillary tangle (NFT) pathology. 7-9 The criteria have therefore been modified (table 1) to incorporate additional items indicative of LB pathology. Distinction is made between clinical features or investigations that are suggestive of DLB, i.e., have been demonstrated to be significantly more frequent than in

As there are no biological markers for the antemortem diagnosis of degenerative parkinsonian disorders, diagnosis currently relies upon the presence and progression of clinical features and confirmation depends on neuropathology. Clinicopathologic studies have shown significant false-positive and false-negative rates for diagnosing these disorders, and misdiagnosis is especially common during the early stages of these diseases. It is important to establish a set of widely accepted diagnostic criteria for these disorders that may be applied and reproduced in a blinded fashion. This review summarizes the findings of the SIC Task Force for the study of diagnostic criteria for parkinsonian disorders in the areas of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy, multiple system atrophy, and corticobasal degeneration. In each of these areas, diagnosis continues to rest on clinical findings and the judicious use of ancillary studies.

Abbreviations: BA = Brodmann area; CAMCOG = Cambridge Cognitive Examination; DLB = dementia with Lewy bodies; FWHM = full width at half maximum; MMSE = Mini-Mental State Examination; MNI = Montreal Neurological Institute; PDD = Parkinson's disease with dementia; ROI = region of interest; SPM = statistical parametric mapping; TIV = total intracranial volume; UPDRS III = Uni®ed Parkinson's Disease Rating Scale III; VaD = vascular dementia; VBM = voxel-based morphometry.

Background Dementia with Lewy bodies (DLB) needs to be distinguished from other types of dementia because of important diff erences in patient management and outcome. Current clinically based diagnostic criteria for DLB have limited accuracy. Severe nigrostriatal dopaminergic degeneration occurs in DLB, but not in Alzheimer's disease or most other dementia subtypes, off ering a potential system for a biological diagnostic marker. The primary aim of this study was to investigate the sensitivity and specifi city, in the ante-mortem diff erentiation of probable DLB from other causes of dementia, of single photon emission computed tomography (SPECT) brain imaging with the ligand ¹²³I-2βcarbometoxy-3β-(4-iodophenyl)-N-(3-fl uoropropyl) nortropane (¹²³I-FP-CIT), which binds to the dopamine transporter (DAT) reuptake site. Diagnostic accuracy, positive and negative predictive values, and inter-reader agreement were the secondary endpoints and a subgroup of possible DLB patients was also included.

Lewy bodies, the pathological hallmark of dementia with Lewy bodies (DLB), are large juxtanuclear inclusions of aggregated ␣-synuclein. However, the small number of cortical Lewy bodies relative to the total neuron count does not correlate with the extent of cognitive impairment. In contrast to dopaminergic neurons in Parkinson's disease, nerve cell loss is usually less prevalent in the cortex of DLB, suggesting a different mechanism of neurodegeneration.

Objectives-Alzheimer's disease and vascular dementia are associated with an increase in changes in white matter on MRI. The aims were to investigate whether white matter changes also occur in dementia with Lewy bodies and to examine the relation between white matter lesions and the cognitive and noncognitive features of dementia with Lewy bodies, Alzheimer's disease, and vascular dementia. Methods-Proton density and T2 weighted images were obtained on a 1.0 Tesla MRI scanner in patients with dementia with Lewy bodies (consensus criteria; n=27, mean age=75.9 years), Alzheimer's disease (NINCDS/ADRDA; n=28, mean age=77.4 years), vascular dementia (NINDS/AIREN; n=25, mean age=76.8 years), and normal controls (n=26, mean age=76.2 years). Cognitive function, depressive symptoms, and psychotic features were assessed using a standardised protocol. Periventricular hyperintensities (PVHs), white matter hyperintensities (WMHs) and basal ganglia hyperintensities (BGHs) were visually rated blind to diagnosis using a semiquantitative scale. Results-Periventricular hyperintensities were positively correlated with age and were more severe in all dementia groups than controls. Total deep hyperintensities scores (WMHs plus BGHs) were significantly higher in all dementia groups than controls and higher in patients with vascular dementia than those with dementia with Lewy bodies or Alzheimer's disease. In all patients with dementia, frontal WMHs were associated with higher depression scores and occipital WMHs were associated with an absence of visual hallucinations and delusions.

Parkinson's disease dementia (PDD) are common forms of dementia that substantially affect quality of life. Currently, the only treatment licensed for PDD is rivastigmine, and there are no licensed treatments for DLB. We aimed to test the safety and efficacy of the N-methyl D-aspartate (NMDA) receptor antagonist memantine in patients with PDD or DLB.

Background: Abnormal hyperphosphorylation of the microtubule-associated protein tau and its incorporation into neurofibrillary tangles are major hallmarks of the pathogenesis of Alzheimer disease (AD). Different tau phosphoepitopes can be sensitively detected in cerebrospinal fluid (CSF).

The present study describes the pathological progression of longitudinally followed cases with levodopa-responsive Parkinson's disease who came to autopsy during the Sydney Multicenter Study of Parkinson's disease. Standardised clinical and neuropathological assessments over Wve epochs of time veriWed three diVerent clinicopathological groups. A group of younger onset patients with a typical long duration clinical course of Parkinson's disease. This group of cases had Lewy body distributions consistent with the Braak staging of disease. In this group, brainstem Lewy bodies dominate in those surviving to 5 years; by 13 years, 50% of cases have a limbic distribution of Lewy bodies; and by 18 years, all will have at least this pathological phenotype. Approximately 25% of cases had an early malignant, dementia-dominant syndrome and severe neocortical disease consistent with dementia with Lewy bodies. The last group had an older onset, shorter survival, and a more complex disease course with higher Lewy body loads and a higher proportion with additional neuropathologies. These cases with higher loads of Lewy bodies and shorter survivals suggest that widespread Lewy body pathology either occurs at the onset of clinical disease or rapidly inWltrates the brain. In these cases with shorter survivals, there was more plaque pathology, supporting a more aggressive and linked phenotype. Our data suggest that the selection of similar study cohorts by pathology alone would not be able to diVerentiate the three diVerent phenotypes identiWed. The data are also not consistent with a unitary concept of the pathogenesis of Lewy body disease.

Mutations in ␣-synuclein (␣S) and parkin cause heritable forms of Parkinson disease (PD). We hypothesized that neuronal parkin, a known E3 ubiquitin ligase, facilitates the formation of Lewy bodies (LBs), a pathological hallmark of PD. Here, we report that affinity-purified parkin antibodies labeled classical LBs in substantia nigra sections from four related human disorders: sporadic PD, inherited ␣S-linked PD, dementia with LBs (DLB), and LB-positive, parkin-linked PD. Anti-parkin antibodies also detected LBs in entorhinal and cingulate cortices from DLB brain and ␣S inclusions in sympathetic gangliocytes from sporadic PD. Double labeling with confocal microscopy of DLB midbrain sections revealed that ϳ90% of anti-␣S-reactive LBs were also detected by a parkin antibody to amino acids 342 to 353. Accordingly, parkin proteins, including the 53-kd mature isoform, were present in affinity-isolated LBs from DLB cortex. Fluorescence resonance energy transfer and immunoelectron microscopy showed that ␣S and parkin co-localized within brainstem and cortical LBs. Biochemically, parkin appeared most enriched in cytosolic and postsynaptic fractions of adult rat brain, but also in purified, ␣S-rich presynaptic elements that additionally contained parkin's E2-binding partner, UbcH7. We conclude that parkin and UbcH7 are present with ␣S in subcellular compartments of normal brain and that parkin frequently co-localizes with ␣S aggregates in the characteristic LB inclusions of PD and DLB. These results suggest that functional parkin proteins may be required during LB formation. Two missense mutations in ␣-synuclein (␣S), A30P and A53T, cause rare autosomal-dominant forms of Parkinson disease (PD), 1,2 and a variety of mutant parkin genotypes are linked to autosomal-recessive parkinsonism with predominantly juvenile or young adult onset. 3,4 Clinically, a subset of parkin-linked cases are virtually indistinguishable from sporadic PD. 4,5 Neuropathologically, sporadic and ␣S-linked PD share neuronal loss and Lewy body (LB) inclusions in selective brainstem nuclei. 6 -8 The etiology of sporadic PD remains largely unknown, but mechanisms involving oxidative stress and mitochondrial dysfunction have been implicated. 9 In the related disorder, dementia with LBs (DLB), both brainstem and cortical neurons are affected by LB formation. 10 -12 ␣S and ubiquitin (Ub) represent the principal known protein constituents of these inclusions. In contrast, LBs are generally absent in parkin-linked PD brains, 16 -20 with one recently reported exception. The 465-amino acid parkin protein contains an N-terminal Ub-like domain linked to a C-terminal RING box 22 that contains two canonical RING-finger domains (C 3 H 1 C 4 ) and an imperfect, third RING finger motif (C 6 H 1 C 1 ), also referred to as "in-between-RING" 23 or "double-RING-finger-linked" domain 24 ( ). As such, parkin is a likely member of a class of zinc-binding proteins that comprises several Ub ligases. 25,26 Indeed, parkin has been shown to act as an E3 Ub ligase in transfected cell cultures and in vitro assays, in which it principally recruits one of two E2 Ub-conjugating proteins at its RING box, UbcH7 22,28 or UbcH8. 29 In general, the transfer of more than four activated Ub molecules from an E2 protein onto a substrate, a process facilitated by an E3 Ub ligase, provides a signal for proteasomal degradation of the substrate. In cell culture systems, parkin fusion proteins have also been shown to interact with the synaptic vesicle protein, CDC-rel1, 29 the ␣S-binding protein, synphilin-1, 31 and actin filaments. 32 Furthermore, parkin has been found to be up-regulated

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disease associated with extrapyramidal features which differ from those of Parkinson's disease, including reduced effectiveness of L-dopa and severe sensitivity reactions to neuroleptic drugs. Distinguishing Alzheimer's disease from DLB is clinically relevant in terms of prognosis and appropriate treatment. Dopaminergic activities have been investigated at coronal levels along the rostrocaudal striatal axis from a post-mortem series of 25 DLB, 14 Parkinson's disease and 17 Alzheimer's disease patients and 20 elderly controls. [ 3 H]Mazindol binding to the dopamine uptake site was significantly reduced in the caudal putamen in DLB compared with controls (57%), but not as extensively as in Parkinson's disease (75%), and was unchanged in Alzheimer's disease. Among three dopamine receptors measured (D1, D2 and D3), the most striking changes were apparent in relation to D2. In DLB, [ 3 H]raclopride binding to D2 receptors was significantly reduced in the caudal putamen (17%) compared with controls, and was significantly lower than in Parkinson's disease at all levels. D2 binding was significantly elevated at all coronal levels in Parkinson's disease compared with controls, most extensively in the rostral putamen (71%). There was no change from the normal pattern of D2 binding in Alzheimer's disease. The only significant Abbreviations: ANOVA ϭ analysis of variance; DLB ϭ dementia with Lewy bodies; HVA ϭ homovanillic acid; 7-OH-DPAT ϭ R(

Objective-To test the hypotheses that visuoperceptual and attentional ability are disproportionately impaired in patients having dementia with Lewy Bodies (DLB) compared with Alzheimer's disease (AD). Methods-A comprehensive battery of neuropsychological tasks designed to assess working, episodic, and semantic memory, and visuoperceptual and attentional functions was given to groups of patients with DLB (n=10) and AD (n=9), matched for age, education, and mini mental state examination (MMSE), and to normal controls (n=17). Results-Both patient groups performed equally poorly on tests of episodic and semantic memory with the exception of immediate and delayed story recall, which was worse in the AD group. Digit span was by contrast spared in AD. The most striking diVerences were on tests of visuoperceptual/spatial ability and attention. Whereas patients with AD performed normally on several subtests of the visual object and space perception battery, the DLB group showed substantial impairments. In keeping with previous studies, the AD group showed deficits in selective attention and set shifting, but patients with DLB were more impaired on virtually every test of attention with deficits in sustained, selective, and divided attention. Conclusions-Patients with DLB have substantially greater impairment of attention, working memory, and visuoperceptual ability than patients with AD matched for overall dementia severity. Semantic memory seems to be equally aVected in DLB and AD, unlike episodic memory, which is worse in AD. These findings may have relevance for our understanding of the genesis of visual hallucinations, and the diVerential diagnosis of AD and DLB. (J Neurol Neurosurg Psychiatry 2001;70:157-164)

The complement system provides an innate defence mechanism against pathogenic microorganisms. Although viewed for many years as an immune-privileged organ, the central nervous system contains many components of the immune system, including components of the complement system that are synthesized by astrocytes, microglia, and neurons. During the past two decades, a wide range of inflammatory markers, typically absent in the normal elderly population, have been reported in Alzheimer's disease brains. It is becoming evident that sustained brain inflammation might be an essential cofactor in Alzheimer disease and other neurodegenerative disorders such as Parkinson disease, dementia with Lewy bodies, Huntington's and prion diseases. The complement system may be useful in eliminating aggregated and toxic proteins associated with these neurological disorders and thus have a protective effect. However, an exaggerated or insufficient activation of the complement system can have deleterious effect through the activation of microglia, secretion of many proinflammatory cytokines, and generation of oxidative products. The role of complement-mediated inflammation in Alzheimer disease has drawn greater attention recently in view of new therapeutic advances made in the management of the disease. This review is meant to update the role of complement in Alzheimer's disease and other neurodegenerative disorders in view of recent vaccination and immunotherapeutic approaches.

Background: Brain iron promotes oxidative damage and protein oligomerization that result in highly prevalent age-related proteinopathies such as Alzheimer's disease (AD), Parkinson's disease (PD), and Dementia with Lewy Bodies (DLB). Men are more likely to develop such diseases at earlier ages than women but brain iron levels increase with age in both genders. We hypothesized that brain iron may influence both the age-and gender-related risks of developing these diseases. Methods: The amount of iron in ferritin molecules (ferritin iron) was measured in vivo with MRI by utilizing the field dependent relaxation rate increase (FDRI) method. Ferritin iron was measured in four subcortical nuclei [caudate (C), putamen (P), globus pallidus (G), thalamus (T)], three white matter regions [frontal lobe (Fwm), genu and splenium of the corpus callosum (Gwm, Swm)] and hippocampus (Hipp) in 165 healthy adults aged 19-82. Results: There was a high correlation (r > 0.99) between published post-mortem brain iron levels and FDRI. There were significant age-related changes in ferritin iron (increases in Hipp, C, P, G, and decreases in Fwm). Women had significantly lower ferritin iron than men in five regions (C, T, Fwm, Gwm, Swm). Conclusions: This is the first demonstration of gender differences in brain ferritin iron levels. It is possible that brain iron accumulation is a risk factor that can be modified. MRI provides the opportunity to assess brain iron levels in vivo and may be useful in targeting individuals or groups for preventive therapeutic interventions.

Background: Lewy body disease is a heterogeneous group of neurodegenerative disorders characterized by a-synuclein accumulation that includes dementia with Lewy bodies (DLB) and Parkinson's Disease (PD). Recent evidence suggests that impairment of lysosomal pathways (i.e. autophagy) involved in a-synuclein clearance might play an important role. For this reason, we sought to examine the expression levels of members of the autophagy pathway in brains of patients with DLB and Alzheimer's Disease (AD) and in a-synuclein transgenic mice.

Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB.

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, 123 Ilabelled 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.

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 [ 123 I]-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.

Abstract : Neuronal nicotinic receptors have been implicated in schizophrenia on the basis of the high incidence of tobacco smoking in patients, abnormalities in cytisine and α-bungarotoxin (αBGT) binding in the hippocampus, and linkage between auditory P50 deficits and the region of chromosome 15 coding the α7 subunit. In another disease associated with psychosis, dementia with Lewy bodies (DLB), in which visual hallucinations predominate, reductions in nicotine binding have been identified in various cortical and subcortical regions. We investigated both αBGT and nicotine binding autoradiographically in different thalamic nuclei in autopsy brain tissue from patients with schizophrenia and DLB. αBGT binding in the reticular nucleus was moderately reduced (25%) in schizophrenia and more extensively reduced (50%) in DLB. There were no significant alterations in nicotine binding in schizophrenia, and in DLB, a trend towards moderate reductions in most nuclei reached significance in the lateral dorsal nucleus. It is concluded that widespread abnormalities of thalamic nicotine are not implicated in schizophrenia or DLB, but that reticular αBGT binding may be involved to a lesser and greater extent in the pathophysiology or psychopathology of both disorders.

Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) on [ 123 I]MIBG myocardial scintigraphy has been reported in Parkinson's disease (PD) and dementia with Lewy bodies (DLB). We hypothesized that cardiac sympathetic denervation might account for the pathomechanism. To elucidate the extent, frequency and pattern of cardiac sympathetic nerve involvement in Lewy body disease and related neurodegenerative disorders, we immunohistochemically examined heart tissues from patients with PD (n=11), DLB (n=7), DLB with Alzheimer's disease (DLB/AD; n=4), multiple system atrophy (MSA; n=8), progressive supranuclear palsy (PSP; n=5), pure AD (n=10) and control subjects (n=5) together with sympathetic ganglia from patients with PD (n=5) and control subjects (n=4), using an antibody against tyrosine hydroxylase (TH). TH-immunoreactive nerve fibers in the hearts had almost entirely disappeared in nearly all the patients with PD, DLB and DLB/AD, whereas they were well preserved in all the patients with PSP and pure AD as well as in all except for one patient with MSA. In PD, neurons in the sympathetic ganglia were preserved in all except for one patient. Decreased cardiac uptake of MIBG in Lewy body disease reflects actual cardiac sympathetic denervation, which precedes the neuronal loss in the sympathetic ganglia.

alpha-Synuclein and ubiquitin are two Lewy body protein components that may play antagonistic roles in the pathogenesis of Lewy bodies. We examined the relationship between alpha-synuclein, ubiquitin, and lipids in Lewy bodies of fixed brain sections or isolated from cortical tissues of dementia with Lewy bodies. Lewy bodies exhibited a range of labeling patterns for alpha-synuclein and ubiquitin, from a homogeneous pattern in which alpha-synuclein and ubiquitin were evenly distributed and overlapped across the inclusion body to a concentric pattern in which alpha-synuclein and ubiquitin were partially segregated, with alpha-synuclein labeling concentrated in the peripheral domain and ubiquitin in the central domain of the Lewy body. Lipids represented a significant component in both homogeneous and concentric Lewy bodies. These results suggest that Lewy bodies are heterogeneous in their subregional composition. The segregation of alpha-synuclein to Lewy body peripheral domain is consistent with the hypothesis that alpha-synuclein is continually deposited onto Lewy bodies.

Intracellular proteinaceous inclusions (Lewy bodies and Lewy neurites) of R-synuclein are pathological hallmarks of neurodegenerative diseases such as Parkinson's disease, dementia with Lewy bodies (DLB), and multiple systemic atrophy. The molecular mechanisms underlying the aggregation of R-synuclein into such filamentous inclusions remain unknown, although many factors have been implicated, including interactions with lipid membranes. To model the effects of membrane fields on R-synuclein, we analyzed the structural and fibrillation properties of this protein in mixtures of water with simple and fluorinated alcohols. All solvents that were studied induced folding of R-synuclein, with the common first stage being formation of a partially folded intermediate with an enhanced propensity to fibrillate. Protein fibrillation was completely inhibited due to formation of -structure-enriched oligomers with high concentrations of methanol, ethanol, and propanol and moderate concentrations of trifluoroethanol (TFE), or because of the appearance of a highly R-helical conformation at high TFE and hexafluoro-2-propanol concentrations. At least to some extent, these conformational effects mimic those observed in the presence of phospholipid vesicles, and can explain some of the observed effects of membranes on R-synuclein fibrillation.

α-Synuclein (αSN) brain pathology is a conspicuous feature of several neurodegenerative diseases. These include prevalent conditions such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and the Lewy body variant of Alzheimer's disease (LBVAD), as well as rarer conditions including multiple systems atrophy (MSA), and neurodegeneration with brain iron accumulation type-1 (NBIA-1). Common in these diseases, some referred to as α-synucleinopathies, are microscopic proteinaceous insoluble inclusions in neurons and glia that are composed largely of fibrillar aggregates of αSN. This molecular form of αSN contrasts sharply with normal αSN, which is an abundant soluble presynaptic protein in brain neurons. αSN is a highly conserved protein in vertebrates and only seven of its 140 amino acids differ between human and mouse. Flies lack an αSN gene. Implicated in neurotoxicity are two αSN mutants (A53T and A30P) that cause extremely rare familial forms of PD, αSN fibrils and protofibrils, soluble protein complexes of αSN with 14-3-3 protein, and phosphorylated, nitrosylated, and ubiquitylated αSN species. Unlike rare forms of fPD caused by mutations in αSN, disease mechanisms in most α-synucleinopathies implicate wildtype αSN and seem to converge around oxidative damage and impairments in protein catabolism. It is not known whether these causalities involve αSN from the beginning, but defects in the handling of this protein seem to contribute to disease progression because accumulation of toxic αSN forms damage neurons. Here, we summarize the main structural features of αSN and its functions, and discuss the molecular αSN species implicated in human disease and transgenic animal models of α-synucleinopathy in fly and rodents. 

This study was designed to assess the effects of rivastigmine (Exelon ® ) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, pa-tients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.

Cerebral glucose metabolism using positron emission tomography (PET) with 18 F-fluorodeoxyglucose was examined in 11 patients with probable Alzheimer's disease (AD), 6 patients with probable, and 1 patient with autopsy-confirmed dementia with Lewy bodies (DLB) as well as in 10 age-matched normal control subjects. Among widespread cortical regions showing glucose hypometabolism in the DLB group, the metabolic reduction was most pronounced in the visual association cortex compared to that in the AD group. Using a metabolic ratio of 0.92 in the visual association cortex as a cutoff (mean-2 SD of normal control subjects), DLB could be distinguished from AD with a sensitivity of 86% and a specificity of 91%. In contrast, apolipoprotein E4 allele frequency and cerebrospinal fluid tau levels did not differ significantly between the two groups. In order to further dissect out neuropathological correlates of the dysfunctional occipital lobe, postmortem brains from 19 patients with AD and 17 with DLB as well as 11 brains from normal controls were examined. A distinct and extensive spongiform change with coexisting gliosis was variably noted throughout cerebral white matter with relative sparing of gray matter in DLB. Notably, the white matter spongiform change and gliosis was most prominently and consistently found in the occipital region of DLB, and the severity of the spongiform change in each brain region generally paralleled to the regional difference in reduced glucose metabolism between the living AD and DLB patients. These findings suggest that (1) among several potential antemortem biomarkers in the diagnosis of DLB, measures of the glucose metabolism in the occipital cortex may be an informative diagnostic aid to distinguish DLB from AD; and (2) a pathological process that generates wide-spread spongiform change and gliosis in long projection fibers may contribute, at least in part, to the characteristic imaging features of DLB.

Parkinson's disease (PD) is one of the most common neurodegenerative disorders, affecting about 1% of the population over the age of 60. In addition to motor abnormalities, there are several non-motor signs and symptoms that may create a considerable burden for patients and caregivers. Dementia is common and affects approximately 40% of PD patients during the course of the disease, the risk for the development of dementia being 6 times higher than in non-PD age-matched controls. In most cases, PD patients with dementia (PDD) display a dysexecutive syndrome and visuospatial deficits, while memory is relatively unaffected. The overlap between PDD and dementia with Lewy bodies suggests that they likely share similar underlying neuropathological processes.

As the differential diagnosis of dementias based on established clinical criteria is often difficult, biomarkers for applicable diagnostic testing are currently under intensive investigation. Amyloid plaques deposited in the brain of patients suffering from Alzheimer's disease, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) mainly consist of carboxy-terminally elongated forms of amyloid-beta (Ab) peptides, such as Ab1-42. Absolute Ab1-42 levels in CSF have shown diagnostic value for the diagnosis of Alzheimer's disease, but the discrimination among Alzheimer's disease, DLB and PDD was poor. A recently established quantitative urea-based Ab-sodium-dodecylsulphate-polyacrylamide-gel-electrophoresis with Western immunoblot

Background: Attentional deficits are described in the consensus clinical criteria for the operationalized diagnosis of dementia with Lewy bodies (DLB) as characteristic of the condition. In addition, preliminary studies have indicated that both attentional impairments and fluctuation of attentional impairments are more marked in patients with DLB than in patients with Alzheimer disease (AD), although neuropsychological function has not previously been examined in a large prospective cohort with confirmed diagnostic accuracy against postmortem diagnosis.

Objective-Although both orthostatic hypotension and urinary incontinence have been reported in a number of parkinsonian syndromes, such as Parkinson's disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP), diVerences in the evolution of these features have not been studied systematically in pathologically confirmed cases. Methods-77 cases with pathologically confirmed parkinsonian syndromes (PD, n=11; MSA, n=15; DLB, n=14; CBD, n=13; PSP, n=24), collected up to 1994, formed the basis for a multicentre clinicopathological study organised by the NINDS to improve the diVerential diagnosis of parkinsonian disorders. The present study determined the time course-that is, latency to onset and duration from onset to death, of symptomatic orthostatic hypotension, and urinary incontinence in the NINDS series. Furthermore, the diagnostic validity of a predefined latency to onset within 1 year of disease onset of symptomatic orthostatic hypotension or urinary incontinence was analysed. Results-Significant group diVerences for latency, but not duration, of symptomatic orthostatic hypotension and urinary incontinence were found. Latencies to onset of either feature were short in patients with MSA, intermediate in patients with DLB, CBD, and PSP, and long in those with PD. Symptomatic orthostatic hypotension occurring within the first year after disease onset predicted MSA in 75% of cases; early urinary incontinence was less predictive for MSA (56%). Conclusion-Latency to onset, but not duration, of symptomatic orthostatic hypotension or urinary incontinence diVerentiates PD from other parkinsonian syndromes, particularly MSA.

We investigated the relative differences in dopaminergic function through the whole brain in patients with Parkinson's disease without dementia (PD) and with dementia (PDD) using 6-[ 18 F]¯uoro-L-dopa ( 18 F-dopa) PET and a voxel-by-voxel analysis. The 10 PD and 10 PDD patients were equivalently disabled, having mean scores of 3.2 T 0.6 and 3.2 T 0.7, respectively, on the Hoehn and Yahr rating scale. 18 F-dopa in¯ux constant (Ki) images of those patients and 15 normal age-matched subjects were transformed into standard stereotactic space. The signi®cant differences between the groups (expressed in mean regional Ki values) were localized with statistical parametric mapping (SPM) on a voxelby-voxel basis. Compared with the normal group, SPM localized declines of the 18 F-dopa Ki bilaterally in the putamen, the right caudate nucleus and the left ventral midbrain for the PD group (P < 0.01, corrected). Compared with the normal group, the PDD group showed reduced 18 F-dopa Ki bilaterally in the striatum, midbrain and anterior cingulate area (P < 0.01, corrected). A relative difference in 18 F-dopa uptake between PD and PDD was the bilateral decline in the anterior cingulate area and ventral striatum and in the right caudate nucleus in the PDD group (P < 0.001, corrected). Accordingly, we conclude that dementia in PD is associated with impaired mesolimbic and caudate dopaminergic function.

Involvement of the olfactory bulb by Lewy-type α-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical α-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included α-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the unified Parkinson's Disease Rating Scale (Spearman R −0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Protein misfolding and inclusion formation are common events in neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) or Huntington's disease (HD). a-Synuclein (aSyn) is the main protein component of inclusions called Lewy bodies (LB) which are pathognomic of PD, Dementia with Lewy bodies (DLB), and other diseases collectively known as LB diseases. Heat shock proteins (HSPs) are one class of the cellular quality control system that mediate protein folding, remodeling, and even disaggregation. Here, we investigated the role of the small heat shock proteins Hsp27 and aB-crystallin, in LB diseases. We demonstrate, via quantitative PCR, that Hsp27 messenger RNA levels are $2-3-fold higher in DLB cases compared to control. We also show a corresponding increase in Hsp27 protein levels. Furthermore, we found that Hsp27 reduces aSyn-induced toxicity by $80% in a culture model while aB-crystallin reduces toxicity by $20%. In addition, intracellular inclusions were immunopositive for endogenous Hsp27, and overexpression of this protein reduced aSyn aggregation in a cell culture model.

The relation between disturbances of cholinergic neurotransmission and delusions (DELs) has not been investigated in degenerative dementias such as dementia with Lewy bodies (DLB). A cohort of dementia patients were assessed with standardized clinical evaluations (including the Columbia University Scale for Psychopathology in Alzheimer's Disease), which were repeated annually until death. DLB was confirmed neuropathologically in 21 patients. Neurochemical evaluation included M1 receptor autoradiography (pirenzepine binding), biochemical measurement of choline acetyltransferase (ChAT), and acetylcholinesterase (AChE) histochemistry in brain regions hypothesized to be involved in the genesis of psychosis. Compared with 11 age-matched controls, ChAT and pirenzepine levels were most extensively reduced in the temporal and parietal neocortex of DLB patients. In Brodmann area 36, DELs were significantly associated with elevated pirenzepine binding (131.0 vs 93.5, t ‫؍‬ 2.7), whereas visual hallucinations were associated with significant reductions in ChAT (1.7 vs 2.5, t ‫؍‬ 2.5). There were no significant associations with other areas or with cholinesterase. Although DELs and visual hallucinations were both linked with disturbances in cholinergic neurotransmission, the nature of the associations was different. Upregulation of the postsynaptic muscarinic receptor may be central in the genesis of DELs, with important treatment implications.

Dementia with Lewy bodies (DLB) is the second most common cause of neurodegenerative dementia in older people that has only been recognized in the past decade and that remains widely underdiagnosed. At postmortem examination, affected patients show numerous ␣-synuclein-positive Lewy bodies (LB) in many parts of the cerebral cortex, particularly neocortical and limbic areas in addition to the nigral LB degeneration characteristic of Parkinson's disease (PD). Clinical presentation, unlike PD, is with progressive cognitive decline with particular deficits of visuospatial ability as well as frontal executive function accompanied by usually only mildly to moderately severe parkinsonism, which is often akineto-rigid without the classical parkinsonian rest-tremor. Further accompanying features include spontaneous recurrent visual hallucinations and conspicuous fluctuations in alertness and cognitive performance. The two main differential diagnoses are Alzheimer's disease (AD) and Parkinson's disease dementia (PDD).