Lewy Body Densities Research Articles

Disease progression modelling reveals heterogeneity in trajectories of Lewy-type α-synuclein pathology

Lewy body (LB) diseases, characterized by the aggregation of misfolded α-synuclein proteins, exhibit notable clinical heterogeneity. This may be due to variations in accumulation patterns of LB neuropathology. Here we apply a data-driven disease progression model to regional neuropathological LB density scores from 814 brain donors with Lewy pathology. We describe three inferred trajectories of LB pathology that are characterized by differing clinicopathological presentation and longitudinal antemortem clinical progression. Most donors (81.9%) show earliest pathology in the olfactory bulb, followed by accumulation in either limbic (60.8%) or brainstem (21.1%) regions. The remaining donors (18.1%) initially exhibit abnormalities in brainstem regions. Early limbic pathology is associated with Alzheimer’s disease-associated characteristics while early brainstem pathology is associated with progressive motor impairment and substantial LB pathology outside of the brain. Our data provides evidence for heterogeneity in the temporal spread of LB pathology, possibly explaining some of the clinical disparities observed in Lewy body disease.

Regional differences in synaptic degeneration are linked to alpha-synuclein burden and axonal damage in Parkinson’s disease and dementia with Lewy bodies

Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+ and SV2A+ puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

GWAS OF BRAIN ENDOPHENOTYPES: ASSOCIATION OF AUTOPSY-BASED LEWY BODY COUNTS WITH MOVEMENT DISORDER RISK LOCI

Abstract We performed a genome wide association study (GWAS) of neocortical Lewy body density. Case material were 308 autopsies of Japanese-American men (mean age at death 87.5 years; 11% with mild, and 30% with severe cognitive impairment prior to death). Lewy bodies were assessed by manual count of alpha-synuclein stained neocortical sections from the frontal, temporal, parietal, and occipital lobes. Genetic association was tested by linear models controlling for age at death assuming an additive genotypic effect. Top hits include a locus on chromosome 1q32 previously associated with amyotrophic lateral sclerosis (p=5.8e-8), intronic variants on the dopaminergic neuron axonal guidance gene EPHB1 previously associated with Parkinson’s disease (PD) (p=8.4e-6), and a locus containing two independent intron 1 variants on CSMD1, a known risk factor for autosomal dominant PD (p=1.5e-6). Complement inhibitor protein CSMD1 is a type 1 transmembrane cell adhesion molecule implicated in axonal guidance and the development, maintenance, and pruning of synapses in the adult brain. Intermediate hits include genes encoding cell adhesion molecules and a second complement inhibitor implicated in the regulation of synapses (TRAPPC9). This converging evidence points to cell adhesion proteins and complement mediated synaptic regulation in the etiology of Lewy body lesions.

Neuronal and glial characterization in the rostrocaudal axis of the human anterior olfactory nucleus: Involvement in Parkinson's disease.

Hyposmia is one of the prodromal symptoms of Parkinson’s disease (PD) and a red flag in clinical diagnosis. Neuropathologically, this sign correlates with α-synuclein involvement in the anterior olfactory nucleus (AON). Neurodegeneration, microgliosis, and astrogliosis in AON are poorly studied, and bulbar AON is the focus of these studies with contradictory results. Additionally, male sex is a risk marker for developing PD, but sexual dimorphism of neural and glial populations in the AON has rarely been considered. The aim of this study was to analyze the density of NeuN, Iba-1, GFAP, and Lewy bodies (LBs), as well as the relationship of these cell type markers with pathology along the rostrocaudal axis of the AON (bulbar, retrobulbar, cortical anterior, and posterior divisions). Cavalieri, optical fractionator, and area fraction fractionator stereological approaches were used for the volume, cell populations and LBs densities, area fraction, and percentage of overlap. Iba-1 and α-syn intensities were measured using ImageJ. In non-PD (NPD) cases, the volume was lower in the AON at the extremes of the rostrocaudal axis than in the intermediate divisions. Cortical anterior AON volume decreased in PD compared with NPD cases. NeuN density decreased rostrocaudally in AON portions in NPD and PD cases. This occurred similarly in Iba-1 but only in PD samples. Iba-1 intensity significantly increased in bulbar AON between PD and NPD. No changes were found in astrocytes. Eight percent of NeuN, 0.1% of Iba-1, and 0.1% of GFAP areas overlapped with LBs area along the AON portions. The data indicate that bulbar AON, which is the most rostral portion in this axis, could play a major role in the pathology. This could be related to the larger area occupied by LBs in these divisions.

Retinal degeneration in Parkinson's disease

AbstractVisual dysfunctions that Parkinson disease (PD) patients suffer are some of the first signs of the pathology. The aim of this work is to characterize some of the cellular alterations that occur in PD retinas and could lead to the reported visual impairments and also to determine if the retina can be used as an early biomarker for Parkinson disease. Wholemount retinas from PD and controls were immunostained using antibodies against p‐α‐synuclein, tyrosine hydroxylase and calretinin. Dopaminergic cells morphology, density and number of synaptic contacts with AII amacrine cells was established. Cells in the ganglion cell layer were immunostained and cell density was calculated. Microglia activation and gliosis were analyzed in retina and optic nerves. Posphorylated‐α‐synuclein was found in the retina within ganglion cells, axons, dendrites and in structures resembling Lewy Bodies. P‐α‐synuclein and Lewy bodies density significantly correlated between retina and brain. Dopaminergic cells in PD and synaptic contacts with AII amacrines were diminished, indicating alterations in the dopaminergic circuitries. Optic nerve remodeling and gliosis were found in PD. PD affects different cells and circuitries of the retina in a way that may explain some of the visual alterations reported in patients. Ganglion cell degeneration and optic nerve remodeling events in PD may explain the OCT layers thinning described in PD patients. The significant p‐α‐synuclein correlation suggests that the synucleinopathy occurs in the retina in a way analogous to the brain and thus, the retina could be considered as an early biomarker in Parkinson disease. Support: Michael J. Fox Foundation for Parkinson’s Research; Generalitat Valenciana Prometeo/2016/158, MINECO‐FEDER‐BFU2015‐67139‐R; Instituto Carlos III (RD16/0008/0016); MECD FPU 14/03166.

Regional neuropathology distribution and verbal fluency impairments in Parkinson's disease

BackgroundVerbal fluency deficits are common in patients with Parkinson's disease. The association of these impairments with regional neuropathological changes is unexplored. ObjectivesDetermine if patients with verbal fluency impairments have greater neuropathological burden in frontal, temporal, and limbic regions and if Lewy bodies or neurofibrillary tangles were associated with verbal fluency impairments. MethodsData was derived from the Arizona Study of Aging and Neurodegenerative Disorders. 47 individuals who completed phonemic and semantic verbal fluency tasks and met clinicopathological criteria for Parkinson's disease (with and without comorbid Alzheimer's disease) were included. Impairment on fluency tasks was defined by normative data, and the density of neuropathology in temporal, limbic, and frontal regions was compared between groups. ResultsIndividuals with semantic fluency impairments had greater total pathology (Lewy bodies + neurofibrillary tangles) in limbic structures (W = 320.0, p = .033, rpb = .33), while those who had phonemic fluency impairments had increased total neuropathology in frontal (W = 364.5, p = .011, rpb = .37), temporal (W = 356.5, p = .022, rpb = .34), and limbic regions (W = 357.0, p = .024, rpb = .34). Greater Lewy body density was found in those with verbal fluency impairments, though trends for greater neurofibrillary tangle density were noted as well. ConclusionsImpaired phonemic fluency was associated with higher Lewy body and tangle burden in frontal, temporal, and limbic regions, while impaired semantic fluency was associated with greater limbic pathology. Though neurofibrillary tangles trended higher in several regions in those with impaired verbal fluency, higher Lewy body density in general was associated with verbal fluency deficits. Implications for research and clinical practice are discussed.

Laminar degeneration of frontal and temporal cortex in Parkinson disease dementia.

To investigate cortical laminar degeneration in Parkinson's disease (PD) with dementia (PDD). Changes in density of α-synuclein-immunoreactive Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG) together with surviving neurons, abnormally enlarged neurons (EN), vacuoles, and glial cell nuclei were measured across cortical laminae of frontal and temporal cortex in fifteen cases of PDD using quantitative methods and polynomial curve-fitting. Most frequently, LB and LN were distributed across all laminae, while LG were distributed in upper cortical laminae. Low densities of EN were present in most cases distributed across all cortical laminae. Densities of vacuoles and glia were greatest in upper and lower cortical laminae, respectively. In most gyri, there were no spatial correlations between the densities of LB, LN, and LG. Cortical degeneration of frontal and temporal lobes in PDD affects all cortical laminae. Laminar distributions may result from the spread of α-synuclein pathology from subcortical regions and subsequent spread via the cortico-cortical pathways. This spread may be a major factor in the development of dementia in PD.

Brainstem Aminergic Nuclei and Late-Life Depressive Symptoms

The neurobiologic basis of late-life depressive symptoms is not well understood. To test the hypothesis that neurodegeneration and neuronal density in brainstem aminergic nuclei are related to late-life depressive symptoms. DESIGN, SETTING, PARTICIPANTS, AND EXPOSURE: Longitudinal clinicopathological cohort study at residences of participants in the Chicago, Illinois, metropolitan area. Participants included 124 older persons without dementia in the Rush Memory and Aging Project who had annual evaluations for a mean (SD) of 5.7 (2.8) years, died, and underwent a postmortem neuropathological examination that provided estimates of the densities of Lewy bodies, neurofibrillary tangles, and aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area. The number of depressive symptoms (mean [SD], 1.61 [1.48]; range, 0-6; skewness, 0.94) on the Center for Epidemiological Studies Depression Scale averaged across annual evaluations. Brainstem Lewy bodies were associated with depressive symptoms, and the association was attenuated in those taking antidepressant medication. Brainstem tangles were associated with more depressive symptoms in those without cognitive impairment but with fewer symptoms in those with mild cognitive impairment. Lower density of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was robustly associated with a higher level of depressive symptoms (mean [SE] estimate, -0.014 [0.003]; P < .001; 16.3% increase in adjusted R2). The association was not modified by medication use or cognitive impairment. Neither tyrosine hydroxlyase-immunoreactive neurons in the locus ceruleus nor tryptophan hydroxlyase-immunoreactive neurons in the dorsal raphe nucleus were related to depressive symptoms. The results suggest that the mesolimbic dopamine system, especially the ventral tegmental area, has an important role in late-life depressive symptoms.

A quantitative study of α-synuclein pathology in fifteen cases of dementia associated with Parkinson disease.

The α-synuclein-immunoreactive pathology of dementia associated with Parkinson disease (DPD) comprises Lewy bodies (LB), Lewy neurites (LN), and Lewy grains (LG). The densities of LB, LN, LG together with vacuoles, neurons, abnormally enlarged neurons (EN), and glial cell nuclei were measured in fifteen cases of DPD. Densities of LN and LG were up to 19 and 70 times those of LB, respectively, depending on region. Densities were significantly greater in amygdala, entorhinal cortex (EC), and sectors CA2/CA3 of the hippocampus, whereas middle frontal gyrus, sector CA1, and dentate gyrus were least affected. Low densities of vacuoles and EN were recorded in most regions. There were differences in the numerical density of neurons between regions, but no statistical difference between patients and controls. In the cortex, the density of LB and vacuoles was similar in upper and lower laminae, while the densities of LN and LG were greater in upper cortex. The densities of LB, LN, and LG were positively correlated. Principal components analysis suggested that DPD cases were heterogeneous with pathology primarily affecting either hippocampus or cortex. The data suggest in DPD: (1) ratio of LN and LG to LB varies between regions, (2) low densities of vacuoles and EN are present in most brain regions, (3) degeneration occurs across cortical laminae, upper laminae being particularly affected, (4) LB, LN and LG may represent degeneration of the same neurons, and (5) disease heterogeneity may result from variation in anatomical pathway affected by cell-to-cell transfer of α-synuclein.

Neural reserve, neuronal density in the locus ceruleus, and cognitive decline.

To test the hypothesis that higher neuronal density in brainstem aminergic nuclei contributes to neural reserve. Participants are 165 individuals from the Rush Memory and Aging Project, a longitudinal clinical-pathologic cohort study. They completed a mean of 5.8 years of annual evaluations that included a battery of 19 cognitive tests from which a previously established composite measure of global cognition was derived. Upon death, they had a brain autopsy and uniform neuropathologic examination that provided estimates of the density of aminergic neurons in the locus ceruleus, dorsal raphe nucleus, substantia nigra, and ventral tegmental area plus summary measures of neuronal neurofibrillary tangles and Lewy bodies from these nuclei and medial temporal lobe and neocortex. Neuronal densities in each nucleus were approximately normally distributed. In separate analyses, higher neuronal density in each nucleus except the ventral tegmental area was associated with slower rate of cognitive decline, but when modeled together only locus ceruleus neuronal density was related to cognitive decline (estimate = 0.003, SE = 0.001, p < 0.001). Higher densities of tangles and Lewy bodies in these brainstem nuclei were associated with faster cognitive decline even after controlling for pathologic burden elsewhere in the brain. Locus ceruleus neuronal density, brainstem tangles, and brainstem Lewy bodies had independent associations with rate of cognitive decline. In addition, at higher levels of locus ceruleus neuronal density, the association of Lewy bodies with cognitive decline was diminished. Density of noradrenergic neurons in the locus ceruleus may be a structural component of neural reserve.

Spotlight on the October 11 Issue

This study investigated whether the cumulative exposure of levodopa was a factor in accelerating the disease process in 96 patients with Parkinson disease. No link was established based on measurements of nigral neuronal counts and Lewy body densities, providing support for the safe institution of early levodopa therapy. See p. 1420 From editorialists LeWitt, Dubow, and Singer: “Based on the limits of what is known, clinicians should realize that the notion of levodopa-induced toxicity is at best hypothetical and with considerable counterevidence, including the current study presented by Parkkinen et al.” See p. 1414 From …

Testing an aetiological model of visual hallucinations in Parkinson's disease

The exact pathogenesis of visual hallucinations in Parkinson's disease is not known but an integrated model has been proposed that includes impaired visual input and central visual processing, impaired brainstem regulation of sleep-wake cycle with fluctuating vigilance, intrusion of rapid eye movement dream imagery into wakefulness and emergence of internally generated imagery, cognitive dysfunction and influence of dopaminergic drugs. In a clinical study, we assessed motor and non-motor function, including sleep, mood, autonomic and global, frontal and visuoperceptive cognitive function in patients with and without visual hallucinations. A subgroup of patients underwent detailed ophthalmological assessment. In a separate pathological study, histological specimens were obtained from cases of pathologically proven Parkinson's disease and a retrospective case notes review was made for reporting of persistent formed visual hallucinations. An assessment of Lewy body and Lewy neurite pathology was carried out in five cortical regions as recommended by diagnostic criteria for dementia with Lewy Bodies and in brainstem nuclei. Ninety-four patients (mean age 67.5 ± 9.5 years) participated in the clinical study of whom 32% experienced visual hallucinations. When corrected for multiple comparisons, patients with visual hallucinations had significantly greater disease duration, treatment duration, motor severity and complications, sleep disturbances, in particular excessive daytime somnolence and rapid eye movement sleep behavioural disorder, disorders of mood, autonomic dysfunction and global, frontal and visuoperceptive cognitive dysfunction. Of the 94 patients, 50 (53%) underwent ophthalmological assessment. There were no differences in ocular pathology between the visual hallucination and non-visual hallucination groups. In a logistic regression model the four independent determinants of visual hallucinations were rapid eye movement sleep behavioural disorder (P = 0.026), autonomic function (P = 0.004), frontal cognitive function (P = 0.020) and a test of visuoperceptive function (object decision; P = 0.031). In a separate study, post-mortem analysis was performed in 91 subjects (mean age at death 75.5 ± 8.0 years) and persistent visual hallucinations were documented in 63%. Patients in the visual hallucinations group had similar disease duration but had significantly higher Lewy body densities in the middle frontal (P = 0.002) and middle temporal gyri (P = 0.033) and transentorhinal (P = 0.005) and anterior cingulate (P = 0.020) cortices but not parietal cortex (P = 0.22). Using a comprehensive assessment of the clinical, demographic and ophthalmological correlates of visual hallucinations in Parkinson's disease, the combined data support the hypothesized model of impaired visual processing, sleep-wake dysregulation and brainstem dysfunction, and cognitive, particularly frontal, impairment all independently contributing to the pathogenesis of visual hallucinations in Parkinson's disease. These clinical data are supported by the pathological study, in which higher overall cortical Lewy body counts, and in particular areas implicated in visuoperception and executive function, were associated with visual hallucinations.

Does levodopa accelerate the pathologic process in Parkinson disease brain?

Several in vitro studies have suggested levodopa (L-dopa) to be toxic to dopaminergic neurons and that it can modulate the aggregation process of α-synuclein. We investigated the relationship between cumulative lifetime dose of l-dopa and nigral neuronal count and Lewy body (LB) pathology in Parkinson disease (PD). Density of pigmented neurons was measured unilaterally in a single section of substantia nigra (SN) with delineation of the dorsal and ventral tiers in 96 cases of PD with well-documented clinical records relating to antiparkinsonian drug treatment. Cortical and nigral LB densities were determined using a morphometric approach. Mean lifetime dose of L-dopa correlated significantly (p < 0.001) with duration of PD in the entire study population (n = 96) and it was not possible to disentangle their individual effect. This was not the case in a subgroup analysis of younger onset patients with a longer duration of PD (n = 40) who showed no significant correlation between L-dopa and total SN neuronal density (p = 0.07), after adjustment for duration of illness. There was, however, a lower neuronal density in the ventral (p = 0.02) but not in the dorsal (p = 0.27) tier detected with the cumulative dose of L-dopa. We found no difference in L-dopa dose between Braak PD stages (p = 0.58). Furthermore, the subgroup analysis showed no relationship of L-dopa dose to either cortical (p = 0.47) or nigral (p = 0.48) LB density. Chronic use of L-dopa in PD does not enhance progression of PD pathology as far as can be determined by our observations with SN neuronal counts and LB densities.

The pattern of cortical atrophy in Parkinson’s disease with mild cognitive impairment according to the timing of cognitive dysfunction

The density of Lewy bodies or the concurrent β-amyloid pathology would act as modulators in the relative timing of dementia during the course of Parkinson's disease. Depending on the temporal relationship between the onset of parkinsonism and that of cognitive impairment, patients with Parkinson's disease with mild cognitive impairment were divided into two groups of earlier (<1 year) and later (≥1 year) cognitive decline, and cortical atrophy patterns and correlation of gray matter and timing of cognitive decline were analyzed using voxel-based morphometry. The morphometric analysis showed that patients with earlier cognitive decline demonstrated greater cortical atrophy in the inferior parietal and orbitofrontal areas than did those with later cognitive decline. Additionally, the anatomical bases of the timing of their cognitive decline differed in terms of correlation patterns. These data suggest that the pathological burden in Parkinson's disease with mild cognitive impairment may be more severe in patients with earlier cognitive decline than in those with later cognitive decline, and that the neural basis corresponding to the timing of cognitive decline may differ in these patients.

Glucocerebrosidase mutations do not cause increased Lewy body pathology in Parkinson's disease

Mutations in the glucocerebrosidase (GBA) gene have been implicated in increased formation of Lewy bodies (LBs) in Parkinson's disease (PD). We found GBA mutation status not to be significantly associated with the density of cortical LBs, after adjusting for sex, age at death, duration of PD and presence of dementia. Comparison of GBA carriers to PD controls found no difference in Alzheimer's disease pathological findings. Our results do not support GBA carriers to have a more advanced neuropathologic disease i.e. increased density of protein aggregates.

Lewy- and Alzheimer-type pathologies in Parkinson's disease dementia: which is more important?

The relative importance of Lewy- and Alzheimer-type pathologies to dementia in Parkinson's disease remains unclear. We have examined the combined associations of α-synuclein, tau and amyloid-β accumulation in 56 pathologically confirmed Parkinson's disease cases, 29 of whom had developed dementia. Cortical and subcortical amyloid-β scores were obtained, while tau and α-synuclein pathologies were rated according to the respective Braak stages. Additionally, cortical Lewy body and Lewy neurite scores were determined and Lewy body densities were generated using morphometry. Non-parametric statistics, together with regression models, receiver-operating characteristic curves and survival analyses were applied. Cortical and striatal amyloid-β scores, Braak tau stages, cortical Lewy body, Lewy neurite scores and Lewy body densities, but not Braak α-synuclein stages, were all significantly greater in the Parkinson's disease-dementia group (P<0.05), with all the pathologies showing a significant positive correlation to each other (P<0.05). A combination of pathologies [area under the receiver-operating characteristic curve=0.95 (0.88-1.00); P<0.0001] was a better predictor of dementia than the severity of any single pathology. Additionally, cortical amyloid-β scores (r=-0.62; P=0.043) and Braak tau stages (r=-0.52; P=0.028), but not Lewy body scores (r=-0.25; P=0.41) or Braak α-synuclein stages (r=-0.44; P=0.13), significantly correlated with mini-mental state examination scores in the subset of cases with this information available within the last year of life (n=15). High cortical amyloid-β score (P=0.017) along with an older age at onset (P=0.001) were associated with a shorter time-to-dementia period. A combination of Lewy- and Alzheimer-type pathologies is a robust pathological correlate of dementia in Parkinson's disease, with quantitative and semi-quantitative assessment of Lewy pathology being more informative than Braak α-synuclein stages. Cortical amyloid-β and age at disease onset seem to determine the rate to dementia.

Disentangling the Relationship between Lewy Bodies and Nigral Neuronal Loss in Parkinson's Disease

Progressive rostral spread of Lewy body (LB) pathology is thought to reflect the clinical course of Parkinson's disease (PD) although several studies have suggested that LBs are not the toxic species responsible for cell death. We investigated the relationship between nigral dopaminergic cell loss, distribution and density of α-synuclein-immunoreactive LBs and duration of motor symptoms in 97 patients with PD. Density of pigmented neurons was measured in a single section of one half of the substantia nigra (SN) with delineation of the dorsal and ventral tiers whereas the cortical and nigral LB densities were determined using a morphometric approach. The density of nigral neurons was estimated to decrease by 2% each year after confirmation of the clinical diagnosis of PD but showed marked heterogeneity with some PD patients with longer duration of illness still possessing a significant number of preserved pigmented nigral neurons at the time of death. An average 15% of surviving nigral neurones contained LBs and the age-adjusted proportion of LB-bearing neurons appeared relatively stable throughout the disease duration. No difference was observed in the age at death or duration of disease with respect to Braak PD stages. The nigral neuronal density was unrelated to either the Braak PD stage or to cortical LB densities. We conclude that nigral neuronal loss is slow and shows considerable variation in PD. Our data also provides no support for a primary pathogenic role of LBs as neither their distribution nor density was associated with the severity of nigral cell loss.

Ante mortem amyloid imaging and β-amyloid pathology in a case with dementia with Lewy bodies

The association between ante mortem [11C]-Pittsburgh Compound B (PiB) retention and β-amyloid (Aβ) load, Lewy body (LB) and neurofibrillary tangle (NFT) densities were investigated in a pathologically confirmed case of dementia with Lewy bodies (DLB). A 76 year old man presenting with a clinical diagnosis of DLB had undergone PiB-positron emission tomography (PET), 18F FDG-PET and magnetic resonance imaging (MRI) 18 months before death. The pathologic diagnosis was DLB neocortical-type with low-likelihood of Alzheimer's disease by NIA-Reagan criteria. Sections from regions of interest (ROI) on post-mortem examination were studied. A significant correlation was found between cortical Aβ density and PiB retention in the 17 corresponding ROIs (r = 0.899; p < 0.0001). Bielschowsky silver stain revealed mostly sparse neocortical neuritic plaques, whereas diffuse plaques were frequent. There was no correlation between LB density and PiB retention (r = 0.13; p = 0.66); nor between NFT density and PiB retention (r = −0.36; p = 0.17). The ROI-based analysis of imaging and histopathological data confirms that PiB uptake on PET is a specific marker for Aβ density, but cannot differentiate neuritic from diffuse amyloid plaques in this case with DLB.

Evidence in favor of Braak staging of Parkinson's disease

Recently, Braak and coworkers proposed a pathologic staging scheme for Parkinson disease (PD). In this staging, scheme substantia nigra pathology occurs at midstage disease, while involvement of anterior olfactory nucleus, medulla, and pontine tegmentum occur earlier. In the last stages, Lewy bodies (LBs) involve cortical areas. The general principles of the proposed staging system have been confirmed in several studies of PD, but it does not appear to fit with all LB disorders. We studied the density and distribution of LBs with alpha-synuclein immunohistochemistry in normal elderly with incidental LBs (N = 12); progressive supranuclear palsy (PSP) with incidental LBs (N = 18); Lewy body disease (LBD) with minimal or no Alzheimer type pathology (N = 52); LBD with concomitant Alzheimer disease (AD) (N = 84); and cases of AD with amygdala predominant LBs (N = 64). The proportion of cases that fit the PD staging scheme was 67% for incidental LBs; 86% for PSP with LBs; 86% for pure LBD; and 84% for LBD with AD; but only 6% for AD with amygdala predominant LBs. The PD staging scheme is valid, except in the setting of advanced AD. In this situation, LBs may be unrelated to PD and more likely related to factors inherent to AD and the selective vulnerability of the amygdala to both Alzheimer and alpha-synuclein pathologies.

Brain α-synuclein accumulation in multiple system atrophy, Parkinson's disease and progressive supranuclear palsy: a comparative investigation

Alpha-synuclein is a major component of Lewy bodies and glial cytoplasmic inclusions, pathological hallmarks of idiopathic Parkinson's disease and multiple system atrophy, and it is assumed to be aetiologically involved in these conditions. However, the quantitative status of brain alpha-synuclein in different Parkinsonian disorders is still unresolved and it is uncertain whether alpha-synuclein accumulation is restricted to regions of pathology. We compared membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein, both the full-length 17 kDa and high molecular weight species, by western blotting in autopsied brain of patients with Parkinson's disease (brainstem-predominant Lewy body disease: n = 9), multiple system atrophy (n = 11), progressive supranuclear palsy (n = 16), and of normal controls (n = 13). Brain of a patient with familial Parkinsonism-dementia due to alpha-synuclein locus triplication (as positive control) showed increased membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein levels with abundant high molecular weight immunoreactivity. In multiple system atrophy, a massive increase in 17 kDa membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein was observed in highly pathologically affected regions, including putamen (+1760%, range +625-2900%), substantia nigra [+1000% (+356-1850%)], and white matter of internal capsule [+2210% (+430-6830%)] together with numerous high molecular weight species. Levels of 17 kDa membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein were only modestly increased in less affected areas (cerebellar cortex, +95%; caudate, +30%; with both also showing numerous high molecular weight species) and were generally normal in cerebral cortices. In both Parkinson's disease and progressive supranuclear palsy, membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein levels were normal in putamen and frontal cortex whereas a trend was observed for variably increased 17 kDa membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein concentrations [+184% (-60% to +618%)] with additional high molecular weight species in Parkinson's disease substantia nigra. No obvious correlation was observed between nigral membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein accumulation and Lewy body density in Parkinson's disease. Two progressive supranuclear palsy cases had membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein accumulation in substantia nigra similar to multiple system atrophy. Several Parkinson's disease patients had very modest high molecular weight membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein accumulation in putamen. Levels of 17-kDa membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein were generally positively correlated with those of high molecular weight membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein and there was a trend for a positive correlation between striatal dopamine loss and 17-kDa membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein concentrations in multiple system atrophy. Brain membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein accumulations in Parkinson's disease and multiple system atrophy are regionally specific, suggesting that these sporadic alpha-synucleinopathies, unlike familial Parkinsonism-dementia, are not associated with a simple global over-expression of the protein. Despite a similar extent of dopamine depletion, the magnitude of brain membrane-associated, sodium dodecyl sulfate-soluble alpha-synuclein changes is disease specific, with multiple system atrophy clearly having the most severe accumulation. Literature discrepancies on alpha-synuclein status in 'Parkinson's disease' might be explained by inclusion of cases not having classic brainstem-predominant Lewy body disease and by variable alpha-synuclein accumulation within this diagnostic classification.