Dementia With Lewy Bodies Pathology Research Articles

α-Synuclein aggregates in labial salivary glands of idiopathic rapid eye movement sleep behavior disorder.

To assess whether biopsy of the labial minor salivary glands safely detects phosphorylated α-synuclein (pAS) deposits in idiopathic rapid eye movement sleep behavior disorder (IRBD), a condition that precedes the cardinal manifestations of synuclein disorders associated with Lewy-type pathology, namely, Parkinson's disease (PD) and dementia with Lewy bodies (DLB). In a prospective study, labial biopsy of the minor salivary glands was performed in 62 patients with IRBD, 13 patients with PD, and 10 patients with DLB who were initially diagnosed with IRBD, and in 33 controls. Aggregates of pAS were assessed by immunohistochemistry using antiserine 129-pAS antibody and the conformation-specific 5G4 antibody. Sufficient biopsy material containing glandular parenchyma was obtained in all participants. Deposits of pAS were found in 31 of 62 (50%) participants with IRBD, 7 of 13 (54%) with PD, 5 of 10 (50%) with DLB, and in one of the 33 (3%) controls. Participants with IRBD, PD, and DLB with and without pAS immunoreactivity did not differ in demographic and clinical features. Adverse events were lip bruising (9.2%), swelling (6.6%), pain (2.4%), and numbness (1.7%) which were mild and transitory and did not require treatment. Labial minor salivary glands biopsy proved to be a safe and useful procedure to identify pAS in participants with IRBD, and in participants with PD and DLB initially diagnosed with IRBD. The biopsy provides direct histopathological evidence that IRBD represents a synucleinopathy and that could be useful for histological confirmation of synuclein pathology in PD and DLB.

Differential α-synuclein expression contributes to selective vulnerability of hippocampal neuron subpopulations to fibril-induced toxicity.

The accumulation of misfolded α-synuclein (aSyn) and neuron loss define several neurodegenerative disorders including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). However, the precise relationship between pathology and neurotoxicity and why these processes disproportionately affect certain neuron subpopulations are poorly understood. We show here that Math2-expressing neurons in the hippocampal Cornu ammonis (CA), a region significantly affected by aSyn pathology in advanced PD and DLB, are highly susceptible to pathological seeding with pre-formed fibrils (PFFs), in contrast to dentate gyrus neurons, which are relatively spared. Math2+ neurons also exhibited more rapid and severe cell loss in both in vitro and in vivo models of synucleinopathy. Toxicity resulting from PFF exposure was dependent on endogenous aSyn and could be attenuated by N-acetyl-cysteine through a glutathione-dependent process. Moreover, aSyn expression levels strongly correlate with relative vulnerability among hippocampal neuron subtypes of which Math2+ neurons contained the highest amount. Consistent with this, antisense oligonucleotide (ASO)-mediated knockdown of aSyn reduced the neuronal pathology in a time-dependent manner. However, significant neuroprotection was observed only with early ASO intervention and a substantial reduction of aSyn pathology, indicating toxicity occurs after a critical threshold of pathological burden is exceeded in vulnerable neurons. Together, our findings reveal considerable heterogeneity in endogenous aSyn levels among hippocampal neurons and suggest that this may contribute to the selective vulnerability observed in the context of synucleinopathies.

Reader response: Odor identification as a biomarker of preclinical AD in older adults at risk.

Lafaille-Magnan et al.1 reported that the association between odor identification deficits and cognition in older adults at increased risk of Alzheimer disease (AD) was driven by the presence of AD-related CSF biomarkers rather than the effects of age or other confounders. In addition, the findings were best explained by CSF tau rather than β-amyloid levels. These findings agree with postmortem observations that neurofibrillary tangles in the mesiotemporal lobe robustly predict olfactory deficits in the elderly.2 Dementia with Lewy bodies (DLB) is the second most common type of dementia; odor identification deficits in this hypodopaminergic disorder tend be more severe than in AD.3 However, tau pathology in DLB is substantially less severe compared to AD, including the mesiotemporal lobe.4

White matter hyperintensities on MRI in dementia with Lewy bodies, Parkinson's disease with dementia, and Alzheimer's disease

BackgroundIn dementia with Lewy bodies (DLB) and Parkinson's disease with dementia (PDD), it is still debated whether white matter hyperintensities (WMH) on MRI reflect atherosclerotic cerebrovascular changes or Alzheimer's disease (AD)-related pathology such as cerebral amyloid angiopathy. To examine AD-related pathology in DLB and PDD, we compared the severity of WMH and medial temporal lobe atrophy among patients with DLB, PDD, non-demented PD (PDND), and AD. MethodsWe retrospectively studied sex- and age-matched outpatients with AD, DLB, PDD, and PDND, as well as subjects without central nervous system disorders as normal controls (n=50 each). All subjects underwent 1.5-T MRI examinations, and WMH detected by T2-weighted images or fluid-attenuated inversion recovery images were semiquantified according to the Fazekas method. Medial temporal lobe atrophy (MTA) was visually assessed by the MTA score. ResultsWMH were more prominent in AD, DLB, and PDD patients than in PDND patients and normal controls (NCs). DLB as well as AD showed more severe WMH than PDD. Visual assessment of medial temporal lobe atrophy showed that AD patients had the most severe atrophy, followed by DLB, PDD, and PDND patients, and NC subjects in that order. MTA scores showed significant correlations with WMH severity. ConclusionOur results indicated that DLB was more similar to AD than to PDD in terms of MRI findings, suggesting that WMH in DLB may reflect mainly AD-related pathology rather than atherosclerotic cerebrovascular changes.

Dementia with Lewy bodies and Parkinson's disease-dementia: current concepts and controversies.

Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD), although sharing many clinical, neurochemical and morphological features, according to DSM-5, are two entities of major neurocognitive disorders with Lewy bodies of unknown etiology. Despite considerable clinical overlap, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia often preceding parkinsonism in DLB and onset of cognitive impairment after onset of motor symptoms in PDD. Both are characterized morphologically by widespread cortical and subcortical α-synuclein/Lewy body plus β-amyloid and tau pathologies. Based on recent publications, including the fourth consensus report of the DLB Consortium, a critical overview is given. The clinical features of DLB and PDD include cognitive impairment, parkinsonism, visual hallucinations, and fluctuating attention. Intravitam PET and post-mortem studies revealed more pronounced cortical atrophy, elevated cortical and limbic Lewy pathologies (with APOE ε4), apart from higher prevalence of Alzheimer pathology in DLB than PDD. These changes may account for earlier onset and greater severity of cognitive defects in DLB, while multitracer PET studies showed no differences in cholinergic and dopaminergic deficits. DLB and PDD sharing genetic, neurochemical, and morphologic factors are likely to represent two subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases), beginning with incidental Lewy body disease-PD-nondemented-PDD-DLB (no parkinsonism)-DLB with Alzheimer's disease (DLB-AD) at the most severe end, although DLB does not begin with PD/PDD and does not always progress to DLB-AD, while others consider them as the same disease. Both DLB and PDD show heterogeneous pathology and neurochemistry, suggesting that they share important common underlying molecular pathogenesis with AD and other proteinopathies. Cognitive impairment is not only induced by α-synuclein-caused neurodegeneration but by multiple regional pathological scores. Recent animal models and human post-mortem studies have provided important insights into the pathophysiology of DLB/PDD showing some differences, e.g., different spreading patterns of α-synuclein pathology, but the basic pathogenic mechanisms leading to the heterogeneity between both disorders deserve further elucidation. In view of the controversies about the nosology and pathogenesis of both syndromes, there remains a pressing need to differentiate them more clearly and to understand the processes leading these synucleinopathies to cause one disorder or the other. Clinical management of both disorders includes cholinesterase inhibitors, other pharmacologic and nonpharmacologic strategies, but these have only a mild symptomatic effect. Currently, no disease-modifying therapies are available.

Hippocampal α-Synuclein in Dementia with Lewy Bodies Contributes to Memory Impairment and Is Consistent with Spread of Pathology.

Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.SIGNIFICANCE STATEMENT This study provides a detailed neuropathologic analysis of hippocampal Lewy pathology in human patients with autopsy-confirmed dementia with Lewy bodies. The approach-informed by regional molecular markers, concurrent Alzheimer's pathology analysis, and relevant clinical data-helps tease out the relative contribution of Lewy pathology to memory dysfunction in the disease. Levels of Lewy pathology were found to be highest in the hippocampal CA2 subregion and entorhinal cortex, implicating a potentially overlooked circuit in disease pathogenesis. However, correlation with memory performance was strongest with CA1. This unexpected finding suggests that Lewy pathology must reach a critical burden across hippocampal circuitry to contribute to memory dysfunction beyond that related to other factors, notably coexisting Alzheimer's disease tau pathology.

Gene expression profiling of brain samples from patients with Lewy body dementia

Dementia with Lewy Bodies (DLB) is the second most common neurodegenerative disorder in the elderly. The development and progression of DLB remain unclear. In this study we used next generation sequencing to assess RNA expression profiles and cellular processes associated with DLB in the anterior cingulate cortex, a brain region affected by DLB pathology. The expression measurements were made in autopsy brain tissues from 8 DLB subjects and 10 age-matched controls using AmpliSeq technology with ion torrent sequencing. The analysis of RNA expression profiles revealed 490 differentially expressed genes, among which 367 genes were down-regulated and 123 were up-regulated. Functional enrichment analysis of genes differentially expressed in DLB indicated downregulation of genes associated with myelination, neurogenesis, and regulation of nervous system development. miRNA binding sites enriched in these mRNAs yielded a list of candidate miRNAs participating in DLB pathophysiology. Our study provides a comprehensive picture of gene expression landscape in DLB, identifying key cellular processes associated with DLB pathology.

Imaging in Dementia With Lewy Bodies: An Overview.

Dementia with Lewy bodies (DLB) while common in older age can present a diagnostic challenge to clinicians and is often misdiagnosed as Alzheimer disease (AD). Imaging studies have improved our understanding of the neurobiological changes in DLB during life and how they differ from AD. This has led to significant advances in the development of new techniques, such as dopaminergic imaging, which can aid the clinical diagnosis. Other functional imaging methods also show promise in helping to assess the influence of differing pathologies in DLB, most notably, AD-related and vascular pathology during life. This article will provide an overview of the main imaging findings in DLB.

Phenotypic differences based on staging of Alzheimer's neuropathology in autopsy-confirmed dementia with Lewy bodies

IntroductionThe goal was to compare subgroups of dementia with Lewy Bodies (DLB) using neuropathological measures to differentiate ‘pure’ Lewy body (LB) dementia from ‘mixed’ DLB [co-occurring LB and Alzheimer's disease (AD) pathology] to facilitate diagnostic decision-making and future development of interventions based on predicted type(s) of neuropathology. Studies comparing these groups are rare relative to those differentiating ‘pure’ AD and all-cause DLB, and are limited by insufficient sample size, brief cognitive batteries, and/or absence of autopsy confirmation. To address these limitations, we assessed cognition and other features in a large, autopsy-confirmed DLB sample using an extensive neuropsychological battery. MethodsSubjects from an AD research center autopsy series satisfying DLB pathology criteria were divided by an AD neuropathology index into DLB-LB (Braak stage 0–3) (n = 38) and DLB-AD (Braak stage 4–6) (n = 41) and compared on baseline variables from chart reviews and standardized measures. ResultsDLB-LB subjects were more impaired on visuospatial constructions, visual conceptual reasoning, and speed of processing, but less impaired on verbal memory and confrontation naming. All-type hallucinations occurred more frequently in DLB-LB, while delusions were common in both groups. Groups were similar in education and age at onset, and in baseline age, dementia severity, and functional capacity. ConclusionSalient findings included greater impairment on visual tasks and speed of processing and more frequent reports of all-type hallucinations in DLB-LB compared to DLB-AD. Relatively intact confrontation naming in DLB-LB and no differences in reported delusions were of note. Identifying differences in phenotypic features can improve prediction of underlying neuropathology.

Associations between TOMM40 Poly-T Repeat Variants and Dementia in Cases with Parkinsonism.

Mitochondrial dysfunction has been implicated in the pathophysiology of Parkinson's disease (PD)-related pathologies. To investigate the role of the Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) variants in PD without dementia (PDND), PD with dementia (PDD) and in Dementia with Lewy bodies (DLB). 248 individuals, including 92 PDND, 55 PDD, and 101 DLB, were included. The rs10524523 locus in the TOMM40 gene (TOMM40 poly-T repeat) is characterized by a variable number of T residues that were classified into three groups based on length; short (S), long (L), and very long (VL). We tested log-additive genetic model of association with dementia and adjusted for age, sex, and APOEɛ4 carrier status. We analyzed cerebrospinal fluid (CSF) levels of Aβ42 and Tau, biomarkers related to Alzheimer's disease (AD). PDD/DBL status and abnormal CSF AD biomarkers (Aβ42 and Aβ42/Tau ratio) were both associated with the APOEɛ4 allele (p < 0.014) and the L allele of TOMM40 poly-T repeat (p < 0.008). The VL allele was less frequently observed in the PDD/DLB group (p = 0.013). In APOE-ɛ4 adjusted analyses, the relationships between the L and VL alleles and dementia status as well as CSF AD biomarkers were not significant. When adjusting for APOE-ɛ4, however, there were associations between S carrier status and PDD/DLB (p = 0.019) and abnormal CSF levels of Aβ42/Tau ratio (p = 0.037) although these were not significant after adjustment for multiple comparisons. Our results do not support the notion that TOMM40 poly-T repeat variants have independent effects on PDD and DLB pathology. This relationship seems to be driven by APOE-ɛ4.

Plasma sphingolipid changes with autopsy-confirmed Lewy body or Alzheimer's pathology

IntroductionThe clinical and pathological phenotypes of Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) often overlap. We examined whether plasma lipids differed among individuals with autopsy-confirmed Lewy Body pathology or AD pathology. MethodsWe identified four groups with available plasma 2 years before death: high (n = 12) and intermediate-likelihood DLB (n = 14) based on the third report of the DLB consortium; dementia with Alzheimer's pathology (AD; n = 18); and cognitively normal with normal aging pathology (n = 21). Lipids were measured using ESI/MS/MS. ResultsThere were overall group differences in plasma ceramides C16:0, C18:1, C20:0, and C24:1 and monohexosylceramides C18:1 and C24:1. These lipids did not differ between the high-likelihood DLB and AD groups, but both groups had higher levels than normals. Plasma fatty acid levels did not differ by group. DiscussionPlasma ceramides and monohexosylceramides are elevated in people with dementia with either high-likelihood DLB or AD pathology.

Microglia in dementia with Lewy bodies

Microglial activation (neuroinflammation) is often cited as a pathogenic factor in the development of neurodegenerative diseases. However, there are significant caveats associated with the idea that inflammation directly causes either α-synuclein pathology or neurofibrillary degeneration (NFD). We have performed immunohistochemical studies on microglial cells in five cases of dementia with Lewy bodies (DLB), median age 87, and nine cases of non-demented (ND) controls, median age 74, using tissue samples from the temporal lobe and the superior frontal gyrus. Three different antibodies known to label microglia and macrophages were employed: iba1, anti-CD68, and anti-ferritin. All DLB cases showed both α-synuclein pathology (Lewy bodies and neurites) and NFD ranging from Braak stage II to IV. In contrast, all controls were devoid of α-synuclein pathology but did show NFD ranging from Braak stage I to III. Using iba1 labeling, our current results show a notable absence of activated microglia in all cases with the exception of two controls that showed small focal areas of microglial activation and macrophage formation. Both iba1 and ferritin antibodies revealed a mixture of ramified and dystrophic microglial cells throughout the regions examined, and there were no measurable differences in the prevalence of dystrophic microglial cells between DLB and controls. Double-labeling for α-synuclein and iba1-positive microglia showed that cortical Lewy bodies were surrounded by both ramified and dystrophic microglial cells. We found an increase in CD68 expression in DLB cases relative to controls. Since microglial dystrophy has been linked to NFD and since it did not appear to be worse in DLB cases over controls, our findings support the idea that the additional Lewy body pathology in DLB is not the result of intensified microglial dystrophy. CD68 is likely associated with lipofuscin deposits in microglial cells which may be increased in DLB cases because of impaired proteostasis. Overall, we conclude that neurodegenerative changes in DLB are unlikely to result directly from activated microglia but rather from dysfunctional ones.

Serum peptides as candidate biomarkers for dementia with Lewy bodies.

For diagnosis of dementia with Lewy bodies (DLB), we tried to find blood biomarkers for the disease. Serum peptides were comprehensively detected by mass spectrometry. Peptides of interest were identified by tandem mass spectrometry. One hundred forty-six peptides were detected in a training set consisting of 30 DLB patients, 30 patients with Alzheimer's disease (AD), and 28 healthy control (HC) subjects. Multivariate analysis for discriminating the DLB group from the non-DLB (AD and HC) group using ion intensity of four peptides (2898, 4052, 4090, and 5002 m/z) showed sensitivity of 93.3% and specificity of 87.9% (DLB/nonDLB-4P model). In a testing set consisting of 20 DLB patients, 30 AD patients, and 14 HC subjects, this model showed sensitivity of 90.0% and specificity of 88.6%. DLB/nonDLB-4P model detected 86.7% and 90.0% of the AD patients as non-DLB in the training and testing sets, respectively, and discriminated all the 15 patients with amnestic mild cognitive impairment as non-DLB. Notably, a combination of two peptides (1737 and 5002 m/z) showed sensitivity of 95.0% and specificity of 93.3% for discriminating the DLB group from the AD group (DLB/nonDLB-2P model) in the testing set. The peptides used in these models included fragments from complement 4b, Wnt-2b, and lipopolysaccharide-binding protein, which were reported to be involved in the pathology of DLB or Parkinson's disease and hippocampal neurogenesis. Serum peptide profiles would provide useful DLB biomarker candidates, which may be implicated in the pathophysiology of the disease.

Cortical Metabolic and Nigrostriatal Abnormalities Associated With Clinical Stage-Specific Dementia With Lewy Bodies

The aims of this study were to investigate the hypometabolic regions of FDG PET compared with the nigrostriatal dopamine pathway abnormalities in TRODAT-1 scan in patients with dementia with Lewy bodies (DLBs) at mild and dementia stages as well as to validate the correlation among networks being constructed with clinical data. A total of 25 DLB patients were classified into 2 functional groups stratified by the Clinical Dementia Rating (CDR) Scale (CDR 0.5: n = 14, mild stage; CDR 1 or 2: n = 11, dementia stage) compared with 9 age-matched controls. Neuroimaging survey was applied using information derived from FDG PET by performing voxel-based analysis and a semiquantitative Tc-TRODAT-1 scan to correlate these results with the cognitive and Unified Parkinson's Disease Rating Scale. Compared with normal database, the patients with mild stage showed hypometabolism in the temporal regions, anterior cingulate cortex, inferior orbital region, thalamus, and caudate nucleus. Although at the dementia stage, more extensive cortical hypometabolism involving occipital region were found. The dopamine transporter levels derived from TRODAT-1 scan had excellent discrimination in diagnosing DLB compared with age-matched normal controls (1.58 [0.2] and 1.84 [0.1], P < 0.01) but without significant differences between mild and dementia stages. The sophisticated cortical-brainstem networks by FDG PET and TRODAT-1 yielded good clinical correlation. The networks yielded from FDG PET and TRODAT-1 revealed good correlation with clinical data and that nigrostriatal pathway abnormalities are preceded by typical occipital hypometabolism in mild stage of DLB. Dopamine transporter levels may serve as early diagnostic tool and FDG PET as staging indicator for DLB pathology.

Dementia with Lewy bodies: basis of cingulate island sign.

To investigate clinical, imaging, and pathologic associations of the cingulate island sign (CIS) in dementia with Lewy bodies (DLB). We retrospectively identified and compared patients with a clinical diagnosis of DLB (n=39); patients with Alzheimer disease (AD) matched by age, sex, and education (n=39); and cognitively normal controls (n=78) who underwent 18F-fluorodeoxyglucose (FDG) and C11 Pittsburgh compound B (PiB)-PET scans. Among these patients, we studied those who came to autopsy and underwent Braak neurofibrillary tangle (NFT) staging (n=10). Patients with a clinical diagnosis of DLB had a higher ratio of posterior cingulate to precuneus plus cuneus metabolism, cingulate island sign (CIS), on FDG-PET than patients with AD (p<0.001), a finding independent of β-amyloid load on PiB-PET (p=0.56). Patients with CIS positivity on visual assessment of FDG-PET fit into the group of high- or intermediate-probability DLB pathology and received clinical diagnosis of DLB, not AD. Higher CIS ratio correlated with lower Braak NFT stage (r=-0.96; p<0.001). Our study found that CIS on FDG-PET is not associated with fibrillar β-amyloid deposition but indicates lower Braak NFT stage in patients with DLB. Identifying biomarkers that measure relative contributions of underlying pathologies to dementia is critical as neurotherapeutics move toward targeted treatments.

Pattern of brain atrophy rates in autopsy-confirmed dementia with Lewy bodies

Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared with Alzheimer's disease dementia (AD) on magnetic resonance imaging. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from 2 serial MRIs in autopsy-confirmed DLB patients (n = 20) and mixed DLB/AD patients (n = 22), compared with AD (n = 30) and elderly nondemented control subjects (n = 15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to control subjects. The mixed DLB/AD patients displayed greater atrophy rates in the whole brain, temporoparietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline, and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and these rates can be used as biomarkers of AD progression in patients with LB pathology.

Clinical and multimodal biomarker correlates of ADNI neuropathological findings

BackgroundAutopsy series commonly report a high percentage of coincident pathologies in demented patients, including patients with a clinical diagnosis of dementia of the Alzheimer type (DAT). However many clinical and biomarker studies report cases with a single neurodegenerative disease. We examined multimodal biomarker correlates of the consecutive series of the first 22 Alzheimer’s Disease Neuroimaging Initiative autopsies. Clinical data, neuropsychological measures, cerebrospinal fluid Aβ, total and phosphorylated tau and α-synuclein and MRI and FDG-PET scans.ResultsClinical diagnosis was either probable DAT or Alzheimer’s disease (AD)-type mild cognitive impairment (MCI) at last evaluation prior to death. All patients had a pathological diagnosis of AD, but only four had pure AD. A coincident pathological diagnosis of dementia with Lewy bodies (DLB), medial temporal lobe pathology (TDP-43 proteinopathy, argyrophilic grain disease and hippocampal sclerosis), referred to collectively here as MTL, and vascular pathology were present in 45.5%, 40.0% and 22.7% of these patients, respectively. Hallucinations were a strong predictor of coincident DLB (100% specificity) and a more severe dysexecutive profile was also a useful predictor of coincident DLB (80.0% sensitivity and 83.3% specificity). Occipital FDG-PET hypometabolism accurately classified coincident DLB (80% sensitivity and 100% specificity). Subjects with coincident MTL showed lower hippocampal volume.ConclusionsBiomarkers can be used to independently predict coincident AD and DLB pathology, a common finding in amnestic MCI and DAT patients. Cohorts with comprehensive neuropathological assessments and multimodal biomarkers are needed to characterize independent predictors for the different neuropathological substrates of cognitive impairment.

Striatal Dopamine Transporter Binding Does Not Correlate with Clinical Severity in Dementia with Lewy Bodies

Patients who have dementia with Lewy bodies (DLB) show both clinical and histopathologic overlap with Alzheimer disease patients and Parkinson disease patients. In this study, we correlated the core features of DLB (dementia, parkinsonism, hallucinations, and fluctuations) with striatal dopamine transporter (DAT) availability as assessed with SPECT and (123)I-N-(3-iodoprop-2E-enyl)-2-β-carbomethoxy-3β-(4-methylphenyl) nortropane ((123)I-PE2I) in patients with newly diagnosed DLB. Two hundred eighty-eight patients were consecutively included in the study as they were referred for diagnostic SPECT scanning of DAT with (123)I-PE2I. Of those patients, 51 had, on the basis of clinical guideline criteria, a probable-DLB diagnosis at follow-up 16 ± 11.6 mo later. Before or on the day of the SPECT scan, DLB patients had a routine neurologic examination including Hoehn and Yahr grading and were cognitively evaluated with the Mini Mental State Examination. There was no correlation between Mini Mental State Examination, Hoehn and Yahr score, fluctuations or hallucinations, and striatal DAT availability as measured with (123)I-PE2I and SPECT. In patients with newly diagnosed DLB, symptoms are not associated with a reduction in striatal DAT despite its firm involvement in DLB pathology.

Amyloid Pathology Influences Aβ1-42 Cerebrospinal Fluid Levels in Dementia with Lewy Bodies

A significant proportion of patients with dementia with Lewy bodies (DLB) show Alzheimer's disease (AD) pathology like senile plaques and neurofibrillary tangles. Biomarkers in cerebrospinal fluid (CSF), such as amyloid-β1-42 (Aβ1-42), total tau (T-tau), and hyperphosphorylated tau (P-tau181P), are linked to the different pathological hallmarks of AD. We set up a study to investigate the influence of AD co-pathology on CSF biomarker concentrations and profiles in autopsy-confirmed DLB. DLB patients with senile plaques showed significantly lower CSF Aβ1-42 concentrations than DLB patients without senile plaques, but not compared to the AD patients. There were no significant differences in CSF T-tau or P-tau181P concentrations between DLB patients with and without neurofibrillary tangles. A correlation was found between the number of APOE ε4 alleles and Aβ1-42 CSF levels in DLB patients with senile plaques. Although the CSF biomarkers Aβ1-42, T-tau, and P-tau181P have an added diagnostic value for the differential dementia diagnosis, concomitant amyloid pathology in DLB limits the use of CSF Aβ1-42 for the differential diagnosis of AD versus DLB.

Prevalence and Pathology of Dementia with Lewy Bodies in the Oldest Old: A Comparison with Other Dementing Disorders

Background: While the prevalence of Alzheimer disease (AD) increases with age, little is known about the frequency of dementia with Lewy bodies (DLB) in the oldest old. A retrospective hospital-based study compared the relative prevalence of DLB among very old individuals. Methods: 1,100 consecutive autopsy cases of demented patients aged over 70 years (mean age: 83.9 ± 5.4 years) were examined using standardized neuropathological methods and current diagnostic consensus criteria. Results: Evaluation of three age groups (8th–10th decade) showed a significant increase in the relative prevalence of AD with cerebrovascular lesions including mixed dementia, while AD with Lewy body (LB) pathology showed a mild but insignificant age-related increase. Both ‘pure’ AD and vascular dementia showed a mild but insignificant decline, while DLB (without severe AD pathology) decreased progressively. While the severity of Lewy pathology in DLB slightly decreased with age, concomitant Alzheimer-like pathology increased progressively. Conclusion: Whether DLB in the oldest old represents a distinct group is a matter of discussion, but the relative prevalence of AD with LB in our sample remained fairly stable.