Pure Dementia With Lewy Bodies Research Articles

Neuroinflammation is associated with Alzheimer’s disease co-pathology in dementia with Lewy bodies

BackgroundNeuroinflammation and Alzheimer’s disease (AD) co-pathology may contribute to disease progression and severity in dementia with Lewy bodies (DLB). This study aims to clarify whether a different pattern of neuroinflammation, such as alteration in microglial and astroglial morphology and distribution, is present in DLB cases with and without AD co-pathology.MethodsThe morphology and load (% area of immunopositivity) of total (Iba1) and reactive microglia (CD68 and HLA-DR), reactive astrocytes (GFAP) and proteinopathies of alpha-synuclein (KM51/pser129), amyloid-beta (6 F/3D) and p-tau (AT8) were assessed in a cohort of mixed DLB + AD (n = 35), pure DLB (n = 15), pure AD (n = 16) and control (n = 11) donors in limbic and neocortical brain regions using immunostaining, quantitative image analysis and confocal microscopy. Regional and group differences were estimated using a linear mixed model analysis.ResultsMorphologically, reactive and amoeboid microglia were common in mixed DLB + AD, while homeostatic microglia with a small soma and thin processes were observed in pure DLB cases. A higher density of swollen astrocytes was observed in pure AD cases, but not in mixed DLB + AD or pure DLB cases. Mixed DLB + AD had higher CD68-loads in the amygdala and parahippocampal gyrus than pure DLB cases, but did not differ in astrocytic loads. Pure AD showed higher Iba1-loads in the CA1 and CA2, higher CD68-loads in the CA2 and subiculum, and a higher astrocytic load in the CA1-4 and subiculum than mixed DLB + AD cases. In mixed DLB + AD cases, microglial load associated strongly with amyloid-beta (Iba1, CD68 and HLA-DR), and p-tau (CD68 and HLA-DR), and minimally with alpha-synuclein load (CD68). In addition, the highest microglial activity was found in the amygdala and CA2, and astroglial load in the CA4. Confocal microscopy demonstrated co-localization of large amoeboid microglia with neuritic and classic-cored plaques of amyloid-beta and p-tau in mixed DLB + AD cases.ConclusionsIn conclusion, microglial activation in DLB was largely associated with AD co-pathology, while astrocytic response in DLB was not. In addition, microglial activity was high in limbic regions, with prevalent AD pathology. Our study provides novel insights into the molecular neuropathology of DLB, highlighting the importance of microglial activation in mixed DLB + AD.

A Preliminary Comparison of the Methylome and Transcriptome from the Prefrontal Cortex Across Alzheimer's Disease and Lewy Body Dementia.

Pathological amyloid-β and α-synuclein are associated with a spectrum of related dementias, ranging from Alzheimer's disease (AD) and dementia with Lewy bodies (DLB) to Parkinson disease dementia (PDD). While these diseases share clinical and pathological features, they also have unique patterns of pathology. However, epigenetic factors that contribute to these pathological differences remain unknown. In this preliminary study, we explore differences in DNA methylation and transcription in five neuropathologically defined groups: cognitively unimpaired controls, AD, pure DLB, DLB with concomitant AD (DLBAD), and PDD. We employed an Illumina Infinium 850k array and RNA-seq to quantify these differences in DNA methylation and transcription, respectively. We then used Weighted Gene Co-Network Expression Analysis (WGCNA) to determine transcriptional modules and correlated these with DNA methylation. We found that PDD was transcriptionally unique and correlated with an unexpected hypomethylation pattern compared to the other dementias and controls. Surprisingly, differences between PDD and DLB were especially notable with 197 differentially methylated regions. WGCNA yielded numerous modules associated with controls and the four dementias: one module was associated with transcriptional differences between controls and all the dementias as well as having significant overlap with differentially methylated probes. Functional enrichment demonstrated that this module was associated with responses to oxidative stress. Future work that extends these joint DNA methylation and transcription analyses will be critical to better understanding of differences that contribute to varying clinical presentation across dementias.

Clinical Trajectories at the End of Life in Autopsy-Confirmed Dementia Patients With Alzheimer Disease and Lewy Bodies Pathologies.

Evaluating and understanding the heterogeneity in dementia course has important implications for clinical practice, health care decision-making, and research. However, inconsistent findings have been reported with regard to the disease courses of the 2 most common dementias: Alzheimer disease (AD) and dementia with Lewy bodies (DLB). Using autopsy-confirmed diagnoses, we aimed to examine the disease trajectories in the years before death among patients with dementia with pure AD, pure DLB, or mixed (AD and DLB) pathologies. The current retrospective longitudinal study included 62 participants with autopsy-confirmed diagnoses of pure AD (n = 34), mixed AD and DLB (AD + DLB; n = 17), or pure DLB (n = 11) from the Predictors 2 Cohort Study, a prospective, clinic-based, cohort of patients with dementia. Generalized estimating equation models, with time zero at death, were used to examine the trajectory of cognition (Folstein Mini-Mental State Examination [MMSE]), function (activities of daily living [ADL]), and Dependence Scale among patients with different autopsy-confirmed diagnosis (pure AD, AD + DLB, and pure DLB). The models were adjusted for age, sex, education, and baseline features including extrapyramidal signs, MMSE, ADL, and Dependence Scale. The participants on average received 9.4 ± 4.6 assessments at 6-month intervals during a mean 5.4 ± 2.9 years of follow-up. The 3 groups were similar in both cognition and function status at baseline. Cognition and function were highly correlated among patients with AD + DLB but not in pure AD or pure DLB at baseline. Patients of the 3 groups all declined in both cognition and function but had different trajectories of decline. More specifically, the patients with pure DLB experienced approximately double the rate of both cognitive decline and functional decline than the patients with pure AD, and the mixed pathology group showed double the rate of functional decline as compared to pure AD. In this longitudinal study, we found that among patients with dementia, those with Lewy body pathology experienced faster cognitive and functional decline than those with pure AD pathology.

Dementia with Lewy bodies (DLB) with amyloid co‐pathology has a distinct CSF proteomics profile compared to pure DLB and Alzheimer disease

AbstractBackgroundIn dementia with Lewy bodies (DLB), amyloid co‐pathology is common and associated with an unfavorable prognosis. For targeted treatment development for DLB, we need to establish 1) whether the presence of amyloid marks co‐occurring Alzheimer disease (AD), and 2) how DLB with amyloid differs from DLB without amyloid. We employ proteomics in cerebrospinal fluid (CSF), an established method to assess biological dysregulation in vivo, for characterization of DLB with amyloid pathology.MethodWe selected individuals from the ADC and UPENN cohorts, with DLB diagnosis with abnormal amyloid based on CSF (n=65), DLB with normal amyloid (n=45), AD dementia (n=235), and cognitively healthy controls with normal amyloid (n=252, Table 1). CSF protein levels (n=810) were measured using the Olink proximity extension assay. We compared protein levels between groups using ANCOVA’s adjusted for age and sex, and FDR‐controlled p‐values. To aid identification of proteins that contribute to disease processes, we developed a neural network model prototype. We trained the model to learn simultaneously a low dimensional representation of the data and a dementia classifier. The assumption is that biologically important proteins show the strongest influence on the low network dimension, because these proteins contribute to classification and/or share information with multiple proteins.ResultThe DLB‐amyloid group showed mostly decreased CSF protein levels, in particular compared to AD dementia (68%, Table 2). Compared to DLB‐pure, DLB‐amyloid has 132 decreased and 3 increased protein levels, which were most significantly enriched for KEGG pathways: cytokine‐cytokine receptor interaction and axon guidance; and for GO‐biological terms related to positive regulation of neurogenesis, axonogenesis, and neuronal differentiation. In DLB‐amyloid, most AD‐related proteins were normal or decreased, and multiple additional proteins were specifically decreased (Figure 1) These DLB‐amyloid associated proteins were enriched for GO‐biological terms related to chemotaxis and VEGF‐A induced cell proliferation.ConclusionThe CSF proteome in DLB with amyloid pathology differed from AD dementia and DLB pure, and the changes may be linked to disturbed axonal maintenance and growth. This data indicate that amyloid pathology in DLB is not an independent co‐pathology. Complementary to pathology studies, we have started to disentangle mechanisms of mixed pathology in vivo.

The presence of Alzheimer’s disease pathology in dementia with Lewy bodies is related to increased neocortical α‐synuclein load and different α‐synuclein morphology

AbstractBackgroundThe presence of Alzheimer’s disease (AD) type pathology in dementia with Lewy bodies (DLB) has been linked to a more rapid disease progression. We aimed to examine the relation between load of AD‐type pathology and load and morphology of α‐synuclein pathology in DLB brains.MethodWe included 50 donors from the Netherlands Brain Bank fulfilling clinical criteria for ‘probable DLB’ and limbic or neocortical Lewy body disease. Levels of AD‐type pathology according to NIA‐AA guidelines were either absent to low (pure DLB, n = 15), or intermediate to high (mixed DLB/AD, n = 35). We visually rated α‐synuclein‐positive and amyloid‐β‐positive morphologies, and we quantitatively measured amyloid‐β, hyperphosphorylated tau (HPF‐tau) and α‐synuclein load in fifteen brain regions. Regional amyloid‐β and HPF‐tau levels in DLB donors were compared to eight AD donors without α‐synuclein pathology (pure AD).ResultMixed DLB/AD compared to pure DLB donors showed a shorter disease duration (6 ± 3 vs. 8 ± 3 years, p = 0.021), more diffuse intraneuronal α‐synuclein positivity (p = 0.002) but not more glial α‐synuclein positivity, and a higher overall α‐synuclein load (F = 25.7, p < 0.001), specifically in the parietal (p = 0.006), temporal (p = 0.002) and occipital cortex (p = 0.006). Mixed DLB/AD was related to more capillary cerebral amyloid angiopathy (CAA) (49% vs. 7%, p < 0.001). Within cortical regions, α‐synuclein load was most strongly related to amyloid‐β and HPF‐tau load in the temporal (Pearson’s r = 0.38 and 0.50 respectively) and occipital cortex (r = 0.43 and 0.42 respectively). While controlling for age at death, mixed DLB/AD compared to pure AD showed lower HPF‐tau load in frontal (p = 0.043) and parietal cortices (p = 0.002), but not in temporal cortex (p = 0.48), and no differences in amyloid‐β load in the frontal (p = 0.57), parietal (p = 0.56) and temporal cortex (p = 0.10).ConclusionThe presence of AD‐type pathology in DLB was related to more diffuse intraneuronal α‐synuclein positivity, a higher neocortical α‐synuclein load and more capillary CAA. This study provides evidence for different neuropathological profiles in DLB, which may contribute to clinical heterogeneity in this disease.

Cognitive decline profiles differ in Parkinson disease dementia and dementia with Lewy bodies.

To examine whether domain-specific patterns of cognitive impairment and trajectories of decline differed in patients with clinically diagnosed Parkinson disease dementia (PDD) (N = 29) and autopsy-confirmed dementia with Lewy bodies (DLB) (N = 58) or Alzheimer disease (AD) (N = 174) and to determine the impact of pooling patients with PDD and DLB in clinical trials targeting cognition. Patients were matched on demographics and level of global cognitive impairment. Patterns of cross-sectional performance and longitudinal decline were examined in 4 cognitive domains: Visuospatial, Memory, Executive, and Language. Power analyses were performed to determine the numbers of participants needed to adequately power a hypothetical clinical trial to slow cognitive decline in pure PDD, pure DLB, or a mixed PDD/DLB group. Both DLB and PDD were more impaired and declined more rapidly than AD in the Visuospatial domain. Patients with PDD exhibited the most impairment and fastest decline in Executive, although patients with DLB also declined faster than AD. Memory was more impaired in AD than DLB and in both compared with PDD; however, all 3 groups declined at comparable rates. In contrast, PDD declined at a slower rate on Language measures than DLB or AD. Power analyses suggest that Visuospatial and Executive outcome measures would be most sensitive in PDD, but Memory and Language in DLB. DLB and PDD differ from each other, and from AD, in a cognitive domain-specific manner. As such, different outcome measures may be most sensitive to detecting changes in DLB vs PDD, suggesting that the 2 should be analyzed separately in clinical trials.

INDEL Length and Haplotypes in the β-Synuclein Gene: A Key to Differentiate Dementia with Lewy Bodies?

Lewy body diseases (LBD) include Parkinson's disease (PD) and dementia with Lewy bodies (DLB) and together with Alzheimer's disease (AD) they show an important neuropathological and clinical overlap. The human alpha- and beta-synuclein genes (SNCA and SNCB) are key factors for the development of Lewy body diseases. Here, we aimed to analyze the genotype distribution of potentially functional SNPs in SNCA and SNCB, perform haplotype analysis for SNCB, and to identify functional insertion and deletion (INDEL) variations within the regulatory region of SNCB which might be responsible for the drastically diminished beta-synuclein levels reported for pure DLB. Thus, we genotyped brain samples from AD, DLB, PD, and healthy controls for two SNCA and four SNCB SNPs. We also analyzed INDEL variations upstream of SNCB, determined SNCB expression levels, and correlated INDEL lengths with expression levels. Applying Fisher's exact, chi-square, ANOVA tests, and the ΔΔCt method, we found disease-specific genotype distribution of SNCA and SNCB SNPs. Additionally, we identified three INDEL variations upstream of SNCB and showed that the INDEL allele lengths were associated with SNCB expression levels. INDEL alleles associated with low SNCB expression were accumulated in pure DLB. Finally, one major and four minor DLB specific SNCB haplotypes were identified with Haploview and Arlequin. In summary, our study showed that different SNCA and SNCB genotypes are associated with the development of either PD or DLB, and that the frequencies of genotypes associated with low SNCB expression are elevated in DLB.

Gray matter atrophy in dementia with Lewy bodies with and without concomitant Alzheimer's disease pathology.

We aimed to study if patients with dementia with Lewy bodies (DLB) who have concomitant Alzheimer's disease (AD) pathology (detected antemortem by cerebrospinal fluid [CSF] biomarkers) have additional loss of gray matter volume. Ninety-eight DLB patients were divided into a "pure DLB" (DLB/AD-, n= 62) and a "mixed DLB" group (DLB/AD+, n= 36) and matched for age and symptom duration to 84 AD patients and 75 controls. We compared visual atrophy ratings, and in a subset, we analyzed cortical thickness and subcortical gray matter volumes. DLB/AD+ patients had more pronounced medial temporal lobe atrophy (MTA) compared to DLB/AD- (mean [total] MTA score 2.5 vs. 1.3, p= 0.02). Global and parietal atrophy scores were comparable between the 3 dementia groups and differed from controls. MTA score was associated with CSF Aβ-42, while posterior cortical and global atrophy scores were associated with CSF tau. Cortical thinning was found in DLB/AD-, DLB/AD+, and AD compared to controls. Concomitant AD pathology seems to cause additional (hippocampal) atrophy in DLB, and this may contribute to a more devastating disease course in DLB/AD+ patients.

Improving the identification of dementia with Lewy bodies in the context of an Alzheimer\u2019s-type dementia

BackgroundDementia due to Alzheimer’s disease (AD) and dementia with Lewy bodies (DLB) are the two most common neurodegenerative causes of dementia. They commonly occur together, especially in older people, but clinical identification of these diseases in dementia is difficult in such circumstances. We therefore conducted a study using cases with both comprehensive prospective clinical assessments and complete neuropathological examination to determine if it is possible to identify such mixed cases clinically and to determine features which may identify DLB in the presence of AD dementia.MethodsAt Newcastle Brain Bank we identified subjects who had a clinical diagnosis of dementia and who also had autopsy diagnoses of pure AD, pure DLB, or mixed AD+DLB. All subjects had undergone prospective longitudinal clinical assessments. Mixed AD+DLB patients met neuropathological criteria for both DLB (limbic/neocortical Lewy body disease) and AD (Braak stage V/VI and CERAD B/C). The records of these subjects were carefully reviewed by two specialists in old-age psychiatry blind to autopsy findings to determine baseline and final clinical diagnoses based on these detailed records. The presence of characteristic Lewy body symptoms and other clinical information was also recorded.ResultsOf 59 subjects included, 19 were AD, 18 DLB, and 22 mixed AD+DLB. At baseline no subjects were correctly identified as having mixed AD+DLB and by final diagnosis only 23% were identified. The only symptom which helped in identifying the presence of Lewy body disease in the context of a mixed AD+DLB dementia was complex visual hallucinations.ConclusionsWhilst the identification of DLB in the context of a dementia with an AD pattern is difficult, the emergence of complex visual hallucinations in the context of such a degenerative dementia suggests the presence of Lewy body disease and should encourage a careful assessment. Biomarkers appear likely to be necessary to help improve identification of different disease subtypes underlying dementia.

DEMENTIA WITH LEWY BODIES IS ASSOCIATED WITH GREATER DEPENDENCE: AN AUTOPSY STUDY

Dependence has been linked to caregiver burden and cost of care in dementia. However, dependence levels have not been well described in Dementia with Lewy bodies (DLB). To address this issue, we analyzed and compared dependence data as well as cognitive, motor, and neuropsychiatric data from a cohort of autopsy-confirmed cases of DLB and Alzheimer's disease (AD). The sample was derived from the Predictors Study, a multicenter cohort study of patients with probable AD or DLB. The current study includes 42 patients who underwent autopsy and met pathologic criteria for AD (12 subjects) or DLB (9 pure DLB and 12 DLB plus AD). At the baseline visit, the Dependence Scale was administered to measure the amount of assistance required by patients, yielding a dependence level, ranging from 0 (totally independent) to 5 (totally dependent). The dependence level, cognitive function (measured by Mini–Mental State Examination, MMSE) and non-cognitive symptoms were compared between groups using ANOVA. Regression models were used to evaluate the association between pathology groups and dependence level. The average (SD) dependence level at baseline evaluation was 2.47 (1.39) and 3.33 (1.09), respectively, for the 21 autopsy-confirmed AD and 21 DLB patients (p = 0.044). There was no statistically significant difference (p = 0.17in baseline MMSE between the two groups: DLB mean (SD) = 19 (5.3), AD mean (SD) = 21 (3.6). A higher percentage of DLB patients than AD patients presented with extrapyramidal signs (70.6% vs. 20.0%, p = 0.002) and delusions (63.2% vs. 25%, p = 0.016). Compared to AD patients, DLB patients had a 0.95 (p = 0.025) higher dependence level after adjusting for age, sex, and education. The association remained significant (b = 0.86, p = 0.044) after additional adjustment for MMSE. To our knowledge, this is the first study to use an autopsy-confirmed cohort to compare dependence levels between DLB and AD. DLB patients had statistically significantly greater dependence level than AD patients even after adjusting for age, sex, education, and MMSE. The wide spectrum of cognitive and non-cognitive symptoms observed in DLB likely impacts dependence and thus may affect the level of care and cost associated with this disorder.

IDENTIFICATION OF AN ITGA7 VARIANT ASSOCIATED WITH ALZHEIMER’S DISEASE AND MULTIPLE OTHER NEURODEGENERATIVE DISEASES

The genetic causes of mixed Alzheimer's Disease (AD) and Dementia with Lewy Bodies (DLB) pathology remain unclear. In the current study we searched for exonic variants contributing to dual pathology in younger patients. We analyzed whole exome sequencing data collected through Stanford University and the Alzheimer's Disease Sequencing Project (ADSP). High impact (missense or nonsense) variants found in autopsy-confirmed mixed AD/DLB cases (age < 75 years, n=143) were screened against older, autopsy-confirmed pure AD controls (age > 85 years, n=274) and clinically-defined healthy controls (age > 80 years, n=4572). Variants seen in at least two dual path cases and none of the older, pure AD controls or healthy controls were examined further. For the remaining variants, we searched other neurodegenerative exome databases to determine their specificity to mixed AD/DLB pathology. For our top variant we performed immunohistochemical staining of autopsy-confirmed AD/DLB mixed pathology brain tissue. Finally, we explored potential functional effects of the variant by examining gene expression in post-mortem temporal cortex RNA-seq data from AD cases (n=82) and controls (n=80). The initial screening process yielded eleven variants present in at least two dual pathology cases and none of the healthy controls or older pure AD cases. Of these, we focused on rs76938320-A (NP_001138468.1:p. Ser700Leu, MAF=0.0002) on exon 18 of ITGA7 because of its predicted probable damaging effect using in silico prediction tools, its presence in three younger AD cases (age < 80 years) in ADSP, its high frequency in the ALS exome database, and the finding of a homozygous carrier with TDP43 and tau pathology. ITGA7 transcript isoforms that contain exon 18 show significantly higher expression in AD temporal cortex tissue when compared to controls (P < 0.001) in the Mayo Clinic Transcriptomics data set. Immunohistochemical staining of AD, AD/DLB, DLB, and vascular dementia brain tissue suggest that AD and AD/DLB tissue express higher levels of ITGA7 than vascular controls and pure DLB. Convergent data from exome sequencing, immunohistochemical stains, and transcriptomic analysis suggest that this ITGA7 variant may predispose not only to mixed AD/DLB pathology but to the development of multiple proteinopathies. Normalized FPKM values of the three ITGA7 transcript isoforms encoding rs76938420 are significantly higher in AD cases (n = 82) than in controls (n = 80).ITGA7 transcript expression values in post-mortem brain tissue were corrected for subject age at death, gender, RIN, source, and cell type markers. *** P < 0.001. ITGA7 neuronal cytoplasmic immunoreactivity in post-mortem brain tissue. Mixed DLB/AD and AD cases demonstrate stronger neuronal cytoplasmic immunoreactivity for ITGA7 when compared to vascular dementia and DLB cases. ITGA7 immunoreactivity is strongest within neurons containing neurofibrillary tangles.

GBA Mutations Are Associated With Earlier Onset and Male Sex in Dementia With Lewy Bodies.

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are Lewy body diseases characterized by similar pathological features. Several studies have shown a relation between alterations in the glucocerebrosidase gene (GBA) and the development of LB diseases. Here, we explored the role of GBA mutations in Spanish DLB patients. GBA mRNA sequences were analyzed in a neuropathological (50 DLB, 43 PD, and 34 control brains) and in a clinical cohort (47 DLB patients and 131 unaffected individuals). Sixteen GBA mutation carriers were identified, 5 of which were brains with pure DLB. The most common mutation, E326K, was strongly associated with pure DLB and PD with dementia. GBA mutations were overrepresented in men and associated with earlier DLB onset. GBA mutations are also an important risk factor for DLB development in the Spanish population, are associated with earlier disease onset, and are more prevalent in men. © 2015 International Parkinson and Movement Disorder Society.

Neuropathologically mixed Alzheimer's and Lewy body disease: burden of pathological protein aggregates differs between clinical phenotypes.

Multiple different pathological protein aggregates are frequently seen in human postmortem brains and hence mixed pathology is common. Mixed dementia on the other hand is less frequent and neuropathologically should only be diagnosed if criteria for more than one full blown disease are met. We quantitatively measured the amount of hyperphosphorylated microtubule associated tau (HP-τ), amyloid-β protein (Aβ) and α-synuclein (α-syn) in cases that were neuropathologically diagnosed as mixed Alzheimer's disease (AD) and neocortical Lewy body disease (LBD) but clinically presented either as dementia due to AD or LBD, the latter including dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). Our study group consisted of 28 cases (mean age, 76.11 SE: ±1.29 years; m:f, 17:11) of which 19 were neuropathologically diagnosed as mixed AD/DLB. Clinically, 8 mixed AD/DLB cases were diagnosed as AD (cAD), 8 as DLB (cDLB) and 3 as PDD (cPDD). In addition, we investigated cases that were both clinically and neuropathologically diagnosed as either AD (pure AD; n = 5) or DLB/neocortical LBD (pure DLB; n = 4). Sections from neocortical, limbic and subcortical areas were stained with antibodies against HP-τ, Aβ and α-syn. The area covered by immunopositivity was measured using image analysis. cAD cases had higher HP-τ loads than both cDLB and cPDD and the distribution of HP-τ in cAD was similar to the one observed in pure AD whilst cDLB showed comparatively less hippocampal HP-τ load. cPDD cases showed lower HP-τ and Aβ loads and higher α-syn loads. Here, we show that in neuropathologically mixed AD/DLB cases both the amount and the topographical distribution of pathological protein aggregates differed between distinct clinical phenotypes. Large-scale clinicopathological correlative studies using a quantitative methodology are warranted to further elucidate the neuropathological correlate of clinical symptoms in cases with mixed pathology.

QUANTIFICATION OF PATHOLOGICAL LESIONS DETECTS CLINICOPATHOLOGICAL PHENOTYPES OF MIXED AD/LBD

Dementing disorders are defined neuropathologically by their most prevalent pathology. However, some brains of demented subjects show high burdens of neuropathological hallmark lesions of more than one disease. Cases that neuropathologically fulfil criteria for both Alzheimer's disease (AD) and Lewy body disease (LBD - Dementia with Lewy bodies (DLB) or Parkinson's disease dementia (PDD)) are classified as mixed AD/LBD. Using semi-quantitative scoring, no differences were detected in mixed AD/LBD between cases that presented clinically with AD or LBD. We investigated whether a quantitative approach could reveal differences in the amounts of AD and LBD pathology in mixed AD/LBD cases. 19 mixed AD/LBD cases, which presented clinically as AD (n=8), DLB (n=8) or PDD (n=3), 5 pure AD and 5 pure DLB cases (mean age 75.26 +/- 9.1 years) were stained for antibodies against tau, β amyloid and α-synuclein and percentage burden of each pathology was quantified in neocortical, limbic and brainstem regions. Differences in the burden of pathology between clinically AD and LBD in various regions were detected quantitatively, as a significant increase in the amount of tau pathology was observed in the hippocampus (p<0.05), striatum (p<0.05), neocortex (p<0.05) and locus coeruleus (p<0.01) in clinically AD compared to LBD patients, respectively. When compared against the PDD phenotype, clinically AD cases have greater burden of tau pathology in the majority of areas analysed. Of note, we found an increase of α-synuclein in the substantia nigra of clinically AD and DLB cases compared to clinically PDD cases. When comparing neuropathologically mixed AD/LBD with pure AD and DLB cases we observed an increase in all 3 protein aggregates in the substantia nigra in the mixed AD/LBD group. Moreover, we found a significant correlation between hyperphosphorylated tau and α synuclein (p<0.01 and R 2 =0.616) in mixed AD/LBD group. Our findings suggest that cases neuropathologically diagnosed as mixed AD/LBD can be separated into different clinico-pathological phenotypes when quantitative neuropathological methods are applied. However, the question whether clinical diagnosis reflects the primary underlying pathology, which may be confounded by concomitant pathologies, warrants further investigation.

New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases

Lewy body diseases (LBDs) include dementia with Lewy bodies (DLB) and Parkinson disease (PD). Alpha-synuclein (AS) aggregation is a key event in the pathogenesis of LBDs and beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo. Recently, BS has been shown to interact directly with AS regulating its functionality and preventing its oligomerization, and a molecular subgroup of pure DLB lacks BS in cortical regions. In this study, we characterized four new BS transcript variants and analyzed their expression in neuronal and non-neuronal tissue, and their differential expression in frozen samples of three areas from brains of patients with pure Lewy body pathology (LBP), common LBP, Alzheimer pathology, and of controls. Relative mRNA expression was determined by real-time PCR with neuron-specific enolase 2 and synaptophysin as housekeeping genes, and expression changes were evaluated by the ΔΔCt method. Two main findings are in concordance with earlier studies. First, all BS isoforms are drastically diminished in the cortex of patients with pure LBP that had presented clinically as DLB but not PD with dementia. Second, an important shift of the isoform expression ratio was observed in the temporal cortex of all LBD cases, and the minor isoforms, normally absent in the midbrain, were detected in the caudate nucleus of all DLB samples. Our results provide further evidence for the role of minor transcript variants in the development of complex diseases and provide new insights into the pathogenesis of LBDs that may be important for the understanding of molecular mechanisms involved in these complex diseases.

Neuropathology underlying clinical variability in patients with synucleinopathies

Abnormal aggregates of the synaptic protein, α-synuclein, are the dominant pathology in syndromes known as the synucleinopathies. The cellular aggregation of the protein occurs in three distinct types of inclusions in three main clinical syndromes. α-Synuclein deposits in neuronal Lewy bodies and Lewy neurites in idiopathic Parkinson's disease (PD) and dementia with Lewy bodies (DLB), as well as incidentally in a number of other conditions. In contrast, α-synuclein deposits largely in oligodendroglial cytoplasmic inclusions in multiple system atrophy (MSA). Lastly, α-synuclein also deposits in large axonal spheroids in a number of rarer neuroaxonal dystrophies. Disorders are usually defined by their most dominant pathology, but for the synucleinopathies, clinical heterogeneity within the main syndromes is well documented. MSA was originally viewed as three different clinical phenotypes due to different anatomical localization of the lesions. In PD, recent meta-analyses have identified four main clinical phenotypes, and clinicopathological correlations suggest that more severe and more rapid progression of pathology with chronological age, as well as the involvement of additional neuropathologies, differentiates these phenotypes. In DLB, recent large studies show that clinical diagnosis is too insensitive to identify the syndrome itself, although clinicopathological studies suggest variable clinical features occur in the different pathological forms of this syndrome (pure DLB, DLB with Alzheimer's disease (AD), and AD with amygdala predominant Lewy pathology). The recognition of considerable heterogeneity within the synucleinopathy syndromes is important for the identification of factors involved in changing their pathological phenotype.

Relative preservation of MMSE scores in autopsy-proven dementia with Lewy bodies

Recent studies raised questions about the severity of cognitive impairment associated with dementia with Lewy bodies (DLB). However, there have been few analyses of large, multicenter data registries for clinical-pathologic correlation. We evaluated data from the National Alzheimer's Coordinating Center registry (n = 5,813 cases meeting initial inclusion criteria) and the University of Kentucky Alzheimer's Disease Center autopsy series (n = 527) to compare quantitatively the severity of cognitive impairment associated with DLB pathology vs Alzheimer disease (AD) and AD+DLB pathologies. Mini-Mental State Examination (MMSE) scores showed that persons with pure DLB had cognitive impairment of relatively moderate severity (final MMSE score 15.6 +/- 8.7) compared to patients with pure AD and AD+DLB (final MMSE score 10.7 +/- 8.6 and 10.6 +/- 8.6). Persons with pure DLB pathology from both data sets had more years of formal education and were more likely to be male. Differences in final MMSE scores were significant (p < 0.01) between pure DLB and both AD+DLB and pure AD even after correction for education level, gender, and MMSE-death interval. Even in cases with extensive neocortical LBs, the degree of cognitive impairment was most strongly related to the amount of concomitant AD-type neurofibrillary pathology. Dementia with Lewy bodies can constitute a debilitating disease with associated psychiatric, motoric, and autonomic dysfunction. However, neocortical Lewy bodies are not a substrate for severe global cognitive impairment as assessed by the Mini-Mental State Examination. Instead, neocortical Lewy bodies appear to constitute or reflect an additive disease process, requiring Alzheimer disease or other concomitant brain diseases to induce severe global cognitive deterioration.

Low sensitivity in clinical diagnoses of dementia with Lewy bodies

The success of future neurodegenerative disease (ND) therapies depends partly on accurate antemortem diagnoses. Relatively few prior studies have been performed on large, multicenter-derived datasets to test the accuracy of final clinical ND diagnoses in relation to definitive neuropathological findings. Data were analyzed from the University of Kentucky Alzheimer's Disease Center autopsy series and from the National Alzheimer's Coordinating Center (NACC) registry. NACC data are derived from 31 different academic medical centers, each with strong clinical expertise and infrastructure pertaining to NDs. The final clinical diagnoses were compared systematically with subsequent neuropathology diagnoses. Among subjects meeting final inclusion criteria (N = 2,861 for NACC Registry data), the strength of the associations between clinical diagnoses and subsequent ND diagnoses was only moderate. This was particularly true in the case of dementia with Lewy bodies (DLB): the sensitivity of clinical diagnoses was quite low (32.1% for pure DLB and 12.1% for Alzheimer's disease (AD + DLB) although specificity was over 95%. AD clinical diagnoses were more accurate (85.0% sensitivity and 51.1% specificity). The accuracy of clinical DLB diagnoses became somewhat lower over the past decade, due apparently to increased "over-calling" the diagnosis in patients with severe cognitive impairment. Furthermore, using visual hallucinations, extrapyramidal signs, and/or fluctuating cognition as part of the clinical criteria for DLB diagnosis was of minimal utility in a group (N = 237) with high prevalence of severe dementia. Our data suggest that further work is needed to refine our ability to identify specific aging-related brain disease mechanisms, especially in DLB.

Twin pairs discordant for neuropathologically confirmed Lewy body dementia

Aim: Little is known about the concordance rate in twins for dementia with Lewy bodies (DLB). The rate of agreement between clinical and pathological diagnoses for DLB is typically low,...

P3-060: Cerebrospinal fluid markers in dementia with Lewy bodies (DLB) in comparison with Alzheimer′s disease (AD)

AD and DLB present with similar clinical features and biological markers to differentiate both disorders are still lacking. Pathologically, most cases with pure DLB exhibit a diffuse plaque-only pathology with rare or absent neocortical neurofibrillary tangles, as opposed to the wide cortical neurofibrillary-tau involvement in AD. We analyzed CSF markers chosen as to reflect some of these underlying pathological differences. CSF samples of 33 cases with probable AD (NINCDS-ADRA criteria) without parkinsonism, 25 cases will all the core features of DLB (Consortium criteria) and 46 age-matched controls were analyzed. Total tau, Ab1–42 amyloid, IL-1b and IL-6 levels were measured by sandwich ELISA using commercially available kits (Innogenetics NV, Belgium and Diaclone Research, France). Tau protein: AD cases had significantly higher levels (500 ± 399 pg/ml, mean ± SD) than DLB cases (213 ± 243) and controls (200 ± 243) (p< 0.0001). There were no differences between DLB and control groups. The most efficient cutoff point (250 pg/ml) provided a 76% specificity to distinguish AD and DLB cases. b-amyloid: AD (348 ± 309 pg/ml) and DLB cases (320 ± 233) had lower b-amyloid levels than controls (462 ± 352) but the differences did not reach statistical significance. The combination of tau/ b-amyloid levels provided the best value to differenciate AD vs controls (cut-off point 0.5, sensitivity 82,5%, specificity 75%) but was worse than tau values alone to discriminate between AD and DLB. Interleukine 1b: IL-1b levels in the three groups were within the lowest values of the standard curve. There were no significant differences among AD (2.17 ± 3.00 pgr/ml), DLB (2.60 ± 2.97) cases and controls (2.02 ± 3.28). Interleukine 6: AD (7.14 ± 5.74 pgr/ml) and DLB (6.14 ± 5.00) cases showed slightly higher IL-6 levels than controls (4.96 ± 4.72) but the differences among the three groups were not significant. Tau levels in CSF may contribute to the clinical distinction between AD and DLB. b-amyloid CSF levels are similar in AD and DLB cases and tend to be lower than in controls. Interleukine CSF concentrations do not distinguish between both dementia disord.