Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases

Ruffmann, Claudio; Calboli, FC; Bravi, Ilaria; Gverić, Djordje; Curry, LK; Smith, Adam J. de; Pavlou, Sofia; Buxton, JL; Blakemore, Alexandra I. F.; Takousis, Petros; Molloy, Sophie; Piccini, Paola; Dt, Dexter; Roncaroli, Federico; Gentleman, S. M.; Middleton, Lefkos T.

doi:10.1111/nan.12294

Cited by 73 publications

(100 citation statements)

References 66 publications

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“…7 However, additional research has reported that Aβ plaques 8,20 or a summation of NFT, Aβ, and SYN pathological changes 21 were the strongest correlates of a shorter MDI in LBSD. There are several potential reasons for these discrepancies.…”

Section: Discussionmentioning

confidence: 96%

“…However, our multi-center cohort is one of the largest reported series of clinically-characterized patients with roughly equal numbers of PDD and DLB patients which allowed for comparisons across four levels of Braak/CERAD scores and a continuous measure of average cerebral NFT/NP scores. In contrast, previous studies had limited evaluations of NFT pathology by collapsing Braak stages for dichotomous comparisons 8 or by examining categorical Braak NFT stages only 20 in smaller samples with relative imbalances of PDD/DLB 20,21 or only non-demented PD or PDD 8 . Although in this study we focused on LBSD patients who developed dementia (PDD/DLB) and did not examine PD patients who came to autopsy prior to the onset of dementia (PDND), we have previously published a series of autopsy-confirmed PDND patients 6 and found the majority of cases had a low level of tau pathology—35/44 (79%) of cases had low Braak tau stages=0–II (i.e.…”

Section: Discussionmentioning

confidence: 99%

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Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Irwin

Grossman

Weintraub

et al. 2017

The Lancet Neurology

417

413

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Background There exists great heterogeneity in patient survival and the time interval between motor symptom and dementia onset (MDI) across Lewy body spectrum disorders (LBSD). The goal of this study is to identify genetic and pathological findings that have the strongest association with these features of clinical heterogeneity in LBSD. Methods In this retrospective study, we examined symptom onset, and genetic and neuropathological data from a cohort of LBSD patients with autopsy-confirmed α-synucleinopathy (as of Oct 1, 2015) recruited from 5 clinical research centres in 5 cities in the USA. Using histopathology techniques and markers, we assessed the burden of tau neurofibrillary tangles, neuritic plaques, α-synuclein inclusions, and other pathologic changes in cortical regions using averaged ordinal scores and genotyped cases for variants associated with LBSD. We evaluated the time interval from onset of motor symptoms to dementia (MDI) and overall survival in groups with varying levels of co-morbid Alzheimer’s disease pathology (AD) according to current National Institute on Aging–Alzheimer’s Association neuropathological criteria and used multivariate regression to control for age at death and gender. Findings This study included 213 patients who had been followed to autopsy and met inclusion criteria of clinical LBSD with autopsy-confirmed α-synculeinopathy. Patient groups were characterized by no (n=49,23%), low-level (n=56,26%), intermediate-level (n=45,21%) or high-level (n=63,30%) AD neuropathology. Across groups of increasing levels of AD neuropathology, there were higher cerebral α-synuclein scores, shorter MDI, and shorter disease duration (p<0·0001 all). Multivariate regression found independent negative associations of cerebral tau score with MDI (β= −4·0, 95% CI −5·5 to −2·6; p<0·0001) (R2=0·22, p<0·0001) and with survival (β=−2·0, 95% CI −3·2 to −0·8; p<0·0001) (R2=0·15, p<0·0001) in models including age at death, gender, cerebral neuritic plaque scores, cerebral α-synuclein, presence of cerebrovascular disease, MAPT haplotype, and APOE genotype as covariates. Interpretation AD neuropathology is common in LBSD and confers a worse prognosis for each increasing level of neuropathological change. Cerebral neurofibrillary tau tangle burden, α-synuclein pathology, and amyloid plaque pathology are the strongest pathological predictors of a shorter MDI and survival in LBSD. In the future, clinical diagnostic criteria which use reliable biomarkers for AD neuropathology in LBSD should help identify the most appropriate patients for clinical trials of emerging therapies targeting tau, amyloid-beta or α-synuclein, and stratify them by level of AD neuropathology. Funding NIH (NIA/NINDS).

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Section: Discussionmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 99%

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Irwin

Grossman

Weintraub

et al. 2017

The Lancet Neurology

417

413

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“…Although α-synuclein deposition in Lewy bodies is the core neuropathologic feature of the LBD, tau and Aβ co-pathologies are commonly observed in most patients with DLB and PDD at autopsy (2–6). Supporting their contribution to cognitive function in these diseases, neuropathological studies of DLB and PDD have tied both tau and Aβ to severity of dementia (3–5).…”

Section: Discussionmentioning

confidence: 99%

“…In individuals with DLB and PDD, co-existent Alzheimer’s disease (AD) pathology, in the form of extracellular amyloid plaques and intracellular paired helical filaments of tau, is commonly observed at autopsy (2–6). The relevance of these protein aggregates to the course of these diseases has been based primarily on clinico-pathological correlations.…”

Section: Introductionmentioning

confidence: 99%

Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases

et al. 2016

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IMPORTANCEThe causes of cognitive impairment in dementia with Lewy bodies (DLB) and Parkinson disease (PD) are multifactorial. Tau pathologic changes are commonly observed at autopsy in individuals with DLB and PD dementia, but their contribution to these diseases during life is unknown.OBJECTIVE To contrast tau aggregation in DLB, cognitively impaired persons with PD (PD-impaired), cognitively normal individuals with PD (PD-normal), and healthy persons serving as control participants, and to evaluate the association between tau aggregation, amyloid deposition, and cognitive function. DESIGN, SETTING, AND PARTICIPANTSThis cross-sectional study was conducted from January 1, 2014, to April 28, 2016, in a tertiary care center's memory and movement disorders units. Twenty-four patients with Lewy body disease (7 DLB, 8 PD-impaired, and 9 PD-normal) underwent multimodal brain imaging, cognitive testing, and neurologic evaluation, and imaging measures were compared with those of an independently acquired group of 29 controls with minimal brain amyloid burden as measured with carbon 11-labeled Pittsburgh Compound B ([ 11 C]PiB) positron emission tomography (PET). EXPOSURES Imaging with fluorine 18-labeled AV-1451 ([ 18 F]AV-1451) (formerly known as [ 18 F]T807), [ 11 C]PiB PET, magnetic resonance imaging (MRI), neurologic examination, and detailed cognitive testing using the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating scale. MAIN OUTCOMES AND MEASURES Main outcomes were differentiation of diagnostic groups on the basis of [ 18 F]AV-1451 binding, the association of [ 18 F]AV-1451 binding with [ 11 C]PiB binding, and the association of [ 18 F]AV-1451 binding with cognitive impairment. All but 3 individuals underwent amyloid imaging with [ 11 C]PiB PET. The hypotheses being tested were formulated before data collection. Mini-Mental State Examination (range, 0-30, with 30 being best) and Clinical Dementia Rating scale sum-of-boxes scale (range, 0-18, with 0 being best) were used for assessment of cognitive function. RESULTSIn patients with DLB, cortical [ 18 F]AV-1451 uptake was highly variable and greater than in the controls, particularly in the inferior temporal gyrus and precuneus. Foci of increased [ 18 F]AV-1451 binding in the inferior temporal gyrus and precuneus were also evident in PD-impaired patients. Elevated cortical [ 18 F]AV-1451 binding was observed in 4 of 17 patients with Lewy body disease with low cortical [ 11 C]PiB retention. For DLB and PD-impaired patients, greater [ 18 F]AV-1451 uptake in the inferior temporal gyrus and precuneus was associated with increased cognitive impairment as measured with the MMSE and the Clinical Dementia Rating scale sum-of-boxes score.CONCLUSIONS AND RELEVANCE Patients with Lewy body disease manifest a spectrum of tau pathology. Cortical aggregates of tau are common in patients with DLB and in PD-impaired patients, even in those without elevated amyloid levels. When present, tau deposition is associated with cognitive impairment. These findings support...

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“…In this study, DLB and PDD cases were grouped together as one Lewy body dementia cohort to investigate effects of antidepressant treatment on neurogenesis and cognition. Whilst the 1-year rule is still routinely clinically applied to differentiate between the two dementia forms, several studies have suggested differences in amyloid load and Lewy body cortical load [47,48,49,50,51] which could also have an impact on the rate of neurogenesis. It would, therefore, be of interest to take this into consideration in future studies investigating neurogenesis in DLB/PDD.…”

Section: Discussionmentioning

confidence: 99%

Importance of Proactive Treatment of Depression in Lewy Body Dementias: The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study

Gatt

Ekonomou

Somani

et al. 2017

Dement Geriatr Cogn Disord

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Objective: To examine the impact of selective serotonin reuptake inhibitors (SSRIs) and depression on neurogenesis and cognition in dementia with Lewy bodies (DLB) and Parkinson disease dementia (PDD). Methods: Late-stage progenitor cells were quantified in the subgranular zone (SGZ) of the hippocampal dentate gyrus of DLB/PDD patients (n = 41) and controls without dementia (n = 15) and compared between treatment groups (unmedicated, SSRIs, acetyl cholinesterase inhibitors [AChEIs], combined SSRIs and AChEIs). Results: DLB/PDD patients had more doublecortin-positive cells in the SGZ compared to controls. The doublecortin-positive cell count was higher in the SGZ of patients treated with SSRIs and correlated to higher cognitive scores. Conclusion: SSRI treatment was associated with increased hippocampal neurogenesis and preservation of cognition in DLB/PDD patients.

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Cortical Lewy bodies and Aβ burden are associated with prevalence and timing of dementia in Lewy body diseases

Cited by 73 publications

References 66 publications

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Neuropathological and genetic correlates of survival and dementia onset in synucleinopathies: a retrospective analysis

Tau Positron Emission Tomographic Imaging in the Lewy Body Diseases

Importance of Proactive Treatment of Depression in Lewy Body Dementias: The Impact on Hippocampal Neurogenesis and Cognition in a Post-Mortem Study

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