A toxic subset of soluble α-synuclein species in dementia with Lewy body

There are a relatively small number of disorders that account for the majority of dementia in the elderly that is not Alzheimer disease (AD): cerebrovascular disease, Lewy body disease (α-synucleinopathies), and the frontotemporal lobar degenerations. Cerebrovascular disease and Lewy body disease account for most non-AD dementia among persons in the eighth decade of life and beyond. These two frequently co-occur with AD but can occur in their pure forms rarely (in the case of dementia associated with cerebrovascular disease) or more commonly (in the case of Lewy body disease). There is no one cognitive or behavioral syndrome associated with cerebrovascular disease; however, attempts to isolate a common theme suggest that cognitive slowing is typical of cerebrovascular contributions to cognitive impairment. Cerebrovascular pathology relevant to cognitive impairment accumulates subclinically more commonly than it causes acute, strokelike declines in cognition. Dementia with Lewy bodies is a multidimensional disorder that includes a nonamnestic dementia, Parkinson disease or at least some parkinsonian features, a disorder of sleep and wakefulness, autonomic disturbances, and depression. The disorders of sleep prominently include rapid eye movement sleep behavior disorder, excessive daytime sleepiness, visual hallucinations, and marked fluctuations in level of alertness. The frontotemporal lobar degenerations are nearly as common as causes of dementia in persons under age 65 as is AD. The group of disorders includes two cognitive syndromes (primary progressive aphasia and behavior variant frontotemporal dementia) and two neuropathologic subtypes (tauopathy and TDP43 proteinopathy) and is associated with three major autosomal dominant genetic mutations (in MAPT, GRN, and C9ORF72). Key words: dementia with Lewy bodies, frontotemporal lobar degenerations, vascular cognitive impairment

Download Full-text

Spectrum of Lewy body dementias: relationship of Parkinson’s disease dementia to dementia with Lewy bodies

Cognitive Impairment and Dementia in Parkinson's Disease ◽

10.1093/med/9780199681648.003.0018 ◽

2015 ◽

pp. 241-260 ◽

Cited By ~ 1

Author(s):

Clive Ballard ◽

Sara Garcia-Ptacek ◽

Inger van Steenoven ◽

Dag Aarsland

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Parkinson’S Disease Dementia ◽

Relationship Of

Download Full-text

A-030 Sensitivity and Specificity of Measures for Dementia with Lewy Bodies

Archives of Clinical Neuropsychology ◽

10.1093/arclin/acaa068.030 ◽

2020 ◽

Vol 35 (6) ◽

pp. 820-820

Author(s):

Duarte A ◽

Alcina J ◽

Rodriguez M

Keyword(s):

Sensitivity And Specificity ◽

Lewy Body ◽

Neuropsychological Tests ◽

Dementia With Lewy Body ◽

Block Design ◽

Neuropsychological Testing ◽

Verbal Learning ◽

Lewy Bodies ◽

Target Population ◽

Specificity And Sensitivity

Abstract The present review aimed to examine sensitivity and specificity across neuropsychological tests for Dementia with Lewy Body (DLB), to enhance diagnostic utility. A systematic search of the literature was conducted. Databases used: PsycInfo, Discovery Service for Carlos Albizu University-Miami, PsycARTICLES. Data selection criteria entailed articles from 2010–2020. Search terms included: Dementia with Lewy body, sensitivity, specificity, neuropsychological assessment, neuropsychological testing. Original search yielded 27 results, from those, only 8 articles contained sensitivity and specificity regarding DLB. The target population of review were older adults 65 and older. The assessment measures analyzed were the BSID, HVLT, MMSE QSPT, SAI, MMSE, and ICS, and others. Findings of eight studies were evaluated regarding sensitivity and specificity across neuropsychological assessments for DLB. Among the most specific and sensitive measures were the Alba Screening Instrument (ASI; sensitivity 90.7%, specificity 93.6%), and a combination of the Auditory Verbal Learning Test (AVLT) percent retention, Block Design, Trail Making Test--Part A, and Benton Visual Form Discrimination (specificity 96.1% and sensitivity 88.6%). Lower specificity and sensitivity were found in Illusory contour (ICs-4; specificity and sensitivity of 37.1% and 88.6%) and the Minimental State Examination-Pentagon Test (MMSE-QSPT; specificity 78.67% and sensitivity 70.29%). Other tests and combinations were explored. Specificity ranged from 76% to 96.1%, while sensitivity ranged from 37.1% to 90.7% throughout the neuropsychological tests examined. One major limitation across the studies constituted lack of pathological, post-mortem, confirmation. Additionally, while the use of cutoff scores across assessments appeared to enhance the sensitivity and specificity, it seemed to compromise the diagnostic accuracy of AD.

Download Full-text

Diagnostic accuracy of dopaminergic imaging in prodromal dementia with Lewy bodies

Psychological Medicine ◽

10.1017/s0033291718000995 ◽

2018 ◽

Vol 49 (3) ◽

pp. 396-402 ◽

Cited By ~ 15

Author(s):

Alan J. Thomas ◽

Paul Donaghy ◽

Gemma Roberts ◽

Sean J. Colloby ◽

Nicky A. Barnett ◽

...

Keyword(s):

Diagnostic Accuracy ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Lewy Body Disease ◽

High Specificity ◽

Diagnostic Confidence ◽

Neuropsychological Assessments ◽

Diagnostic Symptoms ◽

Prodromal Dementia

AbstractBackgroundDopaminergic imaging has high diagnostic accuracy for dementia with Lewy bodies (DLB) at the dementia stage. We report the first investigation of dopaminergic imaging at the prodromal stage.MethodsWe recruited 75 patients over 60 with mild cognitive impairment (MCI), 33 with probable MCI with Lewy body disease (MCI-LB), 15 with possible MCI-LB and 27 with MCI with Alzheimer's disease. All underwent detailed clinical, neurological and neuropsychological assessments and FP-CIT [123I-N-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)] dopaminergic imaging. FP-CIT scans were blindly rated by a consensus panel and classified as normal or abnormal.ResultsThe sensitivity of visually rated FP-CIT imaging to detect combined possible or probable MCI-LB was 54.2% [95% confidence interval (CI) 39.2–68.6], with a specificity of 89.0% (95% CI 70.8–97.6) and a likelihood ratio for MCI-LB of 4.9, indicating that FP-CIT may be a clinically important test in MCI where any characteristic symptoms of Lewy body (LB) disease are present. The sensitivity in probable MCI-LB was 61.0% (95% CI 42.5–77.4) and in possible MCI-LB was 40.0% (95% CI 16.4–67.7).ConclusionsDopaminergic imaging had high specificity at the pre-dementia stage and gave a clinically important increase in diagnostic confidence and so should be considered in all patients with MCI who have any of the diagnostic symptoms of DLB. As expected, the sensitivity was lower in MCI-LB than in established DLB, although over 50% still had an abnormal scan. Accurate diagnosis of LB disease is important to enable early optimal treatment for LB symptoms.

Download Full-text

18F-fluorodeoxyglucose positron emission tomography in dementia with Lewy bodies

Brain Communications ◽

10.1093/braincomms/fcaa040 ◽

2020 ◽

Vol 2 (1) ◽

Author(s):

Jonathan Graff-Radford ◽

Timothy G Lesnick ◽

Rodolfo Savica ◽

Qin Chen ◽

Tanis J Ferman ◽

...

Keyword(s):

Lewy Body ◽

Dementia With Lewy Bodies ◽

Rating Scale ◽

Clinical Course ◽

Lewy Bodies ◽

Lewy Body Disease ◽

Diffuse Lewy Body Disease ◽

18F Fluorodeoxyglucose ◽

Alzheimer’S Pathology ◽

Fluorodeoxyglucose Pet

Abstract Among individuals with dementia with Lewy bodies, pathologic correlates of clinical course include the presence and extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease. The objectives of this study are to determine (i) whether 18F-fluorodeoxyglucose PET signature patterns of dementia with Lewy bodies are associated with the extent of coexisting Alzheimer’s pathology and the presence of transitional or diffuse Lewy body disease and (ii) whether these 18F-fluorodeoxyglucose pattern(s) are associated with clinical course in dementia with Lewy bodies. Two groups of participants were included: a pathology-confirmed subset with Lewy body disease (n = 34) and a clinically diagnosed group of dementia with Lewy bodies (n = 87). A subset of the clinically diagnosed group was followed longitudinally (n = 51). We evaluated whether 18F-fluorodeoxyglucose PET features of dementia with Lewy bodies (higher cingulate island sign ratio and greater occipital hypometabolism) varied by Lewy body disease subtype (transitional versus diffuse) and Braak neurofibrillary tangle stage. We investigated whether the PET features were associated with the clinical trajectories by performing regression models predicting Clinical Dementia Rating Scale Sum of Boxes. Among autopsied participants, there was no difference in cingulate island sign or occipital hypometabolism by Lewy body disease type, but those with a lower Braak tangle stage had a higher cingulate island sign ratio compared to those with a higher Braak tangle stage. Among the clinically diagnosed dementia with Lewy bodies participants, a higher cingulate island ratio was associated with better cognitive scores at baseline and longitudinally. A higher 18F-fluorodeoxyglucose PET cingulate island sign ratio was associated with lower Braak tangle stage at autopsy, predicted a better clinical trajectory in dementia with Lewy body patients and may allow for improved prognostication of the clinical course in this disease.

Download Full-text

Analysis of α-synuclein species enriched from cerebral cortex of humans with sporadic dementia with Lewy bodies

Brain Communications ◽

10.1093/braincomms/fcaa010 ◽

2020 ◽

Vol 2 (1) ◽

Cited By ~ 3

Author(s):

John B Sanderson ◽

Suman De ◽

Haiyang Jiang ◽

Matteo Rovere ◽

Ming Jin ◽

...

Keyword(s):

Molecular Weight ◽

Cerebral Cortex ◽

High Molecular Weight ◽

Dementia With Lewy Bodies ◽

Morphological Changes ◽

Lewy Bodies ◽

Small Subset ◽

Causative Role ◽

Human Brain Tissue ◽

Number Of Patients

Abstract Since researchers identified α-synuclein as the principal component of Lewy bodies and Lewy neurites, studies have suggested that it plays a causative role in the pathogenesis of dementia with Lewy bodies and other ‘synucleinopathies’. While α-synuclein dyshomeostasis likely contributes to the neurodegeneration associated with the synucleinopathies, few direct biochemical analyses of α-synuclein from diseased human brain tissue currently exist. In this study, we analysed sequential protein extracts from a substantial number of patients with neuropathological diagnoses of dementia with Lewy bodies and corresponding controls, detecting a shift of cytosolic and membrane-bound physiological α-synuclein to highly aggregated forms. We then fractionated aqueous extracts (cytosol) from cerebral cortex using non-denaturing methods to search for soluble, disease-associated high molecular weight species potentially associated with toxicity. We applied these fractions and corresponding insoluble fractions containing Lewy-type aggregates to several reporter assays to determine their bioactivity and cytotoxicity. Ultimately, high molecular weight cytosolic fractions enhances phospholipid membrane permeability, while insoluble, Lewy-associated fractions induced morphological changes in the neurites of human stem cell-derived neurons. While the concentrations of soluble, high molecular weight α-synuclein were only slightly elevated in brains of dementia with Lewy bodies patients compared to healthy, age-matched controls, these observations suggest that a small subset of soluble α-synuclein aggregates in the brain may drive early pathogenic effects, while Lewy body-associated α-synuclein can drive neurotoxicity.

Download Full-text

In dementia with Lewy bodies, Braak stage determines phenotype, not Lewy body distribution

Neurology ◽

10.1212/01.wnl.0000266626.64913.0f ◽

2007 ◽

Vol 69 (4) ◽

pp. 356-359 ◽

Cited By ~ 59

Author(s):

D. Weisman ◽

M. Cho ◽

C. Taylor ◽

A. Adame ◽

L. J. Thal ◽

...

Keyword(s):

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Braak Stage ◽

Body Distribution

Download Full-text

Insular cortex sub-region-dependent distribution pattern of α-synuclein immunoreactivity in Parkinson’s disease and dementia with Lewy bodies

10.1101/156984 ◽

2017 ◽

Author(s):

Yasmine Y. Fathy ◽

Frank Jan de Jong ◽

Anne-Marie van Dam ◽

Annemieke J.M. Rozemuller ◽

Wilma D.J. van de Berg

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Distribution Pattern ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Insular Cortex ◽

Disease Stage ◽

Incidental Lewy Body Disease ◽

Lewy Body Diseases

AbstractThe insular cortex is a heterogeneous and widely connected brain region. It plays a role in autonomic, cognitive, emotional and somatosensory functions. Its complex and unique cytoarchitecture includes a periallocortical agranular, pro-isocortical dysgranular, and isocortical granular sub-regions. In Parkinson’s disease (PD), the insula shows α-synuclein inclusions in advanced stages of the disease and its atrophy correlates with cognitive deficits. However, little is known regarding its regional neuropathological characteristics and vulnerability in Lewy body diseases. The aim of this study is to assess the distribution pattern of α-synuclein pathology in the insular sub-regions and the selective vulnerability of its different cell types in PD and dementia with Lewy bodies (DLB). Human post-mortem insular tissues from 10 donors with incidental Lewy body disease (iLBD), PD, DLB, and age-matched controls were immunostained for α-synuclein and glial fibrillary acid protein (GFAP). Results showed that a decreasing gradient of α-synuclein pathology was present from agranular to granular sub-regions in iLBD, PD and PD with dementia (PDD) donors. The agranular insula was heavily inflicted, revealing various α-synuclein immunoreactive morphological structures, predominantly Lewy neurites (LNs), and astroglial synucleinopathy. While dysgranular and granular sub-regions showed a decreasing gradient of inclusions and more Lewy bodies (LBs) in deeper layers. In DLB, this gradient was less pronounced and severe pathology was observed in the granular insula compared to PDD and regardless of disease stage. Protoplasmic astrocytes showed α-synuclein inclusions and severe degenerative changes increasing with disease severity. While few von Economo neurons (VENs) in the fronto-insular region revealed inclusions, particularly in PDD patients. Our study reports novel findings on the differential involvement of the insular sub-regions in PD and particular involvement of the agranular sub-region, VENs and astrocytes. Thus, the differential cellular architecture of the insular sub-regions portrays the topographic variation and vulnerability to α-synuclein pathology in Lewy body diseases.

Download Full-text

Parkinsonism and Related Dementias

10.1093/med/9780197512166.003.0079 ◽

2021 ◽

pp. 680-688

Author(s):

Rodolfo Savica ◽

Pierpaolo Turcano ◽

Bradley F. Boeve

Keyword(s):

Differential Diagnosis ◽

Parkinson Disease ◽

Progressive Supranuclear Palsy ◽

Frontotemporal Dementia ◽

Lewy Body ◽

Dementia With Lewy Bodies ◽

Lewy Bodies ◽

Corticobasal Degeneration ◽

Corticobasal Syndrome ◽

Progressive Course

The differential diagnosis for dementia is wide. A slowly progressive course for parkinsonism suggests a degenerative cause and helps to narrow the differential diagnosis considerably. In patients with dementia in combination with parkinsonism (often collectively termed the parkinsonism-related dementias), the 4 most common neurodegenerative entities are 1) Lewy body dementias (which include dementia with Lewy bodies and Parkinson disease with dementia); 2) corticobasal syndrome or corticobasal degeneration; 3) Richardson syndrome or progressive supranuclear palsy; and 4) frontotemporal dementia with parkinsonism.

Download Full-text