Neurobiology of Lewy Body Dementias

Author(s):  
James E. Galvin ◽  
Jose Tomas Bras

Lewy body dementia (LBD) is the second most common form of neurocognitive disorder after Alzheimer’s disease and covers two related diagnoses: Dementia with Lewy Bodies and Parkinson’s Disease Dementia. Despite being a common disorder, diagnosis outside expert academic centers remains a significant challenge. The core pathological feature of LBD is the cortical Lewy body; however, many cases will have coexistent Alzheimer disease pathology. Genetic risk factors for LBD include mutations in genes for alpha-synuclein (SNCA) and galactocerbrosidase (GBA). Dopamine transporter imaging remains the most sensitive but platforms for measuring alpha-synuclein are being developed. Current therapies focus on symptomatic relief but experimental cell and animal models are providing new insights for the development of disease-modifying therapeutics.

2021 ◽  
Author(s):  
Ivan A Kuznetsov ◽  
Andrey V Kuznetsov

This paper reports a minimal model simulating the growth of a Lewy body (LB). The LB is assumed to consist of a central spherical core, which is composed of membrane fragments and various dysfunctional intracellular organelles, and a halo, which is composed of alpha-synuclein fibrils. Membrane fragments and alpha-synuclein monomers are assumed to be produced in the soma at constant rates. The growth of the core and the halo are simulated by the Finke-Watzky model. Analytical solutions describing the growth of the core and the halo are obtained.


BJPsych Open ◽  
2020 ◽  
Vol 6 (4) ◽  
Author(s):  
Ajenthan Surendranathan ◽  
Joseph P. M. Kane ◽  
Allison Bentley ◽  
Sally A. H. Barker ◽  
John-Paul Taylor ◽  
...  

Background Lewy body dementia, consisting of both dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), is considerably under-recognised clinically compared with its frequency in autopsy series. Aims This study investigated the clinical diagnostic pathways of patients with Lewy body dementia to assess if difficulties in diagnosis may be contributing to these differences. Method We reviewed the medical notes of 74 people with DLB and 72 with non-DLB dementia matched for age, gender and cognitive performance, together with 38 people with PDD and 35 with Parkinson's disease, matched for age and gender, from two geographically distinct UK regions. Results The cases of individuals with DLB took longer to reach a final diagnosis (1.2 v. 0.6 years, P = 0.017), underwent more scans (1.7 v. 1.2, P = 0.002) and had more alternative prior diagnoses (0.8 v. 0.4, P = 0.002), than the cases of those with non-DLB dementia. Individuals diagnosed in one region of the UK had significantly more core features (2.1 v. 1.5, P = 0.007) than those in the other region, and were less likely to have dopamine transporter imaging (P < 0.001). For patients with PDD, more than 1.4 years prior to receiving a dementia diagnosis: 46% (12 of 26) had documented impaired activities of daily living because of cognitive impairment, 57% (16 of 28) had cognitive impairment in multiple domains, with 38% (6 of 16) having both, and 39% (9 of 23) already receiving anti-dementia drugs. Conclusions Our results show the pathway to diagnosis of DLB is longer and more complex than for non-DLB dementia. There were also marked differences between regions in the thresholds clinicians adopt for diagnosing DLB and also in the use of dopamine transporter imaging. For PDD, a diagnosis of dementia was delayed well beyond symptom onset and even treatment.


SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A330-A330
Author(s):  
Rupa Koothirezhi ◽  
Pratibha Anne ◽  
Minh Tam Ho ◽  
Brittany Monceaux ◽  
Cesar Liendo ◽  
...  

Abstract Introduction Dementia with Lewy bodies (DLB) is one of the most common types of degenerative dementia after Alzheimer’s dementia. The core clinical features for diagnosis includes cognitive fluctuations, visual hallucinations, rapid eye movement (REM) sleep behavior disorder (RBD), and parkinsonism. Other symptoms include daytime drowsiness, longer daytime naps, prolonged staring spells, and episodes of disorganized speech. REM behavioral disorder (RBD) is commonly associated with DLB, occurring in 85 percent of individuals, often early in the course of the disease. It can precede the clinical diagnosis of DLB by up to 20 years. Report of case(s) A seventy-six-year-old female with a history of well controlled obstructive sleep apnea was diagnosed with REM behavioral disorder in 2012. She had presented with episodes of screaming, attempt to ambulate during sleep, resulting in injury. Her polysomnogram revealed evidence of REM without atonia and a screaming episode during REM. Her RBD symptoms were controlled with clonazepam and melatonin with less frequency of the RBD episodes. The patient gradually started noticing memory issues and by January 2020 she was diagnosed with dementia and was initiated on Aricept. Within 7 months of diagnosis of dementia, she started reporting vivid hallucinations that were not threatening or violent compared to her violent content of RBD. Physical exam revealed impaired cognitive function and mild intermittent resting tremor of the right hand. The neurological exam was normal including normal tone, strength, and gait. She also reported repeated falls and fractures. The diagnosis of Lewy body dementia was made based on the presence of 2 core clinical features. Conclusion The current management of these conditions is mainly symptomatic. In the evolution of neurodegenerative disorder, RBD precedes other conditions like LBD, parkinsonism, etc. Research suggests that alpha-synuclein neurodegeneration is the common pathology behind these conditions. The understanding that RBD presents at the beginning of the evolution, provides us with a unique opportunity for preemptive treatment to prevent further degeneration in turn preventing the debilitation consequence like dementia, parkinsonism, neuroleptic sensitivity, and dysautonomia. Further research is needed for developing these early interventional strategies. Support (if any) NOne


Author(s):  
Rahel Feleke ◽  
Regina H. Reynolds ◽  
Amy M. Smith ◽  
Bension Tilley ◽  
Sarah A. Gagliano Taliun ◽  
...  

AbstractParkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB) are three clinically, genetically and neuropathologically overlapping neurodegenerative diseases collectively known as the Lewy body diseases (LBDs). A variety of molecular mechanisms have been implicated in PD pathogenesis, but the mechanisms underlying PDD and DLB remain largely unknown, a knowledge gap that presents an impediment to the discovery of disease-modifying therapies. Transcriptomic profiling can contribute to addressing this gap, but remains limited in the LBDs. Here, we applied paired bulk-tissue and single-nucleus RNA-sequencing to anterior cingulate cortex samples derived from 28 individuals, including healthy controls, PD, PDD and DLB cases (n = 7 per group), to transcriptomically profile the LBDs. Using this approach, we (i) found transcriptional alterations in multiple cell types across the LBDs; (ii) discovered evidence for widespread dysregulation of RNA splicing, particularly in PDD and DLB; (iii) identified potential splicing factors, with links to other dementia-related neurodegenerative diseases, coordinating this dysregulation; and (iv) identified transcriptomic commonalities and distinctions between the LBDs that inform understanding of the relationships between these three clinical disorders. Together, these findings have important implications for the design of RNA-targeted therapies for these diseases and highlight a potential molecular “window” of therapeutic opportunity between the initial onset of PD and subsequent development of Lewy body dementia.


2021 ◽  
Author(s):  
James E. Galvin ◽  
Stephanie Chrisphonte ◽  
Iris Cohen ◽  
Keri K. Greenfield ◽  
Michael J. Kleiman ◽  
...  

2021 ◽  
Vol 23 (5) ◽  
pp. 1-8
Author(s):  
Alison Killen

Background Lewy body dementia is the second most common form of age-related neurodegenerative dementia. It has two forms: dementia with Lewy bodies and Parkinson's disease dementia. Methods There are specific core symptoms associated with dementia with Lewy bodies. Optimum care requires awareness of the features associated with these, as well as appropriate support and management strategies, which are provided in this article. Results The core features of dementia with Lewy bodies are visual hallucinations, cognitive fluctuations, Parkinsonism and rapid eye movement sleep behaviour disorder. Appropriate psychosocial strategies includes psychoeducation, social support and environmental modification. Adoption of these approaches can reduce adverse outcomes. Conclusions The core features of dementia with Lewy bodies can significantly impair quality of life. Nursing and residential care staff are ideally placed to address this through the implementation of psychosocial strategies both directly, and through the provision of psychoeducation for family caregivers.


Author(s):  
Jagan A. Pillai ◽  
James B. Leverenz

This chapter discusses the Pathogenesis of Lew Body Dementia. The Lewy body dementias (LBDs) are a spectrum of dementing neurodegenerative disorders underpinned by the pathological accumulation of α- synuclein protein in both intraneuronal inclusions, “Lewy bodies, ” and neuronal processes, “Lewy neurites”. The chapter concludes that, as with other forms of cognitive impairment in the aged, the pathophysiology of cognitive impairment in LBD is likely multifactorial. Although it appears that α- synuclein pathology, particularly in the limbic and neocortical regions are linked to cognitive changes, other pathologies such as AD likely also play a role. Emphasizing the complexity, a number of genetic factors have been implicated in the LBDs, some specifically with associations to the synucleinopathies and some with other pathophysiologic processes. This complexity will need to be considered as therapeutic interventions are evaluated for the LBD.


1998 ◽  
Vol 4 (6) ◽  
pp. 360-363 ◽  
Author(s):  
E. Jane Byrne

Dementia with cortical Lewy bodies (LBD) was first described by Okazakiet alin 1961 and is now recognised as a relatively common cause of the dementia syndrome. The true prevalence of LBD is unknown. In post-mortem studies of patients diagnosed as having dementia in life, the mean frequency of Lewy body dementia is 12.5% (Byrne, 1997). Clinically diagnosed LBD (using operational clinical criteria) is found in 10–23% of patients presenting to, or in the care of, psychogeriatric services (Collertonet al, 1996). What is not yet certain is its nosological status; opinion is divided between regarding it as a variety of Alzheimer's disease (the Lewy body variant), a distinct disease (senile dementia of the Lewy body type) or a spectrum disorder related to both Parkinson's disease and to Alzheimer's disease (Byrne, 1992).


2017 ◽  
Author(s):  
Luis R. Peraza ◽  
Ruth Cromarty ◽  
Xenia Kobeleva ◽  
Michael J. Firbank ◽  
Alison Killen ◽  
...  

AbstractDementia with Lewy bodies (DLB) and Alzheimer’s disease (AD) require differential management despite presenting with symptomatic overlap. A human electrophysiological difference is a decrease of dominant frequency (DF) −the highest power frequency between 4-15Hz– in DLB; a characteristic of Parkinsonian diseases. We analysed electroencephalographic (EEG) recordings from old adults: healthy controls (HCs), AD, DLB and Parkinson’s disease dementia (PDD) patients. Brain networks were assessed with the minimum spanning tree (MST) within six EEG bands: delta, theta, high-theta, alpha, beta and DF. Patients showed lower alpha band connectivity and lower DF than HCs. Lewy body dementias showed a randomised MST compared with HCs and AD in high-theta and alpha but not within the DF. The MST randomisation in DLB and PDD reflects decreased brain efficiency as well as impaired neural synchronisation. However, the lack of network topology differences at the DF indicates a compensatory response of the brain to the neuropathology.


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