Lumateperone for treatment of psychotic symptoms in Lewy body disease: A case report.

Individuals experiencing Lewy body disease (LBD) are particularly vulnerable to the adverse effects of neuroleptics. This sensitivity has been employed by some authorities as a diagnostic component for this disorder. At present, we do not have any Food and Drug Administration-approved antipsychotic for the management of psychotic symptoms in this condition. We present the first case of an LBD patient, showing favorable response in psychotic symptoms with lumateperone, a novel atypical neuroleptic. Our report revealed improvements in cognition, psychosis, and sleep following the initiation of lumateperone without concurrent emergence of extrapyramidal side effects, autonomic instability, parkinsonian features, or cognitive decline, which are typically seen when treated with available antipsychotic medications. Clinicians may wish to consider potential usefulness of lumateperone when managing patients with this disabling condition. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Pimavanserin Treatment for Psychosis in Patients with Dementia with Lewy Bodies: A Case Series.

BACKGROUND Many patients with dementia with Lewy bodies (DLB) experience cholinesterase inhibitor- and antipsychotic-resistant psychosis. The new second-generation antipsychotic pimavanserin has been used with some success in the treatment of psychosis in other forms of dementia, including Alzheimer disease and Parkinson disease dementia. It is possible that pimavanserin may also be useful in the treatment of psychosis in DLB. We sought to describe the disease course and treatment of psychosis in 4 patients with DLB who were prescribed pimavanserin after other medications failed to reduce the frequency or severity of hallucinations and delusions. CASE REPORT This is a case series of 4 male patients (ages 56 to 74 at the beginning of the reports) who developed DLB and psychosis (eg, visual illusions, visual and olfactory hallucinations, and paranoid delusions). All 4 patients were prescribed cholinesterase inhibitors (eg, donepezil or rivastigmine) prior to pimavanserin, and only 1 patient experienced improved psychosis while on cholinesterase inhibitors. All 3 patients who were prescribed first-generation antipsychotics (eg, haloperidol) or traditional second-generation antipsychotics (eg, olanzapine, risperidone, or quetiapine) experienced initial or lasting side effects with no improvement of psychosis. Conversely, all 4 patients tolerated pimavanserin well, and 3 of the 4 patients experienced significant improvement of psychosis (eg, fewer hallucinations, fewer delusions, reduced paranoia, and/or reduced distress or agitation related to hallucinations and delusions) when prescribed pimavanserin. CONCLUSIONS This case series suggests that pimavanserin is tolerable in older males with DLB and that it may be useful for the reduction of distressful hallucinations, delusions, and paranoia in patients with DLB.

Editorial for the Special Issue "Animal Models of Parkinson's Disease and Related Disorders".

Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by age-dependent motor dysfunction and degeneration of the midbrain dopaminergic neurons [...].

Transmission of Soluble and Insoluble α-Synuclein to Mice.

The neurodegenerative synucleinopathies, which include Parkinson disease, multiple-system atrophy, and Lewy body disease, are characterized by the presence of abundant neuronal inclusions called Lewy bodies and Lewy neurites. These disorders remain incurable, and a greater understanding of the pathologic processes is needed for effective treatment strategies to be developed. Recent data suggest that pathogenic misfolding of the presynaptic protein, α-synuclein (α-syn), and subsequent aggregation and accumulation are fundamental to the disease process. It is hypothesized that the misfolded isoform is able to induce misfolding of normal endogenous α-syn, much like what occurs in the prion diseases. Recent work highlighting the seeding effect of pathogenic α-syn has largely focused on the detergent-insoluble species of the protein. In this study, we performed intracerebral inoculations of the sarkosyl-insoluble or sarkosyl-soluble fractions of human Lewy body disease brain homogenate and show that both fractions induce CNS pathology in mice at 4 months after injection. Disease-associated deposits accumulated both near and distal to the site of the injection, suggesting a cell-to-cell spread via recruitment of α-syn. These results provide further insight into the prion-like mechanisms of α-syn and suggest that disease-associated α-syn is not homogeneous within a single patient but might exist in both soluble and insoluble isoforms.

Patterns of anti-inflammatory drug use and risk of dementia: a matched case-control study.

BACKGROUND AND PURPOSE: There is limited primary-care-based evidence about a potential association between anti-inflammatory therapy and dementia subtypes. The present study addressed this limitation by using electronic health records from a large primary care database. METHOD: A case-control study was implemented using electronic medical records. Cases had a diagnosis of dementia between 1992 and 2014. Up to four controls matched on age, gender, family practice and index date were selected for each case. Use of non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoid drugs represented the exposure variables. Primary outcome measures included all-cause dementia and main dementia subtypes, including Alzheimer disease (AD), vascular dementia (VaD) and Lewy body dementia (LBD). Data were analysed using conditional logistic regression. RESULTS: The study identified 31,083 patients with AD, 23,465 with VaD and 1694 with LBD. Ever-used NSAIDs were associated with a modest increase in the risk of all-cause dementia (odds ratio 1.04, 95% confidence interval 1.02-1.05, P < 0.006), whilst no association was apparent for ever-used glucocorticoids (0.98, 0.96-1.01, P = 0.152). There was no evidence for an association between NSAIDs and AD (1.03, 0.99-1.06, P = 0.07) or LBD (1.13, 0.99-1.29, P = 0.08). However, a significant increase in the risk for VaD (1.33, 1.29-1.38, P < 0.001) was observed. Similar patterns emerged for glucocorticoid therapy. CONCLUSION: In a large primary care population, there was no robust evidence for a potential association between anti-inflammatory drugs and risk of AD or LBD. NSAIDs and glucocorticoid drugs were associated with higher risk of VaD.

α-Synuclein strains cause distinct synucleinopathies after local and systemic administration.

Misfolded protein aggregates represent a continuum with overlapping features in neurodegenerative diseases, but differences in protein components and affected brain regions. The molecular hallmark of synucleinopathies such as Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are megadalton α-synuclein-rich deposits suggestive of one molecular event causing distinct disease phenotypes. Glial α-synuclein (α-SYN) filamentous deposits are prominent in multiple system atrophy and neuronal α-SYN inclusions are found in Parkinson's disease and dementia with Lewy bodies. The discovery of α-SYN assemblies with different structural characteristics or 'strains' has led to the hypothesis that strains could account for the different clinico-pathological traits within synucleinopathies. In this study we show that α-SYN strain conformation and seeding propensity lead to distinct histopathological and behavioural phenotypes. We assess the properties of structurally well-defined α-SYN assemblies (oligomers, ribbons and fibrils) after injection in rat brain. We prove that α-SYN strains amplify in vivo. Fibrils seem to be the major toxic strain, resulting in progressive motor impairment and cell death, whereas ribbons cause a distinct histopathological phenotype displaying Parkinson's disease and multiple system atrophy traits. Additionally, we show that α-SYN assemblies cross the blood-brain barrier and distribute to the central nervous system after intravenous injection. Our results demonstrate that distinct α-SYN strains display differential seeding capacities, inducing strain-specific pathology and neurotoxic phenotypes.

Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice.

The accumulation of misfolded proteins is a fundamental pathogenic process in neurodegenerative diseases. However, the factors that trigger aggregation of α-Synuclein (α-Syn), the principal component of the intraneuronal inclusions known as Lewy bodies (LBs), and Lewy neurites (LNs), which characterize Parkinson's disease (PD) and dementia with LBs (DLB), are poorly understood. We show here that in young asymptomatic α-Syn transgenic (Tg) mice, intracerebral injections of brain homogenates derived from older Tg mice exhibiting α-Syn pathology accelerate both the formation of intracellular LB/LN-like inclusions and the onset of neurological symptoms in recipient animals. Pathological α-Syn propagated along major central nervous system (CNS) pathways to regions far beyond injection sites and reduced survival with a highly reproducible interval from injection to death in inoculated animals. Importantly, inoculation with α-Syn amyloid fibrils assembled from recombinant human α-Syn induced identical consequences. Furthermore, we show for the first time that synthetic α-Syn fibrils are wholly sufficient to initiate PD-like LBs/LNs and to transmit disease in vivo. Thus, our data point to a prion-like cascade in synucleinopathies whereby cell-cell transmission and propagation of misfolded α-Syn underlie the CNS spread of LBs/LNs. These findings open up new avenues for understanding the progression of PD and for developing novel therapeutics.

Proteasomal abnormalities in cortical Lewy body disease and the impact of proteasomal inhibition within cortical and cholinergic systems.

Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex -- marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for alpha-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.

Exacerbation of Lewy bodies dementia due to memantine.

INTRODUCTION: Lewy body dementia (DLB) is common but frequently misdiagnosed as Alzheimer's disease plus delirium or parkinsonism. DRUGS USED IN THIS DISORDER CAN CAUSE EXACERBATIONS: neuroleptic medication is relatively contraindicated because some patients show severe neuroleptic sensitivity, antiparkinsonian medication has the potential to exacerbate psychotic symptoms, and even cholinesterase inhibitors, while relatively safe, have provoked adverse responses in some DLB patients. There are few data available about the use of memantine in DLB. CASE PRESENTATION: A 74-year-old man was diagnosed with Alzheimer disease and parkinsonism. After memantine was started he developed severe fluctuations in awareness, visual hallucinations, agitation, and worsened parkinsonism. When he was evaluated thoroughly, the diagnosis was revised to Lewy body dementia, leading to changes in treatment that were associated with dramatic improvement in the patient's mental status. CONCLUSIONS: In our patient, motor and cognitive symptoms worsened with memantine treatment; these resolved after memantine was discontinued.