The Lessebo Effect in Disease Modification Trials in Parkinson's Disease

Background

The impact of expectation of benefit on outcomes is well established in Parkinson's disease (PD). A reduction of a treatment effect due to a perceived placebo allocation (lessebo effect) in randomized controlled trials (RCTs) was documented for symptomatic treatments.

Objectives

To evaluate the lessebo effect in disease modification RCTs (DMT) in PD.

Methods

Subject-level meta-analyses of active treatment arms of DMT (n = 1149 subjects): FS-1, FS-TOO (probability of placebo allocation/P_(placebo) = 0.33) and DATATOP, PRECEPT, QE2 (P_(placebo) = 0.25). We tested the association between P_(placebo) and time to dopaminergic treatment initiation using a marginal Cox proportional hazards model.

Results

The adjusted hazard ratio (P_(placebo) = 0.25 vs. 0.33) for initiation of dopaminergic treatment was 1.15 (95% CI: 0.92–1.43).

Conclusions

We did not observe the lessebo effect in DMT. The necessary use of a placebo (and no active comparator) is a limitation. The prospective measurement of expectation of benefit could help to evaluate the many impacts of placebo use. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

脑血管病和锥体外系疾病的神经保护治疗

许多神经系统疾病都能造成神经功能障碍，如不及时治疗，可能会造成不可逆的神经损伤。因此，神经保护治疗越来越受到人们的重视。无论是采用物理方法，还是神经保护剂，均可以降低疾病对神经的损伤，促进神经功能的恢复。本文仅就脑血管病和锥体外系病变的神经保护治疗作一综述。     

Creutzfeldt－Jakob病与Alzheimer病并存

本文报告１例病程长达１２年，经组织病理与免疫组化染色方法证实的Ｃｒｅｕｔｚｆｅｌｄｔ－Ｊａｋｏｂ病与Ａｌｚｈｅｉｍｅｒ病并存病例。     

Dementia in Parkinson Disease

In 520 patients with parkinsonism seen over eight years, 168 (32%) had moderate to marked dementia. Although the demented patients were older than the nondemented patients (70.4 versus 65.5 years), the incidence of dementia in Parkinson's disease (PD) was tenfold higher than among controls (similarly aged spouses of PD patients), and dementia is held to be related more to the disease than to age. Demented patients, in addition to being older, developed PD later, were more severely involved in a shorter time, and responded less well to levodopa. It is suggested that PD with dementia may represent a different disorder from PD without dementia.     

Psychoses in Parkinson's Disease

Psychotic symptoms occur in up to 40% of patients with Parkinson's disease (PD) and other degenerative parkinsonian disorders, usually but not exclusively in the context of their pharmacologic treatment. We describe the following six psychotic syndromes in PD based on existing literature: (1) hallucinations with preserved insight; (2) medication-induced psychotic disorders (in clear consciousness); (3) delirium; (4) schizophrenia-like psychotic disorders (in clear consciousness and in the absence of medication treatment); (5) schizophrenia with subsequent development of PD; and (6) other psychotic disorders. Psychosis in PD has been noted to be a marker for illness deterioration. Psychotic symptoms can profoundly affect the quality of life for PD patients and their families and may increase the economic burden of this illness. Various approaches have been used to treat psychotic symptoms in PD. We critically review this literature, which is limited, but includes studies indicating promise for "atypical" antipsychotics in these patients. Further elucidation of the phenomenology, course, pathophysiology, and treatment of the different psychotic disorders in PD is urgently needed.     

Exosomes in Viral Disease

Viruses have evolved many mechanisms by which to evade and subvert the immune system to ensure survival and persistence. However, for each method undertaken by the immune system for pathogen removal, there is a counteracting mechanism utilized by pathogens. The new and emerging role of microvesicles in immune intercellular communication and function is no different. Viruses across many different families have evolved to insert viral components in exosomes, a subtype of microvesicle, with many varying downstream effects. When assessed cumulatively, viral antigens in exosomes increase persistence through cloaking viral genomes, decoying the immune system, and even by increasing viral infection in uninfected cells. Exosomes therefore represent a source of viral antigen that can be used as a biomarker for disease and targeted for therapy in the control and eradication of these disorders. With the rise in the persistence of new and reemerging viruses like Ebola and Zika, exploring the role of exosomes become more important than ever.     

Exosomes in Parkinson's Disease

Exosomes, nano-sized extracellular vesicles secreted by most cell types, are found in all kinds of biological fluids and tissues, including the central nervous system(CNS). The proposed functions of these vesicles include roles in cell–cell signaling, removal of cellular debris, and transfer of pathogens between cells. Many studies have revealed that exosomes derived from the CNS occur in the cerebrospinal fluid and peripheral body fluids,and their contents are altered during disease, making them an appealing target for biomarker development in Parkinson's disease(PD). Exosomes have been shown to spread toxic a-synuclein(asyn) between cells and induce apoptosis, which suggests a key mechanism underlying the spread of asyn aggregates in the brain and the acceleration of pathology in PD. However, potential neuroprotective roles of exosomes in PD have also been reported. On the treatment side, as drug delivery vehicles, exosomes have been used to deliver small interfering RNAs and catalase to the brain, and have shown clear therapeutic effects in a mouse model of PD. These features of exosomes in PD make them extremely interesting from the point of view of developing novel diagnostic and therapeutic approaches.     

Functional Ability in Executive Variant Alzheimer's Disease and Typical Alzheimer's Disease

A frontal, or executive, variant of Alzheimer's disease (EAD) has been described in the literature in which frontal dysfunction accompanies temporal and parietal changes in the early stages of the illness. However, no study has empirically investigated associated aspects, such as neuropsychiatric symptoms, instrumental activities of daily living, or caregiver burden in this EAD subgroup. We compared the performance of two subgroups of mild Alzheimer's disease patients (e.g., EAD and typical Alzheimer's disease; TAD) on neuropsychological and associated measures. Results revealed that the EAD group, selected based on poor executive scores, did not significantly differ from the TAD group on nonexecutive neuropsychological tests of intelligence, language, verbal and nonverbal memory, or visual-spatial abilities. However, the EAD group evidenced more severe neuropsychiatric symptoms, impaired activities of daily living, and greater caregiver distress than the TAD group. Thus, the EAD subgroup is characterized by executive dysfunction, neuropsychiatric symptoms, and functional disability in excess of that seen in TAD. Whether our EAD subgroup represents an actual frontal variant of Alzheimer's disease awaits replication in a larger sample including neuroimaging and pathological confirmation, as well as longitudinal assessment of cognition and neuropsychiatric symptoms.