Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Dementia: Dementia Types.

Dementia, also called major neurocognitive disorder, is characterized by a chronic progressive loss of cognitive function in the absence of fluctuating consciousness. It represents a primarily geriatric syndrome that may be caused by one of several underlying conditions. There is insufficient evidence to support universal screening for cognitive impairment in older adults; however, clinicians should be alert to patient and caregiver concerns about cognitive changes and investigate such concerns with validated cognitive assessment tools. Alzheimer disease is the leading cause and prototypical form of dementia, presenting insidiously and causing progressive cognitive impairment with increasing severity over a period of years. Vascular dementia is the second most common form of dementia and often co-occurs with other progressive cognitive disorders. Lewy body dementias encompass Parkinson disease dementia and dementia with Lewy bodies, which have similar features and are differentiated primarily by the order of motor and cognitive symptom onset. Frontotemporal dementias occur earlier than other forms of dementia, progress rapidly, and often have a genetic component. An understanding of the conditions that cause dementia will assist clinicians in making an accurate diagnosis and providing appropriate treatment recommendations and counseling regarding the diagnosis and prognosis.

Depression in dementia with Lewy bodies: a critical update.

Depression with an estimated prevalence of 35% is a frequent manifestation of dementia with Lewy bodies (DLB), having negative effects on cognitive performance and life expectancy, yet the underlying neurobiology is poorly understood and most likely heterogeneous. Depressive symptoms in DLB can occur during the clinical course and, together with apathy, is a common prodromal neuropsychiatric symptom of this neurocognitive disorder in the group of Lewy body synucleinopathies. There are no essential differences in the frequency of depression in DLB and Parkinson disease-dementia (PDD), while its severity is up to twice as high as in Alzheimer disease (AD). Depression in DLB that is frequently underdiagnosed and undertreated, has been related to a variety of pathogenic mechanisms associated with the basic neurodegenerative process, in particular dysfunctions of neurotransmitter systems (decreased monoaminergic/serotonergic, noradrenergic and dopaminergic metabolism), α-synuclein pathology, synaptic zinc dysregulation, proteasome inhibition, gray matter volume loss in prefrontal and temporal areas as well as dysfunction of neuronal circuits with decreased functional connectivity of specific brain networks. Pharmacotherapy should avoid tricyclic antidepressants (anticholinergic adverse effects), second-generation antidepressants being a better choice, while modified electroconvulsive therapy, transcranial magnetic stimulation therapy and deep brain stimulation may be effective for pharmacotherapy-resistant cases. Since compared to depression in other dementias like Alzheimer disease and other parkinsonian syndromes, our knowledge of its molecular basis is limited, and further studies to elucidate the heterogeneous pathogenesis of depression in DLB are warranted.

The Mechanisms of the Roles of α-Synuclein, Amyloid-ß, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics.

Lewy body diseases (LBD) are pathologically defined as the accumulation of Lewy bodies composed of an aggregation of α-synuclein (αSyn). In LBD, not only the sole aggregation of αSyn but also the co-aggregation of amyloidogenic proteins, such as amyloid-ß (Aß) and tau, has been reported. In this review, the pathophysiology of co-aggregation of αSyn, Aß, and tau protein and the advancement in imaging and fluid biomarkers that can detect αSyn and co-occurring Aß and/or tau pathologies are discussed. Additionally, the αSyn-targeted disease-modifying therapies in clinical trials are summarized.

Biomarkers of diagnosis, prognosis, pathogenesis, response to therapy: Convergence or divergence? Lessons from Alzheimer's disease and synucleinopathies.

Alzheimer's disease (AD) is the most common disorder associated with cognitive impairment. Recent observations emphasize the pathogenic role of multiple factors inside and outside the central nervous system, supporting the notion that AD is a syndrome of many etiologies rather than a "heterogeneous" but ultimately unifying disease entity. Moreover, the defining pathology of amyloid and tau coexists with many others, such as α-synuclein, TDP-43, and others, as a rule, not an exception. Thus, an effort to shift our AD paradigm as an amyloidopathy must be reconsidered. Along with amyloid accumulation in its insoluble state, ß-amyloid is becoming depleted in its soluble, normal states, as a result of biological, toxic, and infectious triggers, requiring a shift from convergence to divergence in our approach to neurodegeneration. These aspects are reflected-in vivo-by biomarkers, which have become increasingly strategic in dementia. Similarly, synucleinopathies are primarily characterized by abnormal deposition of misfolded α-synuclein in neurons and glial cells and, in the process, depleting the levels of the normal, soluble α-synuclein that the brain needs for many physiological functions. The soluble to insoluble conversion also affects other normal brain proteins, such as TDP-43 and tau, accumulating in their insoluble states in both AD and dementia with Lewy bodies (DLB). The two diseases have been distinguished by the differential burden and distribution of insoluble proteins, with neocortical phosphorylated tau deposition more typical of AD and neocortical α-synuclein deposition peculiar to DLB. We propose a reappraisal of the diagnostic approach to cognitive impairment from convergence (based on clinicopathologic criteria) to divergence (based on what differs across individuals affected) as a necessary step for the launch of precision medicine.

Exosomes for the diagnosis and treatment of dementia.

PURPOSE OF REVIEW: Dementia is a syndrome with several possible pathologies. To date, definitive methods for diagnosis and treatment of sub-types of dementia have not been established. Emerging evidence suggests that exosomes can provide important information for the diagnosis and treatment of several subtypes of dementia. This article reviews recent studies on the application of exosomes in dementia. RECENT FINDINGS: Exosomes are involved in the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD) through transporting toxic proteins such as amyloid beta (Aß), tau, and α-synuclein. Exosomal microRNAs (miR) and proteins reflect the disease state, and therefore, exosomes can be used as diagnostic markers for diseases such as AD, PD, Huntington's disease (HD), vascular dementia (VaD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD). Mesenchymal stem cell (MSC)-derived exosomes have been shown to ameliorate disease pathology, and improve cognitive function in AD, PD, and VAD. SUMMARY: Recent studies have shown that exosomes could be novel diagnostic agents for dementia because they contain molecules that could be potential biomarker candidates indicative of the type and stage of dementia. Therapeutic application of exosomes in dementia has revealed that exosomes only, or exosomes loaded with an active pharmaceutical ingredient (API), ameliorate disease phenotype of dementia. Further work is needed to exploit this potential.

Recent advances in Lewy body dementia: A comprehensive review.

Lewy Body Dementia is the second most frequent neurodegenerative illness proven to cause dementia, after Alzheimer's disease (AD). It is believed to be vastly underdiagnosed, as there is a significant disparity between the number of cases diagnosed clinically and those diagnosed via neuropathology at the time of postmortem autopsy. Strikingly, many of the pharmacologic treatments used to treat behavioral and cognitive symptoms in other forms of dementia exacerbate the symptoms of DLB. Therefore, it is critical to accurately diagnose DLB as these patients require a specific treatment approach. This article focuses on its pathophysiology, risk factors, differentials, and its diverse treatment modalities. In this study, an English language literature search was conducted on Medline, Cochrane, Embase, and Google Scholar till April 2022. The following search strings and Medical Subject Headings (MeSH) terms were used: "Lewy Body Dementia," "Dementia with Lewy bodies," and "Parkinson's Disease Dementia." We explored the literature on Lewy Body Dementia for its epidemiology, pathophysiology, the role of various genes and how they bring about the disease, biomarkers, its differential diagnoses and treatment options.

Challenges in diagnosis and management of delirium in Lewy body disease.

BACKGROUND: Delirium is an acute onset and fluctuating impairment of cognition, attention and arousal, often precipitated by acute illness. Lewy body disease (LBD) is an umbrella term for a range of clinical conditions, including Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB). People living with LBD seem to be more susceptible to delirium than those with other subtypes of dementia. AIM: To describe the challenges in clinical diagnosis and management of LBD. METHODS: A systematic review of published literature on diagnosis and management of delirium in LBD. RESULTS: Delirium is particularly challenging to diagnose in LBD as many of the clinical characteristics which define delirium such as inattention, fluctuating arousal, complex visual hallucinations and delusions, are also common to LBD. Distinguishing delirium from LBD can be very difficult clinically especially in the prodromal stages. Both under and over diagnosis of delirium, and under and over treatment of the symptoms have the potential to compromise the care and safety of people with a diagnosed or undiagnosed LBD. Clinicians are currently working with an extremely limited set of evidence-based management options for those with delirium in the context of a LBD diagnosis. For patients with LBD and their families this is an area of clinical practice that needs focused research.

Treatment needs of dementia with Lewy bodies according to patients, caregivers, and physicians: a cross-sectional, observational, questionnaire-based study in Japan.

BACKGROUND: Understanding the treatment needs of patients with dementia with Lewy bodies (DLB) is essential to develop treatment strategies. We examined the treatment needs of patients with DLB and their caregivers and the extent to which the attending physicians understand these treatment needs. METHODS: This was a cross-sectional, observational study conducted using questionnaires for patients, caregivers, and physicians. The study participants included patients, their caregivers, and their attending physicians who were experts in DLB. Fifty-two symptoms that are frequent and clinically important in DLB were pre-selected and classified into seven symptom domains. Treatment needs of patients and caregivers were defined as "symptom that causes them most distress," and the frequency of each answer was tabulated. To assess the physician's understanding of the treatment needs of patients and caregivers, patient-physician and caregiver-physician concordance rates for each answer regarding treatment needs were calculated according to symptom domains. RESULTS: In total, 263 pairs of patients-caregivers and 38 physicians were surveyed. The mean age of patients was 79.3 years, and their mean total score on the Mini-Mental State Examination was 20.9. Thirty-five and 38 symptoms were selected as symptoms causing patients and caregivers most distress, respectively. Memory impairment was most frequently selected for the treatment needs of patients, followed by constipation and bradykinesia. Memory impairment was also most frequently selected by caregivers, followed by visual hallucinations. For the symptom domain that causes patients or caregivers most distress, only about half of the patient-physician pairs (46.9%) and caregiver-physician pairs (50.8%) were matched. Logistic regression analysis identified that concordance rates for treatment needs between patient-physician and caregiver-physician were lower when autonomic dysfunction and sleep-related disorders were selected as the symptom domains that cause most distress. CONCLUSION: There was considerable variability in the treatment needs of patients with DLB and their caregivers. Attending physicians had difficulty understanding the top treatment needs of their patients and caregivers, despite their expertise in DLB, because of various clinical manifestations. Attending physicians should pay more attention to autonomic dysfunction and sleep-related disorders in the treatment of DLB. TRIAL REGISTRATION: UMIN Clinical Trials Registry, UMIN000041844. Registered on 23 September 2020.

Diagnosis and Treatment of Cognitive and Neuropsychiatric Symptoms in Parkinson Disease and Dementia With Lewy Bodies.

PURPOSE OF REVIEW: This article summarizes the underlying biology and current diagnostic and treatment strategies for the cognitive and neuropsychiatric features of Parkinson disease (PD) and dementia with Lewy bodies (DLB). RECENT FINDINGS: Cognitive impairment and neuropsychiatric symptoms have been increasingly recognized in PD and DLB, leading to improved diagnosis and treatment strategies. While PD is most associated with and diagnosed by the presence of motor symptoms, nonmotor symptoms can often be the most debilitating for patients. Neuropsychiatric symptoms are highly prevalent nonmotor features and include cognitive impairment, depression, anxiety, psychosis, impulse control disorders, and apathy. Neuropsychiatric symptoms can be difficult to recognize and diagnose in patients with PD, in part because of comorbidity and symptom overlap with core PD features. Treatment strategies are a combination of pharmacologic and nonpharmacologic interventions used in the general population and those specific to PD. DLB is a clinical dementia syndrome, often with similar cognitive, behavioral, autonomic, and motor features as PD. Moreover, DLB has shared underlying pathophysiology with PD, as both are associated with postmortem findings of α-synuclein neuropathology at autopsy and have shared genetic risk and prodromal symptoms. DLB is clinically differentiated from PD by the presenting features of cognitive impairment in DLB, compared with the variable onset of cognitive impairment occurring 1 year or more after established motor onset in PD. Thus, diagnosis and treatment of cognitive impairment and neuropsychiatric symptoms in DLB are similar to that of PD and have important implications for maintaining patient independence and providing support for caregivers because motor, cognitive, and neuropsychiatric symptoms have an additive effect on patient functional disability. SUMMARY: A careful history and physical examination are often needed to accurately diagnose and treat the heterogeneous cognitive and behavioral symptoms of PD and DLB. Accurate diagnosis and treatment of neuropsychiatric symptoms and cognitive impairment in PD and DLB are important, as these are a considerable source of patient disability and caregiver burden.

Electroconvulsive therapy improves psychotic symptoms in patients with dementia with Lewy bodies.

PURPOSE: The aim of this study was to examine the efficacy and safety of electroconvulsive therapy (ECT) for psychotic symptoms of dementia with Lewy bodies (DLB), and also to determine its use as an adaptive criterion. METHODS: Eight patients aged 66-83 years old (mean 75.4 ± 5.9 years) diagnosed with probable DLB based on the criteria for DLB and who received ECT between September 2013 and December 2019 at Aichi Medical University were enrolled. The efficacy and safety of ECT were retrospectively examined. Psychotic symptoms were evaluated using the Brief Psychiatric Rating Scale (BPRS), while parkinsonism was evaluated based on Hoehn-Yahr (HY) stage, with both scores analyzed and compared statistically between before and after ECT. Additionally, a follow-up survey after undergoing ECT was performed. RESULTS: Two incidents occurred during ECT sessions, arrhythmia in one patient and respiratory arrest in another, both of whom quickly recovered. Following ECT, a significant improvement in BPRS score was noted (p < 0.018, Wilcoxon signed rank test), whereas no significant difference was seen in regard to HY stage (p = 0.059). Follow-up survey findings obtained after ECT (mean observation period 15.9 ± 16.7 months), showed that all eight patients were alive and none had a relapse of psychotic symptoms. CONCLUSION: The present results suggest that ECT for patients with mild to moderate DLB and drug therapy-resistant psychotic symptoms is safe, well tolerated and effective. We consider it worth considering as a DLB therapeutic option.

Promoting independence in Lewy body dementia through exercise: the PRIDE study.

BACKGROUND: Lewy body dementia (LBD) is an aggressive type of dementia of rapid, fluctuating disease trajectory, higher incidence of adverse events, and poorer functional independence than observed in Alzheimer's disease dementia. Non-pharmacological treatments such as progressive, high-intensity exercise are effective in other neurological cohorts but have been scarcely evaluated in LBD. METHODS: The Promoting Independence in Lewy Body Dementia through Exercise (PRIDE) trial was a non-randomised, non-blinded, crossover pilot trial involving older adults with LBD consisting of a baseline assessment, an 8-week wait-list, and an 8-week exercise intervention. The aims of this study were to evaluate the determinants of the primary outcome functional independence, as measured by the Movement Disorder Society Unified Parkinson's Disease Rating Scale, and the feasibility and preliminary efficacy of an exercise intervention on this outcome. Additionally, important clinical characteristics were evaluated to explore associations and treatment targets. The exercise intervention was supervised, clinic-based, high-intensity progressive resistance training (PRT), challenging balance, and functional exercises, 3 days/week. RESULTS: Nine participants completed the baseline cross-sectional study, of which five had a diagnosis of Parkinson's disease dementia (PDD), and four dementia with Lewy Bodies (DLB). Six completed the exercise intervention (three PDD, three DLB). The cohort was diverse, ranging from mild to severe dementia and living in various residential settings. Greater functional independence at baseline was significantly associated with better physical function, balance, cognition, quality of life, muscle mass ratio, walking endurance, faster walking speed and cadence, and lower dementia severity (p < 0.05). Participants declined by clinically meaningful amounts in functional independence, cognition, physical function, muscle mass, and weight over the wait-list period (p < 0.05). Following exercise, participants improved by clinically meaningful amounts in functional independence, cognition, physical function, and strength (p < 0.05). Progressive, high intensity exercise was well-tolerated (> 80% adherence), and only one minor exercise-related adverse event occurred. CONCLUSIONS: PRIDE is the first exercise trial conducted specifically within individuals diagnosed with LBD, and provides important insight for the design of larger, randomized trials for further evaluation of progressive, high-intensity exercise as a valuable treatment in LBD. TRIAL REGISTRATION: The PRIDE trial protocol has previously been prospectively registered (08/04/2016, ANZCTR: ACTRN12616000466448).

Intermittent theta burst stimulation for the treatment of autonomic dysfunction and depressive symptoms in dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is one of the most prevalent forms of neurodegenerative dementia, second to Alzheimer's disease, and autonomic abnormalities and depressive symptoms are common. There are currently no cures or treatments with evidence of disease-modifying effects for DLB, and the treatment for the amelioration of targeted symptoms is challenging due to the risk of side effects and drug-drug interactions. In the present case, we report a female elder with DLB suffering from poor tolerance to the adverse events of numerous approaches. Following intermittent theta burst stimulation (iTBS), the autonomic abnormalities and depressive symptoms remarkably improved without significant side effects.

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials.

[Treatment and Care for Elderly Patients with Dementia with Lewy Bodies Presenting with Delusional Misidentification Syndrome Including Capgras Syndrome: Severe Psychiatric Symptoms Associated with Dementia with Lewy Bodies].

The treatment and care for severe psychiatric symptoms associated with dementia with Lewy bodies is challenging. This is especially true for elderly patients because the use of antipsychotics is associated with an attendant mortality risk. In this article, dementia patients with Lewy bodies who presented with severe psychiatric symptoms such as Capgras syndrome (delusional misidentification syndrome), are described, and pharmacological and non-pharmacological strategies to address these symptoms are discussed. Measures to be avoided include antipsychotic administration and physical restraint, both of which often lead to medical conditions and a bedridden status. Conversely, changing antiparkinsonian drugs (levodopa rather than dopamine agonists), cholinesterase inhibitor administration, physical rehabilitation, and providing a supportive, patient-friendly environment may help improve psychiatric symptoms or maintain functionality. In some cases, electroconvulsive therapy may be effective for severe psychiatric symptoms.

Ultrabrief Right Unilateral Electroconvulsive Therapy for the Treatment of the Neuropsychiatric Symptoms of Dementia with Lewy Bodies.

OBJECTIVES: Dementia with Lewy bodies (DLB) is a debilitating disorder associated with a number of distressing neuropsychiatric symptoms. There is currently limited guidance regarding the most effective strategies of managing these symptoms, and both pharmacologic and nonpharmacologic strategies are often used. Electroconvulsive therapy (ECT) has been reported as a potential nonpharmacologic method to alleviate some of these debilitating neuropsychiatric symptoms. However, there remains a paucity of evidence in current literature. This report aims to add to existing literature regarding ECT in DLB by highlighting successful treatment in seven cases. METHODS: Our study is a retrospective case series of 7 patients with DLB who received treatment with ultrabrief (UB) right unilateral (RUL) ECT for the treatment of agitation and depressive symptoms. Participants included patients with a diagnosis of DLB who were admitted to Emory University Hospital at Wesley Woods from 2011 to 2020 presenting with agitation and/or depressive symptoms after failing pharmacologic intervention. Patients underwent UB RUL ECT administered by a board-certified psychiatrist. After treatment, Pittsburg Agitation Scale and Clinical Global Impression-Improvement scales were recorded as measures of agitation and clinical improvement, respectively. RESULTS: All 7 patients responded to UB RUL ECT with marked improvement in their presenting symptoms of agitation and/or depression without significant adverse effects from treatment. CONCLUSIONS: Ultrabrief RUL ECT seems to be a safe and effective treatment of the agitative and depressive features of DLB.

[Assessment of the knowledge of Lewy body disease by health care professionnels compared to Alzheimer's disease: result of a descriptive analytical study]. / Évaluation des connaissances par les professionnels de santé de la maladie à corps de Lewy comparativement à la maladie d'Alzheimer : résultat d'une étude analytique descriptive.

BACKGROUND: Dementia with Lewy body (DLB) is a common neurodegenerative disease that warrants specific care, which remains largely underdiagnosed. Our objective was to assess the knowledge of DLB by health professionals in comparison with that of Alzheimer's disease (AD), to better understand the reasons of its under-diagnosis. METHODS: We conducted a descriptive and analytical study processing the results of an online questionnaire submitted to French healthcare professionals between December 1, 2020 and March 1, 2021. RESULTS: A total of 490 healthcare professionals responded to the questionnaire. We observed a poorer knowledge of DLB compared to AD both subjective as highlighted on the self-assessment questionnaires and objective since the diagnostic criteria and therapeutic specificities were less known for DLB compared to AD. CONCLUSIONS: DLB appears as a disease that is still too poorly known by health professionals. To improve training is therefore a decisive objective in order to optimize the therapeutic care and support of patients with DLB and their relatives.