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Currently, there is a need for diagnostic markers in Lewy body disorders (LBD). α-synuclein (αSyn) RT-QuIC has emerged as a promising assay to detect misfolded αSyn in clinically or neuropathologically established patients with various synucleinopathies. In this study, αSyn RT-QuIC was used to analyze lumbar CSF in a clinical cohort from the Swedish BioFINDER study and postmortem ventricular CSF in a neuropathological cohort from the Arizona Study of Aging and Neurodegenerative Disorders/Brain and Body Donation Program (AZSAND/BBDP). The BioFINDER cohort included 64 PD/PDD, 15 MSA, 15 PSP, 47 controls and two controls who later converted to PD/DLB. The neuropathological cohort included 101 cases with different brain disorders, including LBD and controls. In the BioFINDER cohort αSyn RT-QuIC identified LBD (i.e. PD, PDD and converters) vs. controls with a sensitivity of 95% and a specificity of 83%. The two controls that converted to LBD were αSyn RT-QuIC positive. Within the AZSAND/BBDP cohort, αSyn RT-QuIC identified neuropathologically verified \"standard LBD\" (i.e. PD, PD with AD and DLB; n = 25) vs. no LB pathology (n = 53) with high sensitivity (100%) and specificity (94%). Only 57% were αSyn RT-QuIC positive in the subgroup with \"non-standard\" LBD (i.e., AD with Lewy Bodies not meeting criteria for DLB or PD, and incidental LBD, n = 23) . Furthermore, αSyn RT-QuIC reliably identified cases with LB pathology in the cortex (97% sensitivity) vs. cases with no LBs or LBs present only in the olfactory bulb (93% specificity). However, the sensitivity was low, only 50%, for cases with LB pathology restricted to the brainstem or amygdala, not affecting the allocortex or neocortex. In conclusion, αSyn RT-QuIC of CSF samples is highly sensitive and specific for identifying cases with clinicopathologically-defined Lewy body disorders and shows a lower sensitivity for non-standard LBD or asymptomatic LBD or in cases with modest LB pathology not affecting the cortex .

INTRODUCTION Apathy is an important syndrome in Lewy body dementia (LBD), although reported prevalences vary. We aimed to estimate the prevalence of apathy in LBD through systematic review and meta‐analysis. METHODS Five databases were searched for articles reporting the prevalence of apathy in LBD (dementia with Lewy bodies [DLB] and Parkinson's disease dementia [PDD]) and prodromal/mild cognitive impairment (MCI) LBD. Linear mixed model random effect meta‐analysis was performed to determine the prevalence of apathy. RESULTS Of 7846 articles identified, 49 met inclusion criteria. The average pooled prevalence of apathy was 57% (95% confidence interval [CI] 52%–63%, I2 = 85.6%) in DLB, 56% (95% CI 43%–70%, I2 = 97.6%) in PDD, 46% (95% CI 32%–61%, I2 = 90.6%) in Lewy body‐MCI, and 38% (95% CI 25%–50%, I2 = 88.1%) in Parkinson's disease‐MCI. DISCUSSION Apathy affects more than half of individuals with LBD. The high prevalence in prodromal DLB supports the notion that apathy may assist in more timely and accurate diagnosis of DLB. Highlights Reported apathy prevalence in Lewy body dementia (LBD) varies widely in the existing literature. The pooled prevalence of apathy was > 50% in LBD and > 40% in prodromal disease stages. Apathy may have utility in earlier, more accurate diagnosis of dementia with Lewy bodies.

In this narrative review, we delved into the intricate interplay between Apolipoprotein E (APOE) alleles (typically associated with Alzheimer’s disease—AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of APOE4 on LB pathology were summarized. We found robust evidence that APOE4 carriage constitutes a risk factor for PDD—APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that APOE4 copies confer an increased hazard towards DLB, as well. Again APOE2 and APOE3 appear unrelated to the risk of conversion. Of note, in individuals with DLB APOE4, carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; APOE-PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the APOE gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive–neuropsychiatric- motor-, and sleep-related manifestations) between APOE alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.

Background Diagnosis of dementia with Lewy bodies (DLB) is challenging, largely due to a lack of diagnostic tools. Cerebrospinal fluid (CSF) biomarkers have been proven useful in Alzheimer’s disease (AD) diagnosis. Here, we aimed to identify novel CSF biomarkers for DLB using a high-throughput proteomic approach. Methods We applied liquid chromatography/tandem mass spectrometry with label-free quantification to identify biomarker candidates to individual CSF samples from a well-characterized cohort comprising patients with DLB ( n  = 20) and controls ( n  = 20). Validation was performed using (1) the identical proteomic workflow in an independent cohort ( n  = 30), (2) proteomic data from patients with related neurodegenerative diseases ( n  = 149) and (3) orthogonal techniques in an extended cohort consisting of DLB patients and controls ( n  = 76). Additionally, we utilized random forest analysis to identify the subset of candidate markers that best distinguished DLB from all other groups. Results In total, we identified 1995 proteins. In the discovery cohort, 69 proteins were differentially expressed in DLB compared to controls ( p  < 0.05). Independent cohort replication confirmed VGF, SCG2, NPTX2, NPTXR, PDYN and PCSK1N as candidate biomarkers for DLB. The downregulation of the candidate biomarkers was somewhat more pronounced in DLB in comparison with related neurodegenerative diseases. Using random forest analysis, we identified a panel of VGF, SCG2 and PDYN to best differentiate between DLB and other clinical groups (accuracy: 0.82 (95%CI: 0.75–0.89)). Moreover, we confirmed the decrease of VGF and NPTX2 in DLB by ELISA and SRM methods. Low CSF levels of all biomarker candidates, except PCSK1N, were associated with more pronounced cognitive decline (0.37 < r < 0.56, all p  < 0.01). Conclusion We identified and validated six novel CSF biomarkers for DLB. These biomarkers, particularly when used as a panel, show promise to improve diagnostic accuracy and strengthen the importance of synaptic dysfunction in the pathophysiology of DLB.

Background Pimavanserin is approved by the US Food and Drug Administration for the treatment of hallucinations and delusions associated with Parkinson’s disease. We analyzed the effect of pimavanserin on psychosis in patients with Lewy body dementia, including Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), from the phase 3 HARMONY trial. Methods This subgroup analysis included patients with PDD or DLB from HARMONY, a previously completed, multicenter, randomized, discontinuation study of pimavanserin for dementia-related psychosis. Patients with moderate to severe psychosis received pimavanserin 34 mg once daily for 12 weeks (open-label treatment). Those who achieved a sustained response at weeks 8 and 12 were randomized to continue treatment with pimavanserin or discontinue treatment and receive placebo for up to 26 weeks in the double-blind period. The primary endpoint was the time to psychosis relapse as defined by prespecified criteria. Safety was evaluated by adverse events; effects on motor symptoms and cognitive abilities were also assessed. Results Overall, 392 patients were enrolled in HARMONY; 49 patients with PDD and 27 patients with DLB were included in the open-label safety analysis, of whom 46 met response criteria and were randomized to receive pimavanserin ( n  = 22) or placebo ( n  = 24) during the double-blind period. Psychosis relapse risk was significantly lower with pimavanserin vs. placebo (hazard ratio, 0.031; 95% CI, 0.010–0.103; 2-sided nominal P  < 0.0001). Fewer than 50% of patients experienced an adverse event in either treatment period; pimavanserin did not negatively affect motor or cognitive function. Conclusions Psychosis relapse risk was significantly lower with pimavanserin vs. placebo in patients with Lewy body dementia. Pimavanserin was also well tolerated and did not worsen motor or cognitive function. Results should be interpreted cautiously since this study is a post hoc analysis of a previous trial that was not originally designed or powered to draw clinical conclusions based on dementia subgroups. Trial registration ClinicalTrials.gov Identifier: NCT03325556 (registered 18 October 2017).

Dementia with Lewy bodies (DLB) is a clinical diagnosis representing a specific presentation of a pathological α-synucleinopathy (Lewy body disease). DLB is one entity under the broader term Lewy body dementia, which also includes Parkinson’s disease dementia. Recent advances in DLB include publication of updated diagnostic criteria and recognition of prodromal DLB states, including mild cognitive impairment, delirium-onset, and psychiatric-onset forms. Research criteria for the mild cognitive impairment form of DLB were published in 2020. Increasing research shows that concomitant Alzheimer’s disease pathology in individuals with DLB is common in addition to the α-synucleinopathy pathology. This has implications for biomarker use and expected progression. Identifying biomarkers for DLB is an area of active research. Cerebrospinal fluid and skin biopsy tests are now commercially available in the United States, but their role in routine clinical care is not yet established. Additional research and biomarkers are needed. Research suggests that median survival after DLB diagnosis is 3–4 years, but there are rapidly and slowly progressive forms. Most individuals with DLB die of complications of the disease. Clinical trials for individuals with DLB have increased over the last 5 years, targeting both symptoms and underlying pathology. Effective therapies remain an unmet need, however. This review focuses on recent advances with an emphasis on literature that informs clinical care.

Lewy body dementia (consisting of dementia with Lewy bodies and Parkinson's disease dementia) is a common neurodegenerative disease characterised by visual hallucinations, fluctuating attention, motor disturbances, falls, and sensitivity to antipsychotics. This combination of features presents challenges for pharmacological management. Given this, we sought to review evidence for non-pharmacological interventions with patients with Lewy body dementia and their carers. Bibliographic databases were searched using a wide range of search terms and no restrictions were placed on study design, language, or clinical setting. Two reviewers independently assessed papers for inclusion, rated study quality, and extracted data. The search identified 21 studies including two randomised controlled trials with available subgroup data, seven case series, and 12 case studies. Most studies reported beneficial effects of the interventions used, though the only sizeable study was on dysphagia, showing a benefit of honey-thickened liquids. Given the heterogeneity of interventions and poor quality of the studies overall, no quantitative synthesis was possible. Overall, identified studies suggested possible benefits of non-pharmacological interventions in Lewy body dementia, but the small sample sizes and low quality of studies mean no definite recommendations can be offered. Our findings underscore the clear and urgent need for future research on this topic.

Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.

INTRODUCTION Dementia with Lewy bodies (DLB) is inadequately diagnosed and treated, which negatively influences patient outcomes. METHODS This systematic review evaluated qualitative studies of lived experiences from DLB patient and caregiver perspectives to identify gaps and define future research directions. RESULTS The review included 27 studies. Most reported caregiver experiences (67%). Few focused solely on people with DLB.  Three themes emerged: (1) symptoms and impacts; (2) caregivers’ care challenges; and (3) needs and priorities for education, support, and research. Gaps in qualitative literature included small DLB sample sizes, inconsistent diagnostic criteria, variably reported characteristics, merged data across dementia types and stages, and under‐representation of informants and diverse groups. DISCUSSION This review provides the first qualitative evidence synthesis in DLB, highlighting profound impacts of DLB symptoms, but also gaps in understanding direct experiences. Additional qualitative work regarding the lived experience in DLB is needed to inform clinical management and therapeutic development. Highlights Symptoms in dementia with Lewy bodies (DLB) vary greatly across individuals. Existing qualitative studies, though limited, show profound personal impact in DLB. Rigorous, systematic qualitative research in DLB symptom science is needed. Identifying what matters to people with DLB is essential for guiding treatment.

Dementia with Lewy bodies (DLB) is marked by multidomain cognitive impairments, with fluctuations in cognition and alertness being among the most common clinical features. Disruptions in functional connectivity are thought to underlie these fluctuations, but it remains unclear whether such patterns are already present at prodromal stages. We investigated the presence of static and dynamic functional connectivity alterations and their contribution to the clinical phenotype of prodromal DLB, and explored their association with declining locus coeruleus integrity, while considering premorbid intelligence (a proxy for cognitive reserve) as a moderating factor. Three groups of participants on the prodromal spectrum were analyzed: 29 healthy controls, 58 cognitively normal subjects with core clinical features of prodromal DLB (CN-CCF), and 39 subjects with mild cognitive impairment due to Lewy body dementia (MCI-LB). Dynamic and static functional connectivity features were derived from resting-state source-reconstructed high-density EEG, and integrity of the right caudal locus coeruleus was quantified using neuromelanin-sensitive MRI. Robust analyses, such as PERMANOVA, Spearman correlations and general linear models were conducted to study the relationships. We observed a nonlinear trajectory of two functional connectivity metrics—temporal variability (fluidity) and connectedness (average node strength)—across symptom severity, especially in the delta frequency band. Both measures (F(2,123) = 1.86, p =.037; F(2,123) = 1.51, p =.023, respectively) were elevated in the intermediate severity groups—that is, in CN-CCF and possible MCI-LB (i.e., one core clinical feature)—and this was associated with better executive functioning after controlling for age and premorbid intelligence (rho = 0.26, p =.004; rho = 0.28, p =.002, respectively). Additionally, elevated fluidity (rho = − 0.34, p =.034) and average node strength (rho = − 0.37, p =.022) were also correlated with fewer fluctuations in alertness in subjects with MCI-LB. Fluidity was further associated with right caudal locus coeruleus integrity, particularly among individuals with lower premorbid intelligence (F(5,97) = 3.56, p =.005). Our findings indicate that increased dynamic reconfiguration and enhanced connectivity may serve compensatory functions in early DLB, helping temporarily preserve cognition. As DLB progresses, these mechanisms wane, with noradrenergic contributions more evident in individuals with lower cognitive reserve.Clinical trial number Not applicable.