An update on the genetics of dementia with Lewy bodies

The genetic architecture of dementia with Lewy bodies (DLB) is increasingly taking shape. Initially, genetic research focused mainly on linkage and candidate gene studies in small series of DLB patients. More recently, association and exome sequencing studies in larger groups have been conducted, and have shown that several variants in GBA and the APOE ε4 allele are important genetic risk factors for DLB. However, genetic research in DLB is still in its infancy. So far, many genetic studies have been biased and performed in clinically and pathologically heterogeneous populations. Therefore, it is likely that multiple DLB-specific genetic determinants still have to be identified. To further our understanding of the role of genetics in DLB, future genetic studies should be unbiased and performed in large series of DLB patients, ideally with both a clinical diagnosis and pathological confirmation. The combination of genomic techniques with other research modalities, such as proteomic research, is a promising approach to identify novel genetic determinants. More knowledge about the genetics of DLB will increase our understanding of the pathophysiology of the disease and its relation with Parkinson's Disease and Alzheimer's Disease, and may eventually lead to the development of disease modifying treatments

Hallucinations and other psychotic experiences across diagnoses:A comparison of phenomenological features

Although psychotic experiences are prevalent across many psychiatric, neurological, and medical disorders, investigation of these symptoms has largely been restricted to diagnostic categories. This study aims to examine phenomenological similarities and differences across a range of diagnoses. We assessed frequency, severity and phenomenology of psychotic experiences in 350 outpatients including; participants with schizophrenia spectrum disorders, hearing impairment, Parkinson's disease, Lewy Body Dementia, Alzheimer's disease, visual impairment, posttraumatic stress disorder, borderline personality disorder, and participants with recent major surgery. Psychotic phenomena were explored between these groups using the Questionnaire for Psychotic Experiences (QPE). Participants with major psychiatric disorders reported a combination of several psychotic experiences, and more severe experiences compared to all other disorders. Participants with recent major surgery or visual impairment experienced isolated visual hallucinations. Participants with hearing impairment reported isolated auditory hallucinations, whereas the neurodegenerative disorders reported visual hallucinations, occasionally in combination with hallucinations in another modality or delusions. The phenomenology between neurodegenerative disorders, and within major psychiatric disorders showed many similarities. Our findings indicate that the phenomenology of psychotic experiences is not diagnosis specific, but may rather point to the existence of various subtypes across diagnoses. These subtypes could have a different underlying etiology requiring specific treatment.</p

Trajectories and Determinants of Quality of Life in Dementia with Lewy Bodies and Alzheimer's Disease

Background: Quality of Life (QoL) is an important outcome measure in dementia, particularly in the context of interventions. Research investigating longitudinal QoL in dementia with Lewy bodies (DLB) is currently lacking. Objective: To investigate determinants and trajectories of QoL in DLB compared to Alzheimer's disease (AD) and controls. Methods: QoL was assessed annually in 138 individuals, using the EQ5D-utility-score (0-100) and the health-related Visual Analogue Scale (VAS, 0-100). Twenty-nine DLB patients (age 69±6), 68 AD patients (age 70±6), and 41 controls (age 70±5) were selected from the Dutch Parelsnoer Institute-Neurodegenerative diseases and Amsterdam Dementia Cohort. We examined clinical work-up over time as determinants of QoL, including cognitive tests, neuropsychiatric inventory, Geriatric Depression Scale (GDS), and disability assessment of dementia (DAD). Results: Mixed models showed lower baseline VAS-scores in DLB compared to AD and controls (AD: β±SE = -7.6±2.8, controls: β±SE = -7.9±3.0, p < 0.05). An interaction between diagnosis and time since diagnosis indicated steeper decline on VAS-scores for AD patients compared to DLB patients (β±SE = 2.9±1.5, p < 0.1). EQ5D-utility-scores over time did not differ between groups. Higher GDS and lower DAD-scores were independently associated with lower QoL in dementia patients (GDS: VAS β±SE = -1.8±0.3, EQ5D-utility β±SE = -3.7±0.4; DAD: VAS = 0.1±0.0, EQ5D-utility β±SE = 0.1±0.1, p < 0.05). No associations between cognitive tests and QoL remained in the multivariate model. Conclusion: QoL is lower in DLB, while in AD QoL shows steeper decline as the disease advances. Our results indicate that non-cognitive symptoms, more than cognitive symptoms, are highly relevant as they impact QoL

Hallucinations and other psychotic experiences across diagnoses:A comparison of phenomenological features

Although psychotic experiences are prevalent across many psychiatric, neurological, and medical disorders, investigation of these symptoms has largely been restricted to diagnostic categories. This study aims to examine phenomenological similarities and differences across a range of diagnoses. We assessed frequency, severity and phenomenology of psychotic experiences in 350 outpatients including; participants with schizophrenia spectrum disorders, hearing impairment, Parkinson's disease, Lewy Body Dementia, Alzheimer's disease, visual impairment, posttraumatic stress disorder, borderline personality disorder, and participants with recent major surgery. Psychotic phenomena were explored between these groups using the Questionnaire for Psychotic Experiences (QPE). Participants with major psychiatric disorders reported a combination of several psychotic experiences, and more severe experiences compared to all other disorders. Participants with recent major surgery or visual impairment experienced isolated visual hallucinations. Participants with hearing impairment reported isolated auditory hallucinations, whereas the neurodegenerative disorders reported visual hallucinations, occasionally in combination with hallucinations in another modality or delusions. The phenomenology between neurodegenerative disorders, and within major psychiatric disorders showed many similarities. Our findings indicate that the phenomenology of psychotic experiences is not diagnosis specific, but may rather point to the existence of various subtypes across diagnoses. These subtypes could have a different underlying etiology requiring specific treatment

Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach

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