OBJECTIVE: Plasma β-amyloid-1-42/1-40 (Aβ42/40), phosphorylated-tau (P-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) have been widely examined in Alzheimer disease (AD), but little is known about their reflection of copathologies, clinical importance, and predictive value in dementia with Lewy bodies (DLB). We aimed to evaluate associations of these biomarkers with CSF amyloid, cognition, and core features in DLB.
METHODS: This cross-sectional multicenter cohort study with prospective component included individuals with DLB, AD, and healthy controls (HCs), recruited from 2002 to 2020 with an annual follow-up of up to 5 years, from the European-Dementia With Lewy Bodies consortium. Plasma biomarkers were measured by single-molecule array (Neurology 4-Plex E kit). Amyloid status was determined by CSF Aβ42 concentrations, and cognition was assessed by Mini-Mental State Examination (MMSE). Biomarker differences across groups, associations with amyloid status, and clinical core features were assessed by analysis of covariance. Associations with cognitive impairment and decline were assessed by linear regression and linear mixed-effects models.
RESULTS: In our cohort consisting of 562 individuals (HC n = 89, DLB n = 342, AD n = 131; 250 women [44.5%], mean [SD] age of 71 [8] years), sex distribution did not differ between groups. Patients with DLB were significantly older, and had less years of education and worse baseline cognition than HC, but not AD. DLB participants stratified for amyloid status differed significantly in plasma Aβ42/40 ratio (decreased in amyloid abnormal: β = -0.008, 95% CI -0.016 to -0.0003, p = 0.01) and P-tau (increased in amyloid abnormal, P-tau181: β = 0.246, 95% CI 0.011-0.481; P-tau231: β = 0.227, 95% CI 0.035-0.419, both p < 0.05), but not in GFAP (β = 0.068, 95% CI -0.018 to 0.153, p = 0.119), and NfL (β = 0.004, 95% CI -0.087 to 0.096, p = 0.923) concentrations. Higher baseline GFAP, NfL, and P-tau concentrations were associated with lower MMSE scores in DLB, and GFAP and NfL were associated with a faster cognitive decline (GFAP: annual change of -2.11 MMSE points, 95% CI -2.88 to -1.35 MMSE points, p < 0.001; NfL: annual change of -2.13 MMSE points, 95% CI -2.97 to -1.29 MMSE points, p < 0.001). DLB participants with parkinsonism had higher concentrations of NfL (β = 0.08, 95% CI 0.02-0.14, p = 0.006) than those without.
CONCLUSIONS: Our study suggests a possible utility of plasma Aβ42/40, P-tau181, and P-tau231 as a noninvasive biomarkers to assess amyloid copathology in DLB, and plasma GFAP and NfL as monitoring biomarkers for cognitive symptoms in DLB.

Previous observational investigations suggest that structural and diffusion imaging-derived phenotypes (IDPs) are associated with major neurodegenerative diseases; however, whether these associations are causal remains largely uncertain. Herein we conducted bidirectional two-sample Mendelian randomization analyses to infer the causal relationships between structural and diffusion IDPs and major neurodegenerative diseases using common genetic variants-single nucleotide polymorphism (SNPs) as instrumental variables. Summary statistics of genome-wide association study (GWAS) for structural and diffusion IDPs were obtained from 33,224 individuals in the UK Biobank cohort. Summary statistics of GWAS for seven major neurodegenerative diseases were obtained from the largest GWAS for each disease to date. The forward MR analyses identified significant or suggestively statistical causal effects of genetically predicted three structural IDPs on Alzheimer\'s disease (AD), frontotemporal dementia (FTD), and multiple sclerosis. For example, the reduction in the surface area of the left superior temporal gyrus was associated with a higher risk of AD. The reverse MR analyses identified significantly or suggestively statistical causal effects of genetically predicted AD, Lewy body dementia (LBD), and FTD on nine structural and diffusion IDPs. For example, LBD was associated with increased mean diffusivity in the right superior longitudinal fasciculus and AD was associated with decreased gray matter volume in the right ventral striatum. Our findings might contribute to shedding light on the prediction and therapeutic intervention for the major neurodegenerative diseases at the neuroimaging level.

UNASSIGNED: Abnormal cerebrospinal fluid (CSF)/serum albumin ratio (Qalb) levels have been observed in patients with cognitive impairment. Few studies have specifically focused on Lewy Body Disease (LBD), and the results were controversial. Thus, we conducted this systematic review and meta-analysis to investigate Qalb levels in patients with LBD by including data from different studies.
UNASSIGNED: We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases for a collection of studies containing studies comparing Qalb levels in patients with LBD and healthy controls (including healthy controls and other dementia subtypes). In the initial search, 86 relevant papers were retrieved. Standardized mean differences (SMD) in Qalb levels were calculated using a random effects model.
UNASSIGNED: A total of 13 eligible studies were included. Mean Qalb levels were significantly higher in patients with LBD compared to healthy older adults [standardized mean difference (SMD): 2.95, 95% confidence interval (CI): 0.89-5.00, Z = 2.81, p = 0.005]; and were significantly higher in patients with LBD than in patients with Alzheimer\'s disease (AD) (SMD: 1.13, 95% CI: 0.42-1.83, Z = 3.15, p = 0.002);whereas mean Qalb levels were significantly higher in patients with frontotemporal lobar degeneration (FTLD) compared to those with AD (SMD: 1.13, 95% CI,0.14-2.13, Z = 2.24, p = 0.03).
UNASSIGNED: Qalb levels were significantly elevated in LBD patients compared with normal older adults and were higher than those in AD patients and FTLD patients, which helped in the differential diagnosis of LBD from other neurodegenerative diseases.
UNASSIGNED: https://www.crd.york.ac.uk/prospero/, identifier CRD42024496616.

BACKGROUND: To determine whether Lewy body dementia (LBD) patients with likely copathology of Alzheimer\'s disease (AD) exhibit greater neuropsychiatric symptom (NPS) compared to those without likely AD-type copathology.
METHODS: We enrolled 69 individuals diagnosed with Lewy body dementia (LBD), comprising both dementia with Lewy bodies (DLB) (n = 36) and Parkinson\'s disease dementia (PDD) (n = 33). These participants had accessible cerebrospinal fluid (CSF) markers related to Alzheimer\'s disease (AD) and cognitive data. We assessed CSF levels of β-amyloid 42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Employing autopsy-validated CSF thresholds (t-tau/Aβ42 ratio > 0.3, n = 69), we categorized individuals into LBD with AD pathology (LBD + AD, n = 31) and LBD without apparent AD co-pathology (LBD - AD, n = 38). Moreover, the Hamilton Depression Scale (HAMD24), Hamilton Anxiety Scale (HAMA14), and Neuropsychiatric Inventory Questionnaire (NPI-Q) was used to assess the NPS. Spearman correlations were utilized to explore links between NPS and CSF marker profiles.
RESULTS: In terms of neuropsychiatric symptoms, LBD + AD patients demonstrated notably elevated levels of depressive symptoms (HAMD24) in comparison to LBD - AD patients (P < 0.001). However, based on PDD and DLB groups, no significant variations were noted in the neuropsychiatric symptoms(P＞0.05). Moreover, CSF-derived biomarkers of Aβ42, and t-tau/Aβ42 were also associated with HAMD24 total scores in the LBD + AD subsample (P < 0.05).
CONCLUSIONS: There is an association between AD pathological markers and the NPS of LBD. The biologically based classification of LBD may be more advantageous in elucidating clinical heterogeneity than clinically defined syndromes.

UNASSIGNED: We reported imaging findings with complex signs that were corresponded with both dementia with Lewy bodies (DLB) and Alzheimer disease (AD) in the case of a 78-year-old woman. Initially suspected as DLB due to cognitive and movement issues, diagnostic support included the cingulate island sign on 18 F-FDG PET, positive 131 I-MIBG cardiac scintigraphy, and DAT PET. However, MRI indicated hippocampal atrophy, and 18 F-FDG PET showed hypometabolism in the medial temporal lobe, suggesting the possibility of concomitant AD. Subsequent detection of β-amyloid pathology and tau accumulation in the brain further supported the concurrent presence of AD pathology.

BACKGROUND: Lewy body dementia (LBD) ranks second among prevalent neurodegenerative dementias. Previous studies have revealed associations of serum lipid measures with several neurodegenerative diseases. Nevertheless, the potential connection between serum lipids and LBD remains undetermined. In this study, Mendelian randomization (MR) analyses were carried out to assess the causal relationships of several serum lipid measures with the risk of developing LBD.
METHODS: Genome-wide association study (GWAS) data for serum lipids and LBD in European descent individuals were acquired from publicly available genetic summary data. A series of filtering procedures were conducted to identify the genetic variant candidates that are related to serum lipids, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). The causal effects were primarily determined through inverse-variance weighting (IVW)-based analyses.
RESULTS: Neither TG (odds ratio [OR] = 1.149; 95% confidence interval [CI], 0.887-1.489; P = 0.293) nor HDL-C (OR = 0.864; 95% CI, 0.718-1.041; P = 0.124) had causal effects on LBD. However, a causal relationship was identified between LDL-C and LBD (OR = 1.343; 95% CI, 1.094-1.649; P = 0.005), which remained significant (OR = 1.237; 95% CI, 1.015-1.508; P = 0.035) following adjustment for HDL-C and TG in multivariable MR.
CONCLUSIONS: Elevated serum LDL-C increases the risk of LBD, while HDL-C and TG have no significant causal effects on LBD.

BACKGROUND: Epilepsy and dementia are bidirectional. The purpose of this review was to investigate the epidemiological characteristics of and to identify the risk factors for epilepsy in patients with dementia and dementia in patients with epilepsy.
METHODS: We retrieved the PubMed, Embase, Cochrane and Web of Science databases through January 2023. Two individuals screened the articles, extracted the data, and used a random effects model to pool the estimates and 95% confidence intervals (CIs).
RESULTS: From 3475 citations, 25 articles were included. The prevalence of seizures/epilepsy was 4% among dementia patients and 3% among Alzheimer\'s disease (AD) patients. For vascular dementia, Lewy body dementia, and frontotemporal dementia, the pooled period prevalence of seizures/epilepsy was 6%, 3%, and 2%, respectively. Baseline early-onset AD was associated with the highest risk of 5-year epilepsy (pooled hazard ratios: 4.06; 95% CI: 3.25-5.08). Dementia patients had a 2.29-fold greater risk of seizures/epilepsy than non-dementia patients (95% CI: 1.37-3.83). Moreover, for baseline epilepsy, the pooled prevalence of dementia was 17% (95% CI: 10-25%), and that of AD was 15% (95% CI: 9-21%). The pooled results suggested that epilepsy is associated with a greater risk of dementia (risk ratio: 2.83, 95% CI: 1.64-4.88).
CONCLUSIONS: There are still gaps in epidemiology regarding the correlation between dementia types and epilepsy, vascular risk factors, and the impact of antiseizure medication or cognitive improvement drugs on epilepsy and AD comorbidity.

BACKGROUND: The relationship between cerebrospinal fluid pressure (CSFP) and cognition has received little research attention. The purpose of this study was to explore the relationship between CSFP and cognition in patients with Alzheimer\'s disease (AD) and patients with Lewy body dementia (LBD).
METHODS: We included 178 participants, including 137 patients with AD and 41 patients with LBD (including dementia with Lewy bodies (DLBs) and Parkinson\'s disease dementia (PDD)). CSFP was measured by lumbar puncture, and a patient-reported history and laboratory test data were collected. Logistic and linear regression analyses were used to evaluate the associations between CSFP and cognition, the cerebrospinal fluid (CSF) / serum albumin ratio (Qalb), and CSF biomarkers of AD.
RESULTS: The mean age of the included patients was 63.58 ± 8.77 years old, and the mean CSFP was 121 ± 33.72 mmH2O. A total of 76.9% of the patients had a CSFP distribution of [90-170) mmH2O, 46 patients (25.8%) had severe dementia, 83 patients (46.6%) had moderate dementia, 28 patients (15.7%) had mild dementia, and 21 patients (11.8%) had mild cognitive impairment (MCI) (including 16 patients with MCI due to AD and 5 patients with MCI due to LBD). In all patients (p value < 0.001) and in patients with AD (p value = 0.01), the mean cerebrospinal fluid pressure (CSFP) was higher in patients with MCI than in patients with dementia. In multivariate analysis, in all patients (OR: 6.37, 95% confidential interval (CI): 1.76-23.04, p = 0.005) and patients with AD (odds ratio (OR): 5.43, 95% CI: 1.41-20.87, p = 0.005), a CSFP in the lowest quartile ([50-90) mmH2O) was associated with a higher level of severe dementia than a CSFP in the highest quartile ([170-210) mmH2O). In addition, there was a significant linear correlation between CSFP and the Mini-Mental State Examination (MMSE) score in all patients with dementia (r = 0.43, p = 0.04, Durbin-Watson test (D-W test) = 0.75).
CONCLUSIONS: In patients with AD, the mean cerebrospinal fluid pressure was higher in patients with MCI than in patients with dementia, and the decrease in CSFP was related to a more serious dementia level. However, no such relationship was found in patients with LBD.

BACKGROUND: Cognitive disorder, parkinsonism, autonomic dysfunction (AuD) and rapid eye movement sleep behavior disorder (RBD) can occur prior to or simultaneously with Dementia with Lewy Body (DLB) onset. RBD is generally linked with progressive neurodegenerative traits. However, associations between RBD with DLB, RBD without DLB, and RBD duration effects on DLB symptoms remain unclear.
OBJECTIVE: To examine DLB symptom frequency and subtypes in RBD, and explore the effects of different RBD onset times on symptoms in de novo DLB patients.
METHODS: In this multicenter investigation, we consecutively recruited 271 de novo DLB patients. All had standardized clinical and comprehensive neuropsychological evaluations. Subgroup analyses, performed based on the duration of RBD confirmed by polysomnography before the DLB diagnosis, we compared the proportion of patients with cognitive impairment, parkinsonism, and AuD features between groups.
RESULTS: Parkinsonism and AuD incidences were significantly elevated in DLB patients with RBD when compared with patients without RBD. Subgroup analyses indicated no significant differences in parkinsonism between DLB patients who developed RBD ≥10 years prior to the DLB diagnosis and DLB patients without RBD. The incidence of non-tremor-predominant parkinsonism and AuD was significantly higher in DLB patients whose RBD duration before the DLB diagnosis was <10 years when compared with DLB patients without RBD.
CONCLUSIONS: We identified significant symptom and phenotypic variability between DLB patients with and without RBD. Also, different RBD duration effects before the DLB diagnosis had a significant impact on symptomatic phenotypes, suggesting the existence of a slowly progressive DLB neurodegenerative subtype.

Constipation is a common symptom in dementia, and the cause is controversial. Rare clinical studies focused on plasma orexin-A levels and constipation in dementia.
To evaluate the associations between orexin-A and constipation in patients with cognitive impairment.
A total of 21 patients with mild cognitive impairment (MCI), 142 with Alzheimer\'s disease (AD), and 57 with Lewy body dementia (LBD) were conducted. Besides informant-based history, neurological examinations or neuropsychological assessments, plasma levels of orexin-A, and constipation were assessed. The associations between orexin-A and constipation were evaluated by logistic regression models.
There were 47/220 (21.36%) cognitive impairment patients having constipation, and the proportion of constipation in LBD (61.40%) was significantly higher than AD (5.63%) and MCI (19.05%). No significant age or sex differences in the prevalence of constipation were found in the MCI, AD, and LBD groups. We found the cognitive impairment patients with constipation had lower levels of plasma orexin-A [1.00 (0.86, 1.28) versus 1.29 (1.01, 1.50) ng/ml, p < 0.001] than those without. And the plasma levels of orexin-A were significantly associated with the occurrence of constipation after adjusting for all variables in all patients with cognitive impairment (OR = 0.151, 95% CI: 0.042-0.537, p = 0.003). And the same finding was more prominent in the LBD group (p = 0.048).
The decrease of plasma level of orexin-A is closely associated with the occurrence of constipation. Orexin-A has an intestinal protective effect and is involved in the gastrointestinal symptoms of patients with cognitive impairment.