Family History is Associated with Phenotype in Dementia with Lewy Bodies

It is currently unknown whether patients with dementia with Lewy bodies (DLB) with relatives with dementia or Parkinson's disease (familial DLB patients) have a different phenotype than sporadic DLB patients. In this study, we aimed to examine disease onset, rate of cognitive decline, survival, and Alzheimer's disease (AD) biomarkers in patients with familial DLB (n = 154) and sporadic DLB (n = 137), using linear mixed model analysis and Cox regression analysis, among others. Familial patients had a shorter survival (8.0 years) and more often elevated cerebrospinal fluid AD biomarkers (47%) than sporadic patients (9.0 years; p≤0.001; 30%, p = 0.037). Our findings suggest that genetic factors are important in DLB and that the identification of new genetic factors will probably improve the prediction of prognosis

Amyloid-β peptides in cerebrospinal fluid of patients with dementia with Lewy bodies

BACKGROUND: One of the major challenges in diagnosing dementia with Lewy bodies (DLB) is the common co-morbid presence of amyloid pathology. To understand the putative role of altered amyloid-β (Aβ) metabolism in dementia with DLB, we analyzed levels of different cerebrospinal fluid (CSF) Aβ peptides (Aβ38, Aβ40, Aβ42) in DLB, Alzheimer's disease (AD), and cognitively normal controls. METHODS: CSF from patients with DLB (n = 72; age 68 ± 6 years; 10%F; Mini-mental State examination (MMSE) 23 ± 4), AD (n = 38; age 68 ± 6 years; 8%F; MMSE 22 ± 5), and cognitively normal controls (n = 38; age 67 ± 7 years; 13%F; MMSE 29 ± 2) was analyzed using the Meso Scale Discovery assay for human Aβ peptides. We performed general linear models to compare CSF Aβ peptide levels between groups. Associations between CSF Aβ peptides and MMSE score at baseline and longitudinal changes over time were assessed with linear mixed models. RESULTS: For all three CSF Aβ peptides and compared to controls (Aβ38 2676 ± 703 pg/ml, Aβ40 6243 ± 1500 pg/ml, and Aβ42 692 ± 205 pg/ml), we observed lower levels in DLB (Aβ38 2247 ± 638, Aβ40 5432 ± 1340, and Aβ42 441 ± 185, p  0.52) and APOE genotype. Finally, lower Aβ peptide levels were associated with lower MMSE score (β = 1.02-1.11, p < 0.05). CONCLUSION: We demonstrated different profiles of CSF Aβ reduction in DLB and AD. In particular, while AD is characterized by an isolated drop in Aβ42, DLB comes with reductions in Aβ38, Aβ40, and Aβ42. This suggests that amyloid metabolism is affected in DLB, even in the absence of co-morbid AD pathology

Pathologically decreased csf levels of synaptic marker nptx2 in dlb are correlated with levels of alpha-synuclein and vgf

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain

Disease progression in dementia with Lewy bodies: A longitudinal study on clinical symptoms, quality of life and functional impairment

Background and Objectives: Dementia with Lewy Bodies (DLB) is a heterogeneous disease, with variable signs and symptoms across multiple domains. We aimed to identify associations with rate of change in cognition, everyday functioning (IADL) and quality of life (QoL). Methods: We included 121 DLB patients (69 ± 6 yrs, 14%F, MMSE: 25 ± 3) in our prospective cohort (follow-up 2 ± 1 yrs). We described progression of symptoms and cognitive decline over time. Mixed models were used to investigate whether changes in symptoms were associated to changes in IADL (FAQ), QoL (QoL-AD) and caregiver burden (ZBI). Last, we investigated whether baseline symptoms and biomarkers predicted decline in cognition (MMSE), IADL (FAQ) and QoL (QoL-AD). Results: Parkinsonism and RBD were most frequently present early in the disease course, while hallucinations were more likely to develop in a later stage. MMSE (annual change β ± SE = −2.06 ± 0.23), QoL-AD (−1.03 ± 0.20), and FAQ (3.04 ± 0.30) declined over time. Increasing severity of clinical symptoms was associated to increases in FAQ, QoL-AD and caregiver burden. Baseline clinical symptoms were not predictive for decline in these outcomes. By contrast, AD co-pathology (CSF pTau/Aβ42 ratio) was associated to steeper decline in MMSE (−1.23 ± 0.54). Medial temporal atrophy (−0.81 ± 0.26) and global cortical atrophy (−0.73 ± 0.36) predisposed for decline in QoL-AD. Conclusions: Our findings imply that underlying disease processes, rather than clinical symptomatology aid in predicting decline. These findings are relevant for treatment strategies and the development of DLB specific outcome measures

Diagnostic and prognostic value of EEG in prodromal dementia with Lewy bodies

OBJECTIVE: Early biomarkers for dementia with Lewy bodies (DLB) are lacking. To determine whether EEG differentiates the prodromal phase of DLB from other causes of mild cognitive impairment (MCI) and whether EEG is predictive for time to conversion from MCI to DLB, we compared EEGs and clinical follow-up of patients with MCI due to DLB with those of patients with MCI due to Alzheimer disease (MCI-AD). METHODS: We compared 37 patients with MCI who developed DLB during follow-up or had an abnormal 123I-PF-CIT SPECT scan (MCI-DLB) with 67 age-matched patients with MCI-AD. EEGs were assessed visually with a score of increasing abnormality (range 1-5). We performed fast Fourier transform to analyze the power spectrum. With survival analyses, EEG characteristics were related to time to progression to dementia. RESULTS: The visual EEG score was higher in MCI-DLB (score >2 in 60%) compared to MCI-AD (score >2 in 8%, p < 0.001). We found frontal intermittent delta activity in 22% of MCI-DLB, not in MCI-AD. Patients with MCI-DLB had a lower peak frequency (7.5 [6.0-9.9] Hz vs 8.8 [6.8-10.2] in MCI-AD, p < 0.001) and more slow-wave activity. Several individual EEG measures showed good performance to discriminate MCI-DLB from MCI-AD (areas under the curve up to 0.94). In MCI-DLB, high visual EEG score, diffuse abnormalities, and low α2 power were related to time to progression to dementia (hazard ratios 4.1, 9.9, 5.1, respectively). CONCLUSIONS: Profound EEG abnormalities are already present in the prodromal stage of DLB and have diagnostic and prognostic value. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EEG abnormalities are more common in MCI-DLB than MCI-AD

Prodromal Dementia with Lewy Bodies: Clinical Characterization and Predictors of Progression

Objective: The objective of this study was to examine clinical characteristics, cognitive decline, and predictors for time to dementia in prodromal dementia with Lewy bodies with mild cognitive impairment (MCI-LB) compared with prodromal Alzheimer's disease (MCI-AD). Methods: We included 73 MCI-LB patients (12% female; 68 ± 6 years; Mini Mental State Examination, 27 ± 2) and 124 MCI-AD patients (48% female; 68 ± 7 years; Mini Mental State Examination, 27 ± 2) from the Amsterdam Dementia Cohort. Follow-up was available for 61 MCI-LB patients and all MCI-AD patients (3 ± 2 years). We evaluated dementia with Lewy bodies core features, neuropsychiatric symptoms, caregiver burden (Zarit caregiver burden interview), MRI, apolipoprotein genotype, and cerebrospinal fluid biomarkers (tau/Aβ 1–42 ratio). Longitudinal outcome measures included cognitive slopes (memory, attention, executive functions, and language and visuospatial functions) and time to dementia. Results: Parkinsonism was the most frequently present core feature in MCI-LB (69%). MCI-LB patients more often had neuropsychiatric symptoms and scored higher on ZARIT when compared with the MCI-AD patients. Linear mixed models showed that at baseline, MCI-LB patients performed worse on nonmemory cognitive domains, whereas memory performance was worse in MCI-AD patients. Over time, MCI-LB patients declined faster on attention, whereas MCI-AD patients declined faster on the Mini Mental State Examination and memory. Cox proportional hazards regressions showed that in the MCI-LB patients, lower attention (hazard ratio [HR] = 1.6; 95% confidence interval [CI], 1.1–2.3) and more posterior cortical atrophy (HR = 3.0; 95% CI, 1.5–5.8) predicted shorter time to dementia. In the MCI-AD patients, worse performance on memory (HR = 1.1; 95% CI, 1.0–1.2) and executive functions (HR = 1.3; 95% CI, 1.0–1.6) were independently associated with time to Alzheimer's dementia. Conclusion: MCI-LB patients have distinct neuropsychiatric and cognitive profiles with prominent decline in attention when compared with MCI-AD patients. Our results highlight the importance of early diagnosis because symptoms already have an impact in the prodromal stages

EEG Characteristics of Dementia With Lewy Bodies, Alzheimer's Disease and Mixed Pathology

Introduction: Previous studies on electroencephalography (EEG) to discriminate between dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) have been promising. These studies did not consider the pathological overlap of the two diseases. DLB-patients with concomitant AD pathology (DLB/AD+) have a more severe disease manifestation. The EEG may also be influenced by a synergistic effect of the two pathologies. We aimed to compare EEG characteristics between DLB/AD+, "pure" DLB (DLB/AD-) and AD. Methods: We selected probable DLB patients who had an EEG and cerebrospinal fluid (CSF) available, from the Amsterdam Dementia Cohort (ADC). Concomitant AD-pathology was defined as a CSF tau/Aβ-42 ratio > 0.52. Forty-one DLB/AD+ cases were matched for age (mean 70 (range 53-85)) and sex (85% male) 1:1 to DLB/AD- and AD-patients. EEGs were assessed visually, with Fast Fourier Transform (FFT), network- and connectivity measures. Results: EEG visual severity score (range 1-5) did not differ between DLB/AD- and DLB/AD+ (2.7 in both groups) and was higher compared to AD (1.9, p < 0.01). Both DLB groups had a lower peak frequency (7.0 Hz and 6.9 Hz in DLB vs. 8.2 in AD, p < 0.05), more slow-wave activity and more prominent disruptions of connectivity and networks, compared to AD. No significant differences were found between DLB/AD+ and DLB/AD-. Discussion: EEG abnormalities are more pronounced in DLB, regardless of AD co-pathology. This emphasizes the valuable role of EEG in discriminating between DLB and AD. It suggests that EEG slowing in DLB is influenced more by the α-synucleinopathy, or the associated cholinergic deficit, than by amyloid and tau pathology

Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF

Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain