Biomarkers in dementia with Lewy bodies

PhD ThesisDementia with Lewy bodies (DLB) is the second commonest type of neurodegenerative dementia, but accurate antemortem diagnosis remains challenging, especially at the earliest (prodromal) disease stages and in the presence of mixed (Alzheimer) pathology. To investigate this we undertook two studies, an investigation of 123I-FP-CIT imaging as a possible biomarker of prodromal DLB (at the mild cognitive impairment (MCI) stage), and a study of the effect of amyloid deposition measured by 18F-Florbetapir PET on clinical phenotype in established DLB. Methods Prodromal DLB Study: 53 subjects with MCI and symptoms suggestive of Lewy body disease underwent comprehensive clinical and cognitive assessment and 123I-FP-CIT SPECT imaging. Amyloid Imaging Study: 22 DLB, 10 Alzheimer’s disease (AD) and 15 control subjects underwent comprehensive clinical and cognitive assessment, MRI and 18F-Florbetapir PET amyloid imaging. Results Prodromal DLB Study: An abnormal 123I-FP-CIT scan was associated with increased rates of parkinsonism and RBD, but was not associated with a specific pattern of cognitive impairment. The pattern of 123I-FP-CIT binding loss was symmetrical. Males were more likely to have an abnormal scan than females. Amyloid Imaging Study: AD subjects displayed greater amyloid binding than DLB in frontal, temporal, cingulate and striatal regions. There were no significant differences between DLB and controls, but binding in DLB was intermediate between AD and controls in all regions. Frontal:Occipital binding ratio differentiated AD from DLB and controls. There were no consistent effects of amyloid on the phenotype of DLB subjects. ii Conclusions 123I-FP-CIT SPECT appears to be a marker of Lewy body disease in the prodromal stage. Longitudinal analysis is needed to determine its sensitivity and specificity. Amyloid deposition is present in a proportion of DLB subjects, but is not associated with a clear difference in clinical phenotype. Longitudinal follow-up will determine whether it is associated with a difference in disease progression

Associations between multimorbidity and neuropathology in dementia: a case for considering functional cognitive disorders, psychiatric illness, and dementia mimics

Cognitive impairment in older people has a variety of underlying causes. In addition to neurodegenerative causes such as Alzheimer's disease, a dementia-like cognitive disorder may appear due to non-degenerative factors. Multimorbidity has been previously associated with clinical dementia risk, though whether this was due to greater risk of dementia-related neuropathology, or other factors that mimic dementia, was unclear. We provide evidence that physical multimorbidity is not associated with greater pathological changes at autopsy. Other factors related to multimorbidity and cognitive impairments may be important targets for investigation, such as functional cognitive disorders, primary psychiatric disorders (depression, anxiety, psychosis) and polypharmacy

Stratigraphy, age, and provenance of the Eocene Chumstick basin, Washington Cascades; implications for paleogeography, regional tectonics, and development of strike-slip basins: Reply

We welcome the comment by Evans (2022) and the opportunity to further discuss our study of the Chumstick Formation. The correlation of fault-bound nonmarine sedimentary units in central and western Washington has been a topic of interest, and debate, for many years (Frizzell, 1979; Taylor et al., 1988; Gresens et al., 1981; Gresens, 1983; Evans and Johnson, 1989; Evans, 1994; Cheney and Hayman, 2009). However, many questions about the regional correlation of these units were resolved with the publication of a suite of internally consistent high-precision 206Pb/238U zircon dates from volcanic interbeds throughout the early to middle Eocene stratigraphy (Eddy et al., 2016). This data set confirmed the timing of sediment deposition of the different members within the Chumstick Formation. Donaghy et al. (2021) provides a detailed study of the Chumstick Formation, which builds on earlier research by Gresens et al. (1981, 1983), McClincy (1986), and Evans (1994) by incorporating new geochronologic information and additional clast counts, detrital zircon geochronology, and facies mapping. We interpret large parts of the Chumstick Formation to represent a spatially and temporally distinct sedimentary system between the Leavenworth and Entiat fault zones that likely formed as a pull-apart basin. Evans (2022) objects to several of the interpretations presented in Donaghy et al. (2021) regarding the relationship between different members of the Chumstick Formation and surrounding sedimentary units, the timing of strike-slip faulting, and the regional tectonic setting of these rocks. We discuss each of these points in the following sections

The challenges of COVID-19 for people with dementia with Lewy bodies and family caregivers.

Introduction During the current SARS-CoV-2 pandemic dementia has been identified as disproportionally common in adults aged over 65 who develop severe COVID-19.1 Observational data from the International Severe Acute Respiratory and Emerging Infections Consortium also confirms a high prevalence of dementia in older adults hospitalised with COVID-19.2 It is so far unclear whether there is any direct effect of dementia pathologies as dementia is a disease of old age, and thus likely to be associated with a variety of comorbidities, in particular, frailty, which may further exacerbate the risk of severe infection. In addition up to one third of COVID patients have demonstrated neurological sequelae3 and there may be both direct (viral infection within the brain, vascular effects) and indirect effects (e.g. host immunological response, impact of treatment) of SARS-CoV-2 on the brain.4 It is therefore possible that SARS-CoV-2 infection may accentuate any pre-existing neurodegenerative disease

Visuo-perceptual and decision-making contributions to visual hallucinations in mild cognitive impairment in Lewy body disease: insights from a drift diffusion analysis

Background: Visual hallucinations (VH) are a common symptom in dementia with Lewy bodies (DLB); however, their cognitive underpinnings remain unclear. Hallucinations have been related to cognitive slowing in DLB and may arise due to impaired sensory input, dysregulation in top-down influences over perception, or an imbalance between the two, resulting in false visual inferences. Methods: Here we employed a drift diffusion model yielding estimates of perceptual encoding time, decision threshold, and drift rate of evidence accumulation to (i) investigate the nature of DLB-related slowing of responses and (ii) their relationship to visuospatial performance and visual hallucinations. The EZ drift diffusion model was fitted to mean reaction time (RT), accuracy and RT variance from two-choice reaction time (CRT) tasks and data were compared between groups of mild cognitive impairment (MCI-LB) LB patients (n = 49) and healthy older adults (n = 25). Results: No difference was detected in drift rate between patients and controls, but MCI-LB patients showed slower non-decision times and boundary separation values than control participants. Furthermore, non-decision time was negatively correlated with visuospatial performance in MCI-LB, and score on visual hallucinations inventory. However, only boundary separation was related to clinical incidence of visual hallucinations. Conclusions: These results suggest that a primary impairment in perceptual encoding may contribute to the visuospatial performance, however a more cautious response strategy may be related to visual hallucinations in Lewy body disease. Interestingly, MCI-LB patients showed no impairment in information processing ability, suggesting that, when perceptual encoding was successful, patients were able to normally process information, potentially explaining the variability of hallucination incidence

Plasma biomarkers of neurodegeneration in mild cognitive impairment with Lewy bodies

BACKGROUND: Blood biomarkers of Alzheimer's disease (AD) may allow for the early detection of AD pathology in mild cognitive impairment (MCI) due to AD (MCI-AD) and as a co-pathology in MCI with Lewy bodies (MCI-LB). However not all cases of MCI-LB will feature AD pathology. Disease-general biomarkers of neurodegeneration, such as glial fibrillary acidic protein (GFAP) or neurofilament light (NfL), may therefore provide a useful supplement to AD biomarkers. We aimed to compare the relative utility of plasma Aβ42/40, p-tau181, GFAP and NfL in differentiating MCI-AD and MCI-LB from cognitively healthy older adults, and from one another. METHODS: Plasma samples were analysed for 172 participants (31 healthy controls, 48 MCI-AD, 28 possible MCI-LB and 65 probable MCI-LB) at baseline, and a subset (n = 55) who provided repeated samples after ≥1 year. Samples were analysed with a Simoa 4-plex assay for Aβ42, Aβ40, GFAP and NfL, and incorporated previously-collected p-tau181 from this same cohort. RESULTS: Probable MCI-LB had elevated GFAP (p < 0.001) and NfL (p = 0.012) relative to controls, but not significantly lower Aβ42/40 (p = 0.06). GFAP and p-tau181 were higher in MCI-AD than MCI-LB. GFAP discriminated all MCI subgroups, from controls (AUC of 0.75), but no plasma-based marker effectively differentiated MCI-AD from MCI-LB. NfL correlated with disease severity and increased with MCI progression over time (p = 0.011). CONCLUSION: Markers of AD and astrocytosis/neurodegeneration are elevated in MCI-LB. GFAP offered similar utility to p-tau181 in distinguishing MCI overall, and its subgroups, from healthy controls

Predicting cognitive decline using neuropsychiatric symptoms in prodromal Lewy body dementia: A longitudinal study

Introduction: Neuropsychiatric symptoms (NPS) in Lewy body dementias (LBD) occur frequently and early in disease progression. Such symptoms are associated with worse quality of life, caregiver burden and functional limitations. Limited evidence exists, however, outlining the longitudinal relationship between NPS and cognitive decline in prodromal LBD. Methods: 123 participants were derived from three cohort studies. Patients with mild cognitive impairment (MCI) relating to probable dementia with Lewy bodies (MCI-LB, n = 67) and Parkinson's disease (PD-MCI, n = 56) completed comprehensive cognitive and neuropsychiatric assessment and were followed up longitudinally. Linear regression and mixed effects models assessed the relationship between baseline NPS and cognition at baseline and over time. Results: In MCI-LB, overall NPS burden was associated with declines over time in executive function (p = 0.026) and processing speed (p = 0.028) and baseline aberrant motor behaviour was associated with declines in attention (p < 0.025). Anxiety was significantly associated with poorer visuospatial functioning (p = 0.016) at baseline and poorer attention both at baseline (p = 0.017) and across time points (p = 0.024). In PD-MCI, psychosis was associated with poorer executive functioning at baseline (p = 0.008) and across time points (p = 0.002) but had no association with changes longitudinally. Conclusions: Core neuropsychiatric components of LBD are not strongly associated with cognition in prodromal disease. This may suggest that neuropathological mechanisms underlying NPS may not be the same as those underlying cognitive impairment. Non-core NPS, however, may be more directly associated with cognitive change. Future studies utilising neuroimaging techniques are needed to explore the neuropathological basis of NPS in prodromal LBD

In vivo nucleus basalis of Meynert degeneration in mild cognitive impairment with Lewy bodies.

OBJECTIVES: To investigate in vivo degeneration of the cholinergic system in mild cognitive impairment with Lewy bodies (MCI-LB), we studied nucleus basalis of Meynert (NBM) volumes from structural MR images and its relation to EEG slowing and cognitive impairment. METHODS: We studied the NBM using structural MR images in 37 patients with MCI-LB, 34 patients with MCI with Alzheimer's disease (MCI-AD), and 31 healthy control participants. We also tested correlations between NBM volumes and measures of overall cognition and measures of EEG slowing in the MCI groups. RESULTS: Overall NBM volume was reduced in MCI-LB compared to controls with no significant difference between MCI-AD and controls or between the two MCI groups. The voxel-wise analysis revealed bilateral clusters of reduced NBM volume in MCI-LB compared to controls and smaller clusters in MCI-AD compared to controls. There was a significant association between overall NBM volume and measures of overall cognition in MCI-LB, but not in MCI-AD. In both MCI groups, reduced NBM volume was correlated with more severe EEG slowing. CONCLUSIONS: This study provides in vivo evidence that early cholinergic degeneration in DLB occurs at the MCI stage and is related to the severity of cognitive impairment. Furthermore, the results suggest that early EEG slowing in MCI-LB might be in part cholinergically driven. Importantly, these findings suggest an early cholinergic deficit in MCI-LB that may motivate further testing of the effectiveness of cholinesterase inhibitors in this group