Dag Aarsland (United Kingdom)
Kings College London Department of Old Age PsychiatryAuthor Of 6 Presentations
SEX DIFFERENCES IN GREY MATTER NETWORKS IN DEMENTIA WITH LEWY BODIES AND HEALTHY ELDERLY CONTROLS
Abstract
Aims
Dementia with Lewy bodies (DLB) has been considered a predominantly male disease. Considering the transsynaptic spread of the α-synuclein pathology, sex-specific structural connections emanating from the distinct induction sites of the pathology may thus predispose men to develop DLB. To test this hypothesis, we investigated potential sex differences in grey matter networks in probable DLB patients and healthy controls (HCs).
Methods
A total of 119 (68.7±8.4 years) male and 45 female (69.9±9.1 years) DLB patients from three European centres and the Mayo Clinic were included, along with 119 male and 45 female age-matched HCs from the Mayo Clinic. Grey matter volumes of 58 cortical and subcortical brain regions were measured from MRI. Sex-specific grey matter networks for DLB patients and HCs were constructed by correlating each pair of brain regions while adjusting for age, MMSE, intracranial volume, and centre. Network properties of the correlation matrices were compared between sexes and groups.
Results
Networks of male DLB patients and male HCs were characterised by a lower connective strength compared to their respective female counterparts. Grey matter networks of DLB patients, especially in males, tended to subdivide into more distinct clusters than those of HCs. Sex differences in nodal network measures (local efficiency and betweenness centrality) were observed in temporal and parietal regions in DLB patients, and parietal, subcortical, and cerebellar regions in HCs.
Conclusions
Sex differences in the structural grey matter networks in DLB patients and HCs may indicate a sex-dependent network vulnerability to the alpha-synuclein pathology in DLB. Future studies might investigate whether the differences in structural network measures are associated with differences in cognitive scores and clinical symptoms between the sexes.
CHOLINERGIC WHITE MATTER DEGENERATION IN DEMENTIA WITH LEWY BODIES: A COMPARISON OF CLINICAL AND ADVANCED IMAGING METHODS
Abstract
Aims
The cholinergic pathways hyperintensities scale (CHIPS) is a visual rating scale for signal abnormalities in cholinergic white matter pathways on structural magnetic resonance imaging (MRI). Little is known about the association of CHIPS with other cerebrovascular MRI markers of global white matter signal abnormalities (WMSAs) and cholinergic pathways evaluation. We hypothesized that in dementia with Lewy bodies (DLB), disruption of cholinergic pathways by WMSAs would have a more specific impact on cognitive functions and phenotype than the global WMH burden.
Methods
We enrolled 41 probable DLB patients from the SPIN cohort (mean age 75.7 years, 19 females). WMSA were assessed on MRI using CHIPS, the Fazekas visual rating scale, and FreeSurfer. Medial and lateral cholinergic pathways were assessed with tractography. We used linear model to evaluate associations between these four MRI methods and several clinical/cognitive variables (global cognition, several cognitive domains, and core clinical features). Cortical atrophy was assessed using an in-house artificial intelligence-based atrophy rating model (frontal atrophy, medial temporal atrophy, posterior atrophy), and associations with WMSA and cholinergic pathways were tested.
Results
CHIPS scores correlated significantly with Fazekas scores (Cohen’s d = 0.24, p<0.001), FreeSurfer WMSA burden (rs=0.73, p<0.001), and cholinergic pathways (r = 0.44, p=0.006). All four MRI methods’ scores however did not show a significant correlation with any clinical/cognitive variable. CHIPS, Fazekas, and FreeSurfer scores were associated with more frontal atrophy, but not with more medial temporal or posterior atrophy.
Conclusions
Cholinergic white matter degeneration as assessed with CHIPS correlates with global cerebrovascular burden and frontal neurodegeneration in our cohort of DLB patients. Further studies are needed to elucidate potential associations between CHIPS and global cerebrovascular burden and clinical presentation of DLB.
PLASMA AMYLOID, GFAP, AND NFL IN DEMENTIA WITH LEWY BODIES
Abstract
Aims
Plasma biomarkers have been proven to be valuable as early diagnostic and prognostic markers for Alzheimer’s Disease (AD) and AD co-pathology is a common feature in dementia with Lewy bodies (DLB). Here, we aimed to analyze plasma biomarkers in DLB, and evaluate their relation with CSF Aβ42 status, DLB core features and cognitive decline to assess their clinical importance in DLB patients.
Methods
Plasma Aβ42/40, GFAP and NfL were measured by SIMOA in patients with DLB (n=342), AD (n=131), and healthy controls (n=89). Group differences were assessed with ANOVA, or ANCOVA corrected for age. Likewise, associations of biomarkers with amyloid status and DLB core features were assessed in the DLB subset. Associations of baseline plasma biomarkers with cognitive impairment and decline were determined by linear regression and linear mixed effects models, respectively.
Results
Plasma Aβ42/40 was higher in DLB than in AD and comparable to controls, while plasma GFAP and NfL were higher in DLB compared to controls, but comparable to AD. In CSF Aβ42 abnormal DLB patients, plasma Aβ42/40 was significantly lower than in CSF Aβ42 normal DLB patients (no differences in plasma GFAP or NfL). Parkinsonism was related to higher plasma NfL levels. In DLB, higher GFAP and NfL were associated with lower MMSE scores at baseline and predicted faster cognitive decline (GFAP: annual change of -0.0026 MMSE points (95%CI: -0.0041 to -0.0011 MMSE points, p=.001); NfL: annual change of 0.0252 MMSE points (95%CI: -0.0367 to -0.0136 MMSE points, p<.001)).
Conclusions
Our findings suggest plasma GFAP and NfL to be potential prognostic markers for DLB. Plasma Aβ42/40 could become a less invasive alternative for assessing amyloidosis, but further correlation studies in DLB are needed and cut-off values need to be implemented.
THE EUROPEAN INTER-SOCIETAL DIAGNOSTIC WORKFLOW FOR THE BIOMARKER-BASED ETIOLOGICAL DIAGNOSIS OF NEUROCOGNITIVE DISORDERS.
Abstract
Aims
The future availability of disease-modifying drugs for the main forms of neurocognitive disorders further emphasises the need for early aetiological diagnosis using in-vivo biomarkers. As their clinical validation is still ongoing, a European multidisciplinary task force has defined a diagnostic workflow to support clinicians in the rational and combined use of biomarkers in the clinical context.
Methods
Using consensus Delphi procedure, 22 experts from eleven European scientific societies and a representative of a patient advocacy association participated in six rounds and voted on the basis of their opinion and the systematically reviewed scientific evidence.
Results
The workflow is patient-centered and features three waves of assessment (W): W1 defines eleven clinical profiles based on integrated results of clinical history and examination, neuropsychology, MRI, blood tests and EEG (in specific cases); W2 describes the first-line biomarkers according to W1 clinical suspicion; and W3 suggests the second-line biomarkers to disambiguate still undefined aetiology. Biomarker use is strongly recommended below the age of 70 and not recommended above the age of 85. Cerebrospinal fluid (CSF) biomarkers are first-line in the suspect of Alzheimer’s disease and when inconsistent neuropsychological and MRI findings hinder a clear diagnostic hypothesis; if CSF amyloid values are borderline or negative, FDG-PET can subsequently disambiguate cases. FDG-PET is first-line for the clinical profiles leading to suspect frontotemporal lobar degeneration and motor tauopathies and is followed by CSF biomarkers in the case of atypical metabolic patterns, when an underlying AD aetiology is conceivable. When a Lewy body disease is suspected, dopamine transporter SPECT is firstly suggested followed by a cardiac 123I-metaiodobenzylguanidine scintigraphy.
Conclusions
The initiative will promote consistency in the diagnosis of neurocognitive disorders across countries, and rational use of resources.
SPECTRAL ANALYSIS OF THE RESTING-STATE ELECTROENCEPHALOGRAM IN PARKINSON’S DISEASE USING FUNCTIONAL DATA ANALYSIS: A MULTICENTER STUDY
Abstract
Aims
This study aimed 1) To analyze differences in the resting-state electroencephalography (rs-EEG) spectral features of PD and non-PD subjects using Functional Data Analysis (FDA), and 2) To explore, in four independent cohorts, the external validity and reproducibility of the findings using both epoch-to-epoch FDA and averaged-epochs approach.
Methods
We included 169 subjects (85 non-PD; 84 PD) from four centers (Table 1). Rs-EEG signals were preprocessed with a combination of automated pipelines. Sensor-level relative power spectral density (PSD), dominant frequency (DF), and DF variability (DFV) features were extracted. Differences in each feature were compared between PD and non-PD control subjects on averaged-epochs, as well as using FDA, to model the epoch-to-epoch change of each feature.
Results
For averaged-epochs, significantly higher theta relative PSD in PD was found across all datasets. Also, in PD, higher pre-alpha relative PSD was observed in three out of four datasets (Figure 1). For FDA, similar findings were achieved in theta, but all datasets showed consistently significant posterior pre-alpha differences across multiple epochs (Figures 2 & 3).
Conclusions
FDA analysis showed increased generalized theta, with posterior pre-alpha relative PSD as the most reproducible finding in PD across the four cohorts. FDA constitutes a reliable and powerful tool to analyze epoch-to-epoch the rs-EEG.
CEREBROVASCULAR BURDEN IN ALZHEIMER’S DISEASE, DEMENTIA WITH LEWY BODIES AND OTHER DEMENTIAS
Abstract
Aims
To investigate cerebrovascular burden across clinical groups of Alzheimer’s disease (AD), Vascular dementia (VaD), Mixed dementia (MD), Dementia with Lewy Bodies (DLB), Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Mild cognitive impairment (MCI) and cognitively unimpaired controls (CU).
Methods
We included participants from the European DLB Consortium (E-DLB) and the Swedish cohort MemClin. We identified 1600 individuals (AD=242, VaD=60, MD=88, DLB=206, PD=21, PDD=65, MCI=692, CU=226) with visual ratings of white matter changes with the commonly used Fazekas scale, as a marker of cerebrovascular burden. We also analysed visual ratings of medial temporal lobe atrophy (MTA) and cognitive and demographic measures. Cerebrovascular burden was binarized as high (Fazekas 2-3) versus low (Fazekas 0-1). We compared high and low burden groups, across and within diagnoses, in terms of MTA, cognition, gender distribution, age and education.
Results
All diagnostic groups had higher frequencies of cerebrovascular burden compared to the CU reference group (CU=14.16%, AD=37.19%, DLB=53.40%, MCI=32.80%, PD=33.33%, PDD=67.69%, MD=59.09%, VaD=58,33%). CU individuals with a high cerebrovascular burden were older and more often female, and had higher MTA, lower education, and lower cognitive scores. AD patients with a high cerebrovascular burden were older and had higher MTA scores and lower education. DLB and MCI patients with a high cerebrovascular burden were older and had a higher MTA but did not differ in education or cognitive performance. Among patients with PD, PDD, MD and VaD, the high and low burden groups did not differ statistically in any of the investigated variables
Conclusions
The effects of cerebrovascular burden differed across diagnoses, suggesting that the contribution of cerebrovascular pathology to clinical phenotype may be dependent on which copathology it interacts with.