Plasma biomarkers of amyloid, tau, axonal, and neuroinflammation pathologies in dementia with Lewy bodies.

BACKGROUND: Increasing evidence supports the use of plasma biomarkers of amyloid, tau, neurodegeneration, and neuroinflammation for diagnosis of dementia. However, their performance for positive and differential diagnosis of dementia with Lewy bodies (DLB) in clinical settings is still uncertain. METHODS: We conducted a retrospective biomarker study in two tertiary memory centers, Paris Lariboisière and CM2RR Strasbourg, France, enrolling patients with DLB (n = 104), Alzheimer's disease (AD, n = 76), and neurological controls (NC, n = 27). Measured biomarkers included plasma Aß40/Aß42 ratio, p-tau181, NfL, and GFAP using SIMOA and plasma YKL-40 and sTREM2 using ELISA. DLB patients with available CSF analysis (n = 90) were stratified according to their CSF Aß profile. RESULTS: DLB patients displayed modified plasma Aß ratio, p-tau181, and GFAP levels compared with NC and modified plasma Aß ratio, p-tau181, GFAP, NfL, and sTREM2 levels compared with AD patients. Plasma p-tau181 best differentiated DLB from AD patients (ROC analysis, area under the curve [AUC] = 0.80) and NC (AUC = 0.78), and combining biomarkers did not improve diagnosis performance. Plasma p-tau181 was the best standalone biomarker to differentiate amyloid-positive from amyloid-negative DLB cases (AUC = 0.75) and was associated with cognitive status in the DLB group. Combining plasma Aß ratio, p-tau181 and NfL increased performance to identify amyloid copathology (AUC = 0.79). Principal component analysis identified different segregation patterns of biomarkers in the DLB and AD groups. CONCLUSIONS: Amyloid, tau, neurodegeneration and neuroinflammation plasma biomarkers are modified in DLB, albeit with moderate diagnosis performance. Plasma p-tau181 can contribute to identify Aß copathology in DLB.

Neuroanatomical substrates of depression in dementia with Lewy bodies and Alzheimer's disease.

Dementia with Lewy bodies (DLB) and Alzheimer's disease (AD) are often associated with depressive symptoms from the prodromal stage. The aim of the present study was to investigate the neuroanatomical correlates of depression in prodromal to mild DLB patients compared with AD patients. Eighty-three DLB patients, 37 AD patients, and 18 healthy volunteers were enrolled in this study. Depression was evaluated with the Mini International Neuropsychiatric Interview (MINI), French version 5.0.0. T1-weighted three-dimensional anatomical images were acquired for all participants. Regression and comparison analyses were conducted using a whole-brain voxel-based morphometry (VBM) approach on the grey matter volume (GMV). DLB patients presented a significantly higher mean MINI score than AD patients (p = 0.004), 30.1% of DLB patients had clinical depression, and 56.6% had a history of depression, while 0% of AD patients had clinical depression and 29.7% had a history of depression. VBM regression analyses revealed negative correlations between the MINI score and the GMV of right prefrontal regions in DLB patients (p < 0.001, uncorrected). Comparison analyses between DLB patients taking and those not taking an antidepressant mainly highlighted a decreased GMV in the bilateral middle/inferior temporal gyrus (p < 0.001, uncorrected) in treated DLB patients. In line with the literature, our behavioral analyses revealed higher depression scores in DLB patients than in AD patients. We also showed that depressive symptoms in DLB are associated with decreased GMV in right prefrontal regions. Treated DLB patients with long-standing depression would be more likely to experience GMV loss in the bilateral middle/inferior temporal cortex. These findings should be taken into account when managing DLB patients.

Who am I with my Lewy bodies? The insula as a core region of the self-concept networks.

BACKGROUND: Dementia with Lewy bodies (DLB) is characterized by insular atrophy, which occurs at the early stage of the disease. Damage to the insula has been associated with disorders reflecting impairments of the most fundamental components of the self, such as anosognosia, which is a frequently reported symptom in patients with Lewy bodies (LB). The purpose of this study was to investigate modifications of the self-concept (SC), another component of the self, and to identify neuroanatomical correlates, in prodromal to mild DLB. METHODS: Twenty patients with prodromal to mild DLB were selected to participate in this exploratory study along with 20 healthy control subjects matched in terms of age, gender, and level of education. The Twenty Statements Test (TST) was used to assess the SC. Behavioral performances were compared between LB patients and control subjects. Three-dimensional magnetic resonance images (MRI) were acquired for all participants and correlational analyses were performed using voxel-based morphometry (VBM) in whole brain and using a mask for the insula. RESULTS: The behavioral results on the TST showed significantly impaired performances in LB patients in comparison with control subjects (p < .0001). Correlational analyses using VBM revealed positive correlations between the TST and grey matter volume within insular cortex, right supplementary motor area, bilateral inferior temporal gyri, right inferior frontal gyrus, and left lingual gyrus, using a threshold of p = .001 uncorrected, including total intracranial volume (TIV), age, and MMSE as nuisance covariates. Additionally, correlational analysis using a mask for the insula revealed positive correlation with grey matter volume within bilateral insular cortex, using a threshold of p = .005. CONCLUSIONS: The behavioral results confirm the existence of SC impairments in LB patients from the prodromal stage of the disease, compared to matched healthy controls. As we expected, VBM analyses revealed involvement of the insula, among that of other brain regions, already known to be involved in other self-components. While this study is exploratory, our findings provide important insights regarding the involvement of the insula within the self, confirming the insula as a core region of the self-networks, including for high-order self-representations such as the SC.

Infectious Agents as Potential Drivers of α-Synucleinopathies.

α-synucleinopathies, encompassing Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy, are devastating neurodegenerative diseases for which available therapeutic options are scarce, mostly because of our limited understanding of their pathophysiology. Although these pathologies are attributed to an intracellular accumulation of the α-synuclein protein in the nervous system with subsequent neuronal loss, the trigger(s) of this accumulation is/are not clearly identified. Among the existing hypotheses, interest in the hypothesis advocating the involvement of infectious agents in the onset of these diseases is renewed. In this article, we aimed to review the ongoing relevant factors favoring and opposing this hypothesis, focusing on (1) the potential antimicrobial role of α-synuclein, (2) potential entry points of pathogens in regard to early symptoms of diverse α-synucleinopathies, (3) pre-existing literature reviews assessing potential associations between infectious agents and Parkinson's disease, (4) original studies assessing these associations for dementia with Lewy bodies and multiple system atrophy (identified through a systematic literature review), and finally (5) potential susceptibility factors modulating the effects of infectious agents on the nervous system. © 2022 International Parkinson and Movement Disorder Society.

Risk Factors of Caregiver Burden Evolution, for Patients With Subjective Cognitive Decline or Neurocognitive Disorders: A Longitudinal Analysis.

BACKGROUND/OBJECTIVES: The identification of factors used to predict caregiver burden may help preventive care. This study aimed to assess the relationship between evolution of patients with subjective cognitive decline (SCD) or progressive neurocognitive disorder (NCD) and evolution of caregiver burden. DESIGN: Observational, longitudinal study. SETTING: The study was conducted in the Clinical and Research Memory Center of the University Hospital of Lyon (France), between the November 1, 2011 and the June 30, 2014, with a maximum follow-up of 30 months. PARTICIPANTS: The study population included outpatients with SCD or NCD at all stages, and their informal caregiver. MEASUREMENTS: The caregiver burden was assessed during 2 visits of the patients and their caregiver, with the short version of the Zarit Burden Inventory (ZBI). Functional, cognitive performance, and behavioral and psychological symptoms were measured twice, concomitantly with the ZBI, using the Instrumental Activities of Daily Living (IADL) scale, the Mini-Mental State Examination (MMSE), and the Neuropsychiatric Inventory (NPI), respectively. Etiology and stage of the cognitive impairment were collected. RESULTS: The population study included 222 patients (mean age at inclusion: 80 years old, 62.9% females), with an average follow-up 12.6 ± 6 months. Proportion of patients with major NCD at the second visit (62.2%) increased compared with inclusion (50.0%). MMSE and IADL decreased between the 2 visits (P < .001), whereas ZBI increased (mean ZBI: 3.2 ± 2 at baseline, mean ZBI: 3.8 ± 2 at follow-up, P < .001). In unadjusted analyses, ZBI tended to be higher for patients whose MMSE decreased of at least 3 points between the visits. ZBI increased over time when IADL decreased (P value for within-patient effect <.001), while it remained stable when the IADL increased. ZBI increased when NPI increased. After mutual adjustment for change of MMSE, IADL, NPI, and etiologies, increase of ZBI over time remained significant when MMSE decreased at least 3 points between baseline and follow-up, when IADL decreased, and when NPI increased of at least 4 points. CONCLUSIONS: In a study population of patients with SCD or NCD at all stages, concomitant decrease of cognitive performance, increase of functional impairment, and increase neuropsychiatric symptoms over time were independently associated with increased caregiver burden. The identification of risk factors associated with an increased caregiver burden over time may allow a better evaluation of the impact of specific interventions on cognitive, behavioral, and functional dimensions of NCD on caregivers. TRIAL REGISTRATION: ClinicalTrials.govNCT02825732.

Relationship Between Comorbidities in Patients With Cognitive Complaint and Caregiver Burden: A Cross-Sectional Study.

BACKGROUND/OBJECTIVES: Informal caregivers of patients with a cognitive impairment may face exhaustion while taking care of their relatives, and are themselves at higher risk of disease. The objective was to assess the relationship between patients' comorbidities evaluated with the Charlson index, and the caregiver burden, independently of health disorders related to cognitive impairment. DESIGN: Cross-sectional observational study. SETTING: Memory clinic at the University Hospital of Lyon. PARTICIPANTS: Outpatients with cognitive complaint and consulting a Clinical and Research Memory Centre of Lyon (n = 1300). MEASUREMENTS: Comorbidity was measured using the Charlson Comorbidity Index related to age (CCI). The caregiver burden was measured with the short version of the Zarit Burden Interview (ZBI). The relationship was assessed between the CCI and the mini-Zarit and other patients' characteristics: behavior, cognition, autonomy as assessed respectively by the Neuropsychiatric Inventory (NPI), Mini Mental State Examination (MMSE), Instrumental Activities of Daily Living (IADL), etiology, and stage of the cognitive impairment. RESULTS: The study included 1300 outpatients: mean age: 80.8 ± 7 years. The mean CCI was 4.8 ± 1.7. The mini-Zarit score: 3.1 ± 2.0. The caregiver burden increased by 0.22 per unit of CCI (95% confidence interval 0.15-0.28, P < .001) in unadjusted analysis. The caregiver burden remained significantly associated with CCI, after adjustment for the MMSE, IADL, and NPI. CONCLUSION: The caregiver burden is higher when patients' comorbidities increase, independently of behavioral and psychological symptoms, level of functional autonomy, and the stage of the cognitive disease. However, dementia may be the comorbidity that contributes the most to caregiver burden.