Journal of Alzheimer's Disease - Volume 83, issue 4

Authors: Handy, Alex | Lord, Jodie | Green, Rebecca | Xu, Jin | Aarsland, Dag | Velayudhan, Latha | Hye, Abdul | Dobson, Richard | Proitsi, Petroula | on behalf of the Alzheimer’s Disease Neuroimaging initiative | AddNeuroMed, and the GERAD1 Consortium

Article Type: Research Article

Abstract: Background: Blood plasma proteins have been associated with Alzheimer’s disease (AD), but understanding which proteins are on the causal pathway remains challenging. Objective: Investigate the genetic overlap between candidate proteins and AD using polygenic risk scores (PRS) and interrogate their causal relationship using bi-directional Mendelian randomization (MR). Methods: Following a literature review, 31 proteins were selected for PRS analysis. PRS were constructed for prioritized proteins with and without the apolipoprotein E region (APOE+/–PRS) and tested for association with AD status across three cohorts (n  = 6,244). An AD PRS was also tested for association with protein levels …in one cohort (n  = 410). Proteins showing association with AD were taken forward for MR. Results: For APOE ɛ3, apolipoprotein B-100, and C-reactive protein (CRP), protein APOE+ PRS were associated with AD below Bonferroni significance (pBonf, p  < 0.00017). No protein APOE- PRS or AD PRS (APOE+/–) passed pBonf. However, vitamin D-binding protein (protein PRS APOE-, p  = 0.009) and insulin-like growth factor-binding protein 2 (AD APOE- PRS p  = 0.025, protein APOE- PRS p  = 0.045) displayed suggestive signals and were selected for MR. In bi-directional MR, none of the five proteins demonstrated a causal association (p  < 0.05) in either direction. Conclusion: Apolipoproteins and CRP PRS are associated with AD and provide a genetic signal linked to a specific, accessible risk factor. While evidence of causality was limited, this study was conducted in a moderate sample size and provides a framework for larger samples with greater statistical power. Show more

Keywords: Alzheimer’s disease, apolipoprotein B-100, apolipoprotein E, blood proteins, C-reactive protein, insulin-like growth factor binding protein 2, mendelian randomization analysis, polygenic trait, vitamin D-binding protein

DOI: 10.3233/JAD-210462

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1825-1839, 2021

Authors: El Haj, Mohamad | Allain, Philippe | Annweiler, Cédric | Boutoleau-Bretonnière, Claire | Chapelet, Guillaume | Gallouj, Karim | Kapogiannis, Dimitrios | Roche, Jean | Boudoukha, Abdel Halim

Article Type: Research Article

Abstract: Background: In a previous study, we assessed burnout in geriatric healthcare workers during the first lockdown that lasted from March to May 2020 in France, in response to the COVID-19 crisis. Objective: We carried out a follow-up study to assess burnout in the same population during the second lockdown that was implemented at the end of October 2020. Methods: We used an online survey to assess burnout in terms of exhaustion and disengagement in a sample of 58 geriatric healthcare workers. Results: We found higher levels of exhaustion, disengagement, and burnout among geriatric healthcare …workers during the second than during the first lockdown. We also found high levels of exhaustion but moderate disengagement and burnout during the second lockdown. Conclusion: The increased exhaustion, disengagement, and burnout during the second lockdown can be attributed to the increased workload in geriatric facilities throughout this crisis and during the second lockdown due to shortage in staff and increased number of shifts and allocated duties. The high levels of exhaustion reported among geriatric healthcare workers during the second lockdown can reflect their physical fatigue, as well as their feelings of being emotionally overextended and exhausted by their workload. Show more

Keywords: Burnout, COVID-19, disengagement, exhaustion, healthcare professionals

DOI: 10.3233/JAD-210615

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1841-1848, 2021

Authors: Canevelli, Marco | Di Pucchio, Alessandra | Marzolini, Fabrizio | Mayer, Flavia | Massari, Marco | Salvi, Emanuela | Palazzesi, Ilaria | Lacorte, Eleonora | Bacigalupo, Ilaria | Di Fiandra, Teresa | Vanacore, Nicola

Article Type: Research Article

Abstract: Background: Italy has one of the oldest populations in the World and more than one million dementia cases can be estimated at the national level. Objective: The objectives of this national survey include: 1) to report the administrative features and the professional competencies of Centers for Cognitive Disorders and Dementias (CCDDs); 2) to document possible discrepancies by geographic macro-area; and 3) to identify the features of CCDDs that are associated with a better quality in the provision of care. Methods: A survey of Italian CCDDs was conducted between February 2014 and December 2015. A list of …CCDDs was obtained through direct interactions with designed delegates from each Italian region. A questionnaire was defined on five sections concerning: 1) location of the CCDD; 2) access to the CCDD; 3) organization of the CCDD; 4) services and treatments provided; and 5) quantitative data on the activities of the CCDD. Results: Overall, 577 out of the 597 eligible CCDDs returned the completed survey questionnaire (response rate: 96.6%): 260 (45.1%) from Northern Italy, 103 (17.8%) from Central Italy, and 214 (37.1%) from Southern-Islands Italy. More than a third of CCDDs were open only once or twice weekly. A median of 450 (IQR: 200–800) patients regularly attended these services. Most patients (70%) were affected by dementia or mild cognitive impairment (19%). Conclusion: We have provided a snapshot of the organization and activities of CCDDs in Italy and documented existing inequalities in the provision of care. Show more

Keywords: Cognitive disorders, dementia, healthcare services, memory clinics, public health, services, survey

DOI: 10.3233/JAD-210634

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1849-1857, 2021

Authors: Liu, Zihuan | Maiti, Tapabrata | Bender, Andrew R. | for the Alzheimer’s Disease Neuroimaging Initiative

Article Type: Research Article

Abstract: Background: The transition from mild cognitive impairment (MCI) to dementia is of great interest to clinical research on Alzheimer’s disease and related dementias. This phenomenon also serves as a valuable data source for quantitative methodological researchers developing new approaches for classification. However, the growth of machine learning (ML) approaches for classification may falsely lead many clinical researchers to underestimate the value of logistic regression (LR), which often demonstrates classification accuracy equivalent or superior to other ML methods. Further, when faced with many potential features that could be used for classifying the transition, clinical researchers are often unaware of the relative …value of different approaches for variable selection. Objective: The present study sought to compare different methods for statistical classification and for automated and theoretically guided feature selection techniques in the context of predicting conversion from MCI to dementia. Methods: We used data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to evaluate different influences of automated feature preselection on LR and support vector machine (SVM) classification methods, in classifying conversion from MCI to dementia. Results: The present findings demonstrate how similar performance can be achieved using user-guided, clinically informed pre-selection versus algorithmic feature selection techniques. Conclusion: These results show that although SVM and other ML techniques are capable of relatively accurate classification, similar or higher accuracy can often be achieved by LR, mitigating SVM’s necessity or value for many clinical researchers. Show more

Keywords: Alzheimer’s disease, classification, machine learning, mild cognitive impairment, support vector machine, variable selection

DOI: 10.3233/JAD-201398

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1859-1875, 2021

Authors: Pievani, Michela | Mega, Anna | Quattrini, Giulia | Guidali, Giacomo | Ferrari, Clarissa | Cattaneo, Annamaria | D’Aprile, Ilari | Mascaro, Lorella | Gasparotti, Roberto | Corbo, Daniele | Brignani, Debora | Bortoletto, Marta

Article Type: Research Article

Abstract: Background: Default mode network (DMN) dysfunction is well established in Alzheimer’s disease (AD) and documented in both preclinical stages and at-risk subjects, thus representing a potential disease target. Multi-sessions of repetitive transcranial magnetic stimulation (rTMS) seem capable of modulating DMN dynamics and memory in healthy individuals and AD patients; however, the potential of this approach in at-risk subjects has yet to be tested. Objective: This study will test the effect of rTMS on the DMN in healthy older individuals carrying the strongest genetic risk factor for AD, the Apolipoprotein E (APOE ) ɛ4 allele. Methods: We …will recruit 64 older participants without cognitive deficits, 32 APOE ɛ4 allele carriers and 32 non-carriers as a reference group. Participants will undergo four rTMS sessions of active (high frequency) or sham DMN stimulation. Multimodal imaging exam (including structural, resting-state, and task functional MRI, and diffusion tensor imaging), TMS with concurrent electroencephalography (TMS-EEG), and cognitive assessment will be performed at baseline and after the stimulation sessions. Results: We will assess changes in DMN connectivity with resting-state functional MRI and TMS-EEG, as well as changes in memory performance in APOE ɛ4 carriers. We will also investigate the mechanisms underlying DMN modulation through the assessment of correlations with measures of neuronal activity, excitability, and structural connectivity with multimodal imaging. Conclusion: The results of this study will inform on the physiological and cognitive outcomes of DMN stimulation in subjects at risk for AD and on the possible mechanisms. These results may outline the design of future non-pharmacological preventive interventions for AD. Show more

Keywords: Alzheimer’s disease, at-risk healthy subjects, APOE ɛ4 allele, default mode network, functional connectivity, repetitive transcranial magnetic stimulation

DOI: 10.3233/JAD-210659

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1877-1889, 2021

Authors: van de Veen, Dennis | Bakker, Christian | Peetoom, Kirsten | Pijnenburg, Yolande | Papma, Janne M. | The PRECODE Study Group | de Vugt, Marjolein | Koopmans, Raymond

Article Type: Research Article

Abstract: Background: There has been growing interest in young people living with dementia. Future research requires consensus on the terminology and operational definition of this group. Objective: The purpose of this integrative review was to explore and include all operational definitions used to define dementia at a young age. Methods: On August 14, 2020, the PubMed, Embase, Cinahl, and PsycInfo databases were searched for empirical and theoretical literature using Google. Various terms to describe and define ‘dementia’ and ‘at a young age’ were used to collect literature concerning terminology; age-related aspects, including cut-off ages and criteria; and …etiologies of dementia at a young age. Results: The search yielded 6,891 empirical and 4,660 theoretical publications, resulting in the inclusion of 89 publications, including 36 publications containing an explicit discussion and 53 publications as confirmation. ‘Young-onset dementia’ was the most commonly used term of seven identified terms, in the last two decades. The age of 65 years at symptom onset was used most frequently when considering a total of six upper age limits and four criteria to define a cut-off age. Eight lower age limits and an option for subdivision based on age were included. We identified 251 different etiologies and 27 categories of etiologies. Conclusion: Despite relative consensus on the term young-onset dementia and an age at symptom onset being used as a cut-off criterion, much is still unclear concerning possible etiologies of dementia at a young age. In the current study, controversies were detected for discussion in an international consensus study. Show more

Keywords: Definition, operationalization, young-onset dementia

DOI: 10.3233/JAD-210458

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1891-1916, 2021

Authors: Utsumi, Kumiko | Fukatsu, Ryo | Hara, Yuko | Takamaru, Yuji | Yasumura, Shuichi

Article Type: Research Article

Abstract: Background: Many cases of dementia with Lewy bodies (DLB) present with various psychotic features, including hallucinations, depression, catatonia, and delusions before the onset of cognitive impairment. However, the characteristic features of these psychotic symptoms in prodromal DLB have not been sufficiently described. Objective: To clarify and describe the psychotic features of prodromal DLB before overt cognitive impairment. Methods: The authors analyzed the characteristic psychotic features of prodromal DLB in 21 subjects who developed severe psychotic symptoms without dementia and were diagnosed as DLB after the longitudinal observation period. They were then confirmed to have DLB through …indicative and supportive biomarkers of scintigraphy. Results: The psychotic features included a wide variety of symptoms, but convergent to three principal categories: catatonia, delusions-hallucinations, and depression and/or mania. Catatonia was observed in nine cases, five were delusional-hallucinatory, and seven were manic and/or depressive. Seven of the 21 cases exhibited delirium during longitudinal observation. A psychotic state repeatedly appeared without any trigger in 20 of the 21 patients. All subjects developed cognitive impairment at 9.1±4.6 (mean±SD) years after the initial appearance of psychotic symptoms, and subsequently diagnosed with DLB at 71.3±6.1 (mean±SD) years. Conclusion: Elderly patients with psychotic symptoms, such as catatonia, delusion-hallucination, manic and/or depressive features, and delirium without dementia, could indicate symptomatic psychosis or a prodromal stage of any neurocognitive disorder such as DLB. Therefore, further extensive workout (e.g., radioisotope neuroimaging) is required to avoid misdiagnosis. Show more

Keywords: Catatonia, delirium, delusional-hallucinatory feature, dementia with Lewy bodies, manic and/or depressive feature, prodromal

DOI: 10.3233/JAD-210416

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1917-1927, 2021