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

Authors: Cummings, Jeffrey | Schwartz, Gregory G. | Nicholls, Stephen J. | Khan, Aziz | Halliday, Chris | Toth, Peter P. | Sweeney, Michael | Johansson, Jan O. | Wong, Norman C.W. | Kulikowski, Ewelina | Kalantar-Zadeh, Kamyar | Lebioda, Kenneth | Ginsberg, Henry N. | Winblad, Bengt | Zetterberg, Henrik | Ray, Kausik K.

Article Type: Research Article

Abstract: Background: Epigenetic changes may contribute importantly to cognitive decline in late life including Alzheimer’s disease (AD) and vascular dementia (VaD). Bromodomain and extra-terminal (BET) proteins are epigenetic “readers” that may distort normal gene expression and contribute to chronic disorders. Objective: To assess the effects of apabetalone, a small molecule BET protein inhibitor, on cognitive performance of patients 70 years or older participating in a randomized trial of patients at high risk for major cardiovascular events (MACE). Methods: The Montreal Cognitive Assessment (MoCA) was performed on all patients 70 years or older at the time of randomization. …464 participants were randomized to apabetalone or placebo in the cognition sub-study. In a prespecified analysis, participants were assigned to one of three groups: MoCA score≥26 (normal performance), MoCA score 25–22 (mild cognitive impairment), and MoCA score≤21 (dementia). Exposure to apabetalone was equivalent in the treatment groups in each MoCA-defined group. Results: Apabetalone was associated with an increased total MoCA score in participants with baseline MoCA score of≤21 (p  = 0.02). There was no significant difference in change from baseline in the treatment groups with higher MoCA scores. In the cognition study, more patients randomized to apabetalone discontinued study drug for adverse effects (11.3% versus 7.9%). Conclusion: In this randomized controlled study, apabetalone was associated with improved cognition as measured by MoCA scores in those with baseline scores of 21 or less. BET protein inhibitors warrant further investigation for late life cognitive disorders. Show more

Keywords: Alzheimer’s disease, apabetalone, BET inhibitor, clinical trial, epigenetics, montreal cognitive assessment

DOI: 10.3233/JAD-210570

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1703-1715, 2021

Authors: Bommarito, Giulia | Van De Ville, Dimitri | Frisoni, Giovanni B. | Garibotto, Valentina | Ribaldi, Federica | Stampacchia, Sara | Assal, Frédéric | Allali, Gilles | Griffa, Alessandra

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) pathology impacts the response to treatment in patients with idiopathic normal pressure hydrocephalus (iNPH), possibly through changes in resting-state functional connectivity (rs-FC). Objective: To explore the relationship between cerebrospinal fluid biomarkers of AD and the default mode network (DMN)/hippocampal rs-FC in iNPH patients, based on their outcome after cerebrospinal fluid tap test (CSFTT), and in patients with AD. Methods: Twenty-six iNPH patients (mean age: 79.9±5.9 years; 12 females) underwent MRI and clinical assessment before and after CSFTT and were classified as responders (Resp) or not (NResp), based on the improvement at the …timed up and go test and walking speed. Eleven AD patients (mean age: 70.91±5.2 years; 5 females), matched to iNPH for cognitive status, were also included. DMN and hippocampal rs-FC was related to amyloid-β42 and phosphorylated tau (pTau) levels. Results: Lower amyloid-β42 levels were associated with reduced inter- and intra-network rs-FC in NResp, and the interaction between amyloid-β42 and rs-FC was a predictor of outcome after CSFTT. The rs-FC between DMN and salience networks positively correlated to amyloid-β42 levels in both NResp and AD patients. The increase in the inter-network rs-FC after CSFTT was associated with higher pTau and lower amyloid-β42 levels in NResp, and to lower pTau levels in Resp. Conclusion: Amyloid-β42 and pTau impact on rs-FC and its changes after CSFTT in iNPH patients. The interaction between AD biomarkers and rs-FC might explain the responder status in iNPH. Show more

Keywords: Alzheimer’s disease, amyloid, CSF tap test, default mode network, functional connectivity, hippocampus, normal pressure hydrocephalus, tau

DOI: 10.3233/JAD-210534

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1717-1728, 2021

Authors: Vemuri, Prashanthi | Davey, Cynthia | Johansen, Kirsten L. | Zuk, Samantha M. | Reid, Robert I. | Thostenson, Kaely B. | Reddy, Ashritha L. | Jack Jr., Clifford R. | Knopman, David S. | Murray, Anne M.

Article Type: Research Article

Abstract: Background: Chronic kidney disease (CKD), a growing public health issue in the elderly, is associated with increased risk of cognitive impairment. Objective: To investigate the mechanisms through which CKD impacts brain health using longitudinal imaging. Methods: We identified 97 participants (74 CKD and 23 non-CKD) from the BRINK (BRain IN Kidney Disease), a longitudinal study of CKD with two MRI scans (baseline and 3-year follow-up). We measured the associations between baseline and change in kidney disease biomarkers of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR), considered a measure of microvascular inflammation, …and imaging outcomes of cortical thickness and ventricular volume from structural MRI, white matter hyperintensities (WMH) volume from FLAIR images, and fractional anisotropy of the corpus callosum (FACC). Results: There were white matter-specific changes as observed by increased WMH volume and decreased FACC in CKD participants, as well as ventricular volume increase in both CKD and non-CKD groups reflective of aging-related changes. Decline in eGFR was associated with decrease in the FACC, suggesting that subtle early white matter changes due to kidney disease can be captured using DTI. An increase in UACR was associated with increase in ventricular volume. Conclusion: Our results support the role of eGFR as a measure of kidney microvascular disease which is associated with concurrent white matter damage in CKD. Future work is needed to investigate the possible link between endothelial microvascular inflammation (as measured by an increased UACR) and ventricular volume increase. Show more

Keywords: Brain health, chronic kidney disease, diffusion tensor imaging, white matter damage, white matter hyperintensities

DOI: 10.3233/JAD-210604

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1729-1740, 2021

Authors: Zhang, Jing-Jing | Li, Lin | Liu, Dan | Hu, Fei-Fei | Cheng, Gui-Rong | Xu, Lang | Yan, Ping-Ting | Tian, Yuan | Hu, Heng | Yu, Ya-Fu | Gan, Xu-Guang | An, Li-Na | Zhang, Bo | Qian, Jin | Fu, Li-Yan | Cheng, Xi | Lian, Peng-Fei | Zou, Ming-Jun | Chen, Cong | Wu, Qing-Ming | Zeng, Yan

Article Type: Research Article

Abstract: Background: Some studies have demonstrated an association between low and high body mass index (BMI) and an increased risk of dementia. However, only a few of these studies were performed in rural areas. Objective: This cross–sectional study investigated the associations between BMI and cognitive impairment among community–dwelling older adults from rural and urban areas. Methods: 8,221 older persons enrolled in the Hubei Memory & Ageing Cohort Study (HMACS) were recruited. Sociodemographic and lifestyle data, comorbidities, physical measurements, and clinical diagnoses of cognitive impairment were analyzed. Logistic regression was performed to assess the associations of BMI categories …with cognitive impairment. A series of sensitivity analyses were conducted to test whether reverse causality could influence our results. Results: Being underweight in the rural–dwelling participants increased the risk of cognitive impairment. Being overweight was a protective factor in rural–dwelling participants aged 65–69 years and 75–79 years, whereas being underweight was significantly associated with cognitive impairment (OR, 1.37; 95% CI: 1.03–1.83; p  < 0.05). Sensitivity analyses support that underweight had an additive effect on the odds of cognitive impairment and was related to risk of dementia. Interaction test revealed that the differences between urban/rural in the relationship between BMI and cognitive impairment are statistically significant. Conclusion: Associations between BMI and cognitive impairment differ among urban/rural groups. Older people with low BMI living in rural China are at a higher risk for dementia than those living in urban areas. Show more

Keywords: Body mass index, cognitive impairment, community–dwelling older adults, cross–sectional study, rural–urban disparity

DOI: 10.3233/JAD-210295

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1741-1752, 2021

Authors: Pisu, Maria | Martin, Roy C. | Shan, Liang | Pilonieta, Giovanna | Kennedy, Richard E. | Oates, Gabriela | Kim, Young-Il | Geldmacher, David S.

Article Type: Research Article

Abstract: Background: Use of specialists and recommended drugs has beneficial effects for older adults living with Alzheimer’s disease and related dementia (ADRD). Gaps in care may exist for minorities, e.g., Blacks, and especially in the United States (U.S.) Deep South (DS), a poor U.S. region with rising ADRD cases and minority overrepresentation. Currently, we have little understanding of ADRD care utilization in diverse populations in this region and elsewhere in the U.S. (non-DS), and the factors that adversely impact it. Objective: To examine utilization of specialists and ADRD drugs (outcomes) in racial/ethnic groups of older adults with ADRD and …the personal or context-level factors affecting these outcomes in DS and non-DS. Methods: We obtained outcomes and personal-level covariates from claims for 127,512 Medicare beneficiaries with ADRD in 2013–2015, and combined county-level data in exploratory factor analysis to define context-level covariates. Adjusted analyses tested significant association of outcomes with Black/White race and other factors in DS and non-DS. Results: Across racial/ethnic groups, 33%–43% in DS and 43%–50% in non-DS used specialists; 47%–55% in DS and 41%–48% in non-DS used ADRD drugs. In adjusted analyses, differences between Blacks and Whites were not significant. Vascular dementia, comorbidities, poverty, and context-level factor “Availability of Medical Resources” were associated with specialist use; Alzheimer’s disease and senile dementia, comorbidities, and specialist use were associated with drug use. In non-DS only, other individual, context-level covariates were associated with the outcomes. Conclusion: We did not observe significant gaps in ADRD care in DS and non-DS; however, research should further examine determinants of low specialist and drug use in these regions. Show more

Keywords: Access to care, affordability, disparities, drug use, equity, physician availability, socioeconomic context, socioeconomic status, specialist use

DOI: 10.3233/JAD-210240

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1753-1765, 2021

Authors: Ma, Heather | Kiekhofer, Rachel E. | Hooper, Sarah M. | Dulaney, Sarah | Possin, Katherine L. | Chiong, Winston

Article Type: Research Article

Abstract: Background: Advance care planning has been shown to improve end of life decision-making for people with dementia. However, the impact of goals of care conversations between people with dementia and their caregivers has not been characterized. Objective: In this study, we evaluate the association between goals of care conversations and advance care planning outcomes. Methods: Retrospective advance care planning measures were collected via a questionnaire administered to 166 caregivers after the death of the person with dementia for whom they provided care. Results: At time of death, the majority of decedents with dementia had …advance directives, health care agents, and previous goals of care conversations with their caregiver. Goals of care conversations were significantly associated with the perceived usefulness of advance directives, the perceived adherence to advance directives, and decedent dying at their desired place of death, but not with disagreements around end-of-life care. Conclusion: Our findings suggest that goals of care conversations are an important component of advance care planning. These findings support the development of interventions that facilitate such conversations between people with dementia and their caregivers. Show more

Keywords: Advance care planning, Alzheimer’s disease, dementia, patient preference, terminal care

DOI: 10.3233/JAD-210720

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1767-1773, 2021

Authors: Platen, Moritz | Fleßa, Steffen | Rädke, Anika | Wucherer, Diana | Thyrian, Jochen René | Mohr, Wiebke | Scharf, Annelie | Mühlichen, Franka | Hoffmann, Wolfgang | Michalowsky, Bernhard

Article Type: Research Article

Abstract: Background: Low-value care (LvC) is defined as care unlikely to provide a benefit to the patient regarding the patient’s preferences, potential harms, costs, or available alternatives. Avoiding LvC and promoting recommended evidence-based treatments, referred to as high-value care (HvC), could improve patient-reported outcomes for people living with dementia (PwD). Objective: This study aims to determine the prevalence of LvC and HvC in dementia and the associations of LvC and HvC with patients’ quality of life and hospitalization. Methods: The analysis was based on data of the DelpHi trial and included 516 PwD. Dementia-specific guidelines, the “Choosing …Wisely” campaign and the PRISCUS list were used to indicate LvC and HvC treatments, resulting in 347 LvC and HvC related recommendations. Of these, 77 recommendations (51 for LvC, 26 for HvC) were measured within the DelpHi-trial and finally used for this analysis. The association of LvC and HvC treatments with PwD health-related quality of life (HRQoL) and hospitalization was assessed using multiple regression models. Results: LvC was highly prevalent in PwD (31%). PwD receiving LvC had a significantly lower quality of life (b  = –0.07; 95% CI –0.14 – –0.01) and were significantly more likely to be hospitalized (OR = 2.06; 95% CI 1.26–3.39). Different HvC treatments were associated with both positive and negative changes in HRQoL. Conclusion: LvC could cause adverse outcomes and should be identified as early as possible and tried to be replaced. Future research should examine innovative models of care or treatment pathways supporting the identification and replacement of LvC in dementia. Show more

Keywords: Alzheimer’s disease, health-related quality of life, hospitalization, low-value care, patient-centered outcomes

DOI: 10.3233/JAD-210439

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1775-1787, 2021

Authors: Isernia, Sara | Cabinio, Monia | Di Tella, Sonia | Pazzi, Stefania | Vannetti, Federica | Gerli, Filippo | Mosca, Irene Eleonora | Lombardi, Gemma | Macchi, Claudio | Sorbi, Sandro | Baglio, Francesca

Article Type: Research Article

Abstract: Background: The Smart Aging Serious Game (SASG) is an ecologically-based digital platform used in mild neurocognitive disorders. Considering the higher risk of developing dementia for mild cognitive impairment (MCI) and vascular cognitive impairment (VCI), their digital phenotyping is crucial. A new understanding of MCI and VCI aided by digital phenotyping with SASG will challenge current differential diagnosis and open the perspective of tailoring more personalized interventions. Objective: To confirm the validity of SASG in detecting MCI from healthy controls (HC) and to evaluate its diagnostic validity in differentiating between VCI and HC. Methods: 161 subjects (74 …HC: 37 males, 75.47±2.66 mean age; 60 MCI: 26 males, 74.20±5.02; 27 VCI: 13 males, 74.22±3.43) underwent a SASG session and a neuropsychological assessment (Montreal Cognitive Assessment (MoCA), Free and Cued Selective Reminding Test, Trail Making Test). A multi-modal statistical approach was used: receiver operating characteristic (ROC) curves comparison, random forest (RF), and logistic regression (LR) analysis. Results: SASG well captured the specific cognitive profiles of MCI and VCI, in line with the standard neuropsychological measures. ROC analyses revealed high diagnostic sensitivity and specificity of SASG and MoCA (AUCs  > 0.800) in detecting VCI versus HC and MCI versus HC conditions. An acceptable to excellent classification accuracy was found for MCI and VCI (HC versus VCI; RF: 90%, LR: 91%. HC versus MCI; RF: 75%; LR: 87%). Conclusion: SASG allows the early assessment of cognitive impairment through ecological tasks and potentially in a self-administered way. These features make this platform suitable for being considered a useful digital phenotyping tool, allowing a non-invasive and valid neuropsychological evaluation, with evident implications for future digital-health trails and rehabilitation. Show more

Keywords: Dementia, digital medicine, mild cognitive impairment, mild neurocognitive disorder, neuropsychological assessment, serious games, telemonitoring, vascular cognitive impairment, virtual reality

DOI: 10.3233/JAD-210347

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1789-1801, 2021

Authors: Briceño, Emily M. | Gross, Alden L. | Giordani, Bruno J. | Manly, Jennifer J. | Gottesman, Rebecca F. | Elkind, Mitchell S.V. | Sidney, Stephen | Hingtgen, Stephanie | Sacco, Ralph L. | Wright, Clinton B. | Fitzpatrick, Annette | Fohner, Alison E. | Mosley, Thomas H. | Yaffe, Kristine | Levine, Deborah A.

Article Type: Research Article

Abstract: Background: Meta-analyses of individuals’ cognitive data are increasing to investigate the biomedical, lifestyle, and sociocultural factors that influence cognitive decline and dementia risk. Pre-statistical harmonization of cognitive instruments is a critical methodological step for accurate cognitive data harmonization, yet specific approaches for this process are unclear. Objective: To describe pre-statistical harmonization of cognitive instruments for an individual-level meta-analysis in the blood pressure and cognition (BP COG) study. Methods: We identified cognitive instruments from six cohorts (the Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Coronary Artery Risk Development in Young Adults study, Framingham Offspring Study, Multi-Ethnic …Study of Atherosclerosis, and Northern Manhattan Study) and conducted an extensive review of each item’s administration and scoring procedures, and score distributions. Results: We included 153 cognitive instrument items from 34 instruments across the six cohorts. Of these items, 42%were common across ≥2 cohorts. 86%of common items showed differences across cohorts. We found administration, scoring, and coding differences for seemingly equivalent items. These differences corresponded to variability across cohorts in score distributions and ranges. We performed data augmentation to adjust for differences. Conclusion: Cross-cohort administration, scoring, and procedural differences for cognitive instruments are frequent and need to be assessed to address potential impact on meta-analyses and cognitive data interpretation. Detecting and accounting for these differences is critical for accurate attributions of cognitive health across cohort studies. Show more

Keywords: Cognition, dementia, epidemiology, methods

DOI: 10.3233/JAD-210459

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1803-1813, 2021

Authors: Zhang, Zhizhong | Wang, Mengmeng | Yuan, Shuai | Cai, Huan | Zhu, Shuang-Gen | Liu, Xinfeng

Article Type: Research Article

Abstract: Background: Observational studies have reported that coffee consumption was associated with Alzheimer’s disease (AD) and stroke risk. However, the results are inconclusive. Objective: We aimed to evaluate whether genetically predicted coffee consumption is associated with AD and stroke using Mendelian randomization (MR) design. Methods: Summary-level data for AD (n  = 54,162), ischemic stroke (n  = 440,328), and intracerebral hemorrhage (ICH, n  = 3,026) were adopted from publicly available databases. Summary-level data for coffee consumption were obtained from two genome-wide association studies, comprising up to 375,833 subjects. Results: Genetically predicted coffee consumption (cups/day) was associated with an increased …risk of AD (OR = 1.26, 95%CI = 1.05–1.51). Moreover, genetically predicted 50%increase of coffee consumption was associated with an increased risk of ICH (OR: 2.27, 95%CI: 1.08–4.78) but a decreased risk of small vessel stroke (OR: 0.71, 95%CI: 0.51–0.996). Estimate for AD and ICH in FinnGen consortium is directionally consistent. Combined analysis of different databases further confirmed that genetically predicted coffee consumption was associated with an increased risk of AD and ICH. In the multivariable MR analysis, genetically predicted coffee consumption retained a stable effect with AD and ICH when adjusting for smoking (p  < 0.05), while the association with AD attenuated when adjusting for alcohol use. Conclusion: Our results indicate that genetically predicted coffee consumption may be associated with an increased risk of AD and ICH. The underlying biological mechanisms warrant further study. Show more

Keywords: Alzheimer’s disease, coffee, mendelian randomization, stroke

DOI: 10.3233/JAD-210678

Citation: Journal of Alzheimer's Disease, vol. 83, no. 4, pp. 1815-1823, 2021

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