Journal of Alzheimer's Disease - Volume 81, issue 2

Authors: O’Bryant, Sid E. | Zhang, Fan | Petersen, Melissa | Johnson, Leigh | Hall, James | Rissman, Robert A.

Article Type: Research Article

Abstract: Background: The REFLECT trials were conducted to examine the treatment of mild-to-moderate Alzheimer’s disease utilizing a peroxisome proliferator-activated receptor gamma agonist. Objective: To generate a predictive biomarker indicative of positive treatment response using samples from the previously conducted REFLECT trials. Methods: Data were analyzed on 360 participants spanning multiple negative REFLECT trials, which included treatment with rosiglitazone and rosiglitazone XR. Support vector machine analyses were conducted to generate a predictive biomarker profile. Results: A pre-defined 6-protein predictive biomarker (IL6, IL10, CRP, TNFα, FABP-3, and PPY) correctly classified treatment response with 100%accuracy across study arms …for REFLECT Phase II trial (AVA100193) and multiple Phase III trials (AVA105640, AV102672, and AVA102670). When the data was combined across all rosiglitazone trial arms, a global RSG-predictive biomarker with the same 6-protein predictive biomarker was able to accurately classify 98%of treatment responders. Conclusion: A predictive biomarker comprising of metabolic and inflammatory markers was highly accurate in identifying those patients most likely to experience positive treatment response across the REFLECT trials. This study provides additional proof-of-concept that a predictive biomarker can be utilized to help with screening and predicting treatment response, which holds tremendous benefit for clinical trials. Show more

Keywords: Alzheimer’s disease, clinical trial, predictive biomarker, rosiglitazone

DOI: 10.3233/JAD-201610

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 557-568, 2021

Authors: Manera, Valeria | Galperti, Guenda | Rovini, Erika | Zeghari, Radia | Mancioppi, Gianmaria | Fiorini, Laura | Gros, Auriane | Mouton, Aurélie | Robert, Philippe | Cavallo, Filippo

Article Type: Research Article

Abstract: Background: Social apathy, a reduction in initiative in proposing or engaging in social activities or interactions, is common in mild neurocognitive disorders (MND). Current apathy assessment relies on self-reports or clinical scales, but growing attention is devoted to defining more objective, measurable and non-invasive apathy proxies. Objective: In the present study we investigated the interest of recording action kinematics in a social reach-to-grasp task for the assessment of social apathy. Methods: Thirty participants took part in the study: 11 healthy controls (HC; 6 females, mean age = 68.3±10.5 years) and 19 subjects with MND (13 females, mean age = 75.7±6.3 …years). Based on the Diagnostic Criteria for Apathy, MND subjects were classified as socially apathetic (A-MND, N  = 9) versus non-apathetic (NA-MND, N  = 10). SensRing, a ring-shaped wearable sensor, was placed on their index finger, and subjects were asked to reach and grasp a can to place it into a cup (individual condition) and pass it to a partner (social condition). Results: In the reach-to-grasp phase of the action, HC and NA-MND showed different acceleration and velocity profiles in the social versus individual condition. No differences were found for A-MND. Conclusion: Previous studies showed the interest of recording patients’ level of weekly motor activity for apathy assessment. Here we showed that a 10-min reach-to-grasp task may provide information to differentiate socially apathetic and non-apathetic subjects with MND, thus providing a tool easily usable in the clinical practice. Future studies with a bigger sample are needed to better characterize these findings. Show more

Keywords: Apathy, diagnosis, intention, motivation, motor activity, neurocognitive disorders, social behavior, social isolation

DOI: 10.3233/JAD-200966

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 569-582, 2021

Authors: Zhou, Yunzhe | Wang, Yan | Quan, Meina | Zhao, Huiying | Jia, Jianping

Article Type: Research Article

Abstract: Background: Gut microbiota can influence human brain function and behavior. Recent studies showed that gut microbiota might play an important role in the pathogenesis of Alzheimer’s disease (AD). Objective: To investigate the composition of gut microbiota in AD patients and their association with cognitive function and neuropsychiatric symptoms (NPS). Methods: The fecal samples from 60 AD patients (30 with NPS and 30 without NPS) and 32 healthy control subjects (HC) were collected and analyzed by 16S ribosomal RNA sequencing. The functional variations of gut microbiota were predicted using Phylogenetic Investigation of Communities by Reconstruction of Unobserved …States. The correlation between different bacterial taxa and cognitive (Mini-Mental State Examination (MMSE), Clinical Dementia Rating (CDR)), and NPS measures were analyzed. Results: The fecal microbial composition of AD patients was quite distinct from HC. Bifidobacterium, Sphingomonas, Lactobacillus , and Blautia were enriched, while Odoribacter, Anaerobacterium , and Papillibacter were reduced. AD patients with NPS showed decreased Chitinophagaceae, Taibaiella , and Anaerobacterium compared with those without NPS. Functional pathways were different between AD and HC, and between AD patients with and without NPS. Correlation analysis showed that Sphingomonas correlated negatively with MMSE; Anaerobacterium and Papillibacter correlated positively with MMSE and negatively with CDR. Cytophagia, Rhodospirillaceae, and Cellvibrio correlated positively with NPS, while Chitinophagaceae, Taibaiella, and Anaerobacterium correlated negatively with NPS. Conclusion: AD patients have gut microbiota alterations related to cognition, and differential taxa between AD patients with and without NPS associated differently with NPS domains, which helps further understand the pathogenesis of AD and explore potential therapeutic targets. Show more

Keywords: Alzheimer’s disease, cognitive function, gut microbiota, neuropsychiatric symptoms

DOI: 10.3233/JAD-201497

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 583-595, 2021

Authors: Aitken, William W. | Lombard, Joanna | Wang, Kefeng | Toro, Matthew | Byrne, Margaret | Nardi, Maria I. | Kardys, Jack | Parrish, Abraham | Dong, Chuanhui | Szapocznik, José | Rundek, Tatjana | Brown, Scott C.

Article Type: Research Article

Abstract: Background: Neighborhood greenness (vegetative presence) has been linked to multiple health outcomes, but its relationship to Alzheimer’s disease (AD) and non-Alzheimer’s (non-AD) dementia has been less studied. Objective: This study examines the relationship of greenness to both AD and non-AD dementia in a population-based sample of Medicare beneficiaries. Methods: Participants were 249,405 US Medicare beneficiaries aged > 65 years living in Miami-Dade County, FL, from 2010 to 2011. Multi-level analyses examined the relationship of greenness, assessed by mean Census block level Normalized Difference Vegetation Index (NDVI), to odds of each of AD, Alzheimer’s disease and related dementias …(ADRD), and non-AD dementia, respectively. Covariates included age, gender, race/ethnicity, number of comorbid health conditions, and neighborhood income. Results: Higher greenness was associated with reduced risk of AD, ADRD, and non-AD dementia, respectively, adjusting for individual and neighborhood sociodemographics. Compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD by 20%(odds ratio, 0.80; 95%CI, 0.75–0.85), ADRD by 18%(odds ratio, 0.82; 95%CI, 0.77–0.86), and non-AD dementia by 11%(odds ratio, 0.89; 95%CI, 0.82–0.96). After further adjusting for number of comorbidities, compared to the lowest greenness tertile, the highest greenness tertile was associated with reduced odds of AD (OR, 0.94; 95%CI, 0.88–1.00) and ADRD (OR, 0.93; 95%CI, 0.88–0.99), but not non-AD dementia (OR, 1.01; 95%CI, 0.93–1.08). Conclusion: High neighborhood greenness may be associated with lower odds of AD and ADRD. Environmental improvements, such as increasing neighborhood vegetation, may be a strategy to reduce risk for AD and possibly other dementias. Show more

Keywords: Alzheimer’s disease, built environment, dementia, health disparities, Medicare beneficiaries, natural environment, neighborhood greenness, older adults

DOI: 10.3233/JAD-201179

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 597-606, 2021

Authors: Azevedo, Lílian Viana dos Santos | Calandri, Ismael Luis | Slachevsky, Andrea | Graviotto, Héctor Gastón | Vieira, Maria Carolina Santos | Andrade, Caíssa Bezerra de | Rossetti, Adriana Peredo | Generoso, Alana Barroso | Carmona, Karoline Carvalho | Pinto, Ludmilla Aparecida Cardoso | Sorbara, Marcos | Pinto, Alejandra | Guajardo, Tania | Olavarria, Loreto | Thumala, Daniela | Crivelli, Lucía | Vivas, Ludmila | Allegri, Ricardo Francisco | Barbosa, Maira Tonidandel | Serrano, Cecilia M. | Miranda-Castillo, Claudia | Caramelli, Paulo

Article Type: Research Article

Abstract: Background: People with dementia and their family caregivers may face a great burden through social isolation due to the COVID-19 pandemic, which can be manifested as various behavioral and clinical symptoms. Objective: To investigate the impacts of social isolation due to the COVID-19 pandemic on individuals with dementia and their family caregivers. Methods: Two semi-structured questionnaires were applied via telephone to family caregivers of people diagnosed with dementia in three cities in Argentina, Brazil, and Chile, in order to assess clinical and behavioral changes in people with dementia and in their caregivers. …Results: In general, 321 interviews were conducted. A significant decline in memory function has been reported among 53.0%of people with dementia. In addition, 31.2%of individuals with dementia felt sadder and 37.4%had increased anxiety symptoms. These symptoms of anxiety were greater in individuals with mild to moderate dementia, while symptoms of agitation were greater in individuals with severe dementia. Moreover, compulsive-obsessive behavior, hallucinations, increased forgetfulness, altered appetite, and increased difficulty in activities of daily living were reported more frequently among individuals with moderate to severe dementia. Caregivers reported feeling more tired and overwhelmed during this period and these symptoms were also influenced by the severity of dementia. Conclusion: Social isolation during the COVID-19 pandemic triggered a series of negative behavioral repercussions, both for people with dementia and for their family caregivers in these three South American countries. Show more

Keywords: Behavioral symptoms, caregiver, COVID-19, dementia, social isolation

DOI: 10.3233/JAD-201580

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 607-617, 2021

Authors: Marra, Camillo | Piccininni, Chiara | Masone Iacobucci, Giovanna | Caprara, Alessia | Gainotti, Guido | Costantini, Emanuele Maria | Callea, Antonio | Venneri, Annalena | Quaranta, Davide

Article Type: Research Article

Abstract: Background: The assessment of semantic memory may be a useful marker to identify individuals with mild cognitive impairment (MCI) who will progress to Alzheimer’s disease (AD) in the early stages of the disease. Objective: The aim of this five-year follow-up longitudinal study is to assess whether semantic assessment could predict progression in MCI. Methods: A population of MCI (N = 251); mild (N = 178) and moderate AD (N = 114); and a sample of healthy participants (HP; N = 262) was investigated. The five-year follow-up of the MCI group was completed by 178 patients. Semantic and episodic memory measures were used, including a …measure of the discrepancy between categorical and phonological verbal fluency, the semantic–phonological delta (SPD). The main outcome was the progression of MCI due to AD to dementia. Results: A general linear model showed a significant effect of diagnosis on SPD (Wilks’ Lambda = 0.591; p  < 0.001). The estimated marginal means were –0.91 (SE = 0.185) in HP, –1.83 (SE = 0.187) in MCI, –1.16 (SE = 0.218) in mild AD, and –1.02 (SE = 0.275) in moderate AD. Post-hoc comparisons showed a significant difference between MCI and HP (p  < 0.001). The follow-up was completed by 178 MCI individuals. SPD in MCI patients who progress to dementia was significantly lower than in MCI that will not progress (p  = 0.003). Together with the Mini-Mental State Examination, the SPD was the only measure with a significant predicting effect at the five-years follow-up (p  = 0.016). Conclusion: The SPD indicates the impairment of semantic memory in individuals with underlying AD at the MCI early stage, reflecting the early involvement of perirhinal and entorhinal cortices in the earliest stages of AD neuropathological process. Show more

Keywords: Alzheimer’s disease, category fluency task, memory, mild cognitive impairment

DOI: 10.3233/JAD-201452

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 619-627, 2021

Authors: Boström, Gustaf | Freyhult, Eva | Virhammar, Johan | Alcolea, Daniel | Tumani, Hayrettin | Otto, Markus | Brundin, Rose-Marie | Kilander, Lena | Löwenmark, Malin | Giedraitis, Vilmantas | Lleó, Alberto | von Arnim, Christine A.F. | Kultima, Kim | Ingelsson, Martin

Article Type: Research Article

Abstract: Background: Neuroinflammatory processes are common in neurodegenerative diseases such as Alzheimer’s disease (AD) and frontotemporal dementia (FTD), but current knowledge is limited as to whether cerebrospinal fluid (CSF) levels of neuroinflammatory proteins are altered in these diseases. Objective: To identify and characterize neuroinflammatory signatures in CSF from patients with AD, mild cognitive impairment (MCI), and FTD. Methods: We used proximity extension assay and ANOVA to measure and compare levels of 92 inflammatory proteins in CSF from 42 patients with AD, 29 with MCI due to AD (MCI/AD), 22 with stable MCI, 42 with FTD, and 49 …control subjects, correcting for age, gender, collection unit, and multiple testing. Results: Levels of matrix metalloproteinase-10 (MMP-10) were increased in AD, MCI/AD, and FTD compared with controls (AD: fold change [FC] = 1.32, 95% confidence interval [CI] 1.14–1.53, q  = 0.018; MCI/AD: FC = 1.53, 95% CI 1.20–1.94, q  = 0.045; and FTD: FC = 1.42, 95% CI 1.10–1.83, q  = 0.020). MMP-10 and eleven additional proteins were increased in MCI/AD, compared with MCI (q  < 0.05). In FTD, 36 proteins were decreased, while none was decreased in AD or MCI/AD, compared with controls (q  < 0.05). Conclusion: In this cross-sectional multi-center study, we found distinct patterns of CSF inflammatory marker levels in FTD and in both early and established AD, suggesting differing neuroinflammatory processes in the two disorders. Show more

Keywords: Alzheimer’s disease, frontotemporal dementia, mild cognitive impairment, neuroinflammation, proteomics

DOI: 10.3233/JAD-201565

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 629-640, 2021

Authors: Li, Jennifer | Bur, Andres M. | Villwock, Mark R. | Shankar, Suraj | Palmer, Gracie | Sykes, Kevin J. | Villwock, Jennifer A.

Article Type: Research Article

Abstract: Background: Olfactory dysfunction (OD) is an early symptom of Alzheimer’s disease (AD). However, olfactory testing is not commonly performed to test OD in the setting of AD. Objective: This work investigates objective OD as a non-invasive biomarker for accurately classifying subjects as cognitively unimpaired (CU), mild cognitive impairment (MCI), and AD. Methods: Patients with MCI (n  = 24) and AD (n  = 24), and CU (n  = 33) controls completed two objective tests of olfaction (Affordable, Rapid, Olfactory Measurement Array –AROMA; Sniffin’ Sticks Screening 12 Test –SST12). Demographic and subjective sinonasal and olfaction symptom information was also obtained. Analyses …utilized traditional statistics and machine learning to determine olfactory variables, and combinations of variables, of importance for differentiating normal and disease states. Results: Inability to correctly identify a scent after detection was a hallmark of MCI/AD. AROMA was superior to SST12 for differentiating MCI from AD. Performance on the clove scent was significantly different between all three groups. AROMA regression modeling yielded six scents with AUC of the ROC of 0.890 (p  < 0.001). Random forest model machine learning algorithms considering AROMA olfactory data successfully predicted MCI versus AD disease state. Considering only AROMA data, machine learning algorithms were 87.5%accurate (95%CI 0.4735, 0.9968). Sensitivity and specificity were 100%and 75%, respectively with ROC of 0.875. When considering AROMA and subject demographic and subjective data, the AUC of the ROC increased to 0.9375. Conclusion: OD differentiates CUs from those with MCI and AD and can accurately predict MCI versus AD. Leveraging OD data may meaningfully guide management and research decisions. Show more

Keywords: Alzheimer’s disease, machine learning, mild cognitive impairment, olfaction, olfactory dysfunction

DOI: 10.3233/JAD-210175

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 641-650, 2021

Authors: Blumen, Helena M. | Schwartz, Emily | Allali, Gilles | Beauchet, Olivier | Callisaya, Michele | Doi, Takehiko | Shimada, Hiroyuki | Srikanth, Velandai | Verghese, Joe

Article Type: Research Article

Abstract: Background: The motoric cognitive risk (MCR) syndrome is a pre-clinical stage of dementia characterized by slow gait and cognitive complaint. Yet, the brain substrates of MCR are not well established. Objective: To examine cortical thickness, volume, and surface area associated with MCR in the MCR-Neuroimaging Consortium, which harmonizes image processing/analysis of multiple cohorts. Methods: Two-hundred MRIs (M age 72.62 years; 47.74%female; 33.17%MCR) from four different cohorts (50 each) were first processed with FreeSurfer 6.0, and then analyzed using multivariate and univariate general linear models with 1,000 bootstrapped samples (n-1; with resampling). All models adjusted for …age, sex, education, white matter lesions, total intracranial volume, and study site. Results: Overall, cortical thickness was lower in individuals with MCR than in those without MCR. There was a trend in the same direction for cortical volume (p  = 0.051). Regional cortical thickness was also lower among individuals with MCR than individuals without MCR in prefrontal, insular, temporal, and parietal regions. Conclusion: Cortical atrophy in MCR is pervasive, and include regions previously associated with human locomotion, but also social, cognitive, affective, and motor functions. Cortical atrophy in MCR is easier to detect in cortical thickness than volume and surface area because thickness is more affected by healthy and pathological aging. Show more

Keywords: Cognitive complaint, cortical thickness, gait, motoric cognitive risk

DOI: 10.3233/JAD-201576

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 651-665, 2021

Authors: Halaas, Nathalie Bodd | Zetterberg, Henrik | Idland, Ane-Victoria | Knapskog, Anne-Brita | Watne, Leiv Otto | Blennow, Kaj

Article Type: Research Article

Abstract: Background: Delirium is associated with an increased risk of incident dementia and accelerated progression of existing cognitive symptoms. Reciprocally, dementia increases the risk of delirium. Cerebrospinal fluid (CSF) concentration of the dendritic protein neurogranin has been shown to increase in early Alzheimer’s disease (AD), likely reflecting synaptic dysfunction and/or degeneration. Objective: To elucidate the involvement of synaptic dysfunction in delirium pathophysiology, we tested the association between CSF neurogranin concentration and delirium in hip fracture patients with different AD-biomarker profiles, while comparing them to cognitively unimpaired older adults (CUA) and AD patients. Methods: The cohort included hip …fracture patients with (n  = 70) and without delirium (n  = 58), CUA undergoing elective surgery (n  = 127), and AD patients (n  = 46). CSF was collected preoperatively and diagnostically in surgery and AD patients respectively. CSF neurogranin concentrations were analyzed in all samples with an in-house ELISA. Delirium was assessed pre-and postoperatively in hip fracture patients by trained investigators using the Confusion Assessment Method. Hip fracture patients were further stratified based on pre-fracture dementia status, delirium subtype, and AD fluid biomarkers. Results: No association was found between delirium and CSF neurogranin concentration (main analysis: delirium versus no delirium, p  = 0.68). Hip fracture patients had lower CSF neurogranin concentration than AD patients (p  = 0.001) and CUA (p  = 0.035) in age-adjusted sensitivity analyses. Conclusion: The findings suggest that delirium is not associated with increased CSF neurogranin concentration in hip fracture patients, possibly due to advanced neurodegenerative disease and age and/or because synaptic degeneration is not an important pathophysiological process in delirium. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid proteins, delirium, neurotransmitter agents

DOI: 10.3233/JAD-201341

Citation: Journal of Alzheimer's Disease, vol. 81, no. 2, pp. 667-677, 2021