Journal of Alzheimer's Disease - Volume 80, issue 1

Authors: Jayachandran, Muthuvel | Miller, Virginia M. | Lahr, Brian D. | Bailey, Kent R. | Lowe, Val J. | Fields, Julie A. | Mielke, Michelle M. | Kantarci, Kejal

Article Type: Research Article

Abstract: Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer’s disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers. Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women. Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n  = 29), transdermal 17β-estradiol (tE2; n  = 21), or oral conjugated equine estrogen (oCEE; n … = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1–42 (Aβ1–42 ), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs. Results: Only the number of microvesicles positive for Aβ1–42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p  = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p  = 0.045). Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition. Show more

Keywords: Alzheimer’s disease, 17β-estradiol, conjugated equine estrogen, extracellular vesicles, KEEPS, PET imaging

DOI: 10.3233/JAD-201410

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 397-405, 2021

Authors: Li, Mo | Li, Rena | Lyu, Ji-hui | Chen, Jian-hua | Wang, Wei | Gao, Mao-long | Li, Wen-jie | De, Jie | Mu, Han-yan | Pan, Wei-gang | Mao, Pei-xian | Ma, Xin

Article Type: Research Article

Abstract: Background: The choroid is involved directly or indirectly in many pathological conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Objective: The objective of this study was to investigate the association between retinal choroidal properties and the pathology of AD by determining choroidal thickness, hippocampus volume, cognitive functions, and plasma BACE1 activity. Methods: In this cross-sectional study, 37 patients with AD and 34 age-matched controls were included. Retinal choroidal thickness was measured via enhanced depth imaging optical coherence tomography. Hippocampal volume was measured via 3.0T MRI. Cognitive functions were evaluated using the …Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog). Plasma BACE1 activity was analyzed using a fluorescence substrate-based plasma assay, and regression model were to analyze the data. Results: Retinal choroidal thickness was significantly thinner in the AD group than in the control group [(114.81±81.30) μ m versus (233.79±38.29) μ m, p  < 0.05]. Multivariable regression analysis indicated that the ADAS-cog scores (β=–0.772, p  = 0.000) and age (β=–0.176, p  = 0.015) were independently associated with choroidal thickness. The logistic regression model revealed that the subfoveal choroidal thickness was a significant predictor for AD (OR = 0.984, 95% CI: 0.972–0.997). Conclusion: There was a general tendency of choroid thinning as the cognitive function declined. Although choroidal thickness was not a potential indicator for early stage AD, it was valuable in monitoring AD progression. Show more

Keywords: Alzheimer’s disease, choroidal thickness, cognitive performance, hippocampus volume, plasma BACE1 activity

DOI: 10.3233/JAD-201142

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 407-419, 2021

Authors: Rigby, Taylor | Johnson, David K. | Taylor, Angela | Galvin, James E.

Article Type: Research Article

Abstract: Background: Caregivers of persons living with Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and Parkinson’s disease dementia (PDD) are faced with numerous challenges. However, little is known about the caregiving experience across different dementias. Objective: The aims of this cross-sectional study were to examine the differences in the caregiver experience between DLB, PDD, and AD. Methods: Respondents were caregivers (N = 515; 384 DLB, 69 AD, 62 PDD) who completed a 230-question survey including sociodemographics, disease severity, neuropsychiatric symptoms, and measures of grief, burden, depression, quality of life, social support, well-being, care confidence, and mastery/self-efficacy. …Results: There were no differences in caregiver age, sex, race, or education, or in the distribution of disease severity between diagnostic groups. Constructs were highly intercorrelated with positive attributes (caregiver QoL, care recipient QoL, social support, well-being, mastery and care confidence) being inversely correlated with negative attributes (burden, grief, and depression). Across dementia etiologies, no differences were reported for quality of life, social support, depression, well-being, psychological well-being, mastery, care confidence, burden or grief. Instead, we found that the caregiver’s experience was dependent on caregiver characteristics, person living with dementia characteristics and their most disturbing symptom, with behavior, personality changes, and sleep having the greatest effect on constructs. Conclusion: Caregiver ratings of psychosocial constructs may be more dependent on care recipient-caregiver dyad characteristics and the current symptoms than the underlying cause of those symptoms. Interventions to improve the caregiving experience should be developed to address specific psychosocial constructs rather than focusing on disease etiology or stage. Show more

Keywords: Alzheimer’s disease, caregiver burden, caregiver grief, caregiving, dementia with Lewy bodies, depression, Parkinson’s disease dementia, quality of life, social support

DOI: 10.3233/JAD-201326

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 421-432, 2021

Authors: Tondo, Giacomo | Boccalini, Cecilia | Caminiti, Silvia Paola | Presotto, Luca | Filippi, Massimo | Magnani, Giuseppe | Frisoni, Giovanni Battista | Iannaccone, Sandro | Perani, Daniela

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a transitional condition between normal cognition and dementia. [18 F]FDG-PET reveals brain hypometabolism patterns reflecting neuronal/synaptic dysfunction, already in the prodromal MCI phase. Activated microglia is part of the pathogenetic processes leading to neurodegeneration. Objective: Using [11 C]-(R)-PK11195 and [18 F]FDG-PET, we aimed to in vivo investigate the presence of microglial activation, and the relationship with brain glucose metabolism, in single MCI subjects. Methods: Eight MCI subjects underwent both [18 F]FDG-PET and [11 C]-(R)-PK11195 PET. We used validated quantification methods to obtain brain hypometabolism maps and microglia activation peaks …in single subjects. We investigated both the spatial overlap and the relationship between brain glucose hypometabolism and microglia activation, by means of Dice similarity coefficient and using Pearson’s correlation at single subject level. Results: Each MCI showed a specific brain hypometabolism pattern indicative of different possible etiologies, as expected in MCI population (i.e., Alzheimer’s disease-like, frontotemporal dementia-like, hippocampal-type, normal aging type). [11 C]-(R)-PK11195 PET analysis revealed a spatial concordance with regional hypometabolism in all subjects with several clusters of significant microglia activation showing an inverse correlation with the regional metabolism. This was proportional to the strength of between-signals correlation coefficient (β  =  –0.804; p  = 0.016). Conclusion: Microglia activation is present in the prodromal MCI phase of different underlying etiologies, showing spatial concordance and inverse correlation with brain glucose metabolism at single-subject level. These findings suggest a possible contribution of activated microglia to neurodegeneration, showing important implications for local immune activity in the early neurodegenerative processes. Show more

Keywords: Alzheimer’s disease, cognitive dysfunction, dementia, metabolism, microglia, positron emission tomography, tauopathies

DOI: 10.3233/JAD-201351

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 433-445, 2021

Authors: Cong, Cong | Zhang, Wanying | Qian, Xiaojing | Qiu, Wenying | Ma, Chao

Article Type: Research Article

Abstract: Background: Lewy-related pathology (LRP), primarily comprised of α-synuclein, is a typical neuropathological change that has been identified in many neurodegenerative disorders such as Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies. Objective: To investigate the distribution of LRP in the China Human Brain Bank, the co-occurrence of neuropathologic features of Alzheimer’s disease (AD) in LRP cases, and LRP-related cognitive dysfunction. Methods: LRP neuropathological diagnosis was performed in 180 postmortem brains. AD neuropathological diagnosis was then performed in the 21 neuropathologically-diagnosed LRP cases. Antemortem cognitive functioning evaluation (Everyday Cognitive, ECog) was assessed for brain …donors by the immediate kin of the donor within 24 hours after death. Results: 12% (21 in 180) postmortem brains were neuropathologically diagnosed as LRP cases. 86% (18 in 21) aged above 80, 81% (17 in 21) LRP cases combined with AD neuropathology, and 62% (13 in 21) combined with both the intermediate or high-level amyloid-β and phospho-tau pathologies. ECog scores showed significant differences between the groups of LRP brainstem-predominant type and LRP diffuse neocortical type, and between groups of AD and the combined LRP (diffuse neocortical type)-AD. Conclusion: The overlap of neocortical α-synuclein, amyloid-β, phospho-tau, and neuritic plaques in LRP suggested the potential interplay among the common characteristics of proteinopathies in the late stage of neuropathological development of LRP in human brains. The anatomic progression of LRP, the process of α-synuclein spreading from the brainstem to limbic and neocortical regions, might aggravate the deterioration of cognitive function in addition to that effect of AD. Show more

Keywords: α-synuclein, Alzheimer’s disease, amyloid-β, Everyday Cognitive (ECog), Lewy-related pathology, LRP-AD neuropathology, phospho-tau

DOI: 10.3233/JAD-201548

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 447-458, 2021

Authors: Ismail, Zahinoor | McGirr, Alexander | Gill, Sascha | Hu, Sophie | Forkert, Nils D. | Smith, Eric E.

Article Type: Research Article

Abstract: Background: Mild behavioral impairment (MBI) and subjective cognitive decline (SCD) are dementia risk states, and potentially represent neurobehavioral and neurocognitive manifestations, respectively, of early stage neurodegeneration. Both MBI and SCD predict incident cognitive decline and dementia, are associated with known dementia biomarkers, and are both represented in the NIA-AA research framework for AD in Stage 2 (preclinical disease). Objective: To assess the associations of MBI and SCD, alone and in combination, with incident cognitive and functional decline in a population of older adults. We tested the hypothesis that MBI and SCD confer additive risk for decline. …Methods: Cognitively normal participants were followed up annually at Alzheimer’s Disease Centers. Logistic regression assessed the relationship between baseline classification (MBI-SCD-, MBI-SCD+, MBI+SCD-, or MBI+SCD+) and 3-year outcome. Results: Of 2,769 participants (mean age=76), 1,536 were MBI-SCD-, 254 MBI-SCD+, 743 MBI+SCD-, and 236 MBI+SCD+. At 3 years, 349 (12.6%) declined to CDR >0, including 23.1% of the MBI+group, 23.5% of the SCD+group, and 30.9% of the intersection group of both MBI+and SCD+participants. Compared to SCD-MBI-, we observed an ordinal progression in risk (ORs [95% CI]): 3.61 [2.42–5.38] for MBI-SCD+ (16.5% progression), 4.76 [3.57–6.34] for MBI+SCD- (20.7%), and 8.15 [5.71–11.64] for MBI+SCD+(30.9%). Conclusion: MBI and SCD together were associated with the greatest risk of decline. These complementary dementia risk syndromes can be used as simple and scalable methods to identify high-risk patients for workup or for clinical trial enrichment. Show more

Keywords: Mild behavioral impairment, mild cognitive impairment, neuropsychiatric symptoms, preclinical Alzheimer’s disease, subjective cognitive decline

DOI: 10.3233/JAD-201184

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 459-469, 2021

Authors: Asken, Breton M. | Elahi, Fanny M. | La Joie, Renaud | Strom, Amelia | Staffaroni, Adam M. | Lindbergh, Cutter A. | Apple, Alexandra C. | You, Michelle | Weiner-Light, Sophia | Brathaban, Nivetha | Fernandes, Nicole | Karydas, Anna | Wang, Paul | Rojas, Julio C. | Boxer, Adam L. | Miller, Bruce L. | Rabinovici, Gil D. | Kramer, Joel H. | Casaletto, Kaitlin B.

Article Type: Correction

DOI: 10.3233/JAD-219001

Citation: Journal of Alzheimer's Disease, vol. 80, no. 1, pp. 471-474, 2021