Journal of Alzheimer's Disease - Volume 92, issue 1

Authors: Baez, Sandra | Trujillo-Llano, Catalina | de Souza, Leonardo Cruz | Lillo, Patricia | Forno, Gonzalo | Santamaría-García, Hernando | Okuma, Cecilia | Alegria, Patricio | Huepe, David | Ibáñez, Agustín | Decety, Jean | Slachevsky, Andrea

Article Type: Research Article

Abstract: Background: Although social cognition is compromised in patients with neurodegenerative disorders such as behavioral variant frontotemporal dementia (bvFTD) and Alzheimer’s disease (AD), research on moral emotions and their neural correlates in these populations is scarce. No previous study has explored the utility of moral emotions, compared to and in combination with classical general cognitive state tools, to discriminate bvFTD from AD patients. Objective: To examine self-conscious (guilt and embarrassment) and other-oriented (pity and indignation) moral emotions, their subjective experience, and their structural brain underpinnings in bvFTD (n  = 31) and AD (n  = 30) patients, compared to healthy controls (n … = 37). We also explored the potential utility of moral emotions measures to discriminate bvFTD from AD. Methods: We used a modified version of the Moral Sentiment Task measuring the participants’ accuracy scores and their emotional subjective experiences. Results: bvFTD patients exhibited greater impairments in self-conscious and other-oriented moral emotions as compared with AD patients and healthy controls. Moral emotions combined with general cognitive state tools emerged as useful measures to discriminate bvFTD from AD patients. In bvFTD patients, lower moral emotions scores were associated with lower gray matter volumes in caudate nucleus and inferior and middle temporal gyri. In AD, these scores were associated with lower gray matter volumes in superior and middle frontal gyri, middle temporal gyrus, inferior parietal lobule and supramarginal gyrus. Conclusion: These findings contribute to a better understanding of moral emotion deficits across neurodegenerative disorders, highlighting the potential benefits of integrating this domain into the clinical assessment. Show more

Keywords: Alzheimer’s disease, behavioral variant frontotemporal dementia, moral emotions, neural correlates, social cognition

DOI: 10.3233/JAD-221131

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 153-169, 2023

Authors: He, Fei | Luo, Huizi | Yin, Li | Roosaar, Ann | Axéll, Tony | Zhao, Hongwei | Ye, Weimin

Article Type: Research Article

Abstract: Background: Whether poor oral health is associated with dementia risk remains unclear. Objective: We conducted a cohort study of 14,439 participants who were followed up for up to 40 years in Uppsala County, central Sweden, aiming to explore the association between poor oral health, namely the number of tooth loss, dental plaque status, and oral mucosal lesions, and the risk of dementia. Methods: We used Cox proportional hazards regression model to derive cause-specific hazard ratios (HR) and corresponding 95% confidence intervals (CI), while adjusting for baseline potential confounders as well as a time-varying covariate, Charlson’s Comorbidity …Index score. Results: Dementia risk was substantially higher among those with a higher number of tooth loss; compared to the group with tooth loss 0-10, the HRs were 1.21 (95% CI: 1.02, 1.42), 1.17 (95% CI: 0.97, 1.40), and 1.30 (95% CI: 1.09, 1.54) respectively for groups with increasing number of tooth loss. There was some evidence of dose-risk association in this study, with a HR of 1.10 (1.04, 1.18) comparing adjacent groups (ptrend  = 0.001). In a stratified analysis by attained age, tooth loss was more pronouncedly associated with the risk of dementia onset before age 80 (those with 21-32 versus 0-10 lost teeth, HR = 1.82, (95% CI: 1.32, 2.51); HR = 1.22 (95% CI: 1.10, 1.35) comparing adjacent groups, ptrend  < 0.001). Conclusion: In summary, there are some indications that poor oral health, as indicated by more tooth loss, is positively associated with an increased risk of dementia, especially for dementia onset before age 80. Show more

Keywords: Cohort study, dementia, oral health

DOI: 10.3233/JAD-215177

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 171-181, 2023

Authors: Grasset, Leslie | Power, Melinda C. | Crivello, Fabrice | Tzourio, Christophe | Chêne, Geneviève | Dufouil, Carole

Article Type: Research Article

Abstract: Background: The long-term effects of traumatic brain injury (TBI) with loss of consciousness (LOC) on magnetic resonance imaging (MRI) markers of brain health and on dementia risk are still debated. Objective: To investigate the associations of history of TBI with LOC with incident dementia and neuroimaging markers of brain structure and small vessel disease lesions. Methods: The analytical sample consisted in 4,144 participants aged 65 and older who were dementia-free at baseline from the Three City –Dijon study. History of TBI with LOC was self-reported at baseline. Clinical Dementia was assessed every two to three years, …up to 12 years of follow-up. A subsample of 1,675 participants <80 years old underwent a brain MRI at baseline. We investigated the associations between history of TBI with LOC and 1) incident all cause and Alzheimer’s disease (AD) dementia using illness-death models, and 2) neuroimaging markers at baseline. Results: At baseline, 8.3% of the participants reported a history of TBI with LOC. In fully-adjusted models, participants with a history of TBI with LOC had no statistically significant differences in dementia risk (HR = 0.90, 95% CI = 0.60–1.36) or AD risk (HR = 1.03, 95% CI = 0.69–1.52), compared to participants without TBI history. History of TBI with LOC was associated with lower white matter volume (β= –4.58, p  = 0.048), but not with other brain volumes, white matter hyperintensities volume, nor covert brain infarct. Conclusion: This study did not find evidence of an association between history of TBI with LOC and dementia or AD dementia risks over 12-year follow-up, brain atrophy, or markers of small vessel disease. Show more

Keywords: Alzheimer’s disease, brain MRI, dementia, traumatic brain injury

DOI: 10.3233/JAD-220658

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 183-193, 2023

Authors: Tao, Xue | Zhang, Rong | Wang, Liguo | Li, Xiaoling | Gong, Weijun

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) disturbs many patients and family. However, little progress has been made in finding effective treatments. Given AD is a multifactorial disease, luteolin and exercise combination therapy may be more effective than monotherapy. Objective: To explore the therapeutic effect and underlying mechanisms of luteolin and exercise combination therapy in AD treatment. Methods: This study utilized a validated mouse model of AD by bilateral injection of amyloid-β (Aβ)1-42 oligomers into the CA1 region of the hippocampus. By combining with animal behavioral test, thioflavin T detection, immunofluorescence and western blot test, the cognitive-enhancing effects …of luteolin and exercise combination therapy and the underlying mechanisms were investigated. Results: Luteolin (100 mg/kg/d) combined with exercise could significantly improve the performance of AD model mice in novel object recognition test, and the improvement was greater than that of monotherapy. Further experiments showed that luteolin and exercise alone or in combination could reverse the increase of Aβ content, the activation of astrocytes and microglia, and the decrease of the level of autophagy in hippocampus and cortex in AD model induced by Aβ1-42 oligomers. While the combination therapy involved more intact hippocampal and cortical areas, with greater degree of changes. Conclusion: Luteolin and exercise combination therapy prevented Aβ1-42 oligomers-induced cognitive impairment, possibly by decreasing neuroinflammation and enhancing autophagy. The luteolin and exercise combination therapy may be a useful therapeutic option for preventing and/or delaying the progression of memory dysfunction of AD. Show more

Keywords: Aβ1-42 oligomers, autophagy, cognitive impairment, luteolin and exercise combination therapy, neuroinflammation

DOI: 10.3233/JAD-220904

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 195-208, 2023

Authors: Deng, Lan | Wang, Yuanjun

Article Type: Research Article

Abstract: Background: There is a shortage of clinicians with sufficient expertise in the diagnosis of Alzheimer’s disease (AD), and cerebrospinal fluid biometric collection and positron emission tomography diagnosis are invasive. Therefore, it is of potential significance to obtain high-precision automatic diagnosis results from diffusion tensor imaging (DTI) through deep learning, and simultaneously output feature probability maps to provide clinical auxiliary diagnosis. Objective: We proposed a factorization machine combined neural network (FMCNN) model combining a multi-function convolutional neural network (MCNN) with a fully convolutional network (FCN), while accurately diagnosing AD and mild cognitive impairment (MCI); corresponding fiber bundle visualization results …are generated to describe their status. Methods: First, the DTI data is preprocessed to eliminate the influence of external factors. The fiber bundles of the corpus callosum (CC), cingulum (CG), uncinate fasciculus (UNC), and white matter (WM) were then tracked based on deterministic fiber tracking. Then the streamlines are input into CNN, MCNN, and FMCNN as one-dimensional features for classification, and the models are evaluated by performance evaluation indicators. Finally, the fiber risk probability map is output through FMCNN. Results: After comparing the model performance indicators of CNN, MCNN, and FMCNN, it was found that FMCNN showed the best performance in the indicators of accuracy, specificity, sensitivity, and area under the curve. By inputting the fiber bundles of the 10 regions of interest (UNC_L, UNC_R, UNC, CC, CG, CG+UNC, CG+CC, CC+UNC, CG+CC+UNC, and WM into CNN, MCNN, and FMCNN, respectively), WM shows the highest accuracy in CNN, MCNN, and FMCNN, which are 88.41%, 92.07%, and 96.95%, respectively. Conclusion: The FMCNN proposed here can accurately diagnose AD and MCI, and the generated fiber probability map can represent the risk status of AD and MCI. Show more

Keywords: Alzheimer’s disease, deep learning, fiber tracking, fully convolutional networks

DOI: 10.3233/JAD-220519

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 209-228, 2023

Authors: Sedaghat, Sanaz | Ji, Yuekai | Hughes, Timothy M. | Coresh, Josef | Grams, Morgan E. | Folsom, Aaron R. | Sullivan, Kevin J. | Murray, Anne M. | Gottesman, Rebecca F. | Mosley, Thomas H. | Lutsey, Pamela L.

Article Type: Research Article

Abstract: Background: Reduced kidney function is related to brain atrophy and higher risk of dementia. It is not known whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition, which could contribute to elevated risk of dementia. Objective: To investigate whether kidney impairment is associated with higher levels of circulating amyloid-β and brain amyloid-β deposition. Methods: This cross-sectional study was performed within the community–based Atherosclerosis Risk in Communities (ARIC) Study cohort. We used estimated glomerular filtration rate (eGFR) based on serum creatinine and cystatin C levels and urine albumin-to-creatinine ratio (ACR) to …assess kidney function. Amyloid positivity was defined as a standardized uptake value ratios > 1.2 measured with florbetapir positron emission tomography (PET) (n  = 340). Plasma amyloid-β1 - 40 and amyloid-β1 - 42 were measured using a fluorimetric bead-based immunoassay (n  = 2,569). Results: Independent of demographic and cardiovascular risk factors, a doubling of ACR was associated with 1.10 (95% CI: 1.01,1.20) higher odds of brain amyloid positivity, but not eGFR (odds ratio per 15 ml/min/1.73 m2 lower eGFR: 1.08; 95% CI: 0.95,1.23). A doubling of ACR was associated with a higher level of plasma amyloid-β1 - 40 (standardized difference: 0.12; 95% CI: 0.09,0.14) and higher plasma amyloid-β1 - 42 (0.08; 95% CI: 0.05,0.10). Lower eGFR was associated with higher plasma amyloid-β1 - 40 (0.36; 95% CI: 0.33,0.39) and higher amyloid-β1 - 42 (0.32; 95% CI: 0.29,0.35). Conclusion: Low clearance of amyloid-β and elevated brain amyloid positivity may link impaired kidney function with elevated risk of dementia. kidney function should be considered in interpreting amyloid biomarker results in clinical and research setting. Show more

Keywords: Albuminuria, amyloid, glomerular filtration rate, kidney, kidney function, plasma amyloid-β, positron emission tomography

DOI: 10.3233/JAD-220765

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 229-239, 2023

Authors: Lilek, Jaclyn | Ajroud, Kaouther | Feldman, Alexander Z. | Krishnamachari, Sesha | Ghourchian, Shadi | Gefen, Tamar | Spencer, Callen L. | Kawles, Allegra | Mao, Qinwen | Tranovich, Jessica F. | Jack Jr., Clifford R. | Mesulam, M-Marsel | Reichard, R. Ross | Zhang, Hui | Murray, Melissa E. | Knopman, David | Dickson, Dennis W. | Petersen, Ronald C. | Smith, Benjamin | Ashe, Karen H. | Mielke, Michelle M. | Nelson, Kathryn M. | Flanagan, Margaret E.

Article Type: Research Article

Abstract: Background: Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear. Objective: To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate …changes attributed to pathologic AD. Methods: Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X. Results: Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization. Conclusion: Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density. Show more

Keywords: Alzheimer’s disease, cognitive impairment, phosphorylated tau, PSD-95, Simoa Quanterix, synaptic dysfunction, synaptophysin, tau

DOI: 10.3233/JAD-220848

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 241-260, 2023

Authors: Li, Yuanjing | Wang, Mingqi | Cong, Lin | Hou, Tingting | Song, Lin | Wang, Xiang | Shi, Lin | Dekhtyar, Serhiy | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Cognitive reserve (CR) partly explains cognitive variability in the presence of pathological brain aging. Objective: We investigated the interplay of lifelong CR with age, sex, and brain aging markers in cognitive phenotypes among older adults with very limited education. Methods: This population-based cross-sectional study included 179 dementia-free participants (age ≥65 years; 39.7% women; 67.0% had no or elementary education) examined in 2014–2016. We assessed lacunes and volumes of hippocampus, ventricles, grey matter, white matter (WM), and white matter hyperintensities. Lifelong CR score was generated from six lifespan intellectual factors (e.g., education and social support). We …used Mini-Mental State Examination (MMSE) score to assess cognition and Petersen’s criteria to define mild cognitive impairment (MCI). Data were analyzed using general linear and logistic models. Results: The association of higher lifelong CR score (range: –4.0–5.0) with higher MMSE score was stronger in women (multivariable-adjusted β-coefficient and 95% CI: 1.75;0.99–2.51) than in men (0.68;0.33–1.03) (pinteraction  = 0.006). The association of higher CR with MCI (multivariable-adjusted odds ratio and 95% CI: 0.77;0.60–0.99) did not vary by age or sex. Among participants with low CR (<1.4[median]), greater hippocampal and WM volumes were related to higher MMSE scores with multivariable-adjusted β-coefficients being 1.77(0.41–3.13) and 0.44(0.15–0.74); the corresponding figures in those with high CR were 0.15(–0.76–1.07) and –0.17(–0.41–0.07) (pinteraction <0.01). There was no statistical interaction of CR with MRI markers on MCI. Conclusion: Greater lifelong CR capacity is associated with better late-life cognition among people with limited education, possibly by compensating for impact of neurodegeneration. Show more

Keywords: Cognition, cognitive reserve, mild cognitive impairment, neuroimaging, old age

DOI: 10.3233/JAD-220864

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 261-272, 2023

Authors: Wang, Chaoqun | Mao, Ming | Han, Xiaolei | Hou, Tingting | Wang, Xiaojie | Han, Qi | Dong, Yi | Liu, Rui | Cong, Lin | Liu, Cuicui | Imahori, Yume | Vetrano, Davide L. | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Emerging evidence has linked electrocardiographic parameters with serum adhesion molecules and cognition; however, their interrelationship has not been explored. Objective: We sought to investigate the associations of ventricular depolarization and repolarization intervals with serum adhesion molecules and cognitive function among rural-dwelling older adults. Methods: This population-based study engaged 4,886 dementia-free participants (age ≥60 years, 56.2% women) in the baseline examination (March-September 2018) of MIND-China. Of these, serum intercellular and vascular adhesion molecules (ICAM-1 and VCAM-1) were measured in 1591 persons. We used a neuropsychological test battery to assess cognitive function. Resting heart rate, QT, JT …intervals, and QRS duration were assessed with electrocardiogram. Data were analyzed using general linear models adjusting for multiple confounders. Results: Longer JT interval was significantly associated with lower z-scores of global cognition (multivariable-adjusted β= –0.035; 95% confidence interval = –0.055, –0.015), verbal fluency (–0.035; –0.063, –0.007), attention (–0.037; –0.065, –0.010), and executive function (–0.044; –0.072, –0.015), but not with memory function (–0.023; –0.054, 0.009). There were similar association patterns of QT interval with cognitive functions. In the serum biomarker subsample, longer JT and QT intervals remained significantly associated with poorer executive function and higher serum adhesion molecules. We detected statistical interactions of JT interval with adhesion molecules (pinteraction <0.05), such that longer JT interval was significantly associated with a lower executive function z-score only among individuals with higher serum ICAM-1 and VCAM-1. Conclusion: Longer ventricular depolarization and repolarization intervals are associated with worse cognitive function in older adults and vascular endothelial dysfunction may play a part in the associations. Show more

Keywords: Cardiovascular diseases, cognitive function, serum adhesion molecules, ventricular depolarization and repolarization intervals

DOI: 10.3233/JAD-220874

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 273-283, 2023

Authors: Bouges, Shenikqua | Fischer, Barbara L. | Norton, Derek L. | Wyman, Mary F. | Lambrou, Nickolas | Zuelsdorff, Megan | Van Hulle, Carol A. | Ennis, Gilda E. | James, Taryn T. | Johnson, Adrienne L. | Chin, Nathaniel A. | Carlsson, Cynthia M. | Gleason, Carey E.

Article Type: Research Article

Abstract: Background: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer’s disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk. Objective: Examine association of MetS features and processing speed and executive function across three racial groups. Methods: Cognitively unimpaired adults from the Wisconsin Alzheimer’s Disease Research Center and the Wisconsin Registry for Alzheimer’s Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were …assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups. Results: Participant sample sizes varied by outcome analyzed (N  = 714–1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A. Conclusion: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD. Show more

Keywords: African Americans, Alzheimer’s disease and related dementias, American Indian, Black, metabolic syndrome, Native American, race, racialized groups

DOI: 10.3233/JAD-220920

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 285-294, 2023

Authors: Chen, Shanquan | Cardinal, Rudolf N. | Auckland, Kathryn | Gräf, Stefan | O’Brien, John T. | Underwood, Benjamin R.

Article Type: Research Article

Abstract: Background: Persisting symptoms and increased mortality after SARS–CoV–2 infection has been described in COVID-19 survivors. Objective: We examined longer-term mortality in patients with dementia and SARS-CoV-2 infection. Methods: A retrospective matched case-control study of 165 patients with dementia who survived an acute hospital admission with COVID-19 infection, and 1325 patients with dementia who survived a hospital admission but without SARS-CoV-2 infection. Potential risk factors investigated included socio-demographic factors, clinical features, and results of investigations. Data were fitted using a Cox proportional hazard model. Results: Compared to patients with dementia but without SARS-CoV-2 infection, people …with dementia and SARS-CoV-2 infection had a 4.4-fold risk of death (adjusted hazard ratio [aHR] = 4.44, 95% confidence interval [CI] 3.13–6.30) even beyond the acute phase of infection. This excess mortality could be seen up to 125 days after initial recovery but was not elevated beyond this time. Risk factors for COVID-19-associated mortality included prescription of antipsychotics (aHR = 3.06, 95% CI 1.40–6.69) and benzodiazepines (aHR = 3.00, 95% CI 1.28–7.03). Abnormalities on investigation associated with increased mortality included high white cell count (aHR = 1.21, 95% CI 1.04–1.39), higher absolute neutrophil count (aHR = 1.28, 95% CI 1.12–1.46), higher C-reactive protein (aHR = 1.01, 95% CI 1.00–1.02), higher serum sodium (aHR = 1.09, 95% CI 1.01–1.19), and higher ionized calcium (aHR = 1.03, 95% CI 1.00–1.06). The post-acute COVID mortality could be modeled for the first 120 days after recovery with a balanced accuracy of 87.2%. Conclusion: We found an increased mortality in patients with dementia beyond the acute phase of illness. We identified several investigation results associated with increased mortality, and increased mortality in patients prescribed antipsychotics or benzodiazepines. Show more

Keywords: Dementia, longer-term mortality, post-acute COVID-19, SARS-CoV-2

DOI: 10.3233/JAD-221093

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 295-309, 2023

Authors: Wu, Chao | Ma, Ya-Hui | Hu, Hao | Zhao, Bing | Tan, Lan

Article Type: Research Article

Abstract: Background Until recently, studies on associations between neuroinflammation in vivo and cerebral small vessel disease (CSVD) are scarce. Cerebrospinal fluid (CSF) levels of soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a candidate biomarker of microglial activation and neuroinflammation, were found elevated in Alzheimer’s disease (AD), but they have not been fully explored in CSVD. Objective To determine whether CSF sTREM2 levels are associated with the increased risk of CSVD progression. Methods A total of 426 individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database were included in this study. All participants underwent measurements …of CSF sTREM2 and AD pathology (Aβ1-42 , P-tau181P ). The progression of CSVD burden and imaging markers, including cerebral microbleeds (CMBs), white matter hyperintensities and lacunes, were estimated based on neuroimaging changes. Logistic regression and moderation effect models were applied to explore associations of sTREM2 with CSVD progression and AD pathology. Results Higher CSF sTREM2 levels at baseline were associated with increased CSVD burden (OR = 1.28 [95% CI, 1.01–1.62]) and CMBs counts (OR = 1.32 [95% CI, 1.03–1.68]). Similarly, increased change rates of CSF sTREM2 might predict elevated CMBs counts (OR = 1.44 [95% CI, 1.05–1.98]). Participants with AD pathology (Aβ1-42 and P-tau181P ) showed a stronger association between CSF sTREM2 and CSVD progression. Conclusion This longitudinal study found a positive association between CSF sTREM2 and CSVD progression, suggesting that neuroinflammation might promote CSVD. Furthermore, neuroinflammation could be a shared pathogenesis of CSVD and AD at the early stage. Targeting neuroinflammation to intervene the progression of CSVD and AD warrants further investigation. Show more

Keywords: Alzheimer’s disease, amyloid-β, cerebral small vessel disease, microglia, neuroinflammation, sTREM2

DOI: 10.3233/JAD-220731

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 311-322, 2023

Authors: Newton, Princess | Tchounguen, Jonathan | Pettigrew, Corinne | Lim, Chantelle | Lin, Zixuan | Lu, Hanzhang | Moghekar, Abhay | Albert, Marilyn | Soldan, Anja

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) frequently co-occurs with other brain pathologies. Recent studies suggest there may be a mechanistic link between AD and small vessel cerebrovascular disease (CVD), as opposed to simply the overlap of two disorders. Objective: We investigated the cross-sectional relationship between white matter hyperintensity (WMH) volumes (markers of CVD) and cerebrospinal fluid (CSF) biomarkers of AD. Methods: WMH volumes were assessed globally and regionally (i.e., frontal, parietal, temporal, occipital, and limbic). CSF AD biomarkers (i.e., Aβ 40 , Aβ 42 , Aβ 42 /Aβ 40 ratio, phosphorylated tau-181 [p-tau181 ], and total tau …[t-tau]) were measured among 152 non-demented individuals (134 cognitively unimpaired and 18 with mild cognitive impairment (MCI)). Results: Linear regression models showed that among all subjects, higher temporal WHM volumes were associated with AD biomarkers (higher levels of p-tau181 , t-tau, and Aβ 40 ), particularly among APOE ɛ 4 carriers (independent of Aβ 42 levels). Higher vascular risk scores were associated with greater parietal and frontal WMH volumes (independent of CSF AD biomarker levels). Among subjects with MCI only, parietal WMH volumes were associated with a lower level of Aβ 42 /Aβ 40 . In addition, there was an association between higher global WMH volumes and higher CSF t-tau levels among younger participants versus older ones (∼<65 versus 65+ years), independent of Aβ 42 /Aβ 40 and p-tau181 . Conclusion: These findings suggest that although WMH are primarily related to systemic vascular risk and neurodegeneration (i.e., t-tau), AD-specific pathways may contribute to the formation of WMH in a regionally-specific manner, with neurofibrillary tangles (i.e., p-tau) playing a role in temporal WMHs and amyloid (i.e., Aβ 42 /Aβ 40 ) in parietal WMHs. Show more

Keywords: Alzheimer’s disease, amyloid, APOE, cerebrospinal fluid, magnetic resonance imaging, tau, vascular risk, white matter hyperintensity volumes

DOI: 10.3233/JAD-220846

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 323-339, 2023

Authors: Voss, Tiffini | Kost, James | Mercer, Swati Pal | Furtek, Christine | Randolph, Christopher | Lines, Christopher | Egan, Michael F. | Cummings, Jeffrey L.

Article Type: Research Article

Abstract: Background: Delay of progression from prodromal Alzheimer’s disease (AD) to dementia is an important outcome in AD trials. Centralized adjudication is intended to improve the consistency of dementia diagnosis but has not been scrutinized. Objective: To evaluate centralized adjudication for determining progression to dementia compared with Site Investigator opinion or change in Clinical Dementia Rating (CDR). Methods: We used data from the 2-year APECS trial of verubecestat versus placebo in 1,451 prodromal AD participants. Cases were triggered for central adjudication if: 1) the Site Investigator judged the participant had progressed to dementia, or 2) …the participant’s CDR sum-of-boxes score increased ≥2 points from baseline. Post-hoc analyses were performed on pooled treatment-group data to compare methods of assessing progression. Results: 581/1,451 (40%) participants had changes triggering adjudication and most (83%) were confirmed as progression to dementia. Only 66% of those who met CDR criteria (regardless of whether they also met Site Investigator criteria) were adjudicated to have progressed to dementia and just 15% of those who met only CDR criteria were adjudicated to have progressed, representing 5% of progressors. In contrast, 99% of those who met Site Investigator criteria (regardless of whether they also met CDR criteria) were adjudicated to have progressed, and the same was true for those who met only Site Investigator criteria. Conclusion: A positive Site Investigator opinion is an excellent predictor for a positive adjudication decision regarding onset of dementia. Conversely, sole use of CDR sum-of-boxes change ≥2 is inadequate. The benefit of centralized adjudication appears doubtful. Show more

Keywords: Alzheimer’s disease, APECS, Clinical Dementia Rating, diagnosis, mild cognitive impairment, randomized controlled trial

DOI: 10.3233/JAD-220836

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 341-348, 2023

Authors: Toppala, Sini | Ekblad, Laura L. | Viitanen, Matti | Rinne, Juha O. | Jula, Antti

Article Type: Research Article

Abstract: Background: Diabetes increases the risk for cognitive decline, but the mechanisms behind this association remain unknown. Impaired early insulin secretion in elderly men and insulin resistance, both of which are pathophysiological features of type 2 diabetes, have previously been linked to Alzheimer’s disease. Objective: To examine if the early insulin response to oral glucose load predicts cognitive performance after 10 years in men and women aged 45-74 years. Methods: This study was based on a subpopulation of the Health 2000 Survey, a Finnish nationwide, population-based health examination study, and its follow-up, the Health 2011 Study. In …total, 961 45–74-year-old individuals (mean age at baseline 55.6 years, 55.8% women) were examined. An oral glucose tolerance test was performed in 2001–2002, and early insulin response was defined as the ratio of the 30-min increment in insulin concentration to that of glucose concentration. Cognitive function was evaluated at baseline and follow-up with categorical verbal fluency, word-list learning, and word-list delayed recall. Statistical analyses were performed using multivariable linear models adjusted for age, sex, education, APOE &z.epsi; 4 genotype, vascular risk factors including diabetes, and depressive symptoms. Results: A lower early insulin response to glucose load predicted lower performance (β : 0.21, p  = 0.03) and greater decline (β : 0.19, p  = 0.03) in the word-list delayed recall test. Baseline early insulin response did not predict verbal fluency or word-list learning (all p -values≥0.13). Conclusion: Our results suggest that decreased early insulin secretion predicts episodic memory decline in middle-aged to elderly men and women. Show more

Keywords: Cognitive decline, early insulin response, episodic memory, insulin secretion, insulin resistance, oral glucose tolerance test

DOI: 10.3233/JAD-220894

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 349-359, 2023

Authors: Yoshida, Madoka | Uemura, Takeshi | Mizoi, Mutsumi | Waragai, Masaaki | Sakamoto, Akihiko | Terui, Yusuke | Kashiwagi, Keiko | Igarashi, Kazuei

Article Type: Research Article

Abstract: Background: Dementia, including Alzheimer’s disease (AD), is one of the serious diseases at advanced age, and its early detection is important for maintaining quality of life (QOL). Objective: In this study, we sought novel biomarkers for dementia in urine. Methods: Samples of urine were collected from 57 control subjects without dementia, 62 mild cognitive impairment (MCI) patients, and 42 AD patients. Mini-Mental State Examination (MMSE) was evaluated when subjects were examined by medical doctors. Urinary amino acid (lysine)-conjugated acrolein (AC-Acro) was measured using N ɛ -(3-formyl-3, 4-dehydropiperidine) lysine (FDP-Lys) ELISA kit, and taurine content was …measured using a taurine assay kit. Values were normalized by creatinine content which was measured with the colorimetric assay kit. Results: We found that urinary amino acid (lysine)-conjugated acrolein (AC-Acro) and taurine negatively correlated with MMSE score and are significantly lower in dementia patients compared to the normal subjects. When AC-Acro and taurine were evaluated together with age using an artificial neural network model, median relative risk values for subjects with AD, subjects with mild cognitive impairment, and control subjects were 0.96, 0.53, and 0.06, respectively. Conclusion: Since urine is relatively easy to collect, our findings provide a novel biomarker for dementia without invasiveness. Show more

Keywords: Alzheimer’s disease, amino acid-conjugated acrolein (AC-Acro), Mini-Mental State Examination, taurine, urinary biomarkers

DOI: 10.3233/JAD-220912

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 361-369, 2023

Authors: Highet, Blake | Wiseman, James A. | Mein, Hannah | Parker, Remai | Ryan, Brigid | Turner, Clinton P. | Jing, Yu | Singh-Bains, Malvindar K. | Liu, Ping | Dragunow, Mike | Faull, Richard L.M. | Murray, Helen C. | Curtis, Maurice A.

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a substantial reduction of neuroplasticity. Our previous work demonstrated that neurons involved in memory function may lose plasticity because of decreased protein levels of polysialylated neural cell adhesion molecule (PSA-NCAM) in the entorhinal cortex (EC) of the human AD brain, but the cause of this decrease is unclear. Objective: To investigate genes involved in PSA-NCAM regulation which may underlie its decrease in the AD EC. Methods: We subjected neurologically normal and AD human EC sections to multiplexed fluorescent in situ …hybridization and immunohistochemistry to investigate genes involved in PSA-NCAM regulation. Gene expression changes were sought to be validated in both human tissue and a mouse model of AD. Results: In the AD EC, a cell population expressing a high level of CALB2 mRNA and a cell population expressing a high level of PST mRNA were both decreased. CALB2 mRNA and protein were not decreased globally, indicating that the decrease in CALB2 was specific to a sub-population of cells. A significant decrease in PST mRNA expression was observed with single-plex in situ hybridization in middle temporal gyrus tissue microarray cores from AD patients, which negatively correlated with tau pathology, hinting at global loss in PST expression across the AD brain. No significant differences in PSA-NCAM or PST protein expression were observed in the MAPT P301S mouse brain at 9 months of age. Conclusion: We conclude that PSA-NCAM dysregulation may cause subsequent loss of structural plasticity in AD, and this may result from a loss of PST mRNA expression. Due PSTs involvement in structural plasticity, intervention for AD may be possible by targeting this disrupted plasticity pathway. Show more

Keywords: Alzheimer’s disease, calretinin, entorhinal cortex, polysialyltransferase, PSA-NCAM

DOI: 10.3233/JAD-220986

Citation: Journal of Alzheimer's Disease, vol. 92, no. 1, pp. 371-390, 2023