Journal of Alzheimer's Disease - Volume 91, issue 2

Authors: Shirzadi, Zahra | Rabin, Jennifer | Launer, Lenore J. | Bryan, R. Nick | Al-Ozairi, Abdulla | Chhatwal, Jasmeer | Al-Ozairi, Ebaa | Detre, John A. | Black, Sandra E. | Swardfager, Walter | MacIntosh, Bradley J.

Article Type: Research Article

Abstract: Background: Metabolic and vascular risk factors (MVRF) are associated with neurodegeneration and poor cognition. There is a need to better understand the impact of these risk factors on brain health in the decades that precede cognitive impairment. Longitudinal assessments can provide new insight regarding changes in MVRFs that are related to brain imaging features. Objective: To investigate whether longitudinal changes in MVRF spanning up to 25 years would be associated with midlife brain volume and cognition. Methods: Participants were from the CARDIA study (N  = 467, age at year 25 = 50.6±3.4, female/male = 232/235, black/white = 161/306). Three models were developed, each …designed to capture change over time; however, we were primarily interested in the average real variability (ARV) as a means of quantifying MVRF variability across all available assessments. Results: Multivariate partial least squares that used ARV metrics identified two significant latent variables (partial correlations ranged between 0.1 and 0.26, p  < 0.01) that related MVRF ARV and regional brain volumes. Both latent variables reflected associations between brain volume and MVRF ARV in obesity, cholesterol, blood pressure, and glucose. Subsequent bivariate correlations revealed associations among MVRF factors, aggregate brain volume and cognition. Conclusion: This study demonstrates that MVRF variability over time is associated with midlife brain volume in regions that are relevant to later-life cognitive decline. Show more

Keywords: Brain volume, cognition, metabolic syndrome, partial least squares, vascular risk factors

DOI: 10.3233/JAD-220340

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 627-635, 2023

Authors: Wu, Jianfeng | Su, Yi | Zhu, Wenhui | Jalili Mallak, Negar | Lepore, Natasha | Reiman, Eric M. | Caselli, Richard J. | Thompson, Paul M. | Chen, Kewei | Wang, Yalin

Article Type: Research Article

Abstract: Background: Amyloid-β (Aβ) plaques and tau protein tangles in the brain are the defining ‘A’ and ‘T’ hallmarks of Alzheimer’s disease (AD), and together with structural atrophy detectable on brain magnetic resonance imaging (MRI) scans as one of the neurodegenerative (‘N’) biomarkers comprise the “ATN framework” of AD. Current methods to detect Aβ/tau pathology include cerebrospinal fluid (invasive), positron emission tomography (PET; costly and not widely available), and blood-based biomarkers (promising but mainly still in development). Objective: To develop a non-invasive and widely available structural MRI-based framework to quantitatively predict the amyloid and tau measurements. Methods: …With MRI-based hippocampal multivariate morphometry statistics (MMS) features, we apply our Patch Analysis-based Surface Correntropy-induced Sparse coding and max-pooling (PASCS-MP) method combined with the ridge regression model to individual amyloid/tau measure prediction. Results: We evaluate our framework on amyloid PET/MRI and tau PET/MRI datasets from the Alzheimer’s Disease Neuroimaging Initiative. Each subject has one pair consisting of a PET image and MRI scan, collected at about the same time. Experimental results suggest that amyloid/tau measurements predicted with our PASCP-MP representations are closer to the real values than the measures derived from other approaches, such as hippocampal surface area, volume, and shape morphometry features based on spherical harmonics. Conclusion: The MMS-based PASCP-MP is an efficient tool that can bridge hippocampal atrophy with amyloid and tau pathology and thus help assess disease burden, progression, and treatment effects. Show more

Keywords: Alzheimer’s disease, amyloid deposition, Braak12 tau-SUVR, Braak34 tau-SUVR, Centiloid, dictionary and correntropy-induced sparse coding, hippocampal multivariate morphometry statistics, tau deposition

DOI: 10.3233/JAD-220812

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 637-651, 2023

Authors: Hendriks, Stevie | Peetoom, Kirsten | Tange, Huibert | Papma, Janne | van der Flier, Wiesje M. | Koopmans, Raymond | Bakker, Christian | Köhler, Sebastian | de Vugt, Marjolein

Article Type: Research Article

Abstract: Background: Timely diagnosis and adequate care is important for persons with young-onset dementia (YOD) and their caregivers, due to the high impact of the disease. Initiating care can be difficult for the general practitioner (GP) and other healthcare professionals. Objective: Provide insight in the care use of persons with YOD and identify factors influencing care use. Methods: A primary care register was used for this study. Information on the care use of persons with YOD was extracted from the GPs written notes. Information entailed time until start of care use, reasons and factors influencing the GP’s …decision, and reasons and factors influencing actual care use were included. Analyses included quantitative explorative descriptive analyses, and qualitative manifest content analyses. Results: 75 persons with YOD were included in this study. The main reason for GPs to refer for diagnosis was concerns of caregivers. After diagnosis, 72% of the persons were assigned a case manager, 42.7% received day care, and 44% were admitted to a long-term care facility. A higher percentage of persons without a case manager was admitted to a long-term care facility (64%) compared to the persons with a case manager (36%). Reasons for not initiating care were reluctancy of the persons with YOD or their caregivers, the person deceased, or because the GP did not refer for care. Conclusion: Care use differed between persons due to different needs and reasons. Although most persons with YOD receive care in the years after diagnosis, there are still factors that could be improved. Show more

Keywords: Delivery of health care, dementia, middle aged

DOI: 10.3233/JAD-220713

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 653-662, 2023

Authors: Zijlmans, Jend L. | Riemens, Mariska S. | Vernooij, Meike W. | Ikram, M. Arfan | Luik, Annemarie I.

Article Type: Research Article

Abstract: Background: The cognitive reserve hypothesis aims to explain individual differences in susceptibility to the functional impact of dementia-related pathology. Previous research suggested that poor subjective sleep may be associated with a lower cognitive reserve. Objective: The objective was to investigate if actigraphy-estimated sleep and 24-hour activity rhythms are associated with cognitive reserve. Methods: This cross-sectional study included 1,002 participants from the Rotterdam Study (mean age: 65.0 years, standard deviation (SD): 7.1) who were assessed with actigraphy, five cognitive tests, and brain-MRI between 2009– 2014. Sleep and 24-hour activity rhythms were measured using actigraphy (mean days: 6.7, …SD: 0.5). Cognitive reserve was defined as a latent variable that captures variance across cognitive tests, while adjusting for age, sex, education, total brain volume, intracranial volume, and white matter hyperintensity volume. Associations of sleep and 24-hour activity rhythms with cognitive reserve were assessed using structural equation models. Results: Longer sleep onset latency (adjusted mean difference: – 0.16, 95% CI: – 0.24; – 0.08) and lower sleep efficiency (0.14, 95% CI: 0.05; 0.22) were associated with lower cognitive reserve. Total sleep time and wake after sleep onset were not significantly associated with cognitive reserve. After mutual adjustment, only the association of longer sleep onset latency remained significant (– 0.12, 95% CI: – 0.20; – 0.04). The 24-hour activity rhythm was not significantly associated with cognitive reserve. Conclusion: In conclusion, our study suggests that longer sleep onset latency is particularly associated with lower cognitive reserve. Future longitudinal work is needed to assess whether shortening the sleep onset latency could enhance cognitive reserve, in order to limit the susceptibility to the functional impact of dementia-related pathology. Show more

Keywords: Actigraphy, circadian rhythm, cognitive reserve, cohort study, sleep

DOI: 10.3233/JAD-220714

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 663-672, 2023

Authors: Matsuzono, Kosuke | Suzuki, Masayuki | Anan, Yuhei | Ozawa, Tadashi | Mashiko, Takafumi | Koide, Reiji | Tanaka, Ryota | Fujimoto, Shigeru

Article Type: Research Article

Abstract: Background: The relationship between transesophageal echocardiography findings and cognitive function. Objective: This study aimed to establish an association between transesophageal echocardiography findings and cognitive function in stroke survivors. Methods: A single-center study was conducted between April 1, 2017 and March 31, 2022. All subjects that were included had a past history of ischemic stroke and were admitted after >21 days from onset. The participants underwent cognitive function tests including a Mini-Mental State Examination, Revised Hasegawa Dementia Scale, Frontal Assessment Battery, and transesophageal echocardiography. Results: The results of 126 participants were analyzed. The cognitive function …of participants with a spontaneous echo contrast (+) in the left atrium including appendage or of those with an aorta-arch plaque with a maximum thickness ≥4 mm significantly worse while neither the patent foramen ovale nor the branch extending plaque influenced cognitive function (The median cognitive scores of the spontaneous echo contrast (–) versus (+) were 26 versus 22, p  < 0.01** , 26 versus 21, p  < 0.001*** , and 14 versus 11, p  < 0.01** . Those of the aortic-arch plaque max thickness (<4 mm) versus (≥4 mm) were 26 versus 25, p  < 0.05* , 27 versus 24, p  < 0.05* , and 15 versus 13, p  < 0.05* ). Conclusion: Our findings show that spontaneous echo contrast in the left atrium and aortic-arch atheroma detected by transesophageal echocardiography, were negatively associated with cognitive function. Show more

Keywords: Aortic-arch atheroma, cognitive function, examination, spontaneous echo contrast, transesophageal echocardiography

DOI: 10.3233/JAD-220763

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 673-681, 2023

Authors: Walker, Jamie M. | Dehkordi, Shiva Kazempour | Schaffert, Jeff | Goette, William | White III, Charles L. | Richardson, Timothy E. | Zare, Habil

Article Type: Research Article

Abstract: Background: The strongest risk factor for the development of Alzheimer’s disease (AD) is age. The progression of Braak stage and Thal phase with age has been demonstrated. However, prior studies did not include cognitive status. Objective: We set out to define normative values for Alzheimer-type pathologic changes in individuals without cognitive decline, and then define levels that would qualify them to be resistant to or resilient against these changes. Methods: Utilizing neuropathology data obtained from the National Alzheimer’s Coordinating Center (NACC), we demonstrate the age-related progression of Alzheimer-type pathologic changes in cognitively normal individuals (CDR = 0, n … = 542). With plots generated from these data, we establish standard lines that may be utilized to measure the extent to which an individual’s Alzheimer-type pathology varies from the estimated normal range of pathology. Results: Although Braak stage and Thal phase progressively increase with age in cognitively normal individuals, the Consortium to Establish a Registry for Alzheimer’s Disease neuritic plaque score and Alzheimer’s disease neuropathologic change remain at low levels. Conclusion: These findings suggest that an increasing burden of neuritic plaques is a strong predictor of cognitive decline, whereas, neurofibrillary degeneration and amyloid-β (diffuse) plaque deposition, both to some degree, are normal pathologic changes of aging that occur in almost all individuals regardless of cognitive status. Furthermore, we have defined the amount of neuropathologic change in cognitively normal individuals that would qualify them to be “resilient” against the pathology (significantly above the normative values for age, but still cognitively normal) or “resistant” to the development of pathology (significantly below the normative values for age). Show more

Keywords: Alzheimer’s disease, Braak stage, CERAD neuritic plaque score, cognitively normal, resilience, resistance, Thal phase

DOI: 10.3233/JAD-220898

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 683-695, 2023

Authors: Gorenflo, Maria P. | Davis, Pamela B. | Kendall, Ellen K. | Olaker, Veronica R. | Kaelber, David C. | Xu, Rong

Article Type: Research Article

Abstract: Background: Currently there are no effective therapies to prevent or halt the development of Alzheimer’s disease (AD). Multiple risk factors are involved in AD, including ischemic stroke (IS). Aspirin is often prescribed following IS to prevent blood clot formation. Observational studies have shown inconsistent findings with respect to the relationship between aspirin use and the risk of AD. Objective: To investigate the relationship between aspirin therapy after IS and the new diagnosis of AD in elderly patients. Methods: This retrospective cohort study leveraged a large database that contains over 90 million electronic health records to compare …the hazard rates of AD after IS in elderly patients prescribed aspirin versus those not prescribed aspirin after propensity-score matching for relevant confounders. Results: At 1, 3, and 5 years after first IS, elderly patients prescribed aspirin were less likely to develop AD than those not prescribed aspirin: Hazard Ratio = 0.78 [0.65,0.94], 0.81 [0.70,0.94], and 0.76 [0.70,0.92]. Conclusion: Our findings suggest that aspirin use may prevent AD in patients with IS, a subpopulation at high risk of developing the disease. Show more

Keywords: Alzheimer’s disease, aspirin, inflammation, ischemic stroke, mortality

DOI: 10.3233/JAD-220901

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 697-704, 2023

Authors: Delgado-Álvarez, Alfonso | Díez-Cirarda, María | Delgado-Alonso, Cristina | Hernández-Lorenzo, Laura | Cuevas, Constanza | Valles-Salgado, María | Montero-Escribano, Paloma | Gil-Moreno, María José | Matías-Guiu, Jorge | García-Ramos, Rocío | Matias-Guiu, Jordi A.

Article Type: Research Article

Abstract: Background: The Rowland Universal Dementia Assessment Scale (RUDAS) is a cognitive test with favorable diagnostic properties for detecting dementia and a low influence of education and cultural biases. Objective: We aimed to validate the RUDAS in people with Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS). Methods: We enrolled one hundred and fifty participants (60 with AD, 30 with PD, 60 with MS, and 120 healthy controls (HC)). All clinical groups completed a comprehensive neuropsychological battery, RUDAS, and standard cognitive tests of each disorder: MMSE, SCOPA-COG, and Symbol Digit Modalities Test. Intergroup comparisons between …clinical groups and HC and ROC curves were estimated. Random Forest algorithms were trained and validated to detect cognitive impairment using RUDAS and rank the most relevant scores. Results: The RUDAS scores were lower in patients with AD, and patients with PD and MS showed cognitive impairment compared to healthy controls. Effect sizes were generally large. The total score was the most discriminative, followed by the memory score. Correlations with standardized neuropsychological tests were moderate to high. Random Forest algorithms obtained accuracies over 80–90% using the RUDAS for diagnosing AD and cognitive impairment associated with PD and MS. Conclusion: Our results suggest the RUDAS is a valid test candidate for multi-disease cognitive screening tool in AD, PD, and MS. Show more

Keywords: Alzheimer’s disease, cognitive screening test, multiple sclerosis, Parkinson’s disease, RUDAS

DOI: 10.3233/JAD-220907

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 705-717, 2023

Authors: Kostev, Karel | Gessler, Nele | Wohlmuth, Peter | Arnold, Dirk | Bein, Berthold | Bohlken, Jens | Herrlinger, Klaus | Jacob, Louis | Koyanagi, Ai | Nowak, Lorenz | Smith, Lee | Wesseler, Claas | Sheikhzadeh, Sara | Wollmer, Marc Axel

Article Type: Research Article

Abstract: Background: Dementia has been identified as a major predictor of mortality associated with COVID-19. Objective: The objective of this study was to investigate the association between dementia and mortality in COVID-19 inpatients in Germany across a longer interval during the pandemic. Methods: This retrospective study was based on anonymized data from 50 hospitals in Germany and included patients with a confirmed COVID-19 diagnosis hospitalized between March 11, 2020 and July, 20, 2022. The main outcome of the study was the association of mortality during inpatient stays with dementia diagnosis, which was studied using multivariable logistic regression …adjusted for age, sex, and comorbidities as well as univariate logistic regression for matched pairs. Results: Of 28,311 patients diagnosed with COVID-19, 11.3% had a diagnosis of dementia. Prior to matching, 26.5% of dementia patients and 11.5% of non-dementia patients died; the difference decreased to 26.5% of dementia versus 21.7% of non-dementia patients within the matched pairs (n  = 3,317). This corresponded to an increase in the risk of death associated with dementia (OR = 1.33; 95% CI: 1.16–1.46) in the univariate regression conducted for matched pairs. Conclusion: Although dementia was associated with COVID-19 mortality, the association was weaker than in previously published studies. Further studies are needed to better understand whether and how pre-existing neuropsychiatric conditions such as dementia may impact the course and outcome of COVID-19. Show more

Keywords: COVID-19 diagnosis, dementia, elderly, Germany, hospital, mortality

DOI: 10.3233/JAD-220918

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 719-726, 2023

Authors: Mohr, Wiebke | Rädke, Anika | Afi, Adel | Weber, Niklas | Platen, Moritz | Mühlichen, Franka | Scharf, Annelie | Michalowsky, Bernhard | Hoffmann, Wolfgang

Article Type: Research Article

Abstract: Background: Person-centered care (PCC) requires knowledge about patient preferences. Among people living with cognitive impairments (PlwCI), evidence on quantitative, choice-based preferences, which allow to quantify, weigh, and rank care elements, is limited. Furthermore, data on the congruence of patient preferences with physicians’ judgements for PCC are missing. Such information is expected to support the implementation of PCC; state-of-the-art medical care aligned with patients’ preferences. Objective: To elicit patient preferences and physicians’ judgements for PCC and their congruence. Methods: Data from the mixed-methods PreDemCare study, including a cross-sectional, paper-and-pencil, interviewer-assisted analytic hierarchy process (AHP) survey conducted with …n  = 50 community-dwelling PlwCI and n  = 25 physicians. Individual AHP weights (preferences/judgements) were calculated with the principal eigenvector method and aggregated per group by aggregation of individual priorities mode. Individual consistency ratios (CRs) were calculated and aggregated per group. Group differences in preferences/judgements were investigated descriptively by means and standard deviations (SDs) of AHP weights, resulting ranks, and boxplots. Additionally, differences between groups were investigated with independent paired t -test/Mann Whitney U-test. Sensitivity of AHP results was tested by inclusion/exclusion of inconsistent respondents, with an accepted threshold at CR≤0.3 for patients, and CR≤0.2 for physicians, due to better cognitive fitness of the latter group. Results: Patient preferences and physicians’ judgements did not differ significantly, except for the criterion Memory Exercises (AHP weights (mean (SD)): 0.135 (0.066) versus 0.099 (0.068), p  = 0.01). We did not see rank-reversals of criteria after exclusion of inconsistent participants. Mean CR for patients at the criteria level was 0.261, and 0.181 for physicians. Conclusion: Physicians’ judgements in our setting aligned well with patients’ preferences. Our findings may be used to guide the implementation of preference-based PCC. Show more

Keywords: Dementia care, mild cognitive impairment, participatory research, patient-centered care, patient empowerment, patient engagement,, patient preference, physician-patient relations, shared decision-making

DOI: 10.3233/JAD-220753

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 727-741, 2023

Authors: Mathew, Sunu | WuDunn, Darrell | Mackay, Devin D. | Vosmeier, Aaron | Tallman, Eileen F. | Deardorff, Rachael | Harris, Alon | Farlow, Martin R. | Brosch, Jared R. | Gao, Sujuan | Apostolova, Liana G. | Saykin, Andrew J. | Risacher, Shannon L.

Article Type: Research Article

Abstract: Background: The eye has been considered a ‘window to the brain,’ and several neurological diseases including neurodegenerative conditions like Alzheimer’s disease (AD) also show changes in the retina. Objective: To investigate retinal nerve fiber layer (RNFL) thickness and its association with brain volume via magnetic resonance imaging (MRI) in older adults with subjective or objective cognitive decline. Methods: 75 participants underwent ophthalmological and neurological evaluation including optical coherence tomography and MRI (28 cognitively normal subjects, 26 with subjective cognitive decline, 17 patients diagnosed with mild cognitive impairment, and 4 with AD). Differences in demographics, thickness of …RNFL, and brain volume were assessed using ANCOVA, while partial Pearson correlations, covaried for age and sex, were used to compare thickness of the peripapillary RNFL with brain volumes, with p  < 0.05 considered statistically significant. Results: Mean RNFL thickness was significantly correlated with brain volumes, including global volume (right eye r  = 0.235 p  = 0.046, left eye r  = 0.244, p  = 0.037), temporal lobe (right eye r  = 0.242 p  = 0.039, left eye r  = 0.290, p  = 0.013), hippocampal (right eye r  = 0.320 p  = 0.005, left eye r  = 0.306, p  = 0.008), amygdala (left eye r  = 0.332, p  = 0.004), and occipital lobe (right eye r  = 0.264 p  = 0.024) volumes. Conclusion: RNFL thickness in both eyes was positively associated with brain volumes in subjects with subjective and objective cognitive decline. The RNFL, however, did not correlate with the disease, but the small sample number makes it important to conduct larger studies. RNFL thickness may be a useful non-invasive and inexpensive tool for detection of brain neurodegeneration and may assist with diagnosis and monitoring of progression and treatment in AD. Show more

Keywords: Alzheimer’s disease, brain volume, MRI, neurodegeneration, optical coherence tomography, retinal nerve fiber layer

DOI: 10.3233/JAD-210533

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 743-752, 2023

Authors: Chandler, Julie | Kubisiak, Joanna

Article Type: Research Article

Abstract: Background: The high burden of dementia and Alzheimer’s disease (AD) increases substantially as disease progresses. Characterizing early patterns of health care utilization among patients who develop cognitive impairment may deepen our understanding of early disease trajectory and potentially facilitate timely diagnosis and management. Objective: Describe clinical characteristics, healthcare utilization, and costs in early-stage dementia by disease severity and amyloid-β status before enrollment in an observational study (GERAS-US). Methods: Consented patients’ GERAS-US data were linked to available five-years of Medicare claims history before GERAS-US enrollment. Clinical characteristics, comorbidity, and pre-/post-diagnosis healthcare use and costs were assessed. Continuous …and categorical variables were compared between severity and amyloid-status cohorts using t -test and Chi-square statistics; linear regression models were used to compare cost and utilization measures after adjusting for differences in patients’ observation time. Relative likelihood of observed diagnoses, comorbidity, and prescription drug use among cohorts were presented as OR and 90% confidence interval (CI). Results: Of 174 patients clinically diagnosed with early dementia (mild cognitive impairment (MCI): 101; mild dementia (MILD): 73), 55% were amyloid-positive. Memory loss was more likely in MILD versus MCI (OR:1.85, 90% CI 1.10–3.09) and in amyloid-positive versus amyloid-negative cohorts (OR:1.98, 90% CI 1.19–3.29). Mean annual healthcare costs after cognitive impairment/dementia diagnosis were significantly higher for MILD versus MCI ($1191 versus $712, p  = 0.067) and amyloid-negative versus amyloid-positive ($1281 versus $701, p  = 0.034). Diabetes was more prevalent in MILD and amyloid-negative cohorts. Conclusion: Comorbidity and economic burden increased in earliest stages of MCI and MILD and were higher in patients who were amyloid-negative. Show more

Keywords: Amyloid, burden of illness, comorbidity, dementia, economic burden, health care utilization, mild cognitive impairment

DOI: 10.3233/JAD-220415

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 753-765, 2023

Authors: Sun, Jiaojiao | Zhao, Xingfu | Zhou, Jianbang | Dang, Xinghong | Zhu, Shenglong | Liu, Liang | Zhou, Zhenhe

Article Type: Research Article

Abstract: Background: Resting-state function MRI (rs-fMRI) research on successful aging can provide insight into the mechanism of aging with a different perspective from aging-related disease. Objective: rs-fMRI research was used to analyze the brain function characteristics of successful aging. Methods: A total of 47 usual aging individuals and 26 successful aging (SA) individuals underwent rs-fMRI scans and neuropsychological tests. Volume-based rs-fMRI data analysis was performed with DPASF to obtain ALFF, ReHo, DC, and VMHC. Results: The SA group showed increased ALFF in right opercular part of inferior frontal gyrus (Frontal_Inf_Oper_R) and right supramarginal gyrus; increased …ReHo in right middle temporal pole gyrus and decreased ReHo in left superior frontal gyrus and middle occipital gyrus; increased DC in right medial orbitofrontal gyrus and pulvinar part of thalamus; decreased DC in left fusiform gyrus and right medial frontal gyrus; increased VMHC in right medial orbitofrontal gyrus; and decreased VMHC in the right superior temporal gyrus, right and left middle temporal gyrus, right and left triangular part of inferior frontal gyrus. ALFF in Frontal_Inf_Oper_R were found to be significantly correlated with MMSE scores (r  = 0.301, p  = 0.014) and ages (r  = –0.264, p  = 0.032) in all subjects, which could be used to distinguish the SA (AUC = 0.733, 95% CI: 0.604–0.863) by ROC analysis. Conclusion: The brain regions with altered fMRI characteristics in SA group were concentrated in frontal (6 brain regions) and temporal (4 brain regions) lobes. ALFF in Frontal_Inf_Oper_R was significantly correlated to cognitive function and ages, which might be used to distinguish the SA. Show more

Keywords: Amplitude of low frequency fluctuations, degree centrality, regional homogeneity, resting-state fMRI, successful aging, voxel-mirrored homotopic connectivity

DOI: 10.3233/JAD-220780

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 767-778, 2023

Authors: Iban-Arias, Ruth | Trageser, Kyle J. | Yang, Eun-Jeong | Griggs, Elizabeth | Radu, Aurelian | Naughton, Sean | Al Rahim, Md | Tatsunori, Oguchi | Raval, Urdhva | Palmieri, Joshua | Huang, Zerlina | Chen, Lung-Chi | Pasinetti, Giulio Maria

Article Type: Research Article

Abstract: Background: The terrorist attacks on September 11, 2001, on the World Trade Center (WTC) led to intense fires and a massive dense cloud of toxic gases and suspended pulverized debris. In the subsequent years, following the attack and cleanup efforts, a cluster of chronic health conditions emerged among First Responders (FR) who were at Ground Zero for prolonged periods and were repeatedly exposed to high levels of WTC particulate matter (WTCPM). Among those are neurological complications which may increase the risk for the development of Alzheimer’s disease (AD) later in life. Objective: We hypothesize that WTCPM dust exposure …affects the immune cross-talking between the periphery and central nervous systems that may induce brain permeability ultimately promoting AD-type phenotype. Methods: 5XFAD and wild-type mice were intranasally administered with WTCPM dust collected at Ground Zero within 72 h after the attacks. Y-maze assay and novel object recognition behavioral tests were performed for working memory deficits and learning and recognition memory, respectively. Transcriptomic analysis in the blood and hippocampus was performed and confirmed by RT qPCR. Results: Mice exposed to WTCPM dust exhibited a significant impairment in spatial and recognition short and long-term memory. Furthermore, the transcriptomic analysis in the hippocampal formation and blood revealed significant changes in genes related to immune-inflammatory responses, and blood-brain barrier disruption. Conclusion: These studies suggest a putative peripheral-brain immune inflammatory cross-talking that may potentiate cognitive decline, identifying for the first time key steps which may be therapeutically targetable in future studies in WTC FR. Show more

Keywords: Blood-brain barrier, Claudin-5, cognitive decline, MMP-9, neuroinflammation, World Trade Center particulate matter

DOI: 10.3233/JAD-221046

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 779-794, 2023

Authors: Cheng, Zhao-Zhao | Gao, Feng | Lv, Xin-Yi | Wang, Qiong | Wu, Yan | Sun, Bao-Liang | Shen, Yong

Article Type: Research Article

Abstract: Background: Cerebral small vessel disease (CSVD), which comprises the typical features of white matter hyperintensity (WMH) and Vichor-Robin spaces (VRSs) in the brain, is one of the leading causes of aging-related cognitive decline and, ultimately, contributes to the occurrence of dementia, including Alzheimer’s disease (AD). Objective: To investigate whether CSVD imaging markers modify the pathological processes of AD and whether these markers improve AD diagnosis. Methods: 208 participants were enrolled in the China Aging and Neurodegenerative Initiative (CANDI). Fluid AD biomarkers were detected using a single-molecule array, and cerebral small vessel dysfunction was determined using magnetic …resonance imaging. Results: WMH contributed to AD pathology only within the NC and MCI groups (CDR ≤0.5), whereas VRSs had no effect on AD pathology. The associations between AD biomarkers and cognitive mental status were consistent with the presence of CSVD pathology. That is, within individuals without CSVD pathology, the MMSE scores were correlated with AD fluid biomarkers, except for plasma Aβ42 and Aβ40 . Increased plasma p-Tau levels were associated with worse cognitive performance in individuals with WMH (β= –0.465, p  = 0.0016) or VRSs (β= –0.352, p  = 0.0257) pathology. Plasma AD biomarkers combined with CSVD markers showed high accuracy in diagnosing dementia. Conclusion: Findings from this cross-sectional cohort study support the notion that CSVD is a risk factor for dementia and highlights that vascular pathology can promote AD biomarker levels, especially in the early course of the disease. Moreover, our results suggest that adding a vascular category to the ATN framework improves the diagnostic accuracy of AD. Show more

Keywords: Alzheimer’s disease, cerebrovascular disease, Clinical Dementia Rating, Vichor-Robin space, white matter hyperintensity

DOI: 10.3233/JAD-220872

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 795-804, 2023

Authors: Noguchi-Shinohara, Moeko | Hamaguchi, Tsuyoshi | Sakai, Kenji | Komatsu, Junji | Iwasa, Kazuo | Horimoto, Mai | Nakamura, Hiroyuki | Yamada, Masahito | Ono, Kenjiro

Article Type: Research Article

Abstract: Background: Previous in vitro and in vivo studies on Alzheimer’s disease (AD) models have reported that rosmarinic acid (RA) can inhibit the formation of amyloid-β fibrils as well as the oligomerization and deposition of amyloid-β protein. Melissa officinalis (M. officinalis ) extract containing 500 mg of RA is tolerable and safe in healthy individuals and patients with mild AD dementia. Objective: This randomized placebo-controlled double-blind trial aimed to assess the effects of M. officinalis extract on cognition in older adults without dementia. Methods: This study included individuals who were diagnosed with subjective or …mild cognitive impairment (n  = 323). The trial involved M. officinalis extract supplementation (500 mg of RA per day) period of 96 weeks followed by a washout period of 24 weeks. The primary endpoint was the Alzheimer’s Disease Assessment Scale-cognitive subscale score, and the secondary endpoints were other cognitive measure results as well as safety and tolerability. Results: There were no significant differences in cognitive measures between the placebo and M. officinalis groups from baseline to 96 weeks. However, based on the analysis of Clinical Dementia Rating Sum of Boxes scores in participants without hypertension, the score was found to be increased by 0.006 and decreased by 0.085 in the M. officinalis and placebo groups, respectively; this difference was statistically significant (p  = 0.036). Furthermore, there were no differences in vital signs, physical and neurological measures, or hippocampal volume between the two groups. Conclusion: These results indicate that M. officinalis extract may help prevent cognitive decline in older adults without hypertension. Show more

Keywords: Cognitive decline, efficacy, Melissa officinalis extract, prevention, rosmarinic acid

DOI: 10.3233/JAD-220953

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 805-814, 2023

Authors: Luo, Yuting | Lin, Rong | Yan, Yuanjiao | Su, Jiawei | Lin, Shengmei | Ma, Mingping | Li, Hong

Article Type: Research Article

Abstract: Background: Mild cognitive impairment (MCI) is a stage of cognitive ability loss with intact activities of daily living and an increased risk for the development of dementia. Objective: This study evaluated the intervention effect of remote expressive arts program (rEAP) on cognitive function in older adults with MCI and investigated the underlying neurobiological mechanisms. Methods: We assigned 73 older MCI patients to receive rEAP or health education (HE), who underwent neuropsychological evaluation and resting-state functional magnetic resonance imaging before and after treatment. Neuropsychological scores were analyzed using SPSS software, and regional homogeneity (ReHo) values and seed-based …functional connectivity (FC) were analyzed using Matlab software. Results: The rEAP group showed more significant improvements in cognitive function than the HE group. rEAP affected spontaneous brain activity and brain networks. The ReHo values in the right anterior cingulate/paracingulate cortex and the left dorsolateral superior frontal gyrus significantly increased and decreased, respectively, in the rEAP and HE groups. Further, ReHo value changes were significantly associated with the corresponding neuropsychological test score changes in the rEAP group. Moreover, the rEAP group showed decreased FC between the posterior cingulate cortex and the right middle temporal gyrus and increased FC between the ventromedial prefrontal cortex and left angular gyrus. Conclusion: The 12-week rEAP improved cognitive function in MCI patients. Additionally, the alterations of spontaneous brain network connections and activity helped improve and maintain cognitive function in MCI patients. Show more

Keywords: Aged, art therapy, cognitive dysfunction, magnetic resonance imaging, telemedicine

DOI: 10.3233/JAD-215685

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 815-831, 2023

Authors: Heneghan, Amy | Deng, Feng | Wells, Katie | Ritchie, Karen | Muniz-Terrera, Graciela | Ritchie, Craig W. | Lawlor, Brian | Naci, Lorina

Article Type: Research Article

Abstract: Background: It is now acknowledged that Alzheimer’s disease (AD) processes are present decades before the onset of clinical symptoms, but it remains unknown whether lifestyle factors can protect against these early AD processes in mid-life. Objective: We asked whether modifiable lifestyle activities impact cognition in middle-aged individuals who are cognitively healthy, but at risk for late life AD. Participants (40–59 years) completed cognitive and clinical assessments at baseline (N = 206) and two years follow-up (N = 174). Methods: Mid-life activities were measured with the Lifetime of Experiences Questionnaire. We assessed the impact of lifestyle activities, known risk factors for …sporadic late-onset AD (Apolipoprotein E ɛ4 allele status, family history of dementia, and the Cardiovascular Risk Factors Aging and Dementia score), and their interactions on cognition. Results: More frequent engagement in physically, socially, and intellectually stimulating activities was associated with better cognition (verbal, spatial, and relational memory), at baseline and follow-up. Critically, more frequent engagement in these activities was associated with stronger cognition (verbal and visuospatial functions, and conjunctive short-term memory binding) in individuals with family history of dementia. Impaired visuospatial function is one of the earliest cognitive deficits in AD and has previously associated with increased AD risk in this cohort. Additionally, conjunctive memory functions have been found impaired in the pre-symptomatic stages of AD. Conclusion: These findings suggest that modifiable lifestyle activities offset cognitive decrements due to AD risk in mid-life and support the targeting of modifiable lifestyle activities for the prevention of AD. Show more

Keywords: Alzheimer’s disease, cognition, cognitively healthy, lifestyle factors, mid-life, risk factors

DOI: 10.3233/JAD-220267

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 833-846, 2023

Authors: Calderón-Garcidueñas, Lilian | Kulesza, Randy | Greenough, Glen P. | García-Rojas, Edgar | Revueltas-Ficachi, Paula | Rico-Villanueva, Adriana | Flores-Vázquez, Jorge Orlando | Brito-Aguilar, Rafael | Ramírez-Sánchez, Silvia | Vacaseydel-Aceves, Nora | Cortes-Flores, Ana Paulina | Mansour, Yusra | Torres-Jardón, Ricardo | Villarreal-Ríos, Rodolfo | Koseoglu, Emel | Stommel, Elijah W. | Mukherjee, Partha S.

Article Type: Research Article

Abstract: Background: Quadruple aberrant hyperphosphorylated tau, amyloid-β, α-synuclein, and TDP-43 pathology had been documented in 202/203 forensic autopsies in Metropolitan Mexico City ≤40-year-olds with high exposures to ultrafine particulate matter and engineered nanoparticles. Cognition deficits, gait, equilibrium abnormalities, and MRI frontal, temporal, caudate, and cerebellar atrophy are documented in young adults. Objective: This study aimed to identify an association between falls, probable Rapid Eye Movement Sleep Behavior Disorder (pRBD), restless leg syndrome (RLS), and insomnia in 2,466 Mexican, college-educated volunteers (32.5±12.4 years). Methods: The anonymous, online study applied the pRBD and RLS Single-Questions and self-reported night-time sleep …duration, excessive daytime sleepiness, insomnia, and falls. Results: Fall risk was strongly associated with pRBD and RLS. Subjects who fell at least once in the last year have an OR = 1.8137 [1.5352, 2.1426 ] of answering yes to pRBD and/or RLS questions, documented in 29% and 24% of volunteers, respectively. Subjects fell mostly outdoors (12:01 pm to 6:00 pm), 43% complained of early wake up hours, and 35% complained of sleep onset insomnia (EOI). EOI individuals have an OR of 2.5971 [2.1408, 3.1506 ] of answering yes to the RLS question. Conclusion: There is a robust association between falls, pRBD, and RLS, strongly suggesting misfolded proteinopathies involving critical brainstem arousal and motor hubs might play a crucial role. Nanoparticles are likely a significant risk for falls, sleep disorders, insomnia, and neurodegenerative lethal diseases, thus characterizing air particulate pollutants’ chemical composition, emission sources, and cumulative exposure concentrations are strongly recommended. Show more

Keywords: Air pollution, Alzheimer’s disease, falls, Mexico City young urbanites, nanoparticles, PM2.5 , possible REM sleep behavior disorder, quadruple proteinopathies, restless leg syndrome, TDP-43 proteinopathies

DOI: 10.3233/JAD-220850

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 847-862, 2023

Authors: Liu, Yajing | Zeng, Zhenhua | Huang, Shuyun | Shang, Pan | Lv, Zeping | Wang, Yukai | Luo, Jiali | Chen, Jinjuan | Shi, Jian | Huang, Qiaobing | Xie, Haiqun | Chen, Zhongqing

Article Type: Research Article

Abstract: Background: Amnestic mild cognitive impairment (aMCI) is regarded as a transitional state of Alzheimer’s disease, with working memory (WM) impairment. Objective: To investigate the brain activity in aMCI patients during WM tasks with the functional near-infrared spectroscopy (fNIRS) technique, as well as explore the association between brain activity and cognitive function in multiple domains. Methods: This study is a case-control study of 54 aMCI patients and 33 cognitively healthy elderly (NC). All participants underwent neuropsychological assessments. fNIRS was applied to examine the brain activation during the WM task. Multivariable linear regression analysis was applied to evaluate …associations between brain activation and cognitive function in multiple domains. Results: Compared to NC subjects, aMCI patients had lower activation in the bilateral prefrontal, parietal, and occipital cortex during the WM task. Additionally, activation in the left prefrontal, bilateral parietal, and occipital cortex during the encoding and maintenance phase was positively associated with memory function. During memory retrieval, higher activity in the left prefrontal, parietal, and occipital cortex were correlated with higher memory scores. Besides, a positive association also formed between attention function and the activation in the left prefrontal, parietal, and occipital cortex during the WM task. Conclusion: These findings demonstrated that reduced activation in the prefrontal, parietal and occipital cortex during WM might reflect the risk of cognitive impairment, especially memory and attention function in aMCI patients. Given the brain activation visualization, fNIRS may be a convenient and alternative tool for screening the risk of Alzheimer’s disease. Show more

Keywords: Amnestic mild cognitive impairment, brain activation, cognition, functional near-infrared spectroscopy, working memory

DOI: 10.3233/JAD-220815

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 863-875, 2023

Authors: Xu, Ling-Zhi | Li, Bing-Qiu | Li, Fang-Yu | Li, Ying | Qin, Wei | Zhao, Yu | Jia, Jian-Ping

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia among the elderly. Excitotoxicity has been implicated as playing a dominant role in AD, especially related to the hyperactivation of excitatory neurons. Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin-dependent kinase and involved in the pathogenesis of AD, but the roles and mechanisms of DAPK1 in excitotoxicity in AD are still uncertain. Objective: We mainly explored the underlying mechanisms of DAPK1 involved in the excitotoxicity of AD and its clinical relevance. Methods: Differentiated SH-SY5Y human neuroblastoma cells, PS1 V97 L transgenic mice, and human plasma …samples were used. Protein expression was assayed by immunoblotting, and intracellular calcium and neuronal damage were analyzed by flow cytometry. Plasma DAPK1 was measured by ELISA. Results: We found that DAPK1 was activated after amyloid-β oligomers (AβOs) exposure in differentiated SH-SY5Y cells. Besides, we found the phosphorylation of GluN2B subunit at Ser1303 was increased, which contributing to excitotoxicity and Ca2+ overload in SH-SY5Y cells. Inhibiting DAPK1 activity, knockdown of DAPK1 expression, and antagonizing GluN2B subunits could effectively prevent AβOs-induced activation of GluN2B subunit, Ca2+ overload, and neuronal apoptosis. Additionally, we found that DAPK1 was elevated in the brain of AD transgenic mouse and in the plasma of AD patients. Conclusion: Our finding will help to understand the mechanism of DAPK1 in the excitotoxicity in AD and provide a reference for the diagnosis and therapy of AD. Show more

Keywords: Alzheimer’s disease, amyloid-β oligomers, death-associated protein kinase 1, excitotoxicity, GluN2B, N-methyl-D-aspartic acid receptor

DOI: 10.3233/JAD-220747

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 877-893, 2023

Authors: Kleiman, Michael J. | Ariko, Taylor | Galvin, James E.

Article Type: Research Article

Abstract: Background: The detection of subtle cognitive impairment in a clinical setting is difficult. Because time is a key factor in small clinics and research sites, the brief cognitive assessments that are relied upon often misclassify patients with very mild impairment as normal. Objective: In this study, we seek to identify a parsimonious screening tool in one stage, followed by additional assessments in an optional second stage if additional specificity is desired, tested using a machine learning algorithm capable of being integrated into a clinical decision support system. Methods: The best primary stage incorporated measures of short-term …memory, executive and visuospatial functioning, and self-reported memory and daily living questions, with a total time of 5 minutes. The best secondary stage incorporated a measure of neurobiology as well as additional cognitive assessment and brief informant report questionnaires, totaling 30 minutes including delayed recall. Combined performance was evaluated using 25 sets of models, trained on 1,181 ADNI participants and tested on 127 patients from a memory clinic. Results: The 5-minute primary stage was highly sensitive (96.5%) but lacked specificity (34.1%), with an AUC of 87.5% and diagnostic odds ratio of 14.3. The optional secondary stage increased specificity to 58.6%, resulting in an overall AUC of 89.7% using the best model combination of logistic regression and gradient-boosted machine. Conclusion: The primary stage is brief and effective at screening, with the optional two-stage technique further increasing specificity. The hierarchical two-stage technique exhibited similar accuracy but with reduced costs compared to the more common single-stage paradigm. Show more

Keywords: Alzheimer’s disease, clinical decision support, machine learning, mild cognitive impairment, neuropsychological assessment

DOI: 10.3233/JAD-220891

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 895-909, 2023

Article Type: Correction

DOI: 10.3233/JAD-229020

Citation: Journal of Alzheimer's Disease, vol. 91, no. 2, pp. 911-911, 2023