Journal of Alzheimer's Disease - Volume 97, issue 3

Authors: Smith, Hadley Stevens | Robinson, Jill O. | Levchenko, Ariel | Pereira, Stacey | Pascual, Belen | Bradbury, Kathleen | Arbones, Victoria | Fong, Jamie | Shulman, Joshua M. | McGuire, Amy L. | Masdeu, Joseph

Article Type: Research Article

Abstract: Background: Understanding research participants’ responses to learning Alzheimer’s disease (AD) risk information is important to inform clinical implementation of precision diagnostics given rapid advances in disease modifying therapies. Objective: We assessed participants’ perspectives on the meaning of their amyloid positron emission tomography (PET) imaging results for their health, self-efficacy to understand their results, psychological impact of learning their results, experience receiving their results from the clinical team, and interest in genetic testing for AD risk. Methods: We surveyed individuals who were being clinically evaluated for AD and received PET imaging six weeks after the return of …results. We analyzed responses to close-ended survey items by PET result using Fisher’s exact test and qualitatively coded open-ended responses. Results: A total of 88 participants completed surveys, most of whom had mild cognitive impairment due to AD (38.6%), AD (28.4%), or were cognitively unimpaired (21.6%). Participants subjectively understood their results (25.3% strongly agreed, 41.8% agreed), which could help them plan (16.5% strongly agreed, 49.4% agreed). Participants with a negative PET result (n  = 25) reported feelings of relief (Fisher’s exact p  < 0.001) and happiness (p  < 0.001) more frequently than those with a positive result. Most participants felt that they were treated respectfully and were comfortable voicing concerns during the disclosure process. Genetic testing was anticipated to be useful for medical care decisions (48.2%) and to inform family members about AD risk (42.9%). Conclusions: Participants had high subjective understanding and self-efficacy around their PET results and did not experience negative psychological effects. Interest in genetic testing was high. Show more

Keywords: Alzheimer’s disease, genetic testing, neuroimaging, surveys and questionnaires

DOI: 10.3233/JAD-230609

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1261-1274, 2024

Authors: Zhou, Jianguo | Zhao, Mingli | Yang, Zhou | Chen, Liping | Liu, Xiaoli

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), a major dementia cause, lacks effective treatment. MRI-based hippocampal volume measurement using artificial intelligence offers new insights into early diagnosis and intervention in AD progression. Objective: This study, involving 483 AD patients, 756 patients with mild cognitive impairment (MCI), and 968 normal controls (NC), investigated the predictive capability of MRI-based hippocampus volume measurements for AD risk using artificial intelligence and evidence-based medicine. Methods: Utilizing data from ADNI and OASIS-brains databases, three convolutional neural networks (InceptionResNetv2, Densenet169, and SEResNet50) were employed for automated AD classification based on structural MRI imaging. A multitask deep …learning model and a densely connected 3D convolutional network were utilized. Additionally, a systematic meta-analysis explored the value of MRI-based hippocampal volume measurement in predicting AD occurrence and progression, drawing on 23 eligible articles from PubMed and Embase databases. Results: InceptionResNetv2 outperformed other networks, achieving 99.75% accuracy and 100% AUC for AD-NC classification and 99.16% accuracy and 100% AUC for MCI-NC classification. Notably, at a 512×512 size, InceptionResNetv2 demonstrated a classification accuracy of 94.29% and an AUC of 98% for AD-NC and 97.31% accuracy and 98% AUC for MCI-NC. Conclusions: The study concludes that MRI-based hippocampal volume changes effectively predict AD onset and progression, facilitating early intervention and prevention. Show more

Keywords: Alzheimer’s disease, artificial intelligence, deep learning, evidence-based medicine, hippocampal volume, magnetic resonance imaging

DOI: 10.3233/JAD-230733

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1275-1288, 2024

Authors: Wu, Liu-Yun | Chong, Joyce R. | Chong, Jenny P.C. | Hilal, Saima | Venketasubramanian, Narayanaswamy | Tan, Boon Yeow | Richards, Arthur Mark | Chen, Christopher P. | Lai, Mitchell K.P.

Article Type: Research Article

Abstract: Background: Concomitant cerebrovascular diseases (CeVD) have been identified as an important determinant of Alzheimer’s disease (AD) progression. Development of robust blood-based biomarkers will provide critical tools to evaluate prognosis and potential interventional strategies for AD with CeVD. Objective: This study investigated circulating placental growth factor (PlGF), a potent pro-angiogenic factor related to endothelial dysfunction and vascular inflammation, in an Asian memory clinic cohort of non-demented individuals as well as AD, including its associations with neuroimaging markers of CeVD. Methods: 109 patients with AD, 76 cognitively impaired with no dementia (CIND), and 56 non-cognitively impaired (NCI) were …included in this cross-sectional study. All subjects underwent 3T brain magnetic resonance imaging to assess white matter hyperintensities (WMH), lacunes, cortical infarcts, and cerebral microbleeds (CMBs). Serum PlGF concentrations were measured by electrochemiluminescence immunoassays. Results: Serum PlGF was elevated in AD, but not CIND, compared to the NCI controls. Adjusted concentrations of PlGF were associated with AD only in the presence of significant CeVD. Elevated PlGF was significantly associated with higher burden of WMH and with CMBs in AD patients. Conclusions: Serum PlGF has potential utility as a biomarker for the presence of CeVD, specifically WMH and CMBs, in AD. Further studies are needed to elucidate the underlying pathophysiological mechanisms linking PlGF to CeVD, as well as to further assess PlGF’s clinical utility. Show more

Keywords: Alzheimer’s disease, blood biomarkers, cerebral microbleeds, cerebrovascular disease, placental growth factor, white matter hyperintensities

DOI: 10.3233/JAD-230811

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1289-1298, 2024

Authors: Saeed, Amir | Alharazi, Talal | Alshaghdali, Khalid | Rezgui, Raja | Elnaem, Ibtihag | Alreshidi, Bunder Albdullah T. | Tasleem, Munazzah | Saeed, Mohd

Article Type: Research Article

Abstract: Background: The present study investigates the interrelated pathophysiology of depression and Alzheimer’s disease (AD), with the objective of elucidating common underlying mechanisms. Objective: Our objective is to identify previously undiscovered biogenic compounds from the NuBBE database that specifically interact with GluR3. This study examines the bidirectional association between depression and AD, specifically focusing on the role of depression as a risk factor in the onset and progression of the disease. Methods: In this study, we utilize pharmacokinetics, homology modeling, and molecular docking-based virtual screening techniques to examine the GluR3 AMPA receptor subunit. Results: The …compounds, namely ZINC000002558953, ZINC000001228056, ZINC000000187911, ZINC000003954487, and ZINC000002040988, exhibited favorable pharmacokinetic profiles and drug-like characteristics, displaying high binding affinities to the GluR3 binding pocket. Conclusions: These findings suggest that targeting GluR3 could hold promise for the development of therapies for depression and AD. Further validation through in vitro , in vivo , and clinical studies is necessary to explore the potential of these compounds as lead candidates for potent and selective GluR3 inhibitors. The shared molecular mechanisms between depression and AD provide an opportunity for novel treatment approaches that address both conditions simultaneously. Show more

Keywords: ADMET, Alzheimer’s disease, GluR3, homology modeling, major depressive disorder, molecular docking, NuBBEDB

DOI: 10.3233/JAD-230821

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1299-1312, 2024

Authors: Shang, Li | Dong, Liling | Huang, Xinying | Chu, Shanshan | Jin, Wei | Bao, Jialu | Wang, Tianyi | Mao, Chenhui | Gao, Jing

Article Type: Research Article

Abstract: Background: Comorbidities reduce quality of life for people with dementia and caregivers. Some comorbidities share a genetic basis with dementia. Objective: The objective of this study is to assess comorbidity in patients with different dementia subtypes in order to better understand the pathogenesis of dementias. Methods: A total of 298 patients with dementia were included. We collected some common comorbidities. We analyzed the differences in comorbidities among patients with dementia according to clinical diagnosis, age of onset (early-onset: < 65 and late-onset: ≥65 years old) and apolipoprotein (APOE ) genotypes by using the univariate and multivariate approaches. …Results: Among 298 participants, there were 183 Alzheimer’s disease (AD), 40 vascular dementia (VaD), 37 frontotemporal dementia (FTLD), 20 Lewy body dementia (LBD), and 18 other types of dementia. Based on age of onset, 156 cases had early-onset dementia and 142 cases had late-onset dementia. The most common comorbidities observed in all dementia patients were hyperlipidemia (68.1%), hypertension (39.9%), insomnia (21.1%), diabetes mellitus (19.5%), and hearing impairment (18.1%). The prevalence of hypertension and cerebrovascular disease was found to be higher in patients with VaD compared to those with AD (p  = 0.002, p  < 0.001, respectively) and FTLD (p  = 0.028, p  = 0.004, respectively). Additionally, patients with late-onset dementia had a higher burden of comorbidities compared to those with early-onset dementia. It was observed that APOE ɛ4/ɛ4 carriers were less likely to have insomnia (p  = 0.031). Conclusions: Comorbidities are prevalent in patients with dementia, with hyperlipidemia, hypertension, insomnia, diabetes, and hearing impairment being the most commonly observed. Comorbidity differences existed among different dementia subtypes. Show more

Keywords: Alzheimer’s disease, apolipoprotein, comorbidity, dementia, early-onset, late-onset

DOI: 10.3233/JAD-231025

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1313-1322, 2024

Authors: Belkhelfa, Mourad | Bekrar, Samy | Rezaig, Lina | Beder, Narimene | Touri, Faiza | Yousfi, Yamina | Nabi, Hedia | Slimani, Assia | Attal, Nabila | Belarbi, Ayed | Bessaha, Madjid | Touil-Boukoffa, Chafia

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a progressive and irreversible neurodegenerative disorder. It is characterized by a gradual decrease in cognitive function and is considered a disorder in which the intensifying neuronal loss. The autopsy is considered the gold standard for the diagnosis of AD and non-AD dementia. Objective: Our study aims to clarify the involvement of neuroinflammation processes in brain lesions of AD. Methods: The defunct was admitted to the forensic medicine department of Issad Hassani Hospital (Algeria). In order to recover the brain, an autopsy was performed within 24 hours of death and then immediately …fixed in formaldehyde to maintain structural brain integrity for histological and immunohistochemical analysis. Results: Our findings indicate the presence of tissue lesions in the specific brain regions: right middle frontal gyrus, right cingulate gyrus, right putamen and globus pallidus, right caudate nucleus, right hippocampus, inferior parietal lobule, left parahippocampal gyrus, and left hippocampus. Notably, there is a predominant occurrence of lesions: granulovacuolar degeneration, Hirano bodies, cotton-wool, and neuritic plaques. The causes of neurodegenerative processes are probably related to TNF-α, IL-1β, and TGF-β production and iNOS expression by the NF-κB activation pathway in the R-HP, inducing necroptosis. Conclusions: The occurrence of neuroinflammatory responses is linked to tissue lesions in AD. The production of inflammatory cytokines is the basis of this process, which ultimately leads to the necroptosis, which is triggered by neuroinflammation amplification. The inhibition of neuroinflammation by targeting TNF-α/iNOS could stop tissue damage, this may be a promising therapeutic pathway. Show more

Keywords: Alzheimer’s disease, brain, dementia, necroptosis, neurodegenerative disease, neuroinflammation

DOI: 10.3233/JAD-230910

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1323-1339, 2024

Authors: Marin-Marin, Lidón | Renau-Lagranja, Julia | Ávila, César | Costumero, Víctor

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms (NPS) are a common aspect of Alzheimer’s disease (AD). Multiple studies have investigated its brain correlates, but it still remains unclear how they relate with brain atrophy in mild cognitive impairment (MCI). Objective: Our objective was to investigate brain volume in MCI patients as a function of NPS. Methods: We measured grey matter volume, neuropsychological status and NPS (Neuropsychiatric Inventory, NPI), in a sample of 81 MCI patients (43 females). Participants were divided in groups depending on presence (NPS+) or absence (NPS–) of NPS and on type of NPS. Results: We …found lower volume of left temporal pole in patients with depression compared to NPS– (p  = 0.012), and in patients with agitation compared to NPS– in the right middle occipital gyrus (p  = 0.003). We also found a significant correlation between volume of left temporal pole and MMSE (r (78)   = 0.232, p  = 0.019). Finally, NPS+ presented lower cross-sectional cognitive level than NPS– (t (79)   = 1.79, p  = 0.038), and faster cognitive decline (t (48)   = –1.74, p  = 0.044). Conclusions: Our results support the colocalization of structural damage as a possible mechanism underlying the relationship between MCI and depression and provide novel evidence regarding agitation. Moreover, our longitudinal evidence highlights the relevance of an adequate identification of NPS in MCI patients to identify those at risk of faster cognitive decline. Show more

Keywords: Alzheimer’s disease, atrophy, cognitive decline, magnetic resonance imaging, mild cognitive impairment, neuropsychiatric

DOI: 10.3233/JAD-230929

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1341-1351, 2024

Authors: Schwinne, Megan | Alonso, Alvaro | Roberts, Blaine R. | Hickle, Sabrina | Verberk, Inge M.W. | Epenge, Emmanuel | Gikelekele, Guy | Tsengele, Nathan | Kavugho, Immaculee | Mampunza, Samuel | Yarasheski, Kevin E. | Teunissen, Charlotte E. | Stringer, Anthony | Levey, Allan | Ikanga, Jean

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-β42/40 (Aβ42/40 ). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. Objective: This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. Methods: In this cross-sectional study …of 81 Congolese individuals, cognitive assessments (Alzheimer’s Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aβ42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Results: Lower plasma Aβ42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p  < 0.001). These relationships were observed in healthy controls (CSID p  = 0.01, AQ p  = 0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE ɛ 4 allele, did not alter these relationships. Conclusions: Understanding relationships between AD-related screening tests and blood biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations. Show more

Keywords: Alzheimer’s disease, amyloid-β protein, biomarkers, blood-based biomarkers, cognitive test, dementia, tau proteins

DOI: 10.3233/JAD-230976

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1353-1363, 2024

Authors: Getz, Sarah J. | Levin, Bonnie E. | Galvin, James E.

Article Type: Research Article

Abstract: Background: Existing measures of scam susceptibility lack ecological validity and situational variability. Evidence suggests that all adults may be susceptible to scams, though a comprehensive fraud victimization theory remains to be explored. Objective: To identify cognitive and sociodemographic variables that differentiate individuals with high scam susceptibility from those less susceptible. This article describes the development and feasibility of the Assessment of Situational Judgment questionnaire (ASJ), a brief tool designed to detect scam susceptibility. Methods: The 17-item ASJ was developed using a combination of existing scams reported by the Florida Division of Consumer Services and legitimate scenarios. …Participants were presented with scam and legitimate scenarios and queried regarding their willingness to engage. Response options were offered with instructions on a 7-point Likert scale (extremely unlikely to extremely likely). Pilot data from a development sample provided the foundation for the final version of the ASJ. Results: The final version of the ASJ was administered to 183 online participants. The Scam factor (8 items) explained 50.6% of the variance. The Legit factor (9 items) reported on a 7-point Likert scale explaining 10.6% of the variance. A Scam to Legit ratio provides a proxy for overall scam susceptibility. Cut-off scores of 24 on the Scam factor, 47 on the Legit factor, and 0.62 on the ratio optimize measures of scam susceptibility. Conclusions: The ASJ is a brief, ecologically valid measure of scam susceptibility. There is a need for a sensitive and specific tool to detect scam susceptibility in clinical, community, and financial settings. Show more

Keywords: Alzheimer’s disease, deception, decision making, scam susceptibility, vulnerable populations

DOI: 10.3233/JAD-231194

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1365-1379, 2024

Authors: Wu, Deng-Pan | Wei, Yan-Su | Du, Yu-Xuan | Liu, Ling-Ling | Yan, Qiu-Qing | Zhao, Yuan-Dan | Yu, Chao | Liu, Jin-Yuan | Zhong, Zhen-Guo | Huang, Jin-Lan

Article Type: Research Article

Abstract: Background: Mitochondrial dysfunction plays a vital role in the progression of vascular dementia (VaD). We hypothesized that transfer of exogenous mitochondria might be a beneficial strategy for VaD treatment. Objective: The study was aimed to investigate the role of mitochondrial therapy in cognitive function of VaD. Methods: The activity and integrity of isolated mitochondria were detected using MitoTracker and Janus Green B staining assays. After VaD mice were intravenously injected with exogenous mitochondria, Morris water maze and passive avoidance tests were used to detect cognitive function of VaD mice. Haematoxylin and eosin, Nissl, TUNEL, and Golgi …staining assays were utilized to measure neuronal and synaptic injury in the hippocampus of VaD mice. Detection kits were performed to detect mitochondrial membrane potential (ΔΨ ), SOD activity and the levels of ATP, ROS, and MDA in the brains of VaD mice. Results: The results showed that isolated mitochondria were intact and active. Mitochondrial therapy could ameliorate cognitive performance of VaD mice. Additionally, mitochondrial administration could attenuate hippocampal neuronal and synaptic injury, improve mitochondrial ΔΨ , ATP level and SOD activity, and reduce ROS and MDA levels in the brains of VaD mice. Conclusions: The study reports profitable effect of mitochondrial therapy against cognitive impairment of VaD, making mitochondrial treatment become a promising therapeutic strategy for VaD. Show more

Keywords: Alzheimer’s disease, cognitive function, dementia, mitochondrial therapy, oxidative stress, vascular dementia

DOI: 10.3233/JAD-230293

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1381-1392, 2024

Authors: Hou, Yi-Chou | Chueh, Ti-I | Lu, Kuo-Cheng | Liu, Yi-Chien | Chen, Tso-Hsiao | Liu, Shing-Hwa | Chen, Ruei-Ming

Article Type: Research Article

Abstract: Background: Cognitive impairment (CI) is one of the major complications in chronic kidney disease patients, especially those with end-stage renal disease (ESRD). Limited biomarkers have been found that can significantly predict ESRD-associated cognitive decline. Objective: This cohort study aimed to investigate de novo biomarkers for diagnosis of the ESRD-associated CI. Methods: In this cohort study, qualified samples were divided into control (with an estimated glomerular filtration rate (eGFR) of≥60 mL/min and a Mini-Mental State Examination (MMSE) score of > 27), ESRD without CI (eGFR < 15 and MMSE > 27), and ESRD with CI (eGFR < 15 and MMSE < 27) groups. Levels of plasma amyloid-β …(Aβ)1 - 42 , serum indoxyl sulfate, and hematologic and biochemical parameters were measured. Results: Compared to the control group, levels of blood urea nitrogen, creatinine, and indoxyl sulfate were elevated in ESRD patients both without and with CI. Interestingly, ESRD patients with CI had the lowest levels of serum albumin. In contrast, levels of plasma Aβ1 - 42 were significantly higher in the ESRD with CI group than in the control and ESRD without CI groups. In addition, the ratio of plasma Aβ1 - 42 over serum albumin was significantly higher in the ESRD with CI group than in the control or ESRD without CI groups. Importantly, the area under the receiver operating characteristic curve (AUROC) for CI in the total population by the ratio of Aβ1 - 42 over albumin was 0.785 and significant (p  < 0.05). Conclusions: This cohort study has shown that the ratio of plasma Aβ1 - 42 over serum albumin can be a de novo biomarker for the diagnosis and prognosis of ESRD-associated cognitive decline. Show more

Keywords: Albumin, Alzheimer’s disease, amyloid-beta 1-42, biomarker signature, cognitive impairment, end-stage renal disease

DOI: 10.3233/JAD-230747

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1393-1405, 2024

Authors: Gorham, Isabelle K. | Reid, Danielle Marie | Sun, Jie | Zhou, Zhengyang | Barber, Robert C. | Phillips, Nicole R.

Article Type: Research Article

Abstract: Background: Age is known to be the biggest risk factor for Alzheimer’s disease (AD), and Mexican Americans (MAs), who are one of the fastest-aging populations in the United States, are at a uniquely elevated risk. Mitochondrial stress and dysfunction are key players in the progression of AD and are also known to be impacted by lifestyle and environmental exposures/stressors. Objective: This study aimed to identify population-specific differences in indicators of mitochondrial stress and dysfunction associated with AD risk that are detectable in the blood. Methods: Examining blood from both non-Hispanic white (NHW) and MA participants (N = 527, …MA n  = 284, NHW n  = 243), mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) copy numbers were assessed through quantitative PCR. Data was stratified by population and sample type, and multiple linear regression analyses were performed to identify factors that may influence this phenotype of mitochondrial dysfunction. Results: In the MA cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and body mass index, CDR sum of boxes score, the APOE ɛ 2/ɛ 3 genotype, and education. Further, there was a significant relationship between cell-free mtDNA copy number and both education and CDR sum score. In the NHW cohort, there was a significant relationship between cellular mtDNA:nDNA ratio and both age and CDR sum score. Age was associated with cell-free mtDNA in the NHW cohort. Conclusions: This evidence supports the existence of population-based differences in the factors that are predictive of this blood-based phenotype of mitochondrial dysfunction, which may be indicative of cognitive decline and AD risk. Show more

Keywords: Alzheimer’s disease, cognitive decline, mitochondrial dysfunction, mtDNA

DOI: 10.3233/JAD-230880

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1407-1419, 2024

Authors: Takase, Hajime | Hamanaka, Gen | Hoshino, Tomonori | Ohtomo, Ryo | Guo, Shuzhen | Mandeville, Emiri T. | Lo, Eng H. | Arai, Ken

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is a widespread neurodegenerative disorder characterized by progressive cognitive decline, affecting a significant portion of the aging population. While the cerebral cortex and hippocampus have been the primary focus of AD research, accumulating evidence suggests that white matter lesions in the brain, particularly in the corpus callosum, play an important role in the pathogenesis of the disease. Objective: This study aims to investigate the gene expression changes in the corpus callosum of 5xFAD transgenic mice, a widely used AD mouse model. Methods: We conducted behavioral tests for spatial learning and memory in …5xFAD transgenic mice and performed RNA sequencing analyses on the corpus callosum to examine transcriptomic changes. Results: Our results show cognitive decline and demyelination in the corpus callosum of 5xFAD transgenic mice. Transcriptomic analysis reveals a predominance of upregulated genes in AD mice, particularly those associated with immune cells, including microglia. Conversely, downregulation of genes related to chaperone function and clock genes such as Per1 , Per2 , and Cry1 is also observed. Conclusions: This study suggests that activation of neuroinflammation, disruption of chaperone function, and circadian dysfunction are involved in the pathogenesis of white matter lesions in AD. The findings provide insights into potential therapeutic targets and highlight the importance of addressing white matter pathology and circadian dysfunction in AD treatment strategies. Show more

Keywords: Alzheimer’s disease, circadian rhythm, corpus callosum, microglia, molecular chaperones, neuroinflammation, RNA-seq

DOI: 10.3233/JAD-231049

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1421-1433, 2024

Authors: Okahashi, Sayaka | Noguchi, Taiji | Ishihara, Masumi | Osawa, Aiko | Kinoshita, Fumie | Ueda, Ikue | Kamiya, Masaki | Nakagawa, Takeshi | Kondo, Izumi | Sakurai, Takashi | Arai, Hidenori | Saito, Tami

Article Type: Research Article

Abstract: Background: Non-pharmacological interventions effective for depressive mood and bilateral relationships among persons with cognitive impairment (PwCI) and their family caregivers (FCGs) have not been established. Objective: To examine the feasibility of a newly developed group-based art appreciation and self-expression program (NCGG-ART) for dyads of PwCI and their FCGs. Methods: This pilot randomized control trial included 34 dyads of PwCI diagnosed with mild to moderate Alzheimer’s disease or mild cognitive impairment, and their FCGs, from an outpatient rehabilitation service (Holistic Physio-Cognitive Rehabilitation [HPCR]). Participants were randomly divided equally into the HPCR (control group) or NCGG-ART and HPCR …(intervention group) groups. Both included 1-hour weekly, 6-week programs. The primary outcome was depressive symptoms among FCGs assessed using the Patient Health Questionnaire-9 (PHQ-9). Feasibility outcomes included participant satisfaction and motivation. FCGs were interviewed about their experiences and feelings regarding the program, which were analyzed using content analysis. Results: Thirty-two dyads (intervention group:16; control group:16) completed the study period. High participation rates, satisfaction, and motivation were demonstrated throughout the intervention. Scores in the PHQ-9 among FCGs did not show positive effects: mean changes in the score were 1.3 for the intervention group and –0.8 for the control group (Cohen d :0.56). However, the qualitative analysis revealed favorable experiences and feelings of the FCGs, such as positive emotions, social interactions, and person-centered attitudes to and positive relationships with PwCI. Conclusions: This program demonstrated high feasibility with FCGs’ favorable responses to emotions and relationships with PwCI, ensuring future investigations with a confirmatory study design. Show more

Keywords: Alzheimer’s disease, art, caregivers, cognitive dysfunction, dementia, depression, person-centered psychotherapy, positive psychology, psychosocial intervention, qualitative research

DOI: 10.3233/JAD-231143

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1435-1448, 2024

Authors: Márquez, Freddie | Tarraf, Wassim | Stickel, Ariana M. | González, Kevin A. | Testai, Fernando D. | Cai, Jianwen | Gallo, Linda C. | Talavera, Gregory A. | Daviglus, Martha L. | Wassertheil-Smoller, Sylvia | DeCarli, Charles | Schneiderman, Neil | González, Hector M.

Article Type: Research Article

Abstract: Background: Hypertension can have deleterious effects on cognitive function; however, few studies have examined its effects on cognition among Hispanics/Latinos. Objective: To assess associations between hypertension status with 1) change in cognitive performance, and 2) having mild cognitive impairment (MCI) among diverse Hispanics/Latinos. Methods: This population-based, prospective cohort, multisite study included Hispanic/Latino adults aged 45 to 72 years in enrolled in the Hispanic Community Health Study/Study of Latinos at Visit 1 (2008–2011; mean age of 63.40±8.24 years), and the Study of Latinos-Investigation of Neurocognitive Aging at Visit 2 (2016–2018), with a mean follow-up duration …of 7 years (n  = 6,173). Hypertension status was assessed at both visits: normotension (no hypertension), incident hypertension (only at Visit 2), and persistent hypertension (at both visits). We examined change in cognitive performance and having MCI (only assessed at Visit 2) relative to hypertension status and adjusted for demographics and cardiovascular disease risk factors. Results: Compared to normotension, persistent hypertension was associated with significantly increased decline in verbal fluency (β= –0.08; CI = [–0.16;–0.01]; p  < 0.05), and processing speed (β= –0.11; CI = [–0.20;–0.02]; p  < 0.05). Incident hypertension was not associated with significant change in cognitive performance. Both incident (OR = 1.70; CI = [1.16;2.50]; p  < 0.01) and persistent hypertension (OR = 2.13; CI = [1.57;2.88]; p  < 0.001) were associated with significantly higher odds ratios of having MCI. Conclusions: These findings indicate that persistent hypertension is associated with clinical impairment and domain-specific cognitive decline in middle-aged and older Hispanics/Latinos. It underscores the importance of monitoring blood pressure in routine healthcare visits beginning at midlife in this population to reduce the burden of cognitive decline. Show more

Keywords: Alzheimer’s disease, blood pressure, cognitive decline, cognitive function, dementia, epidemiology, Hispanics, hypertension, Latinos, mild cognitive impairment, neuroepidemiology, neuropsychology, population neuroscience

DOI: 10.3233/JAD-230424

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1449-1461, 2024

Authors: Villemagne, Victor L. | Doré, Vincent | Chong, Lee | Kassiou, Michael | Mulligan, Rachel | Feizpour, Azadeh | Taylor, Jack | Roesner, Miriam | Miller, Tamara | Rowe, Christopher C.

Article Type: Research Article

Abstract: Background: 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates intracellular cortisol and its inhibition by the small molecule inhibitor, Xanamem™, may provide a disease-modifying strategy for Alzheimer’s disease (AD). Animal models suggest a range of 30–60% enzyme inhibition may suffice to provide neuroprotection. Objective: To determine the regional brain occupancy of 11β-HSD1 by Xanamem™ in cognitively normal participants (CN) and mild cognitive impairment (MCI)/mild AD patients to investigate potential dosing ranges for future efficacy studies. Methods: Seventeen MCI/AD and 23 CN were included. Regional brain time-activity curves (TAC), standardized uptake values (SUV40–60 ) and volume of distribution (VT …) from Logan plot with image derived input function from 11 C-TARACT positron emission tomography (PET) were used to assess the degree of 11β-HSD1 occupancy by increasing doses of Xanamem™ (5 mg, 10 mg, 20 mg or 30 mg daily for 7 days). Results: All measures showed high 11β-HSD1 occupancy with Xanamem to similar degree in CN and MCI/AD. The dose-response relationship was relatively flat above 5 mg. Respective median (interquartile range [Q1-Q3]) 11β-HSD1 occupancy in the MCI/AD and CN groups after treatment with 10 mg Xanamem were 80% [79–81%] and 75% [71–76%] in the neocortex, 69% [64–70%] and 61% [52–63%] in the medial temporal lobe, 80% [79–80%] and 73% [68–73%] in the basal ganglia, and 71% [67–75%] and 66% [62–68%] in the cerebellum. Conclusions: TAC, SUV40–60 , and VT measures indicate Xanamem achieves high target occupancy levels with near saturation at 10 mg daily. These data support exploration of doses of≤10 mg daily in future clinical studies. Show more

Keywords: Alzheimer’s disease, 11beta-hydroxysteroid dehydrogenase type 1, cortisol, drug development, positron emission tomography, target occupancy

DOI: 10.3233/JAD-220542

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1463-1475, 2024

Authors: García-Alberca, José María | de la Rosa, María Dolores | Solo de Zaldívar, Paloma | Ledesma, María | Oltra, Estela | Esther, Gris | Ocejo, Olga | Torrecilla, Javier | Zafra, Carmen | Sánchez-Fernández, Ana | Mancilla, Tomás | López-Romero, Mercedes | Jerez, Raquel | Santana, Nuria | Lara, José Pablo | Barbancho, Miguel Ángel | Blanco-Reina, Encarnación

Article Type: Correction

DOI: 10.3233/JAD-249001

Citation: Journal of Alzheimer's Disease, vol. 97, no. 3, pp. 1477-1477, 2024